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Cutting-Edge and Time-Honored Strategies for Stereoselective Construction of C−N Bonds in Total Synthesis Artur K. Mailyan,† John A. Eickhoff,† Anastasiia S. Minakova,† Zhenhua Gu,‡ Ping Lu,† and Armen Zakarian*,† †

Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, China

‡

ABSTRACT: The main objective of this review is to provide a comprehensive survey of methods used for stereoselective construction of carbon−nitrogen bonds during the total synthesis of nitrogen-containing natural products that have appeared in the literature since 2000. The material is organized by specific reaction in order of decreasing number of applications in natural product synthesis. About 800 total syntheses of natural products with stereogenic carbon−nitrogen bonds described since 2000 have been reviewed.

CONTENTS 1. Introduction 2. Addition to the Carbon−Nitrogen Double Bond 2.1. Diastereoselective Addition of Carbon Nucleophiles to Uncharged Imines, Oximes, and Hydrazones 2.1.1. Substrate-Directed Addition (Figure 1) 2.1.2. Auxiliary-Directed Addition (Figure 2) 2.2. Diastereoselective Addition to Iminium Cations Generated in Situ 2.2.1. Enamines as a Source of Iminium Cations (Figure 3) 2.2.2. Hemiaminals and Related Reagents as a Source of Iminium Cations (Figure 4) 2.2.3. Imines as a Source of Iminium Cations 2.2.4. Miscellaneous Methods 2.3. Diastereoselective Addition to Nitrones (Figure 5) 2.4. Diastereoselective Mannich Reaction (Figure 6) 2.5. Diastereoselective Picket−Spengler Reaction (Figure 7) 3. Stereoselective Formation of C−N Bonds by Nucleophilic Substitution 3.1. Azides as a Source of Nitrogen (Figure 8) 3.2. Non-Azide Sources of Nitrogen (Figure 9) 3.3. Mitsunobu Reaction (Figure 10) 3.4. Epoxide Opening by Nitrogen Nucleophiles (Figure 11) 4. Asymmetric Catalysis 4.1. Organocatalysis (Figure 12) 4.2. Asymmetric Aminohydroxylation Reactions 4.3. Chiral Brønsted Acid Catalysis and Hydrogen-Bonding Catalysis 4.4. Chiral Lewis Acid Catalysis (Figure 13) 4.5. Asymmetric Allylic N-Alkylation (Figure 14) 4.6. Asymmetric Phase Transfer Catalysis (Figure 15) © 2016 American Chemical Society

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4.7. Asymmetric Hydrogenation (Figure 16) 4.8. Miscellaneous Reactions (Figure 17) Addition to CC Bonds 5.1. Conjugate Addition Reactions 5.1.1. Intermolecular Conjugate Addition of Chiral Amines (Figure 18) 5.1.2. Intermolecular Conjugate Addition Forming C−C Bonds (Figure 19) 5.1.3. Intramolecular Conjugate Addition Reactions (Figure 20) 5.1.4. C−N Bond Formation via Dearomatization (Figure 21) 5.2. Radical Reactions (Figure 22) 5.3. Additions of Nitrogen and Heteroatoms across CC Bonds (Figure 23) 5.4. Stereoselective Aziridination of the CC Bond (Figure 24) Cycloaddition Reactions (Figure 25) 6.1. [4 + 2] Cycloadditions 6.2. [3 + 2] Cycloadditions 6.3. Other Cycloadditions Nitrenoid Rearrangements 7.1. Curtius Rearrangement (Figure 26) 7.2. Beckmann Rearrangement (Figure 27) 7.3. Hofmann Rearrangement (Figure 28) 7.4. Schmidt Reaction (Figure 29) 7.5. Miscellaneous Reactions Reduction of Imines and Enamines (Figure 30) 8.1. Substrate-Directed Reduction 8.2. Auxiliary-Directed Reduction Sigmatropic Rearrangements 9.1. [3,3]-Sigmatropic Rearrangements 9.1.1. Claisen Rearrangement (Figure 31)

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Received: December 4, 2015 Published: March 25, 2016

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DOI: 10.1021/acs.chemrev.5b00712 Chem. Rev. 2016, 116, 4441−4557

Chemical Reviews 9.1.2. Aza-Cope Rearrangement (Figure 32) 9.1.3. Overman Rearrangement (Figure 33) 9.1.4. Ichikawa Rearrangement (Figure 34) 9.2. [1,2]- and [2,3]-Sigmatropic Rearrangements (Figure 35) 10. C−N Bond Formation by Reactions of Enolates 10.1. Aldol and Aza-Aldol Reactions (Figure 36) 10.2. Alkylation of α-Amino Acid Derivatives (Figure 37) 10.3. Miscellaneous Reactions (Figure 38) 11. Diastereoselective Metal-Catalyzed Allylic NAlkylation (Figure 39) 12. Diastereoselective C−H Insertion Reactions (Figure 40) 13. Methods Based on Chiral Organometallic Reagents (Figure 41) 14. Desymmetrization Reactions (Figure 42) 15. Miscellaneous Methods 15.1. Electrocyclizations 15.2. Atroposelective Reactions 15.3. Formation of Aminals and Hemiaminals (Figure 43) 16. Conclusion Associated Content Special Issue Paper Author Information Corresponding Author Notes Biographies Acknowledgments References

Review

by a particular method, and smaller sections include a complete list. The structures in the figures have one or more bonds highlighted in red. The highlighted bond is formed by a method discussed in that section. Since it is given that all methods will lead to the stereoselective introduction of a C−N bond while not necessarily building that bond directly, only the formed bond is highlighted. With continued developments in the field of total synthesis, now with an increasing emphasis on practicality as an emerging standard, the intensity of the effort and the structural diversity of natural products accessed since the turn of the century are truly astounding. There is a sizable group of natural product targets that have been exploited by multiple research groups to test various methodologies; therefore, they appear in more than one section. As a rule, the functional group tolerance for methods that introduce C−N bonds is generally revealeda very useful characteristic of a method that is often uniquely uncovered by total synthesis applications. Although our goal was to provide a fairly comprehensive coverage of the topic from the year 2000, some omissions are unavoidable for a number of reasons, including space limitations.

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2. ADDITION TO THE CARBON−NITROGEN DOUBLE BOND Perhaps not surprisingly, nucleophilic addition to carbon− nitrogen double bonds has been the top method for the construction of stereogenic C−N bonds in complex molecule synthesis. What is surprising, on the other hand, is that this approach leads by a wide margin, with the second most popular method, nucleophilic substitution, coming in at half as many applications between 2000 and late 2014. Due to its size, this section is divided into subsections on the basis of the type of carbon−nitrogen double bond (uncharged imine, iminium cation, nitrone) or common reaction type (Mannich, Pictet− Spengler).

1. INTRODUCTION Among chemical transformations that are in constant demand, the stereoselective construction of carbon−nitrogen bonds is perhaps the most trying. In addition to the usual challenges of chemoselectivity and stereocontrol, the high reactivity and basicity of nonpeptidic nitrogen require special considerations for material isolation, purification, and handling. In many cases, these challenges become particularly acute in total synthesis endeavors that often stretch the limits of methodology and are very good at exposing hidden problems in synthetic methods. The invention and refinement of methods for stereoselective construction of carbon−nitrogen bonds, both catalytic and noncatalytic, is thus sure to continue into the future, driven by the needs for synthesis of valuable materials, not least of which are bioactive compounds of either natural or artificial origin. The goal of this review is to provide a comprehensive survey of methods for stereoselective C−N bond construction that have been employed in completed total synthesis endeavors in the past 15 or so years. Over 800 total syntheses featuring asymmetric C−N bond formation in which the bond is present in the target molecule have been published since early 2000. This review is partitioned into sections organized on the basis of specific methodology used for asymmetric construction of C−N bonds. These sections appear roughly in the order of decreasing number of total synthesis applications. Larger sections are separated further into subsections. Figures that display the collection of featured natural products are presented for each associated section or subsection. For larger sections, these figures provide a representative group of target natural products covering all structural types that have been accessed

2.1. Diastereoselective Addition of Carbon Nucleophiles to Uncharged Imines, Oximes, and Hydrazones

2.1.1. Substrate-Directed Addition (Figure 1). Addition of organomagnesium compounds and related nucleophilic reagents to imines containing stereodirecting groups is a classic method for the stereoselective construction of carbon−nitrogen bonds. Oximes, imines, and hydrazones derived from aldehydes or ketones have been used as substrates for the total synthesis of nitrogen-containing natural products. In this section, examples of total syntheses using additions in which the stereodirecting group is derived from a carbonyl precursor are compiled. In the synthesis of 3H-indole alkaloid (−)-chamobtusin A, an unusual fragmentation of the initial Grignard adduct to cyclic oxime 1-1 was observed (Scheme 1a).1 An excess of allylmagnesium chloride unexpectedly mediated stereoselective aziridine formation, affording 1-3 in 58% yield. This problem was corrected by Pd-catalyzed reduction of the aziridine via π-allylpalladium chemistry. The intermediate nosyl amide 1-4 underwent cyclization to pyrrolidine 1-5 in situ, completing the requisite functionalization. In the total synthesis of the microbial alkaloid (+)-streptazolin (isolated from Streptomyces viridochromogenes), addition of alkynylaluminum reagent generated from 1-7 to D-glyceraldehyde-derived imine 1-6 was used at the early stages of the synthesis (Scheme 1b).2 The addition favors the Felkin−Ahn stereoisomer with a 13:1 diastereoselectivity. 4442


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Figure 1.

nitrogen (Scheme 1c).3 The reaction was carried out in the presence of cerium(III) chloride and boron trifluoride etherate and required the adjacent hydroxyl in unprotected form to occur. The authors suggest that the directing effect of the hydroxyl group is required to facilitate the approach of the organometallic reagent. Similar diastereoselective additions of organometallic reagents to carbon−nitrogen double bonds derived from aldehydes or ketones were used in the syntheses of pyrrolizidine alkaloid (−)-lentiginosine (vinylmagnesium bromide addition to aldimine),4 nortropane alkaloids calystedine A7 and calystegines B2, B3, and B4 (allylzinc bromide addition to aldimine),5,6 polyhydroxylated pyrrole-derived natural γ-amino acid (−)-detoxinine (allenyllithium addition to aldimine),7 (+)-korupensamine B from the Cameroonian liana Ancistrocladus korupensis (methylmagnesium chloride addition to a functionalized 2,3dihydroisoquinoline substrate),8 a nitrosugar unit of everninomicin 13,384-1 (addition of allylmagnesium bromide to O-benzyl oxime),9 and pyrrolizidine alkaloids (+)-alexine and (−)-7-epi-alexine10 and monocyclic piperidine alkaloid (+)-batzellaside B (vinylmagnesium chloride addition to aldimine).11 In a related process known as the borono-Mannich or -Petasis reaction, addition of vinylboronic acids to imines generated in situ from aldehydes and amines has been exploited in the synthesis of pyrrolizidine alkaloids (+)-uniflorine A12,13 and (−)-swainosine (Scheme 2a).14 An advantage of the borono-Mannich reaction is a wide functional group tolerance; for example, no protecting groups are required in the addition of (E)-styrylboronic acid to a D-xylose-derived imine producing amino tetrol 2-3 in 91% yield with high diastereocontrol (Scheme 2a).12 A free α-hydroxy group is required for its stereodirecting ability, and anti-1,2-amino alcohols are formed preferentially. In a rare example of the stereoselective synthesis of an acyclic hemiaminal, diastereoselective addition of methanol to

Scheme 1

In the total synthesis of gelsemoxonine, addition of 1-propynyllithium to cyclic oxime 1-9 was used to establish the stereochemistry of the tetrasubstituted carbon bearing 4443


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unsubstituted indolizine alkaloid, (−)-coniceine21 (perhaps the simplest member in this class of alkaloids), and (S)-coniine ((S)-2-isopropylpiperidine)22 were achieved by addition of allyllithium to the hydrazones derived from (S)-1-amino-2(methoxymethyl)pyrrolidine (SAMP) and 4-(benzyloxy)butanal or isobutyraldehyde, respectively.66 Both reactions afforded the product essentially as a single diastereomer in ∼50% yield after N-acryloylation of the initial adducts. Additions to chiral sulfinimines have been carried out with allylmetal reagents, enolates, and more generic organomagnesium or organolithium reagents, with allylation reactions being featured most frequently in the context of natural product synthesis. Barbier-type allylzinc and allylindium reagents generated in situ as well as allyl Grignard reagents have been employed. p-Toluenesulfinimines and more recently developed tert-butanesulfinimines are by far the most prevalent auxiliaries. Typically, this transformation has been used at early stages of total synthesis endeavors. An example of such early-stage application is the Barbier-type allylation of (R)-N-allylidene-tert-butanesulfinamide (3-1) with ethyl 2-(bromomethyl)acrylate (3-2) in the presence of Zn and LiCl in DMF (Scheme 3a). Addition of 1 equiv of water was necessary to avoid N-allylation of the product with 3-2 by protonating the intermediate zinc sufinamide. Addition product 3-3 was formed in 82% isolated yield with very high diastereocontrol (dr >95:5) and was used as an early intermediate in the total synthesis of (−)-nakadomarin A.23 Propargylation of a more complicated substrate, 3-5, with organozinc reagent 3-6 was used at a more advanced stage in the synthesis of (+)-6-epi-castanospermine (Scheme 3b). The reagent was prepared from propargyl alcohol derivative 3-4 by lithiation and transmetalation with zinc broimide.24 Allylzinc addition to ketimine 3-8 was exploited in the divergent total synthesis of (−)-fasicularin and (−)-lepadiformin A via adduct 3-9 (Scheme 3c). The authors demonstrated the stereocontrol in this case is exercised by the chiral sulfinamide auxiliary; the use of the (S)-diastereomer resulted in the preference for the opposite configuration of the amine stereocenter.25 Related one-pot indium-mediated allylation of the sulfenimine derived from tert-butanesulfinamide and 3-indolecarboxaldehyde (87% yield, dr 10:1) has been used extensively as the first step in the enantioselective synthesis of Strychnos and Aspidosperma alkaloids (−)-leuconicine A and B,26 unusual dihydroazepine Aspidosperma alkaloid (−)-melotenine A,27 and anticancer alkaloids (−)-akuammicine, (−)-norfluorocurarine, and (−)-dihydroakuammicine.28 Tricyclic aminal alkaloids tetraponerines T3 and T4 from Pseodomyrmecine ants29 and pyrrolizidine alkaloid cremastrine30 were also prepared by earlystage indium-mediated allylation of tert-butanesulfinamidederived imines. Addition of allylmagnesium bromide to an imine derived from tert-butanesulfinamide and an aromatic aldehyde, carried out in dichloromethane for best stereoselectivity, was used in the synthesis of neuroactive plant alkaloid (−)-dihydrotetrabenazine31 and Carduus crispus quinolizidine alkaloids (−)-crispine A, (−)-benzo[a]quinolizidine, and (−)-salsolidine.32 On the basis of analysis of the literature, the second most used type of addition to chiral sulfinimines in the total synthesis of alkaloids, after allylation reactions, employs common nonallylic organometallic reagents, primarily Grignard and organolithium reagents. Addition of aryllithium 4-2 to benzoquinone-derived sulfinimine 4-1 is one of the more sophisticated examples (Scheme 4a). This reaction was used in

Scheme 2

N-acylimine 2-8 occurred in the presence of Mg(ClO4)2 with complete stereocontrol in 43% yield from imine precursor 2-4 (Scheme 2b). This reaction was performed in the course of the total synthesis of the cytotoxic natural product pederin.15 The authors attribute high stereocontrol to chelation of magnesium to the imine nitrogen and the oxygen atom of the oxane ring, forcing the approach of methanol from the less congested face, implying kinetic control. Stereoselective intramolecular addition of an alcohol to an imine to form a cyclic hemiaminal was a part of the total synthesis of Apocynaceae alkaloid aspidophylline A.16 A stereoselective multicomponent Ugi reaction was applied in the total synthesis of high-affinity double-stranded DNA binding agent quinaldopeptin, which possesses an unusual cyclic decapeptide structure (Scheme 2c).17 Cyclic imine 2-10, α,β-diamino acid derivative 2-8, and isonitrile 2-9 were combined in a greater than 61% yield do deliver pentapeptide 2-11, which represents about half of the target molecule, as an 84:16 mixture of diastereomers (Scheme 2c). This is a rare, if not the only, application of the Ugi reaction in complex molecule synthesis. 2.1.2. Auxiliary-Directed Addition (Figure 2). In this subsection, we refer to stereoselective auxiliary-directed additions as those in which the stereodirecting group resides on the imine nitrogen. A review of the literature since 2000 revealed that the majority of applications of reactions in this group are additions to chiral sulfinimines.18,19 Additions to chiral hydrazones20 appear to be confined to few applications. In one of these examples, the syntheses of a simple 4444


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Figure 2.

Scheme 3

Scheme 4

the concise six-step total synthesis of Erythrina alkaloid (−)-3demethoxyerythratidinone, in which it sets the challenging stereogenic tetrasubstituted carbon atom at the core of the polycyclic structure.33 The initial adduct 4-3, formed in good yield and complete stereocontrol (dr >98:2), was advanced to the natural product in three additional steps. p-Toluenesulfinimine, the development of which for asymmetric synthesis of 4445


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Scheme 5

diastereomer was observed by 1H NMR. Adduct 5-6 was employed as an early-stage intermediate in the total synthesis of the tetracyclic lupin alkaloid (+)-allomatrine.40 In the total synthesis of indolizine alkaloid (−)-221T, syn addition of N-methoxy-N-methylpropanamide (LiN(SiMe3)2, tetrahydrofuran (THF), −78 °C) to the sulfinimine derived from a 2,4,6triisopropyl sulfinamide and 3-(benzyloxy)propaldehyde delivered the product in 77% yield along with an 18% yield of the anti adduct (Scheme 5c).41 The unusual sulfinyl auxiliary provided the optimal syn:anti selectivity. In the total synthesis of histone deacetylase inhibitors azumamides A and E, which are cyclic tetrapeptides, syn addition of the titanium enolate of 4-methoxybenzyl propanoate to a tert-butanesulfinimine delivered the adduct in >50% yield (Scheme 5d).42 Asymmetric Strecker reaction with tert-butanesulfinimines and trimethylsilyl cyanide catalyzed by scandium triflate in THF was used in the total synthesis of cloroleucine units of marine tetramic acid peptides sintokamides A−E (Scheme 6a).43 Good yields (73−86%) and selectivity (87% to >95%) were observed, validating this approach for the synthesis of amino acid derivatives with sulfinimine auxiliaries. A similar reaction was used in the total synthesis of marine peptides neodysidenin,44 dysidenin, and dysidin.45 Rhodium-catalyzed addition of (2,2-dimethylvinyl)trifluoroborate 6-7 to indole-derived tert-butanesulfinimine 6-6 was used as a key transformation in the synthesis of Penicillum aurantiovirens alkaloid (−)-aurantioclavine (Scheme 6b).46 The adduct was isolated in 81% yield as a single isomer along with a minor amount of its diastereomer. Lower yields and diastereoselectivity were observed with the corresponding Grignard reagent or MIDA (N-methyliminodiacetic acid) boronate. However, the synthesis could not be completed from 6-8, and instead the O-tosylate of 6-8 had to be used. With that substrate, the MIDA boronate proved to be a superior reagent, affording an 81% yield (dr 97:3) of the adduct, while 6-6 gave only a 28% yield of the product. A unique SmI2-mediated reductive cross-coupling of chiral tert-butanesulfinimine 6-9 and aldehyde 6-10 was a central

amines preceded that of tert-butanesulfinimines, served as the chiral auxiliary for the total synthesis of pentacyclic tetrahydronaphthyridine alkaloid (−)-normalindine (Scheme 4b). Addition of the anion generated from sodium bis(trimethylsilyl)amide and 3-cyano-4-methylpyridine (4-5) to sulfinimine 4-4 occurred in 81% yield and 91:9 dr. No reactivity was observed with the related tert-butanesulfinimine. The stereochemistry of the newly formed amine was related to the second stereogenic center of (−)-normalindine via an intramolecular reductive amination, and the synthesis was completed in four additional steps from adduct 4-6.34 Stereoselective additions of Grignard reagents derived from 1-bromo-3,3-dimethoxypropane or 2-(2bromoethyl)-1,3-dioxane to tert-butanesulfinimines of simple aldehydes were effectively (∼80% yields, dr >9:1) exploited at the early stages of the total syntheses of pyrrolizidine alkaloid (+)-amabiline,35 indolizine alkaloid (+)-grandizine,36 and Stemona alkaloids stemaphylline and stemaphylline N-oxide.37 Addition of 2-lithiofuran to L-ascorbic acid-derived sulfinimine (92% yield, dr >12:1) was used in the synthesis of the polyoxy amino acid segment of the nucleoside peptide antibiotic 2′-epipolyoxin J. The furyl group was used as an equivalent of the carboxy group, which was unveiled after subsequent oxidation with RuCl3−NaIO4.38 There are several examples of Mannich-type addition of enolates, mostly ester enolates, to stereodefined sulfinimines applied to the total synthesis of alkaloids. The total synthesis of (−)-pateamine highlights the coupling of two complex fragments, acetate 5-2 and p-toluenesulfinimine 5-1, by this type of reaction (Scheme 5a).39 Enolate generated from 5-2 and LiN(SiMe3)2 added to sulfinimine 5-1 within 10 min at −78 °C, affording the addition product with 85:15 diastereoselectivity. The product was isolated in 63% yield and advanced to (−)-pateamine in this sophisticated application of sulfinimine chemistry. Addition of the lithium enolate derived from phenyl 5-chloropentanoate (5-5) and lithium diisopropylamide (LDA) to sulfinimine 5-4 derived from tert-butanesulfinamide and 4-(trimethylsilyl)crontonaldehyde afforded syn adduct 5-6 in 75% isolated yield (Scheme 5b). Only one 4446


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to pyrroleindoline subunits containing stereogenic aminal or hemiaminal groups. The first steps in the total synthesis of (+)-psychotrimine and (+)-psychotetramine serve as an example.48 A reaction between tryptophan ester 7-1, N-iodosuccinimide (NIS), and 2-iodoaniline afforded pyrroloindole 7-4 in 66% yield as a sole diastereomer, establishing two stereogenic C−N bonds (Scheme 7a). There has been an extensive discussion on the mechanistic subtleties of this powerful transformation, with a general consensus invoking an initial iodination of 2-iodoaniline, the product of which functions as the electrophilic reagent for tryptophan substrate 7-1.49 Reversible formation of complexes between the nitrenium ions and the indole substrate has been proposed to rationalize the high exo-selectivity observed in the formation of 7-4. Several groups used diastereoselective halocyclizations of tryptophan-derived substrates to establish stereochemistry in the pyrroloindole unit of a number of alkaloids. In the total synthesis of dimeric diketopiperazine alkaloids WIN 64821, WIN 64745, and ditryptophenaline, treatment of N-bis(Boc)-D-tryptophan methyl ester (7-5) (Boc = (butyloxy)carbonyl) with 1 equiv of N-bromosuccinimide (NBS) and 1 equiv of pyridinium p-toluenesulfonate (PPTS) afforded pyrroloindole 7-6 virtually as a single diastereomer in 85% yield (Scheme 7b).50,51 It was suggested that the stereochemical outcome is a result of the initial rapid formation of spiroazetidine intermediates, which then undergo rate-limiting stereodifferentiating rearrangement to hexahydropyrroloindole products such as 7-6. Aside from indoles, enamine activation has been a recurrent theme with other cyclic systems, mostly dihydro- or tetrahydropyridines, -pyrazines, or -1,4-oxazines. In one example with a complex substrate, the recent synthesis of (−)-isoschizogamine (two new notable total syntheses of this alkaloid were disclosed in 2015; see refs 52 and 53) was accomplished using the Heathcock precedent, which involves exposing polycyclic tetrahydropyridine 7-7 to mild acidic conditions (aqueous AcOH, reflux), affording product 7-8 with both hemiaminal and aminal groups (Scheme 7c). Oxidation of the hemiaminal with pyridinium dichromate (PDC) completed the synthesis.54 An iminium ion derived from dihydroazepine reagent 7-10 was a central intermediate in the total synthesis of (±)-actinophyllic acid (Scheme 7d).55 The iminium ion 7-11 was generated upon alkylation of the dihydroazepine reagent with acetate 7-9 in the presence of (TMS)OTf under Lewis acidic conditions. Ring closure onto the C3 position of the indole nucleus afforded polycyclic product 7-12, which was subsequently advanced to actinophyllic acid. Other alkaloids recently prepared by chemical syntheses that feature a similar stereogenic C−N bond construction via cyclic iminium ions embedded within heterocyclic ring systems are geissoschizine and N-methylvellosimine,56 (±)-protoemetinol,57 (−)-dibromophakellstatin,58,59 (−)-lepistine,60 and (−)-N(a)-methylervitsine (Figure 3).61 A similar bromocyclization was also used on multigram scales at early stages in the synthesis of hexahydropyrroloindole alkaloids (+)-naseseazines A and B (from Fijian actinomycete Streptomyces sp.)62 and dithiodiketopiperazine alkaloids (+)-bionectins A and C.63 A related selenocyclization induced by N-phenylselenophthalimide to achieve functionalization at the C3a position was applied in the total synthesis of the fungal roquefortine C64 (from Penicillium roqueforti) and the cyclic hexapeptide from Streptomyces alboflavus 313 incorporating a hexahydropyrroloindole unit in NW-G01 (Figure 3).65

Scheme 6

transformation in the enantioselective total synthesis of antimalarial piperidine alkaloid (+)-febrifugine (Scheme 6c).47 As long as the temperature throughout the reaction was maintained below −78 °C, a relatively high selectivity of 86% was obtained, favoring an anti-amino alcohol product among four possible diastereomers. 2.2. Diastereoselective Addition to Iminium Cations Generated in Situ

Nucleophilic addition to imines and iminium ions is the most popular method for the stereoselective construction of C−N bonds applied in the total synthesis of natural products in the past 15 years. Essentially all types of natural products containing nitrogen have been prepared using this general bond construction approach, whether it was featured as a central or routine transformation. Several examples will be highlighted in this subsection, which is divided into four parts on the basis of the source of the reactive iminium cation. 2.2.1. Enamines as a Source of Iminium Cations (Figure 3). Enamines are effective and readily accessible sources of iminium cations, which can be formed by protonation or electrophilic activation of starting enamines. A very broad subset of this type of transformation that found widespread utility in the synthesis of alkaloids is the electrophilic activation of N-substituted indoles at the C2−C3 double bond. About half of the total syntheses discussed in this subsection utilize this approach. Protonation, electrophic halogenation, and oxidation have been the most common methods of electrophilic activation of indoles via the formation of intermediate 3H-indolium cations, typically leading 4447


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Figure 3.

Scheme 7

sulfide.66 In the synthesis of the fungal alkaloid (−)-ardeemin (from Aspergillus fischeri), the pyrroloindole fragment was accessed by cyclopropanation of N-methylindole in a tryptophan-derived precursor, which directly cyclized to the pyrroloindole ring system presumably via an iminium ion

In another application, a unique oxidation of an indole ring with singlet oxygen en route to the synthesis of okaramine N is presumed to occur via an iminium ion intermediate, which cyclizes to afford the 3a-hydroxy hexahydropyrroloindole ring system of the natural product after reduction with dimethyl 4448


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Figure 4.

acid) and kainic acid receptors isolated from the filamentous fungus Eupenicillium shearii PF1191 (Scheme 8b). In one approach,71 an early-stage allylation of hemiaminal 8-3 obtained in one step from (S)-pyroglutamic acid was performed. In contrast to the aforementioned allylation in the synthesis of dysinosin A, treatment of both the N-Boc and N-Cbz substrates with allyltrimethylsilane and titanium(IV) chloride afforded the requisite cis product 8-4 with high stereocontrol, which was higher for the N-Boc derivative shown. In another approach to (−)-kaitocephalin,72 a late-stage allylation with advanced hemiaminal acetate 8-5 was performed. A moderate diastereopreference of 2:1 for the (7R)-epimer 8-6 was achieved with allyl cuprate reagent in the presence of boron trifluoride etherate, while the allyltrimethylsilane/boron trifluoride etherate system afforded the (7S)-epimer exclusively. In yet a more complex application, an intramolecular allylation of an iminium ion generated in situ was performed during the total synthesis of (−)-quinocarcin (Scheme 8c).73 In the presence of ZnCl2 and (TMS)CN in 2,2,2-trifluoroethanol (TFE), morpholino nitrile 8-12 undergoes an initial cyclization to afford all four diastereomeric dicyanopiperazines 8-7, 8-9, 8-10, and 8-11. When these diastereomers are separated and individually resubjected to the reaction conditions, all provide the same cyclized product 8-8 in yields varying from 30% to 61%. Similar trends were observed with the corresponding (Z)-allylsilane. The conversion of 8-12 to 8-8 was carried out in one pot with ZnCl2 and (TMS)CN in TFE at 60 °C in 16 h, giving 8-8 in 46% yield. A similar intramolecular cyclization involving an allylsilane substituent on a piperazine substrate was effectively exploited in the total synthesis of another tetrahydroisoquinoline alkaloid, (−)-lemonomycin.74 Allylation of cyclic iminium ions generated from five- or sixmembered hemiaminal precursors and allyltrimethylsilane or allylmagnesium bromide, usually in the presence of boron

intermediate.67 Oxidative dimerization of tryptamine derivatives with [bis(trifluoroacetoxy)iodo]benzene, which can be viewed as a mechanistically related process, has been used in the synthesis of dimeric pyrroloindole alkaloids meso-chimonanthine, hodgkinsine, and hodgkinsine B.68 Another oxidative coupling of an indole substrate that potentially implicates iminium ions in the construction of the pyrroloindole subunit is featured in the synthesis of (−)-vincorine (Figure 3).69 2.2.2. Hemiaminals and Related Reagents as a Source of Iminium Cations (Figure 4). Aminals and hemiaminals are often stable and convenient precursors of iminium ions for stereoselective C−N bond formation, and in fact are used widely for that purpose in the total synthesis of natural products. Our analysis reveals that the most frequently encountered themes in these applications are allylation with allylic silanes or arylation with aromatic or heteroaromatic substrates. Allylation of iminium ions generated from hemiaminals to access 2-allylpyrrolidines has been used in several applications. One example is the total synthesis of the serine protease inhibitor of marine-origin dysinosin A (Scheme 8a).70 2-Acetoxypyrrolidine 8-1 derived from L-glutamic acid in a few steps was subjected to allylation with allyltributylstannane in the presence of boron trifluoride etherate. Extensive optimization with variation of the solvent, Lewis acid, and nature of the N-substituent was required to achieve 5.5:1 diastereocontrol favoring cis product 8-2. Notably, replacing the N-carboxybenzyl (N-Cbz) group with Boc resulted in the preference for the trans product with 2:1 diastereoselectivity. After ring-closing metathesis with the two allyl groups, the product was advanced to dysinosin A. A similar allylation was exploited in two individual total syntheses of (−)-kaitocephalin, a pyrrolidine-based alkaloid with potent antagonist activity on AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic 4449


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Scheme 8

reaction times, ester 8-17 and its diastereomer are formed exclusively, and this mixture slowly converts to 8-16 upon prolonged treatment under the reaction conditions, ultimately affording the product in 50% isolated yield. A similar arylation was used in another synthesis of (+)-isatisine.83 Another remarkable example of late-stage iminium ion heteroarylation is featured in the total synthesis of (−)-nakadomarin A, a marine alkaloid of the manzamine family isolated from the sponge Amphimedon sp. off the coast of the Kerama Islands in Okinawa (Scheme 8f).84 The reactive iminium ion was obtained after reduction of amide 8-18 with diisobutylaluminum hydride (DIBAL) to hemiaminal followed by its exposure to hydrochloric acid at 90 °C, upon which an arylation product was formed in 41% yield as a single stereoisomer. (−)-Nakadomarin A was produced in one additional step by ring-closing metathesis. Another synthesis of (−)-nakadomarin A utilizes a similar diastereoselective intramolcular iminium ion arylation with a furan substituent, with the key difference that the iminium ion is generated by a cascade Pt-catalyzed cycloisomerization.85 Intramolecular arylation of the N-acyliminium ion derived from piperazine-based hemiaminal 8-20 was used for the construction of the polycyclic ring system of ecteinascidin 743, a potently cytotoxic marine alkaloid from the Caribbean tunicate Ecteinascidia turbinata (Scheme 8g).86 The iminium

trifluoride etherate and mostly in the early stage of the synthetic sequence, was also adopted in the total syntheses of quinolizidine alkaloid (+)-epiquinamide,75 marine alkaloids (±)-halichlorine, (±)-pinnaic acid, and (±)-tauropinnaic acid (from Halichondria okadai),76 simple piperidine alkaloid (+)-deoxyprosopinine,77 indolizine alkaloid (−)-2-epi-lentiginosine,78 and securinega plant alkaloid (−)-norsecurinine.79 An intramolecular variant using propargylic silane was used in the synthesis of (−)-stemoamide.80 An interesting variant of the N-acyliminium allylation reaction was investigated during the synthesis of (+)-negamycin, a microbial antibiotic from Streptomyces purpeofuscus (Scheme 8d).81 In the presence of allyltrimethylsilane and boron trifluoride etherate at −40 °C, 3-methoxyisooxazolidine 8-13 afforded trans-8-14 in 88% yield. This product encoded the full stereochemistry of (+)-negamycin, which was prepared in three additional steps. An excellent example of iminium ion heteroarylation was reported during the course of the total synthesis of bis(indole) alkaloid (+)-isatisine A (from the plant Isatis indigotica, Scheme 8e).82 Exposure of hemiaminal 8-15 and indole to acidic conditions (camphorsulfonic acid, CSA) and CH2Cl2 at room temperature resulted in the formation of the iminium ion, which underwent Freidel−Crafts arylation with indole, affording (+)-isatisine A acetonide 8-16. During shorter 4450


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ion was generated simply upon addition of trifluoroacetic acid (TFA) to a solution of the substrate in trifuoroethanol at room temperature, and the efficient cyclization onto the electron-rich phenolic appendage ensued. Subsequent O-trifluoromethanesulfonation afforded polycyclic product 8-21 containing the piperazine ring of ecteinascidin 743 in 88% yield. Analogous arylations or heteroarylations of hemiaminal-derived iminium ions for the stereoselective construction of C−N bonds have been effectively exploited in the total synthesis of another marine tetrahydroisoquinoline alkaloid, (−)-cribrostatin 4,87 the indole alkaloids desbromoarborescidines A−C from the marine tunicate Pseudidistoma arborescens,88 the inhibitors of ras function bis(indole) alkaloids (−)-conophylline and (−)-conophyllidine,89 and marine alkaloids from Coral Sea sponge Agelas dendromorpha agelastatins.90,91 Other examples of diastereoselective C−N bond construction with iminium ions derived from hemiaminal precursors include (1) intramolecular Morita−Baylis−Hillman reaction in the total synthesis of indolizidine alkaloid grandisine D,92 (2) reactions of Grignard reagents and oxazolidines with ((−)-deoxocassine)93 or without ((−)-deoxycuscohygrine and (−)-dihydrocuscohygrine) boron trifluoride etherate,94 (3) cyclization of O-acetyl hemiaminal onto an appended guanidine substituent in the presence of zinc chloride in the total synthesis of (+)-decarbamoylsaxitoxin and (+)-gonyautoxin 3,95 and (4) a nitroMannich reaction in the synthesis of manzamine A.96 2.2.3. Imines as a Source of Iminium Cations. Uncharged imines themselves can certainly serve as precursors of reactive iminium ions for stereoselective C−N bond formation, and several examples of that can be found in total synthesis applications. One spectacular example can be found in a recent total synthesis of tetracyclic alkaloid (−)-acutumine from the roots of Sinomenium acutum (Scheme 9a).97 Torsional strain presumably controlled the contrasteric selectivity in the addition of alkynyllithium reagent 9-3 to N-methyliminium ion 9-2 generated from the parent imine 9-1 by N-methylation with methyl trifluoromethanesulfonate at −30 °C. When the addition was performed at −90 °C, product 9-4 was isolated in 85% yield as a single stereoisomer, establishing the configuration of the tertiary amine segment of the alkaloid. Similar chemistry had been employed in the synthesis of related hasubanan alkaloids.98 An intriguing spirocyclization setting a stereogenic C−N bond was developed for the synthesis of spiroxindole alkaloids elacomine, isoelacomine,99 and spirotryptostatin B.100 In the synthesis of spirotrytostatin B (Scheme 9b), the N-acyliminium ion formed by treatment of stable imine 9-5 with N-Troc-proline chloroanhydride (Troc = (2,2,2-trichloroethoxy)carbonyl) underwent spirocyclization onto the 2-chloroindole, forming final product 9-7 after hydrolysis of the intermediate chloroindolenine with TFA. All four stereoisomers were formed in a 37:19:7:2 ratio, with good control of stereoselectivity at C18 and low selectivity at spirocenter C3. The major isomer had the desired configuration at both centers and was advanced to the natural product in two additional steps. In the total synthesis of terpene alkaloid sespenine from the endophytic fungus Streptomyces sp., a cascade reaction was initiated by imine protonation (Scheme 9c).101 The cascade integrated an aza-Prins cyclization, a Friedel− Crafts arenium ion formation, and a retro-Friedel−Crafts arenium ion fragmentation to provide polycyclic compound 9-11 with the entire ring system of sespenine. The initial azaPrins cyclization set up the stereochemistry of the asymmetric

Scheme 9

C−N bond of the alkaloid. Minor functional group manipulations completed the synthesis. Uncharged imine activation is also featured in the synthesis of (±)-dibromoagelaspongin in which activation was achieved by an extension of the Pummerer reaction,102 in the synthesis of quinolizidine alkaloid (−)-217A by Mukayama-type [4 + 2] annulation chemistry,103 and in the synthesis of (−)-5,6,11tritetrodotoxin by an extension of Strecker synthesis.104 2.2.4. Miscellaneous Methods. In the synthesis of the potent immunosuppressant alkaloid from the fermentation broth of the Cladobotryum sp. no. 11231, (−)-FR-901483, N-allyl amide 10-1 was converted to iminium triflate 10-2, which was sequentially elaborated by one-pot treatment with two different Grignard reagents to 2,2-disubstituted piperidine 10-4 in 75% overall yield (Scheme 10a).105 In this impressive multicomponent reaction, the stereogenic C−N bond of the natural product was formed with a 9:1 diastereoselectivity. The total syntheses of γ-lactam marine natural products omuralide and (−)-dysibetaine showcase rare examples of the diastereoselective Ugi reaction (Scheme 10b).106,107 Multicomponent coupling of carboxylic acid 10-5, aromatic isonitrile 10-6, and (4-methoxybenzyl)amine in 2,2,2-trifluoroethanol delivered γ-lactam 10-7 in 78% yield as a single diastereomer. The structure of isonitrile 10-6 was designed to mask an indole nucleus, which is conveniently unveiled after acidic treatment of the initial Ugi product. The resulting N-acylindole is a convenient intermediate for further elaboration, and was ultimately used with success to complete the synthesis of omuralide. 2.3. Diastereoselective Addition to Nitrones (Figure 5)

Nucleophilic addition to nitrones has found a few applications in the synthesis of natural products.108 Addition of various Grignard reagents to cyclic carbohydrate-derived nitrones, which typically occurred with very high diastereocontrol, has 4451


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Scheme 10

Scheme 11

afforded nitrone 11-4 under mild condition in high yield. Upon treatment with triethylamine, a complete cyclization to N-hydroxy aminal 11-5 occurred. Another oxidation to N-oxo amidine 11-6 was accomplished with lead tetraacetate (96% yield). Screening several basic conditions revealed that cyclization of 11-6 to indoline spiroaminal 11-7 can be achieved in 93% yield upon exposure to tetrabutylammonium hydroxide in dichloromethane at −8 °C, establishing the unusual polycyclic structure of neoxaline.

Figure 5.

been used in the synthesis of simple pyrrolidine alkaloids such as radicamine B109 and pyrrolizidine alkaloid hyacinthacine A2.110 The resulting hydroxylamine intermediate is usually reduced to the corresponding amine by hydrogenolysis. In the synthesis of nuraminidase inhibitor A-315675, addition of alkynyllithium reagent generated by lithiation of ethyl propiolate to acyclic nitrone 11-1 in the presence of boron trifluoride etherate afforded addition product 11-2 in high yield and stereoselectivity (Scheme 11a).111 This reaction established the stereochemistry of the cyclic nitrogen in A-315675; in this case, the intermediate hydroxylamine was effectively reduced with molybdenum hexacarbonyl in aqueous acetonitrile, which proved to be marginally more productive than the alternative with zinc in acetic acid. Friedel−Crafts-type addition of indoles to nitrones mediated by either a Brønsted acid or indium(III) chloride has been applied in the synthesis of (−)-eudistomins C, E, F, K, and L112 and (−)-isatisine A,113 respectively. In the latter case, the intermolecular addition of indole to the nitrone was accompanied by the reduction of the N−O bond in the presence of InCl3. In the synthesis of the eudistomins,112 the nitrone group was used in place of imine in a formal intramolecular Pictet−Spengler-type cyclization to directly access the tetrahydro-β-carboline ring system with the required oxidation level on the nitrogen atom. Intramolecular addition of amide nitrogen nucleophiles to nitrones was exploited twice in the total synthesis of neoxaline (Scheme 11b).114 The unusual structure of neoxaline features an indoline spiroaminal. In the course of its synthesis, oxidation of functionalized indoline substrate 11-3 with sodium tungstate

2.4. Diastereoselective Mannich Reaction (Figure 6)

The aminoalkylation reaction pioneered by the German chemist Carl Mannich has a long history of application for organic synthesis. Significant progress was achieved in terms of improved reaction conditions,115−117 recently enhanced further by application of organocatalysis.118,119 Thus, it is not surprising that this reaction has become broadly used for the stereoselective construction of the C−N bond in the total synthesis of natural products. In this section, different types of substrate-controlled stereoselective Mannich-type reactions are discussed; application of the catalytic version can be found in section 4. Among various types of Mannich reactions, the intramolecular version that proceeds through the initial formation of an iminium cation appears to be the most robust and efficient. Several examples of this transformation were described by the Fukuyama group during the total syntheses of several alkaloids. For example, the polycyclic core of strychnine was assembled starting from 4-nitrobenzenesulfonamide 12-1, which was initially desulfonated using the standard conditions and then treated with trifluoroacetic acid (TFA) and Me2S to induce transannular formation of the iminium cation and subsequent intramolecular aminoalkylation, ultimately furnishing the advanced pentacyclic intermediate with the requisite stereochemistry (Scheme 12a).120 The same reaction sequence was employed for the assembly of the polycyclic core of aspidophytine, an alkaloid isolated from the dried leaves of the 4452


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Figure 6.

plant Haplophyton cimicidum (Scheme 12b).121 Stereoselective reduction of the 3H-indole and reductive N-methylation were subsequently accomplished with formaldehyde and NaBH3CN. Ester 12-6 was saponified, and the resulting carboxylic acid was submitted to stereoselective oxidative lactonization with K3Fe(CN)6. The latter transformation is known to proceed through the formation of an iminium cation, affording

aspidophytine in 39% yield over two steps. Similar oxidative formation of the iminium cation mediated by (diacetoxyiodo)benzene was employed by Nagasawa and co-workers for the installation of a 2-aminoimidazolidine ring during the synthesis of cylindradine A.122 Another oxidative formation of an iminium cation was reported by Rychnovsky for the installation of a nitrile group into the pyrrolidine ring during the synthesis 4453


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Alkaloid 205 B isolated from skin extracts of the Panamanian frog Dendrobates pumilio was a subject of the total synthesis reported by Toyooka, Nemoto, and co-workers (Scheme 13).127

Scheme 12

Scheme 13

Advanced intermediate 13-1 was reduced to form the corresponding saturated aldehyde, which underwent a Mannich reaction in the presence of p-TsOH via tandem formation of the pyrrolinium cation and its cyclization onto the masked acetate group. Notably, byproduct 13-3 resulting from incomplete cleavage of the dioxolane was isolated in 15% yield along with tricyclic ketone 13-2. As expected, dioxolane 13-3 could be hydrolytically converted to ketone 13-2 in aqueous acetone under acidic conditions. In 2013, the Lawrence group disclosed the biomimetic total synthesis of incargranine B, an alkaloid initially isolated from Incarvillea mairei var. grandiflora. The authors formulated a hypothesis that the originally proposed indolo[1.7]naphthyridine structure (Scheme 14) was incorrect due to the incompatibility of the postulated biosynthetic pathway with two ornithine units presumed to be the origin of the alkaloid. On the basis of the proposed biosynthetic pathway, a revised structure of incargranine B was conjured, and its racemic total synthesis was accomplished, providing material that turned out to be in full agreement with data reported for the authentic sample.128 As a key transformation, dimerization reaction of N-monoalkylaniline 14-1 was performed in 2 M aqueous HCl. The reaction proceeds through the initial cleavage of the dioxolane with subsequent intramolecular cyclization, resulting in the formation of an iminium ion and enamine 14-4. Intermediates 14-4 and 14-5 interact through tandem Mannich/ electrophilic aromatic substitution reactions, ultimately affording diastereomers 14-2 and 14-3 in 50% combined yield. To complete the synthesis, diastereomer 14-3 was subjected to glucosylation followed by global deprotection, providing incargranine B in 27% overall yield. In 2010, Sarpong and Fischer reported the concise total synthesis of Lycopodium alkaloid complanadine A completed in only eight linear steps.129 This natural product possesses an attractive biological profile, enhancing mRNA expression for nerve growth factor (NGF) and enhancing the production of NGF in human glial cells. To accomplish the synthesis, the tetracyclic α-obscurine intermediate 15-8 was prepared in one step starting from enamide 15-1 and amino ketal 15-7 by acid-catalyzed domino condensation (Scheme 15). First, enamide 15-1 underwent hydrolysis to form ketoamide 15-2, which likely forms enol 15-3, which reacts with protonated ketimine 15-6. Intermediate 15-4 was then subjected to

of several Lepadiformine alkaloids (other aspects of this synthesis are discussed in section 13).123 As reported during the total synthesis of morphine, methyl carbamate is another suitable precursor of the N-acyliminium cation for an intramolecular Mannich reaction (Scheme 12c).124 After careful screening of the reaction parameters, Fukuyama and co-workers found that, upon reflux in methanol in the presence of HCl, compound 12-7 was converted to amino ketone 12-8 as a sole product in 94% yield. When the reaction was terminated prior to complete conversion, only the corresponding hemiaminal was observed, with no aldol condensation product detected, confirming that the reaction indeed proceeds exclusively via the aminoalkylation route. A similar transformation was used by the same group for the synthesis of (+)-haplophytine.125 The most recent example in Fukuyama’s series of total syntheses utilizing the Mannich transformation is the preparation of denudatine-type alkaloid lepenine (Scheme 12d).126 In that case, after a smooth removal of the Alloc group in compound 12-9, subsequent Mannich cyclization provided polycyclic amine 12-10 in one pot. 4454


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Scheme 14

Scheme 15

Scheme 16

stereoselective Mannich cyclization. The final condensation gave rise to the desired product 15-9 in 65% yield after treatment with Boc2O. A related concept was employed by Breit for the preparation of other Lycopodium alkaloids such as (+)-clavolonine, (−)-deacetylfawcettiine, and acetylfawcettiine130 and by Hsung for (+)-cylindricines C−E and lepadiformine.131 Lycopodium alkaloids were also a subject of the biogenetically inspired total synthesis reported by the Takayama group. The linear diketone precursor 16-1 was treated with an excess of (+)-camphorsulfonic in CH2Cl2 to provide diastereomeric amines 16-4 and 16-5 with the tetracyclic lycodine skeleton (Scheme 16).132 The major diastereomer was transformed into (+)-flabellidine and (−)-lycodine alkaloids. The reaction presumably proceeds via eniminium intermediates 16-2 and 16-3, which undergo Mannich-type cascade cyclization.

Another remarkable iminium-triggered cascade reaction was developed by Pandey and Kumara in the total synthesis of (+)-vincadifformine (Scheme 17a).133 The nitrogen atom of cyclic imine 17-2 was alkylated with 3-(2-chloroethyl)indole derivative 17-1 to form the corresponding iminium cation. The iminium cation then underwent Mannich reaction with the indole ring to form a mixture of diastereomers 17-4 and 17-5. After subsequent nucleophilic displacement of the iodide, vincadifformine was isolated in 35% yield along with the byproduct 17-3. To explain the observed results, the authors performed the same reaction at lower temperature, which allowed for the detection of both diastereomers 17-4 and 17-5 by HPLC and LC−MS; however, attempts at their isolation proved to be unsuccessful due to low stability, compounded by the concurrent formation of vincadifformine. Nevertheless, the formation of side products at high temperature from the undesired diastereomer was proposed to be the main reason for the moderate yield. 4455


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Scheme 17

Scheme 18

Scheme 19

Hiemstra and co-workers employed a condensation of tryptamine derivative 17-6 with aldehyde 17-7 for the synthesis of four spirocyclic oxindole alkaloids, namely, corynoxine, corynoxine B, corynoxeine, and rhynchophylline (Scheme 17b).134 Initial efforts to perform the cyclization using an organocatalytic approach were unsuccessful; however, in the presence of excess triethylamine, the starting materials reacted at room temperature, producing a mixture of spirocyclic products 17-8 and 17-9 (dr 1:2). Attempts to carry out the reaction with chiral amines resulted in no asymmetric induction. Despite the low diastereoselectivity, the products were separated by column chromatography and individually transformed to the corresponding natural products. In 2004, Amat et al. reported a remarkable formal synthesis wherein the constriction of the uleine alkaloid skeleton was achieved by means of intramolecular Mannich reaction between the indole ring and iminium cation derived from the corresponding 6-substituted lactam (Scheme 18).135 An initial attempt to perform the cyclization using 18-1 as the substrate was unfruitful. Reduction of dithiane 18-1 was performed to simplify the cyclization substrate. Indeed, the cyclization of the crude 6-hydroxylactam conducted in the presence of TiCl4 gave the desired product 18-4 in 35% yield, along with a 6% yield of the regioisomer 18-3. In 2013, Gin, Tan, and co-workers reported the first total synthesis of C18-norditerpenoid alkaloid neofinaconitine utilizing Mannich-type N-acyliminium cyclization as one of the crucial steps (Scheme 19).136 Notably, several members of this class of norditerpenoid alkaloids isolated from Aconitum and Delphinium possess an intriguing biological profile;

however, biological studies of neofinaconitine have not been reported due to its scarcity, thus providing a compelling justification for a scalable synthetic approach to this molecule. Treatment of azepinone 19-1 with Tf2NH first provided Michael-type cyclization to the corresponding cyclic enol ether, which subsequently underwent protonation of the enamide group to give N-acyliminium intermediate 19-5. The intermediate then proceeded to nucleophilic attack by the enol ether to furnish advanced intermediate 19-2. In 2006, the Overman group reported the total synthesis of the marine natural product sarain A isolated from the sponge Reniera sarai collected in the Bay of Naples (Scheme 20). There are two significant features in this total synthesis that we are compelled to highlight in this review. These are (1) substratecontrolled stereoselective conjugate addition of the lithium enolate from α-amino acid derivative 20-1 to acrylate 20-2, furnishing intermediate 20-3, and (2) a BCl3-mediated Mannich-type cyclization of hemiaminal 20-4. Initially, the latter reaction was performed using 8 equiv of BCl3 at −78 °C, resulting in a complex mixture of products; however, upon reduction in the amount of BCl3 to 4 equiv, the desired product was isolated in 35% yield as a 5:1 mixture of diastereomers. Unexpectedly, it was discovered that the performance of the reaction could be dramatically improved when the temperature was raised to 0 °C, enabling the production of the desired tetracyclic product in 85% yield as a sole stereoisomer. The observed temperature effect motivated the authors to seek deeper mechanistic insights into the reaction. Eventually, a conclusion was reached that the second diastereomer unstable 4456


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trifluoroethanol, producing tricyclic guanidine 21-3 in 82% yield and good diastereoselectivity. An unusual cyclization reaction between iminium ions and (Z)-vinylsilanes developed by the Overman group144 was recently utilized in the last steps of the synthesis of cortistatin J, a natural product from the marine sponge Corticium simplex that has exhibited a promising biological profile for cancer therapy (Scheme 22).145 In the final step, aldehyde 21-1,

Scheme 20

Scheme 22

containing the (Z)-vinylsilane moiety, was heated with excess dimethylamine hydrochloride in acetonitrile to furnish cortistatin J as a single diastereomer in excellent yield. The high stereoselectivity of the reaction can be rationalized by the pseudoequatorial position of the dimethyliminium ion in the transition state to avoid an incipient 1,3-diaxial interaction with the ethylene bridge of the tetrahydrofuran ring. Different stable imines are capable of Mannich-type transformations upon activation with Brønsted acids. In 2002, Fukuyama reported an elegant total synthesis of ecteinascidin 743, an alkaloid isolated from the marine tunicate Ecteinascidia turbinate (Scheme 23). The natural product is known under the brand name Yondelis and mainly used as an antitumor drug for the treatment of advanced soft tissue sarcoma. The synthesis of the left segment commenced with the preparation of a highly functionalized (R)-phenylglycinol derivative by diastereoselective Mannich reaction between phenol 23-1 and chiral glycine derivative 23-2, activated by TFA via protonation of the imine group. Simultaneously, the installation of the chiral center of the phenylalanine group in the right segment was achieved by Noyori asymmetric hydrogenation. Subsequently, the third stereogenic C−N center of the molecule was installed by means of the Pd-catalyzed Heck reaction to give advanced intermediate 23-7 in 83% yield.146 Lewis acid-trigerred Mannich cyclization was a key step for the enantioselective synthesis of lycopodine reported by Carter and Yang in 2010 (Scheme 24).147 Treatment of the bicyclic imine 24-1 with Zn(OTf)2 in 1,2-dichloroethane at elevated temperatures in a sealed tube induced a cascade of 1,3-sulfone rearrangement and intramolecular Mannich annulation to yield amine 24-7 skeleton in 79% yield. The unusual 1,3-sulfone migration was rationalized by the initial isomerization of the preformed iminium cation 24-3 to the corresponding enamine 24-4, and subsequent migration of the sulfone group from C8 to C14. Next, diastereoselective protonation of the enamine and epimerimerization at C14 generates iminium species 24-6 followed by intramolecular ring closure via Mannich reaction to furnish the final product. Another large group of Mannich reactions, namely, the addition of metal enolates to uncharged imines, has served as a powerful tool for the stereoselective construction of C−N bonds. For example, Zou and co-workers applied this approach for the total synthesis of deamido bleomycin A2 (Scheme 25),148 a member of the structurally related glycopeptide-derived antibiotics called bleomycins, which have found clinical application for the treatment of several types of cancer. The stereogenic

at 0 °C was further processed via Prins cyclization pathways. Moreover, experiments performed individually with the simplified (E)- and (Z)-enoxysilanes revealed that the (E)-isomer cyclized with excellent stereoselectivity, whereas the (Z)-isomer led to the products in low diastereomeric ratio. Collectively, these results indicated that the (E) and (Z)-isomers could interconvert under the reaction conditions with increased rates at a higher temperature, becoming competitive with the rate of the cyclization.137,138 The Overman group also reported the synthesis of several marine natural products such as crambescidins,139 isocrambescidins,140 and batzelladine F comprised of polycyclic guanidine units.141,142 These complex alkaloids have an intriguing biological profile; in particular, batzelladine F is a potentially useful compound for the treatment of autoimmune diseases. Common to these syntheses is the construction of the tricyclic guanidine core by anti-selective Biginelli condensation143 between suitable α-keto esters and guanidine hemiaminals (Scheme 21). As an example, guanidine 21-1 reacted with compound 21-2 and morpholine acetate followed by heating in Scheme 21

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Scheme 23

of N-acyloxazolidinone 25-2 was added to imine 25-1 to deliver 25-3 in 45% yield as a single epimer. A similar method based on addition of the lithium enolate of chiral N-acyloxazolidinone 26-2 to N-sulfonylimine 26-1 was used by the Liao group for the installation of the benzyl chiral center during the total synthesis of lasubine I (Scheme 26), an

Scheme 24

Scheme 26

Scheme 25

alkaloid from a Lythraceae plant. Once linear precursor 26-4 with three stereogenic centers was established, the piperidine ring was constructed by intramolecular SN2 displacement via the corresponding tosylate.150 In a single bond-forming step, two vicinal nitrogen-substituted stereogenic centers were produced by Williams and DeMong during the synthesis of capreomycin IB (Scheme 27).151 After transmetalatation of the lithium enolate with Me2AlCl and addition of N-benzylimine 27-2, a modest 50−60% yield of a 3.3:1 mixture of diastereomers was obtained. Many attempts to improve the yield or diastereoselectivity were not productive. Later in the synthesis, the 1,2-diphenylethane unit was removed with PdCl2 and H2 over 4 days to form the free α-amino acid. Kitahara and co-workers applied a Mannich-type reaction between imine 28-1 and tetronic acid 28-2 in the total synthesis of cocclulolodine (Scheme 28a). Notably, this reaction does not require any acidic or basic activators and was performed in a mixture of acetonitrile and diethyl ether to ensure precipitation of compound 28-3, driving the equilibrium

C−N bond of the key pyrimidoblamic acid unit 25-3 was installed by a procedure developed by Boger.149 The tin enolate 4458


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tetrahydroisoquinoline core, as well as its analogues containing a piperidine ring. The vast majority of the stereoselective Picket−Spengler reactions in total synthesis have been performed in the diastereoselective mode, whereby the stereochemistry is translated from different phenylalanine or tryptophan derivatives or α-substituted aldehydes. Saframycins, ecteinascidins, renieramycins, quinocarcins, and lemonomycin are representative members of a large family of tetrahydroisoquinoline alkaloids. These alkaloids have attracted significant attention from synthetic chemists because of their novel structures combined with remarkable biological activity and scarcity in nature. In 2009, Liu and co-workers reported an asymmetric total synthesis of renieramycin G, an alkaloid from the Fijian sponge Xestospongia caycedoi. The tetrahydroisoquinoline core of the molecule was obtained from L-tyrosine methyl ester, which, after several modifications of the phenyl group, gave rise to α-amino alcohol 29-1 (Scheme 29a). The latter was reacted with (benzyloxy)acetaldehyde in the presence of trifluoroacetic acid at 0 °C to provide (1R,3S)1,2,3,4-tetrahydroisoquinoline 29-2 in 87% yield. The temperature factor was found to be crucial, since the reaction performed at room temperature produced a mixture of diastereomers in a 5:4 ratio, while nearly no trans diastereomer was found at 0 °C. However, no product 29-2 was detected at −10 °C. After several steps, advanced material 29-3 was treated with neat trifluoromethanesulfonic acid to initiate the second Picket−Spengler reaction, completing the skeleton of the natural product in 82% yield.156 In 2006, Danishefsky and co-workers reported an interesting formal total synthesis of ecteinascidin 743 using a novel vinilogous Picket−Spengler cyclization of 29-8 mediated by TFA, producing advanced hexacyclic intermediate 29-9 as a single diatereomer in moderate yield (Scheme 29c).161,162 Chen and Zhu recently reported the enantioselective total synthesis of (−)-cribrostatin 4 (renieramycin H) using the same approach for the formation of 1,3-cis-tetrahydroisoquinoline 29-6 on the basis of the reaction between aminophenol 29-5 and (benzyloxy)acetaldehyde in the presence of acetic acid (Scheme 29b).157 It is noteworthy that the same reaction conducted in the mixture of toluene and 1,1,1,3,3,3-hexafluoro2-propanol affords a mixture of cis and trans isomers in a 7:2 ratio. Also, according to a previous report,158 treatment of aminophenol 29-5 with ethyl glyoxylate gave the trans isomer as the major product in 61% yield. Moreover, the cis and trans isomers in that case are interconvertable even upon dissolution in CDCl3, and the mixture becomes enriched with the trans isomer once the equilibrium is reached. This observation led the authors to the conclusion that the trans selectivity with ethyl glyoxylate is driven thermodynamically. The Zhu group also successfully synthesized ecteinascidines 597, 583, and 743 employing the diastereoselective Picket−Spengler reaction.159,160 In 2008, the same group reported the total synthesis of quinocarcin, a natural product belonging to the tetrahydroisoquinoline alkaloid family and exhibiting potent antitumor activity against a variety of tumor cell lines. After phenylalanine derivative 30-1 was obtained by means of asymmetric phase transfer catalysis, it was subjected to the reaction with (benzyloxy)acetaldehyde, resulting in the formation of tetrahydroisoquinoline 30-2 as a single cis diastereomer in excellent yield (Scheme 30). Subsequently, the 3,8diazabicyclo[3.2.1]octane ring was installed via an intramolecular nuclephilic attack of the tethered silyl enol ether

Scheme 27

Scheme 28

toward the product, which was isolated in 91% yield by a simple filtration.152 2-[(Trialkylsilyl)oxy]furans have been shown to react with iminium cations in a close analogy to enolates. This method became valuble for the synthesis of quinolizidinone alkaloids lupinine and epiquinamide described by Santos and co-workers (Scheme 28b).153 The authors examined several conditions for the coupling between the acyliminium cation derived from 2-methoxypiperidine carbamate 28-4 and different 2-(trialkylsiloxy)furans. It was determined that the reaction of furan 28-5 in the presence of (TMS)OTf and 1-butyl-3methylimidazolium tetrafluoroborate (BMI·BF4) produced compound 28-6 in 80% yield with high diastereoselectivity (dr 9.7:1). The resulting stereochemistry was rationalized via transition state 28-7, in which the siloxyfuran reacts with the substrate from the Si face. 2.5. Diastereoselective Picket−Spengler Reaction (Figure 7)

The Picket−Spengler reaction154,155 holds comparable significance to the Mannich reaction in the field of natural product synthesis, and in fact may be viewed as a special case of the Mannich reaction culminating in the formation of the 4459


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Figure 7.

Scheme 29

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First, the group of Gao at East China Normal University and subsequently that of Tietze in Germany developed the total synthesis of spirocyclic alkaloid erysotramidine on the basis of the diastereoselective Picket−Spengler reaction as a key step. In the first synthesis, cyclohexanone 32-2 was reacted with amide 32-1 and NaH in dimethyl carbonate to form racemic hemiaminal 32-3, which cyclized in the presence of BF3·Et2O, providing spirocyclic intermediate 32-4 as a single diastereomer in 87% yield (Scheme 32a).165 Disconnections performed by

Scheme 30

Scheme 32

onto the incipient N-acyliminium ion, generated from thioacetal 30-3 in the presence of AgBF4.163 Among nearly 60 natural products in the tetrahydroisoquinoline family, lemonomycin is unique due to its structure that comprises a glycoside at C18. The structural distinctiveness of its combination of the 2,6-dideoxy-4-amino sugar and the diazabicyclo[3.2.1]octane units, as well as its impressive biological profile, inspired the Stoltz group to pursue its total synthesis (Scheme 31).164 Initially, the authors developed an Scheme 31

the Tietze group gave rise to enantiopure 1,4-keto ester 32-5 and (phenylethyl)amine 32-6 as the starting materials, which were subjected to the cascade process involving the Picket− Spengler reaction, which produced a mixture of diastereomers 32-8 and 32-9 in a 4:1 ratio (Scheme 32b). The reaction proceeded through the initial formation of the aluminum amide from AlMe3 and amine 32-6, followed by attack on the ester group to form the amide. The amide tautomerized to cyclic hemiaminals. Upon treatment with TfOH, this mixture forms the iminium cation 32-7, which then reacts with the 1,2-dimethoxyphenyl substituent in the last step.166 Formation of the major isomer can be explained by the thermodynamically preferred attack on the iminium cation anti to the neighboring methylene group (re face), furnishing 32-8 as the major product. A large number of indole alkaloids were synthesized by means of annulation of the piperidine ring onto the indole core

efficient enantio- and diastereoselective procedure for the construction of the diazabicyclo[3.2.1]octane unit by means of dipolar cycloaddition between Oppolzer sultam-derived acrylamide 31-2 and pyrazinonium salt 31-1. After deprotonation with N-methylmorpholine, lactam 31-3 was formed in 72% yield and 94% ee after the sultam removal. Next, aminophenol trifluoroacetate 31-4 was prepared in several steps and then treated at room temperature with aldehyde 31-5 to produce the desired terahydroisoquinoline intermediate 31-6 in excellent yield as the cis diastereomer. 4461


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favored 1,3-trans-1,2,3,4-tetrahydro-β-carbolines under nonacidic conditions, while simple tryptophan derivatives without N-substitution afforded 1,3-cis-carbolines under acidic conditions. In general, the introduction of bulky substituents on the nitrogen atom resulted in the formation of diastereomeric mixtures enriched with the trans isomer under kinetic control. The treatment of such mixtures with different Bronsted acids usually led to the exclusive formation of the thermodynamically stable trans isomer.171 This approach has found a broad application in the total synthesis of natural products containing the 1,2,3,4-tetrahydro-β-carboline fragment with the 1,3-trans configuration in the piperidine ring. For example, during the total syntheses of sarpagine indole alkaloids, namely, talpinine, talcarpine, alstonerine, and anhydromacrosalhine-methine via the asymmetric Picket−Spengler reaction, Cook et al. extensively investigated the reaction between N-benzylprotected tryptophan and different aldehydes.172 Indeed, it was found that the reaction between 34-1 and α-ketoglutaric acid under aprotic conditions resulted in the formation of a 4:1 diastereomer mixture of 34-3 and 34-4 (Scheme 34a). However, when a similar reaction with 4,4-dimethoxybutyrate was performed in the presence of trifluoroacetic acid, only the trans isomer was observed (92% yield). The excellent diastereoselectivity in the acidic media could be understood by the acid-promoted isomerization of the undesired cis isomer 34-4 to the thermodynamically preferred trans isomer 34-3. The proposed mechanism for this isomerization is depicted in Scheme 34b. The iminium cation, formed as a result of the reaction between tryptophan and acetal 34-6, attacks the indole at the C3 position, leading to the formation of isomeric transand cis-spiroindolenines 34-8 and 34-11. Intermediate 34-8

to form tetrahydrocarbolines using the Picket−Spengler protocol. Bailey and co-workers recently described the syntheses of indole alkaloids (−)-raumacline167 and (−)-suaveoline168 utilizing this approach (Scheme 33). For the assembly of Scheme 33

the 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole core, amino nitrile 33-1, initially prepared from L-tryptophan, was treated with 3-(tert-butyldimethylsiloxy)propanal to give the corresponding aldimine, which was cyclized in the presence of trifluoroacetic acid under kinetic control conditions169 to provide the cis product exclusively in 80% yield. This stereoselective approach was also utilized by Sato et al. in the enantioselective synthesis of corynantheidine.170 The Cook group capitalized on the switch between 1,3-cis and 1,3-trans selectivity in the Pictet−Spengler reaction between tryptophan methyl ester and benzaldehyde. It was determined that the reaction of N-substituted tryptophan esters Scheme 34

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could directly undergo the rearrangement to the trans product 34-3 via cation 34-9. At the same time, the unfavored cis-spiroindolenine 34-11 could first rearrange in the same manner and then isomerize at C1 under acidic conditions to produce the more stable trans product 34-3. An identical approach was used by the Cook group for the preparation of a large number of indole alkaloids.173−179 In 2005, Allin et al. reported the total synthesis of deplancheine to highlight the synthetic utility of a method for the stereoselective preparation of indolo[2,3-a]quinolizines based on the cyclization of a pendant aromatic substituent onto an N-acyliminium cation (Scheme 35).180 The reaction of

An alternative way to introduce a stereogenic center bound to a nitrogen atom by means of the Picket−Spengler reaction is through the coupling of aldehydes with a chiral center at the α-position with nonchiral tryptamine derivatives. The Fukuyama group effectively employed this method for the construction of the marine natural product eudistomin C (Scheme 37a) Scheme 37

Scheme 35

β-amino alcohol 35-1 derived from (S)-tryptophan and aldehyde 35-2 in refluxing toluene resulted in the formation of lactam 35-3 as a mixture of diastereomers. This mixture was treated with 2 M HCl to generate the iminium cation, which, upon trans-selective cyclization, gave rise to Pictet−Spengler product 35-4. Danishefsky and co-workers disclosed an intriguing total synthesis of indole alkaloid phalarine, which comprises a very unusual propellane structure incorporating a gramine-related unit. The unit was assembled by means of the Picket−Spengler reaction (Scheme 36).181 The tryptophan derivative 36-1 was treated with formalin in the presence of CSA to produce compound 36-5 containing the pentacyclic core of the natural product in 91% yield and excellent diastereoselectivity. The observed stereoselectivity resulted from two possible cyclization pathways. In pathway a, the cyclization initially occurred at C3 of the indole ring, resulting in formation of the spirocyclic intermediate 36-3, which later underwent suprafacial Wagner− Meerwein rearrangement, thus transferring the stereochemical information from C3 to C2. At the same time, pathway b involved an initial attack of the iminium cation on C2 of the indole core followed by the cyclization onto the phenolic hydroxy group.

isolated from the Caribbean tunicate Eudistoma olivaceum, which, along with other eudistomins, has displayed extremely potent antiviral activity against both DNA and RNA viruses as well as antitumor and antimicrobial activity. Initially, a model 2-(1H-indol-3-yl)ethanamine reacted with Garner aldehyde in the presence of trifluoroacetic acid in CH2Cl2 at −78 °C to selectively introduce a piperidine ring. However, these conditions afforded the undesired diastereomer as the major product (3:1 ratio). After an extensive screening of conditions, it was discovered that annulation of indole 37-1 with Garner aldehyde 37-2 smoothly proceeds with a catalytic amount of chloroacetic acid or dichloroacetic acid in toluene at 0 °C, delivering the desired diastereomer 37-3 with high selectivity.182 Subsequently, eudistomin E was obtained in the same fashion.183 Prasad and Nidhiry utilized a reaction between tryptamine 37-4 and aldehyde 37-5 for the enantioselective synthesis of eburnamonine; however, application of trifluoroacetic acid in CH2Cl2 at −20 °C for the Picket−Spengler reaction resulted in the production of 37-6 with low

Scheme 36

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diastereoselectivity (3:2) (Scheme 37b).184 The Prasad group also accomplished the total syntheses of henrycinols A and B by the reaction of L-tryptophan methyl ester with an enantioenriched aldehyde derived from 2,3-O-isopropylidene-Dthreitol.185 Following the same blueprint, Stork and co-workers reported in 2005 the asymmetric preparation of a classic synthesis target, the indole alkaloid reserpine (Scheme 38).186 The challenging

not been studied extensively. The Takayama group applied this method for the construction of 1,1-disubstituted tetrahydro-βcarboline derivative 39-7 during the course of the enantioselective total synthesis of subincanadines A and B (Scheme 39).187 Scheme 39

Scheme 38

Picket−Spengler cyclization was addressed on the basis of the assumption that the kinetic mode of cyclization of an iminium ion generated regioselectively would lead to the formation of the desired, thermodynamically less stable diastereomer 38-6. The first attempt to perform the desired cyclization led to the formation of the thermodynamically favored epimer at the C3 center. However, it was hypothesized that the iminium cation 38-5 did not participate in the reaction, and the cyclization took place immediately after aldimine formation between amine 38-1 and aldehyde 38-2. To avoid this pathway, compounds 38-1 and 38-2 were subjected to coupling in the presence of excess external nucleophile (potassium cyanide) to form cyanopiperidine 38-3 serving as a masked iminium cation. The initial attempt to perform the desired elimination of nitrile followed by the iminium cyclization in refluxing acetonitrile again resulted in formation of the undesired stereoisomer at the C3 center in 65% yield, indicating that, in this case, the reaction proceeded through a tight ion pair between the iminium and cyanide ions. Since the cyano group occupies an axial position, it can prevent the reaction with the indole function in the “chair-axial” mode and thus lead to a “boat-axial” mode, ultimately resulting in the unwanted stereoisomer. To disrupt the putative tight ion pair, the authors performed the reaction in acidic media (10% 1 N HCl in THF), where the cyanide ion could be easily removed, providing a “free” iminium cation that indeed cyclized to the C3 epimer in 90% yield. Whereas the Picket−Spengler reaction with aldehydes is well-known, the utilization of ketones for such cyclizations has

An initial effort to perform the intermolecular reaction between tryptamine and ketone 39-2, bearing a stereogenic secondary alcohol at the α-position, in the presence of trifluoroacetic acid in refluxing CH2Cl2 was unsuccessful. Instead, the diastereomeric mixture of 1,1-disubstituted tetrahydro-β-carbolines was obtained. Moreover, both products were shown to have low optical rotation values ascribed to the epimerization during the reaction. After screening various acids and solvents, the authors found that the intramolecular cyclization of carbamate 39-4 promoted by (TMS)Cl at −78 °C resulted in the quantitative formation of the desired product as a 9:1 mixture of diastereomers. After a simple recrystallization, pure diastereomer 39-7 was produced in 47% yield and 99% ee. The high diastereoselectivity of the cyclization could be rationalized by the stereochemical arrangement of the acyliminium intermediate in which the indole nucleus attacks from the less hindered side (anti from the side alkyl chain). The acyliminium Picket−Spengler cyclization was also utilized by this group for the synthesis of the proposed structure of eudistomidin B.188

3. STEREOSELECTIVE FORMATION OF C−N BONDS BY NUCLEOPHILIC SUBSTITUTION Nucleophilic substitution is one of the most common and important approaches for stereoselective C−N bond formation in organic chemistry. A predictable stereochemical outcome, broad availability of stereodefined substrates containing a 4464


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Figure 8.

3.1. Azides as a Source of Nitrogen (Figure 8)

suitable living group, and a variety of abundant sources of nucleophilic nitrogen place this methodology on the short list of tools for the design of alkaloid synthesis and preparation of other compounds containing stereogenic C−N bonds. Furthermore, mild reaction conditions and high chemoselectivity make nucleophilic substitution compatible with a wide range of substrates and, more importantly, with late-stage transformations in the assembly of complex chemical structures that put a high demand on functional group compatibility. This section includes a total of 110 references for the utilization of nucleophilic substitution that creates a chiral carbon−nitrogen bond in total synthesis. For convenience, this section is divided into four subsections on the basis of key features of the installation method as well as the source of nucleophilic nitrogen.

The utilization of alkali-metal azides and other equivalents of azide anion as a source of nucleophilic nitrogen found broad application in the total synthesis of natural products. A common set of conditions includes reactions of a chiral substrate with an excess of sodium azide in different aprotic polar solvents at elevated temperatures that proceed through an SN2 pathway with complete inversion of stereochemistry at the reactive chiral center. Wide availability of methods for the preparation of enantiodefined alcohols dictates that the vast majority of nucleophilic substitutions with azides are performed using the corresponding sulfonates as the substrates. In 2006, the Chida group reported a total synthesis of actinobolin, a natural product isolated from the culture broth of Streptomyces griceoviridus that demonstrates a broad antibacterial 4465


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spectrum as well as moderate antitumor activity.189 The installation of nitrogen into the δ-lactone segment of the bicyclic ring system of the molecule was performed by treatment of the corresponding tosylate with sodium azide upon heating in N,N-dimethylformamide (DMF). The advanced intermediate 40-2 was processed through several steps before the azide group was reduced and the D-alanine fragment was finally appended (Scheme 40). Similar amination reactions by

Scheme 42

structure integrating a γ-lactone and δ-lactam (Scheme 42). The latter was assembled by means of a two-step sequence that includes nucleophilic substitution of mesylate in the intermediate 42-1 with subsequent reduction of chiral azide 42-2 and its cyclization onto the desired δ-lactam in one pot. Notably, at elevated temperatures, the reaction leading to the azide also allowed for the removal of the bulky Me3Si group, which previously was shown to preclude formation of the δ-lactam fragment upon reduction of the azide. Lycoposerramines V and W were the targets of the total synthesis reported in 2007 by the Takayama group.204 These natural products were isolated from Lycopodium serratum plants and demonstrated notable acetylcholine esterase inhibition activity. To establish the stereogenic C−N bond of the piperidine unit, the chiral homoallyl alcohol 43-1 was subjected to mesylation under basic conditions followed by azidolysis, leading to advanced intermediate 43-2 (Scheme 43). Subsequent

Scheme 40

nucleophilic substitution with sodium azide in five- or sixmembered ring systems were utilized for the syntheses of (+)-nangustine,190 (+)-febrifugine,191 pachastrissamine (jaspine B),192 dysiherbaine,193 spicamycin,194 and antitumor agent FR901464.195 Carbon−nitrogen bonds in several relatively simple 2-substituted piperidine natural products, specifically (−)andrachcinidine,196 (+)-β-conhydrine,197 (+)-deoxocassine,199 (+)-perhydro-8-indolizidinol,198 and (−)-deoxoprosophylline199 were established by the reaction of different linear sulfonate precursors with sodium azide. In this series, the total synthesis of (−)-epiquinamide A, a nicotinic agonist in central nervous system (CNS) disorders, examplifies the stereoselective installation of both C−N bonds of the alkaloid using the azidolysis strategy (Scheme 41).200 First, butyrolactone

Scheme 43

Scheme 41 steps to establish the piperidine ring include reduction of azide 43-2 and subsequent allylation of the amine followed by ringclosing metathesis and hydrogenation of the resulting cycloalkene. Several total syntheses of glycosylated natural products containing nitrogen were successfully performed utilizing nucleophilic azidolysis. In particular, ganglioside Hp-s1, isolated from the ovary of the sea urchin Diadema setosum or the sperm of the sea urchin Hemicentrotus pulcherrimus and possessing neuritogenic activity, is a molecule of high biological interest. Owing to the difficulty of acquiring material of sufficient quantity and purity, Tsai and co-workers accomplished the first total synthesis of its closest analogue, ganglioside 44-5 (Scheme 44a).205 Installation of the N-containing chiral center in building block 44-2 was performed by reaction of tetrol monomesylate 44-1 with sodium azide in DMF under heating conditions. The introduction of the masked amino group by this method allowed for a buildup of the molecular skeleton first, and then to perform reduction of the azide with subsequent amidation with stearic acid. In a similar manner, Kim and co-workers accomplished the synthesis of agelagalastatin (Scheme 44b), an alkaloid isolated as a mixture of two isomers from marine sponge Agelas sp. and displaying a significant in vitro inhibitory activity against human cell growth.206 After sulfonation of alcohol 44-3 with triflic anhydride, the authors applied a protocol developed by Papa,207 utilizing tetramethylguanidinium azide (TMGA) as the azide anion source.

41-1 was transformed to azide 41-2 in two steps including mesylation and treatment with sodium azide in DMF. Then bicyclic advanced intermediate 41-3 was subjected to the same two-step reaction sequence to introduce the second C−N bond of the target molecule. The synthesis of (+)-epiquinamide A was also independently accomplished by the Barker201 and Ghosh202 groups using a similar strategy for installation of the acetamide moiety. In 2012, Koert and co-workers disclosed an asymmetric total synthesis of the marine alkaloid awajanomycin isolated from the sea mud around Awajishima Island and proved to exhibit cytotoxic activity. 203 Besides intriguing biological data, awajanomycin possesses a unique bridged bicyclic core 4466


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Scheme 44

Scheme 45

Scheme 46

A late-stage SN2 amination via initial azide installation was successfully applied in several total syntheses. For example, Schmalz and co-workers developed the asymmetric synthesis of the natural alkaloid colchicinean important antimitotic agent isolated from meadow affron (Coclchicum autumnale L.).208 After tropolonemethyl ether derivative 45-1 was preassembled, the amination was carried out in three steps by deprotection of the tert-butyldimethylsilyl (TBS) group, mesylation of the resulting alcohol, and azidolysis in dimethyl sulfoxide (DMSO), leading to azide 45-2 in 54% overall yield (Scheme 45a). In addition, a late-stage azidolysis was successfully employed by the Baran group in their synthesis of several indole alkaloids from marine blue-green algae.209,210 For example, for the installation of the isocyanate group of fischerindole G, ketone 45-3 was converted to amine 45-4 via a sequence involving reduction, mesylation, azidolysis, and final reduction of the isolated azide with sodium amalgam (Scheme 45b). Another remarkable example of a late-stage application of amination with azides is the total synthesis of maremycin B, a potent anticancer agent.211 After initial attempts to displace the bromide in γ-butyrolactone intermediate 46-1 were unsuccessful, the labile lactone group was transformed to amide 46-2 by coupling with (S)-methylcysteine using AlMe3 (Scheme 46). Subsequent displacement of the bromine was achieved by modification of the Deshong−Smith212 protocol with tetrabutylammmonium difluorotriphenylsilicate (TBAT) and trimethylsilyl azide. The azide group in advanced intermediate 46-3 was reduced by PMe3 via the Staudinger reaction, and final lactonization gave rise to maremycin B.

An SN2 amination through azides also proved to be useful for the preparation of different α- and β-amino acid precursors for cyclic peptide natural products, such as halipeptins A and D,213 as well as their closly related analogues.214 β-Tyrosine and 3-hydroxyornithine derivatives were prepared by the Maier and Phillips groups in their work directed at the syntheses of chondramide A215 and aburatubolactam A,216 respectively. Different tyrosine derivatives prepared in a similar fashion by Dethe and Ranjan were also useful for the synthesis of the oxazinin family of marine toxins.217 In particular, an interesting approach to the celogentin family of natural products, namely, stephanotic acid methyl ester and celogentin C, was published by Jia and co-workers in 2010 (Scheme 47).218 The key leucine−tryptophan fragment was prepared by a tandem asymmetric Michael addition/bromination/azidation strategy utilizing the Evans auxiliary to control the stereochemistry. After the first two steps of the proposed sequence, compound 47-1 was treated with sodium azide to furnish key intermediate 47-2 in 82% yield. Again, the azide served as a “masked” amine and was reduced only after the macrocyclic system of the target molecule was assembled. 3.2. Non-Azide Sources of Nitrogen (Figure 9)

Simple mono- and disubstituted amines can also serve as useful sources of nitrogen during the construction of stereogenic centers comprising C−N bonds. For example, allylamine was used for SN2-type displacement in homoallyl mesylates to form the corresponding 1,7-dienes, which upon ring-closing metathesis (RCM) with Grubbs II catalyst and subsequent hydrogenation and deprotection led to coniine, pseudoconhydrine, 4467


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(Scheme 48).220 These natural products were isolated from the branches of the deciduous tree Broussonetia kazinoki SIEB (Moraceae), which has been used as a folk medicine in China for a broad spectrum of disease treatment. The synthesis of piperidine intermediate 48-2 was accomplished by a three-step sequence from lactone 48-1. The diol derived from reduction with LiAlH4 was dimesylated and subjected to the ring closure with allylamine to deliver 48-2 in 60% overall yield. At the same time, the pyrrolidine fragment was assembled from D-arabinose utilizing diastereoselective addition of Grignard reagent to nitrone 48-3. Similarly, the heterocyclic cores of several relatively simple piperidine and pyrrolidine natural products, including fagomine derivatives,221 deoxoprosopine,222 and swainsonine,223 were assembled by the reaction between 1,4or 1,5-disulfonates and primary amines. During the synthesis of the anticancer agent piperazimycin A, Ma and co-workers demonstrated that the nucleophilic substitution of sulfonate

Scheme 47

and the sedamine alkaloids.219 The syntheses of broussonetine J2 and its N-acetate, broussonetine I, were also accomplished using allylamine as the nucleophile by the Yu group in 2013

Figure 9. 4468


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Scheme 48

Scheme 50

in the presence of Cs2CO3 (Scheme 50). Stable alkali-metal salts of heterocycles, such as adenine sodium salt, can also serve as a convenient nitrogen nucleophile, as illustrated in the synthesis of 3′-methylaristeromycin.227 The strained azetidine core of the marine natural product penaresidin A, isolated from sponge Penares sp., was also constructed by intramolecular nucleophilic substitution.228 Both stereogenic C−N bonds of penaresidin A were introduced by SN2-type reactions (Scheme 51). The stereocenter in

with hydrazine as a source of nitrogen can also be useful for the installation of the chiral center of the α-substituted hexahydropyridazine ring.224 In 2012, the Carreira group applied a late-stage nucleophilic substitution with a secondary amine for the diastereoselective construction of the pyrrolidine ring of dendrobine (Scheme 49), an alkaloid isolated from the ornamental orchid

Scheme 51

Scheme 49

substrate 51-1 was installed by azidolysis of the corresponding mesylate, and construction of the azetidine unit was accomplished by mesylation of the alcohol followed by cyclization in the presence of NaH. An interesting alcohol α-amination was utilized by Vasella and co-workers in the synthesis of the potent mannosidase inhibitor mannostatin A, isolated from the fermentation broth of Streptoverticillium quantum.229 The synthetic sequence began with the conversion of alcohol 52-1 to trichloroacetimidate 52-2 by addition to trichloroacetonitrile in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and continued by subjecting isolated trichloroacetimidate 52-2 to cyclization in the presence of Hünig’s base (Scheme 52). Subsequently, it was

Dendrobium nobile Lindl, known for its application in traditional Chinese medicine.225 Having constructed the carbocyclic core, the authors applied a one-pot transformation combining bromination with pyrrolidone hydrotribromide (PHT) and nucleophilic displacement by a pendant secondary amine. The regioselectivity of the bromination was explained by the initial formation of N-bromoamine 49-2, which acted as a directing group for the bromination at C10. Application of 4-(dimethylamino)pyridine (DMAP) in the second step was shown to have a critical effect on the conversion by inducing epimerization at the C10 position of α-brominated intermediate 49-3, channeling the material to the isomer with the carbon−bromine bond correctly aligned for SN2 displacement. Certain nitrogen-containing heterocycles can also function as a suitable source of nucleophilic nitrogen after base activation. A synthesis of alkaloid cyclooroidin recently disclosed by the Lovely group serves as a particularly fitting example.226 The key C−N bond was constructed by the intramolecular SN2 displacement of the chlorine atom with the pyrrole nitrogen

Scheme 52

discovered that isolation of intermediate 52-2 was unnecessary, and a one-pot reaction gave rise to 52-3 in 80% yield. Its global 4469


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deprotection resulted in the formation of the target α-amino alcohol in 94−98% yield. A particularly challenging case of amination with a sterically hindered tertiary propargyl acetate was demonstrated by Siegel and co-workers during the total synthesis of complanadine A.230 Tertiary acetate 53-1 reacted with benzylamine in the presence of a catalytic amount of CuCl to afford the corresponding amine in excellent yield and with complete inversion consistent with an SN2-type pathway (Scheme 53). Notably, the

Scheme 54

Scheme 53

terminal alkyne group played a crucial role, presumably through interaction with the copper catalyst, which dramatically facilitates the reaction.231 Deacetylation of compound 53-2 followed by cyclization culminates in the construction of the nitrile, which was subsequently investigated in the final [2 + 2 + 2] cycloaddition reaction. Different guanidine-containing natural products were obtained using the nucleophilic substitution strategy for the installation of challenging stereogenic C−N bonds. In 2006, O̅ mura and co-workers accomplished the synthesis of the important biosynthetic intermediate K01-0509 B comprising 2-iminoimidazolidine substituted at the C5 position (Scheme 54a).232 The advanced acyclic intermediate 54-1 was cyclized to 54-2 through mesylation followed by diastereoselective intramolecular nucleophilic displacement of the mesylate mediated by diisopropylethylamine. Subsequently, this natural product233 and guadinomines B and C2234 were accessed by an approach identical to that of the 2-iminoimidazolidine. The construction of a tricyclic guanidine core of batzelladine A was exercised by the Overman group in a similar manner, using mesylation and itramolecular displacement for the installation of the six-membered ring (Scheme 54b).235 An analogous approach using bromine anion as the leaving group was utilized in 2000 by Snyder for the first total synthesis of the important freshwater toxin cylindrospermopsin.236 SN2′ nucleophilic substitution reactions with nitrogen nucleophiles accompanied by an allyl shift also found application for the construction of stereogenic centers of various natural products. This process frequently proceeds with retention of configuration. For example, in the synthesis of the Amaryllidaceae alkaloid amabiline, Banwell and Findlay utilized tandem one-pot Staudinger reduction/SN2′ displacement of the mesylate group for the diastereospecific installation of the pyrrolidine ring (Scheme 55a).237 In much the same way, the bismuth trifluoromethanesulfonate-catalyzed intramolecular 1,3-chirality transfer reaction for the construction of a tetrahydroisoquinoline ring, developed earlier,238 enabled

Uenishi and co-workers to accomplish the synthesis of several 1-phenethyltetrahydroisoquinoline alkaloids such as (+)-dysoxyline, (+)-colchiethanamine, and (+)-colchiethine (Scheme 55b).239 Jia and co-workers performed a one-pot Scheme 55

Mg(ClO4)2-mediated tandem Boc-deprotection/nucleophilic aminocyclization for the construction of the seven-membered 4470


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ring of cis-claviciptic acid (Scheme 55c).240 It was proposed that the magnesium cation, acting as a mild Lewis acid, coordinates to the alcohol, thus facilitating the intramolecular SN2′ substitution reaction. The observed diastereoselectivity may arise from the steric interactions between the vinylic methyl groups and the methyl ester in the transition state. A notable strategy for the assembly of the hexahydroindole skeleton consisted of an electrocyclic ring opening followed by intramolecular nucleophilic capture of the incipient π-allyl cation 56-3 by the nitrogen of the tethered carbamate. Banwell and co-workers accomplished a short and straightforward total synthesis of both enantiomers of γ-lycorane (Scheme 56).

Scheme 58

Scheme 56

nervous system in animal tests. A mixture of diastereomers 58-1 was treated with trifluoroacetic acid to give the key pyrrolidine intermediate as a single isomer. The stereochemical outcome of the reaction can be rationalized by the initial formation of resonance-stabilized benzylic carbocation 58-3, with additional anchimeric stabilization by the neighboring acetoxy group (58-5). Approach of the carbamate nucleophile from the opposite face then afforded 2,5-trans-substituted pyrrolidine 58-2. A similar substitution was also adopted for the synthesis of polyhydroxypyrrolidine alkaloid radicamine B.244 Chamberlin and Vaswani disclosed application of the SN1-type reaction for the construction of the 5-vinylproline unit of kaitocephalin, a pyrrolidine-based alkaloid isolated from the filamentous fungus Eupenicillium shearii PF1191 that exhibited a significant glutamate receptor antagonistic activity.245 In their intriguing approach, both isomers of the alcohol 59-1 underwent cyclization in the presence of PPh3 and iodine to predominantly produce the required trans-disubstituted pyrrolidine 59-2 (Scheme 59). The observed stereochemical outcome of the reaction was explained by invoking the corresponding allylic carbocation that precedes the cyclization. The transition state minimizing the allylic strain afforded the major product trans-592. Similarly, a diastereoselective SN1-type cyclization of the allylic carbocation generated by electrocyclic ring opening of the dibromocyclopropane group was employed by Fukuyama and co-workers for the synthesis of lyconadin A.246

The chirality of the menthyl carbamate 56-1 was useful for the subsequent separation of diastereomeric hexahydroindoles 56-2 required to complete the enantioselective total synthesis.241 Despite the fact that SN1-type nucleophilic substitution is known to proceed through planar carbocation intermediates that in general cannot translate stereochemical information, there are several examples of total syntheses in which the construction of stereogenic C−N bonds was achieved by application of a formal SN1 displacement. An impressive example of the diastereoselective Ritter reaction was described by Chandra and Johnston in the paper devoted to the synthesis of indole alkaloids hapalindoles K, A, and G.242 The reaction between advanced intermediate 57-1 and (TMS)CN in acidic conditions proceeds with complete retention of configuration (Scheme 57). The observed diastereoselectivity could be Scheme 57

3.3. Mitsunobu Reaction (Figure 10)

Since its discovery in 1967, the Mitsunobu reaction has enjoyed a privileged role in organic synthesis and medicinal chemistry because of its scope, stereospecificity, and mild reaction conditions.247,248 Nevertheless, it has found a relatively narrow application for the stereoselective construction of C−N bonds in total synthesis, probably due to a requirement that the nitrogen nucleophiles employed in this reaction possess N−H acidity with a pKa below 15, and preferably less than 11. This requirement limits the range of nucleophiles to imides, sulfonamides, and purine/purimidine bases and related heterocycles and hydrazoic acid (HN3) and its easier-to-handle derivatives such as diphenylphosphoryl azide (DPPA), trimethylsilyl azide, and zinc azide. Among the aforementioned nucleophiles, sulfonamides and hydrazoic acid derivatives seem to be the most frequently utilized reagents in the total syntheses of alkaloids. For example, Fujioka and co-workers applied the intramolecular Mitsunobu reaction with 4-nitrobenzenesulfonamide

rationalized by the formation of an allylic cation followed by the approach of the nucleophile from the stereoelectronically favored axial site. Both the free and silylated alcohols react with (TMS)CN with almost the same yields and diastereoselectivity. Rao and co-workers developed a straightforward method for the construction of the tetrasubstituted pyrrolidine ring of the alkaloid codonopsinine using an intermolecular SN1 reaction (Scheme 58).243 This natural product was initially isolated in 1969 from Codonopsis elematidea and displayed antibiotic as well as hypotensive activities without affecting the central 4471


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Scheme 59

Scheme 60

An intriguing strategy based on the Mitsunobu reaction for the preparation of orthogonally protected tropone derivative 61-2, a key intermediate for the total synthesis of (−)-trans-dendrochrysine, was developed by the Blechert group (Scheme 61).250 Hydroxyacetate 61-1 was first reacted with Scheme 61

to establish the trans-fused 5,6-bicyclic core of Stemona alkaloid (−)-stenine (Scheme 60).249 By replacing diethyl azodicarboxylate (DEAD) and THF used in the standard conditions with diisopropyl azodicarboxylate (DIAD) in 1,4-dioxane, the yield of the synthesis intermediate 60-2 was increased more than 3-fold.

N-allyl 4-nitro sulfonamide using the standard Mitsunobu conditions followed by nucleophilic acetate displacement with N-allyl O-benzyl carbamate. Both reactions resulted in complete inversion of the configuration. This group applied the same

Figure 10. 4472


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effects against cancer cells, was established by reaction of homoallylic alcohol 64-1 with DPPA in the presence of DEAD and PPh3, followed by reduction of the resulting azide with PPh3 (Scheme 64).259 Other successful examples of stereo-

approach for the synthesis of the dipiperidine alkaloids virgidiarine and virgiboidine.251 The Mitsunobu reaction between N-propargyl 4-nitro sulfonamide and a cyclohexanol derivative was applied for the installation of the stereogenic center of daphenylline, as recently described by Li and co-workers.252 En route to the Amaryllidaceae alkaloid (−)-brunsvigine, Sha and co-workers successfully annulated a pyrrolidine-2-one unit to the cyclohexenol derivative 62-1 (Scheme 62). After

Scheme 64

Scheme 62

selective secondary amine preparation by Mitsunobu azidation employing DPPA and reduction can be found in the syntheses of (+)-awajanomycin,260 kedarcidin chromophore aglycon,261 (−)-α-lycorane,262 and “pyranosyl nikkomycin B”.263 Overman and Paone exploited the Mitsunobu inversion for the introduction of two azide groups during the synthesis of ditryptophenaline and ent-WIN 64821two indole alkaloids possessing an intriguing biological profile (Scheme 65).264

a Mitsunobu reaction between cyclohexenol 62-1 and N-methoxy-N-methyl(tosylamino)acetamide mediated by DEAD and PPh3, the standard Weinreb ketone synthesis triggered by n-BuLi completed the annulation process, delivering 62-3 in 92% overall yield.253 Banwell et al. exploited a similar Mitsunobu reaction for the stereospecific attachment of the nitrogen to the cyclohexene ring in the total synthesis of the non-natural enantiomer of brunsvigine.254 Subsequently, this approach was extended to the synthesis of (−)-brunsvigine and (−)-manthine.255 Taber and co-workers demonstrated that sulfonamide coupling with alcohol 63-1 for the installation of the stereogenic C−N bond in (−)-morphine was unsuccessful. Instead, they developed a three-step sequence consisting of Mitsunobutype azidation with DPPA, Staudinger reaction, and protection of the resulting amine by sulfonation (Scheme 63).256

Scheme 65

Scheme 63

For example, WIN 64821 is a competitive substance P antagonist with submicromolar potency against the human NK 1 receptor and also an antagonist of the cholecystokinin type B receptor. Green and co-workers described the synthesis of allocolchicine NSC 51046 and its analogues using a late-stage azidation of alcohol 66-1265 by a method developed by Viaud and Rollin, in which the zinc azide−pyridine complex serves as the reagent (Scheme 66).266 Azide 66-2 was transformed to NSC 51046 by reduction under hydrogenation conditions with Lindlar catalyst and acylation of the derived amine under the standard conditions. An azidation reaction with DPPA was exploited for the installation of the 1,2-amino alcohol moiety in the structure of scyphostatin, the greatest inhibitor (IC50 = 1.0 μM) of a neutral sphingomyelinase (NSMase) among a large number of other reported NSMase inhibitors. Scyphostatin is considered as a

Several relatively simple examples of installation of the amino group by tandem Mitsunobu azidation/Staudinger reduction or hydrogenation were recently described for the synthesis of the piperidine alkaloids (+)-sedamine257 and (−)-barrenazines A and B.258 The sole chiral center of the phenanthroindolizidine alkaloid (+)-tylophorine, an alkaloid that exhibited inhibitory 4473


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Scheme 66

Scheme 69

lead compound for the development of drugs for the treatment of inflammation and autoimmune diseases.267 It was shown that the initial protection of tertiary cyclohexenyl alcohol was necessary for the successful conversion of the neighboring secondary alcohol to azide 67-2 (Scheme 67). Attempts to synthesis of new antiepileptic ceramide 69-5 (Scheme 69).269 To introduce the stereogenic C−N bond into substrate 69-1, attempts to perform a Mitsunobu displacement with DPPA or with triflic anhydride or mesyl chloride followed by displacement with NaN3 were unproductive. Instead, when phthalimide was used as a “masked” amine under the standard Mitsunobu conditions, substitution product 69-2 was obtained in a good yield. Phthalimide removal with methylamine followed by acylation with stearoyl chloride led to advanced intermediate 69-4 as a single diastereomer.

Scheme 67

3.4. Epoxide Opening by Nitrogen Nucleophiles (Figure 11)

Opening of epoxides with nitrogen nucleophiles is another effective method for the construction of stereogenic C−N bonds because of the availability of chiral epoxides and the versatility of the alcohol products. Application of this method in total synthesis can be classified on the basis of the type of nitrogen nucleophile employed into three groups: those using amines, acetimidates, or azides. Among them, applications of azide reagents appear to be dominant. Epoxides can serve as versatile precursors for aziridine natural products. In 2002, the groups of Williams,270 Fukuyama,271,272 and Ciufolini273 independently accomplished the impressive total syntheses of the potent antitumor antibiotic FR900482 using similar strategies for the construction of the aziridine unit. For example, Ciufolini treated epoxide 70-1 with lithium azide followed by mesylation of the resultant alcohol 70-2, reduction of the corresponding azide, and nucleophilic cyclization in a one-pot protocol to provide aziridine 70-4 (Scheme 70a). The transformation of epoxides into cis-1,2-diamines through an aziridine intermediate was exploited by O̅ mura and co-workers for the synthesis of guadinomines B and C2.234 Regioisomeric aziridines 70-6 and 70-7 obtained from epoxide 70-5 served as intermediates for the preparation of the 3-chloroleucine fragment of chlorodysinosin A via ring opening with cerium trichloride (Scheme 70b).274 Controlling the regioselectivity in the ring opening of oxiranes can be a challenge; often regioselectivity is a direct outcome of different steric environments of the two alternative reactive sites. A typical illustration of this effect is found in the total synthesis of (+)-kalihinol A described by Miyaoka and coworkers (Scheme 71).275 Advanced intermediate 71-1 incorporating a 1-methylhexene oxide moiety was treated with sodium azide to provide a mixture of trans- and cis-decalins

perform azidation of the alcohol by mesylation and nucleophilic displacement with NaN3 or (TMS)N3 resulted in formation of a mixture of diastereomers in low yield. Remarkable chemoselectivity in the Mitsunoby azidation was observed during the synthesis of pamamycin-607 (Scheme 68).268 Scheme 68

In contrast to the aforementioned synthesis, Kang and co-workers submitted tetrol 68-1 to a reaction with HN3, DEAD, and PPh3 where only the least hindered hydroxy group was reactive, and azide 68-2 was isolated in an excellent yield. Despite the numerous examples of successful SN2-type nycleophilic displacement of activated hydroxy groups by the Mitsunobu reaction, unexpected challenges are still encountered. Shaw and co-workers faced such a challenge during the 4474


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Figure 11.

2,3-epoxy alcohols developed by Sharpless279 exploits a directing effect of the hydroxy group with Ti(O-i-Pr)2(N3)2 as the source of the azide, as exemplified in the total synthesis of fumonisin B1, a sphingolipid biosynthesis inhibitor.280 In this case, reasonable selectivity at C2 was achieved by reaction of substrate 72-1 with the titanium reagent in refluxing benzene (Scheme 72). A mixture of (TMS)N3 and Ti(O-i-Pr)4 was also employed for the regioselective epoxide ring opening during the synthesis of largamide H reported by Xu and Ye.281

71-2 and 71-3, both equipped with an identical 1,2-azido alcohol function corresponding to nucleophilic attack on the less hindered secondary site of epoxide 71-1. A similar principle based on steric hindrance for the introduction of stereogenic carbon−nitrogen bonds by epoxide opening is applied in the syntheses of malayamycin A by Hanessian 276,277 and azithromycin by Kim and Kang.278 When the steric environments at both reacting sites are comparable, a directing group can be considered to control the regioselectivity. For example, a regioselective azide opening of 4475


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Scheme 70

Scheme 72

Scheme 73

C2 symmetric diazido tetrol 73-2 in 80% yield as a mixture of isomers (10:1.1:1). Another set of conditions developed by Miyashita allows for the regioselective preparation of syn- and anti-azido alcohols depending on the stereochemistry of the α,β-unsaturated γ,δ-epoxy ester substrate.284 Excellent regioselectivity for the epoxide opening by azide attack on the γ-position along with double inversion of stereochemistry was achieved by Muthyala and Chandrasekhar during the syntheses of (−)-balanol285 and (+)-hyacinthacine A1 (Scheme 74).286 The process presumably involves π-allylpalladium intermediates and a hydroxyl-directed delivery of azide from Me3SiN3, collectively accounting for the high stereo- and regioselectivity. During the synthesis of (+)-methyl β-D-vicenisaminide, Akita and co-workers demonstrated that ring opening of α,β-unsaturated γ,δ-epoxy esters by sodium azide in the presence of acetic acid also exclusively proceeds by nucleophile attack at the γ-position; however, the classic anti products from SN2-type substitutions are produced as expected.287 The Williams group developed a unique methodology based on spirodiepoxides derived from oxidation of allenes. The reaction with azides allows for the stereoselective construction of C−N bonds as has been showcased in the synthesis of epoxomicin, a naturally occurring proteasome inhibitor with anti-inflamatory activity (Scheme 75).288 The synthetic sequence begins with the preparation of chiral allene 75-1, which, after epoxidation from the less hindered face of the trisubstituted π-bond by dimethyldioxirane (DMDO), gives rise to unstable spirodiepoxide 75-2 as the major isomer. The spirodiepoxide is then transformed to α-azido ketone 75-3 by treatment with tetrabutylammonium azide in a one-pot protocol. An attempt to perform the reaction with the allene that contained a mesylate group instead of the O(TBS) group led to the α-epoxy ketone, which, upon reduction, gave the

Scheme 71

Ring opening of 2,3-epoxy alcohols can be directed to C2 by trialkyl borates using the conditions developed by Miyashita and co-workers, which are suitable for nitrogen, sulfur, and carbon nucleophiles.282 This methodology was successfully utilized by Molinski and Rogers for the formal synthesis of zwittermicin A (Scheme 73).283 Treatment of diepoxide 73-1 with NaN3 in the presence of trimethyl borate in DMF afforded 4476


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Scheme 74

Scheme 76

Scheme 75 76-7, whereas the same reaction with Et2AlCl gave a 3.3:1 mixture of 76-7 and 76-8 in 74% yield. The challenging tetrasubstituted carbon center of the Erythrina alkaloid (+)-β-erythroidine was also installed using the intramolecular ring opening of the epoxide by a trichloroacetimidate group (Scheme 77).293 In this case, cyclization in Scheme 77

corresponding amine; however, both products were found to be unstable, and the synthesis was completed using compound 75-3. Trichloroacetimidates derived from chiral α,β-epoxy alcohols can serve as useful precursors for the stereoselective preparation of 1,2- or 1,3-amino alcohols. Chakraborty and Sudhakar successfully employed this strategy to construct the α-methylserine unit of the natural product (+)-conagenin (Scheme 76a), which was isolated from the fermentation broth of Streptomyces roseosporus and exhibited wide-ranging biological activity, including antitumor properties.289 Following the original report by Hatakeyama,290 trichloroacetimidate 76-2 was treated with Et2AlCl in CH2Cl2 to exclusively provide oxazoline 76-3 in 84% yield. Subsequent cleavage of the oxazoline followed by carboxylation of the amine with Boc2O provided α-methylserine precursor 76-4. The groups of Lin and Hatakeyama applied this approach for the construction of the α-disubstituted glucine unit of (+)-sphingofungin291 and (−)-mycestericin E,292 respectively (Scheme 76b). Both groups reported that BF3·Et2O is preferred over Et2AlCl for increased regioselectivity. For example, the ring-opening reaction of trichloroacetimidate mediated by BF3·Et2O occurred with almost exclusive formation of oxazoline

the presence of 0.5 equiv of BF3·Et2O took place selectively at the tetrasubstituted propargylic center of epoxide 77-2 with complete inversion of the stereochemistry to produce dihydroxazine 77-3, which was hydrolyzed and treated with Boc2O to provide advanced intermediate 77-4. A similar route utilizing benzoyl isocyanate as a source of nitrogen was applied in the synthesis of (+)-1-deoxynojirimycin reported in 2009 by Poisson and co-workers (Scheme 78).294 Regioselective opening of the epoxide in a biphasic system was accompanied by an intramolecular migration of the benzoyl group, resulting in substituted oxazolidinone 78-2 in 77% yield over two steps. 4477


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regioselective cyclization in situ with complete inversion of the configuration at the site of substitution. Yang and co-workers applied a late-stage tandem amine deprotection and intramolecular epoxide ring opening for construction of the tetracyclic core of Lycopodonium alkaloid (−)-8-deoxyserratinine (Scheme 82).297 The synthetic sequence

Scheme 78

Scheme 82

Several total syntheses exploited free amines as nucleophiles for ring opening of chiral epoxides. Coltart and co-workers applied this reaction for the late-stage assembly of the 2-(hydroxymethyl)piperidine unit of the important antimalarial drug (+)-mefloquine (Scheme 79). Azide 79-1 prepared Scheme 79

includes the initial treatment of trifluoroacetamide 82-1 with KOH in refluxing methanol followed by Jones oxidation of the intermediate α-amino alcohol to tetracyclic amino diketone 82-2, which was selectively reduced by NaBH4 to furnish the desired product. Subsequently, Zaimoku and Taniguchi used the same approach for the preparation of other Lycopodium alkaloids.298 A successful example of intermolecular ring opening of a chiral epoxide by a primary amine was reported in 2013 by the Martin group during the total synthesis of citrinadin A, an alkaloid isolated from the broth of Penicillium citrinum found to be active against murine leukemia L1210 and human epidermoid carcinoma KB cells.299 Epoxide 83-1 was treated with excess methylamine to provide α-amino alcohol 83-2 as a single product (Scheme 83a). Although no explanation for the

initially was submitted to the tandem Staudinger reduction/ cyclization sequence to provide an amino alcohol that was isolated after protection with the Boc group in 72% yield. In 2004, Jacobsen and co-workers reported a versatile total synthesis of (−)-quinine and (+)-quinidine in which an intramolecular epoxide opening by the piperidine ring was employed for the construction of the bridged bicyclic quinuclidine core (Scheme 80).295 First, advanced intermediate Scheme 80

Scheme 83

80-1 was treated with Et2AlCl and thioanisole to perform a chemoselective cleavage of the benzyl carbamate. Next, the free amine was exposed to microwave irradiation at 200 °C for 20 min to furnish synthetic (−)-quinine in 68% yield over two steps. Another application of the stereoselective epoxide opening by free amines for the construction of a constrained ring system was demonstrated by the Smith group during the assembly of scholarisine A (Scheme 81).296 The formation of tricyclic Scheme 81

observed regioselectivity was offered, it is likely that in the absence of chelating agents the nucleophilic attack occurred at the most electrophilic and less hindered site. Wang and coworkers also applied intermolecular ring opening by primary amine 83-3 with epoxide 83-4 during the synthesis of amphibian alkaloid allopumiliotoxin 267A (Scheme 83b).300 The regioselectivity in this case originates from the amine attack at the less hindered site of epoxide 83-4.

intermediate 81-2 was initiated by hydrogenation of nitrile 81-1 at 100 psi of hydrogen in THF. The primary amine underwent 4478


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4.1. Organocatalysis (Figure 12)

Although oxetanes possess a less rigid structure than oxiranes and therefore are less reactive in nucleophilic ring opening, ring opening can still be performed upon Lewis acid activation. A noteworthy example was reported by Danishefsky and co-workers in the total synthesis of (±)-gelsemine, a classic alkaloid from Gelseminium semperverens (Scheme 84a).301

In the past decade, imine/enamine catalysis rapidly established a prominent position in the total synthesis of alkaloids with an accelerating trajectory in the number of applications.304−307 Although early applications were aimed at the synthesis of simpler compounds, the sophistication of targets increased rapidly to include complex Vinca alkaloids and marine natural products such as diazonamide. Saturated or α,β-unsaturated aldehydes are used as reagents in almost all the reported examples. The types of catalysts can be broadly divided into three categories: (1) proline catalysts, (2) diphenylprolinol catalysts, and (3) imidazolidinone catalysts. In 2006, Itoh and co-workers reported the total synthesis of ent-dihydrocorynantheol by an (S)-proline-catalyzed (30 mol %) Mannich-type reaction between 3-ethyl-3-buten-2-one (85-2) and N-tosyl-3,4-dihydro-β-carboline (85-1) which created the stereogenic C−N bond in the product with 85% yield and 99% ee (Scheme 85a).308 The authors favor the Mannich− Michael mechanism vs a possible Diels−Alder cycloaddition of the enamine dienophile, generated from (S)-proline and 3-ethyl-3-buten-2-one. The same group used another (S)proline-catalyzed Mannich reaction with acetone in the total synthesis of a simple piperidine alkaloid, sedridine.309 Addition of 2-butanone to ethyl [N-(4-methoxyphenyl)imino]acetate catalyzed by (S)-proline (syn, 65% yield, 99% ee) is another example of the organocatalytic Mannich reaction, in this case utilized in the total synthesis of an unnamed antimalarial lipopeptide from Streptomyces sp.310 In early 2009, Hayashi and co-workers disclosed a concise total synthesis of the clinically used neuramidase inhibitor (−)-osteltamivir by a diphenylprolinol-catalyzed multicomponent reaction that generates an asymmetric center bearing a nitro group (Scheme 85b).311,312 The overall process involves an initial conjugate addition of aldehyde 85-5 to tert-butyl 3-nitroacrylate followed by another conjugate addition of the resulting nitroalkane to vinylphosphonate 85-8 and Wittig-type ring closure onto the aldehyde group. Thus, the asymmetric C−N bond is not a direct result of catalysis but rather is a product of thermodynamic control in the secondary steps of this effective multicomponent process. (−)-Cocaine, (+)-methylecgonine, (+)-ferruginine, and related tropane compounds were prepared in 2012 by a short total synthesis commencing with an asymmetric conjugate addition of O-TBS-N-Cbz-hydroxylamine to enal 85-12 in the presence of a 20 mol % concentration of a diphenylprolinol catalyst, directly providing a stereogenic C−N bond with high enantiocontrol (Scheme 85c).313 The conjugate addition was integrated with the Wittig reaction, affording the δ-amino α,β-unsaturated ester in one step. The tropane ring system was accessed with a subsequent intramolecular [3 + 2] dipolar cycloaddition. In another diphenylprolinol-catalyzed conjugate addition to an enal, Bonjoch and co-workers described the synthesis of Lycopodium alkaloid lycoposerramine Z (Scheme 85d).314 In this example, the C−N bond was formed in a diastereoselective Michael addition in a cascade process. After the enantiodetermining addition of β-keto ester 85-16 to 2-butenal, intermediate 85-17 underwent an aldol cyclocondensation to enone 85-18 with a pendant tosyl amide group. Under the reaction conditions, the tosyl amide added to the enone, affording the cis-azadecaline ring system 85-19 in 72% yield and 85% ee.

Scheme 84

The pyrrolidine ring installation was achieved starting from carboxylic acid 84-1, which upon Shiori’s variant of the Curtius rearrangement gave rise to the methyl carbamate 84-2. The oxetane in 84-2 was activated by BF3·Et2O to allow for the displacement with the urethane nitrogen, affording advanced intermediate 84-3 in 64% yield. Carreira and coworkers utilized a recently developed ring opening of oxabicyclo[2.2.1]heptane302 for the synthesis of serine protease inhibitor microcin SF608 (Scheme 84b).303 Oxabicycle 84-4 was subjected to a stereoselective ring opening upon treatment with (TMS)OTf to deliver octahydroindole 84-5 after desilylation. Notably, only the amine moiety participates in the reaction under these conditions, perhaps a consequence of enhanced nucleophilicity compared to that of the distal amide.

4. ASYMMETRIC CATALYSIS Asymmetric catalysis is a fast-growing area when it comes to applications in total synthesis. This section includes a total of 94 citations for applications of various methods of asymmetric catalysis in total synthesis that create a carbon−nitrogen bond of a natural product. 4479


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Figure 12.

Scheme 85

intermediate in the total synthesis of the aforementioned group of six complex alkaloids (Scheme 86b). A tabulated comparative analysis illustrating the remarkable efficiency achieved through this asymmetric catalytic approach relative to previous synthetic efforts in the area is provided by the authors.316 The organocatalytic [4 + 2] cycloaddition of vinylindoles was also utilized by the MacMillan group in the expedient total synthesis of vincorine317 and minovincine,318 with the latter effort featuring 3-butyn-2-one as a ketone dienophile. The iminium catalysis also provided an enantioselective path to the hemiaminal fragment of diazonamide by a conjugate addition of a 3-arylindole to propynal.319 A number of other total syntheses utilize organocatalytic reactions for the asymmetric construction of carbon−nitrogen bonds, which are briefly described here. Ley and co-workers

In 2009, the MacMillan group described the short enantioselective synthesis of the complex Strychnos alkaloid (+)-minfiensine by an enantioselective cascade process initiated by a [4 + 2] cycloaddition between vinylindole 86-1 and propynal (Scheme 86a). Effective iminium catalysis is achieved using this challenging aldehyde, delivering the final polycyclic aminal in 87% yield and 96% ee. The methyl sulfide group was instrumental in a subsequent radical cyclization during the final steps of the synthesis.315 The organocatalytic cascade approach was extended to the analogous methyl selenide-substituted vinylindole 86-6 in a divergent synthesis of six Aspidosperma, Kopsia, and Strychnos alkaloids. The methylselenium substituent imparts the advantage of a better nucleofugicity, enabling a direct access to formylcyclohexa-1,3-diene 86-9, which serves as a common 4480


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Scheme 86

Scheme 87

exploited enantioselective α-amination of aliphatic aldehydes in the context of the total synthesis of chloptosin.320 Chloptosin is a complex dimeric peptide combining two cyclic hexapeptide subunits. The amination reaction was used in the synthesis of piperazic acid, both enantiomers of which are a part of the cyclic hexapeptide in chloptosin. Azodicarboxylates are used as the electrophilic reagents in this reaction catalyzed by 2-(1tetrazinyl)pyrrolidinea more soluble surrogate of proline. Rutjes and co-workers implemented a proline-catalyzed enantioselective Mannich reaction between acetone and N-Boc-2-furanaldimine in the total synthesis of piperidine alkaloid (−)-sedacryptine. The aldimine was generated in situ from the corresponding phenyl sulfite adduct.321 In three separate recent reports, Kumar and co-workers describe α-amination of aliphatic aldehydes with azodicarboxylates catalyzed by proline in the enantioselective synthesis of several piperidine alkaloids. These amination reactions are typically combined with an in situ Wittig olefination to access γ-amino α,β-unsaturated esters as isolated products.322−324 Applications of diphenylprolinol derivatives as catalysts in total synthesis can be classified as those involved in direct or

indirect C−N bond formation. The direct C−N bond formation included enantioselective intramolecular conjugate addition of nitrogen nucleophiles forming piperidines or pyrrolidines in the synthesis of senepodine G,123 cermizine C,325 and (+)-angustureine.326 Electrophilic α-amination of an aldehyde with benzyl azodicarboxylate catalyzed by a dehydrophenylprolinol catalyst was exploited in the early stages of the total synthesis of Lycopodium alkaloids cernuine and cermizine D.327 Related (2S,5S)-2,5-bis[tert-butyldiphenylsiloxy)methyl]pyrrolidine served as a catalyst in a formal [3 + 3] cycloaddition reaction potentially initiated by a direct intramolecular nitrogen nucleophile addition to enal during the total synthesis of (+)-deplancheine and of its enantiomer.328 An “indirect” formation of C−N bonds with diphenylprolinol catalysts involved (1) conjugate addition of azidoacetone via its enolate to an enal in the course of the total synthesis of transdihydrolycoricidine329 and (2) a cascade process initiated by a conjugate addition of a malonamide to enal during the total synthesis of (−)-dihydrocorynantheol and related alkaloids.330 Alonso and co-workers described the enantioselective total synthesis of Amaryllidaceae alkaloid (+)-pancratistatin by a 4481


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formal [3 + 3] annulation reaction between dihydroxyacetone acetonide and an α-nitroacrylate catalyzed by O-methylprolinol, a process involving an initial Michael addition to the nitroalkene followed by aldol cyclization.331 In addition to the aforementioned series of total synthesis applications reported by MacMillan, Barbe and co-workers described a [4 + 2] cycloaddition between acrolein and acylpyridinium serving as a diene in the synthesis of Lycopodium alkaloid (+)-luciduline. The reaction was catalyzed by a phenylalanine-derived chiral imidazolinone catalyst and delivered 51 g of the azabicyclo[2.2.2]octane product in 84% ee.332

Scheme 88

4.2. Asymmetric Aminohydroxylation Reactions

The asymmetric aminohydroxylation reaction333 is a powerful method for the construction of C−N bonds, which, in the context of total synthesis, has been primarily utilized in the preparation of amino acid subunits of peptidic natural products (Scheme 87).334−337 α,β-Unsaturated esters are preferred substrates for the osmium-catalyzed reaction when high regiocontrol is expected. There are two important variants of aminohydroxylation. An example of the first one was utilized in the synthesis of (−)-ephedraline338 and utilizes (DHQD)2PHAL, which favors the formation of β-amino α-hydroxy esters (Scheme 87a). The regioselectivity is especially high with styrenes and 3-aryl acrylates. With (DHQD)2AQN, the opposite regiochemical outcome is generally achieved, affording α-amino β-hydroxy esters. The syntheses of ustiloxin D339,340 and (+)-caprazol341,342 are examples of this approach, which is sometimes referred to as “regioinverted aminohydroxylation” (Scheme 87b,c). In the former, a 3-aryl acrylate is the substrate, while, in the latter, it is an aliphatic unsaturated ester. With isolated alkenes, the regioselectivity of aminohydroxylation is low, as was observed during the total synthesis of simple piperidine alkaloid (−)-cassine (Scheme 87d)343 and acyclic amino alcohols crucigasterins A, B, and D.344 4.3. Chiral Brønsted Acid Catalysis and Hydrogen-Bonding Catalysis

Asymmetric catalysis based on recent advances in chiral Brønsted acid and hydrogen-bonding catalysis is gaining traction. Among a few reports in this area, Zhang and Antilla described the total synthesis of (−)-debromoflustramine B capitalizing on phosphoric acid catalysis in the formation of a hemiaminal unit within the central pyrrolidinoindole.345 In this reaction, the asymmetric formation of the C−N bond is a secondary process following an initial conjugate addition of indole to methyl vinyl ketone, creating a chiral quaternary center (Scheme 88a). Hiemstra and co-workers applied an asymmetric Pictet−Spengler reaction catalyzed by chiral 1,1′-bi2-naphthol (BINOL) phosphoric acids in the synthesis of (−)-arboricine,346 (+)-yohimbine,347 and corynantheine348 alkaloids. Early examples of the application of chiral thioureas for hydrogen-bonding catalysis in total syntheses appear from the Jacobsen group, who described an asymmetric Pictet−Spengler reaction for the synthesis of (+)-yohimbine349 and a Mannich addition/cyclization between 88-5 and enone 88-6 en route to (+)-reserpine (Scheme 88b).350 In the synthesis of (+)-yohimbrine (Scheme 88c), the initial condensation of tryptamine (88-10) with aldehyde 88-11 afforded an intermediate imine. Its treatment with acetyl chloride in the presence of a 10 mol % concentration of of thiourea catalyst 88-12 at cryogenic

conditions for 23 h accomplished the asymmetric Pictet− Spengler cyclization to 88-13 in 81% yield and 94% ee. The key thiourea-catalyzed reaction in the more recent synthesis of reserpine followed a more complicated path as it introduces two new stereocenters for a total of four new possible stereoisomeric products.350 The reaction was studied in some greater detail by the authors. With n-hexylamine as an achiral additive, an equimolar mixture of trans products 88-8 and 88-9 was produced exclusively (Scheme 88b). With thiourea catalyst 88-7, three isomers were formed in an 11.5:1:1.8 ratio favoring the desired 88-9. With ent-88-7, the catalyst-controlled selectivity was confirmed by the observed formation of 88-8 as the major component of an 11.9:1:2.1 mixture of three isomeric products. After screening several BINOL phosphoric acid and thiourea catalysts for an asymmetric Pictet−Spengler reaction in the course of a divergent total synthesis of indole alkaloids (−)-mitragynine, (+)-paynantheine, and (+)-speciogynine, Hiemstra and co-workers found cinchona-derived thiourea catalysts provided the highest enantiocontrol and yield by a notable margin.351 4482


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aldehydes and was used in the total synthesis of (+)-sedridine and (+)-allosedridine (Scheme 89b).354 An intriguing addition of an amide to an aldehyde catalyzed by chiral BINOL-derived phosphoric acid (S)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′binaphthyl-2,2′-diyl hydrogenphosphate (CAS number 87494863-7) [(S)-TRIP)] was used in the formation of the characteristic hemiaminal group in (−)-zampanolide, a cytotoxic marine macrolide from the marine sponge Fasciospongia rimosa.355

Scheme 89

4.4. Chiral Lewis Acid Catalysis (Figure 13)

Despite the long history of asymmetric catalysis with Lewis acids, the number of applications of this approach to the creation of stereogenic C−N bonds in total synthesis since 2000 has been surprisingly limited. In 2014, Wang and Reisman described the enantioselective total synthesis of (−)-lansai B and (+)-nocardioazines A and B.356 A central reaction in the synthesis of these pyrroloindoline alkaloids is a SnCl4-mediated and 3,3′-dichloro-BINOLcatalyzed formal [3 + 2] cycloaddition between indoles and α-amino acrylates creating a stereogenic C−N bond (Scheme 90a). The precise details of the mechanism for this intriguing process remain uncertain, but there is an emerging consensus that a Lewis acid-assisted Brønsted catalysis is operative in this case rather than a direct Lewis acid catalysis by BINOL·SnCl4. The same group reported the asymmetric synthesis of the epidithiodiketopiperazine alkaloid acetylaranotin by another [3 + 2] cycloaddition catalyzed by the CuI/brucin-OL catalyst system (Scheme 90b). 357 This reaction delivers substituted pyrrolidine 90-4 at an early stage of the synthesis by cycloaddition between an N-substituted carbanion generated from unsaturated imine 90-3 and tert-butyl acrylate in 77% yield and >98% ee. This reaction establishes the stereochemistry for the remainder of the synthesis of this unusual alkaloid. Jana and Struder reported an application of Cu(Walphos)catalyzed asymmetric hetero-Diels−Alder cycloaddition between an arylcyclohexa-1,3-diene and 2-nitrosopyridine in the synthesis

Desymmetrization of cyclohexadienones mediated by thiourea catalysis was exploited in the total synthesis of (−)-mesembrine by Gu and You reported in 2011 (Scheme 89a).352 Wulff and co-workers developed 3,3′diphenyl-[2,2′]binaphthalene]-1,1′diol (cf. 89-6) (VIPOL) and VIPOL boroxinates as a different class of hydrogen-bonding catalysts. The former was used in an imine aziridination reaction in the context of the enantioselective total synthesis of LFA-1 antagonist BIRT-377,353 while the latter catalyzed a direct asymmetric aminoallylation of

Figure 13. 4483


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ee and 81% yield as the first step in the synthesis of dipeptide aminopeptidase inhibitor bestatin 1.363 Salen−Cr-catalyzed asymmetric opening of the monoepoxide derived from 1,4cyclohexadiene with trimethylsilyl azide affording (1S,2S)-2azido-4-cyclohexen-1-ol was used at the early stages of the enantioselective synthesis of tetracyclic Securinega alkaloid (+)-virosine A.364 An intriguing double Michael cycloaddition between a 2-keto ester and a nitroalkene creating four stereogenic centers, one of which is a C−N bond, catalyzed by a chiral Ni complex was implemented in the total synthesis of the tetracyclic Stemona alkaloid (−)-stenine.365

Scheme 90

4.5. Asymmetric Allylic N-Alkylation (Figure 14)

Catalytic asymmetric allylic alkylation is a powerful method for the construction of stereogenic C−N bonds and has been

Figure 14.

applied to the synthesis of alkaloids in the past several years.366 In 2010, Hamada and co-workers described the synthesis of Nitraria tangutorum alkaloid (−)-tangutorine using an earlystage catalytic asymmetric allylic N-alkylation of N-Boctryptamine with allylic carbonate 91-1 (Scheme 91a).367 This Scheme 91

of Amaryllidaceae alkaloid (+)-trans-dihydronarciclasine (Scheme 90c).358 Regioselectivity remains an unmet challenge for this type of cycloaddition reaction, which typically affords an equimolar mixture of regioisomers with high enantiocontrol. With the substrate required for the total synthesis, cycloadducts 90-6 and 90-7 were obtained in 51% yield (92% ee) and 48% yield (>99% ee), respectively. The dienophile has been delivered from the face of the diene opposite the aryl substituent exclusively. Adduct 90-7 was subsequently advanced to (+)-trans-dihydronarciclasine. Other applications of Lewis acid catalysis for the stereoselective formation of C−N bonds in total synthesis include the salen−Al-catalyzed aldol-type reaction between an oxazole and a substituted benzaldehyde in the synthesis of the cyclic peptide phomopsin B,359 La(NO3)3-H-D-Val-O-t-Bu-catalyzed electrophilic amination of a malonamide with di-tert-butyl azodicarboxylate for the total synthesis of long-chain aliphatic tertiary α-amino acids mycestericins F and G,360 Ti-BINOLatecatalyzed enantioselective 1,3-dipolar cycloaddition between diazoacetates and α-substituted acroleins (specifically metacrolein) in the synthesis of marine alkaloid manzacidin A,361 and enantioselective conjugate addition of amino malonomononitriles to 3-silyl acrylates catalyzed by a μ-oxo dimer derived from a salen−Al complex for the synthesis of (+)-lactacystin.362 Shibasaki La-BINOL catalyst enabled an enantioselective addition of 2-phenyl-1-nitroethane to ethyl glyoxalate in 93%

impressive reaction is catalyzed by an [η3-allyl-PdCl]2− (S,Rp)DIAPHOX (DIAPHOX = diaminophosphine oxide) catalyst system and affords allylic amine 91-2 in nearly quantitative yield and 95% ee. The product is then elaborated in a stepwise manner to set up an intramolecular Pictet−Spengler 4484


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cyclization that affords the pentacyclic ring system of the alkaloid. Subsequent refuctionalization completes the synthesis. Trost and Dong reported strategic uses of two C−N bondforming allylic alkylations during the synthesis of agelastatin Aa popular synthesis target from a deep-water marine sponge, Agelas dendromorpha. 368 The first reaction is desymmetrization of cis-1,4-cyclopent-2-enediol bis-tert-butyl carbonate with methyl 2-bromo-5-pyrrolecarboxylate in the presence of [η3-allyl-PdCl]2 and 1,2-diaminocyclohexanederived catalyst (R,R)-Lst, which installs the C−N bond in N-substituted pyrrole 91-3 in 83% yield and 92% ee (Scheme 91b). After the methyl ester in the product was converted to the corresponding N-methoxy amide 91-4, the next allylic alkylation was performed with the same catalyst system. Although the chiral ligand is not necessary, a higher yield of 91% was realized compared to the 71% yield obtained with 1,4-bis(diphenylphosphino)butane (dppb). The Helmchen group has been active in exploiting iridiumcatalyzed asymmetric allylic N-alkylation chemistry in the synthesis of several natural products, namely, simple piperidine alkaloids prosopsis, dendrobate, and spruce alkaloids (such as (+)-241D),369,370 (−)-α-kainic acid,371 pyrrolizine and indolizine alkaloids such as xenovenine,372 and dihydroquinoline (−)-angustureine.373 The total synthesis of pentacyclic alkaloids securinine and (−)-norsecurinine was accomplished by a palladium-catalyzed N-allylation of succinimide with vinyloxirane using the Trost catalyst system similar to that used in the aforementioned synthesis of agelastatin.374

Scheme 92

4.6. Asymmetric Phase Transfer Catalysis (Figure 15)

4.7. Asymmetric Hydrogenation (Figure 16)

catalysis for the asymmetric Michael reaction between benzyl N-(diphenylmethylidene)glycinate (92-4) and vinyl ketones mediated by bisammonium salts such as 92-8 (Scheme 92b).379 The addition product 92-6, in this case formed in 84% yield and 82% ee, was advanced to complete the asymmetric total synthesis of Clarkia cylindrica alkaloid (+)-cylindricine.

Phase transfer catalysis applications in total synthesis appear to be confined to the synthesis of amino acids, specifically to the

Similarly to phase transfer catalysis, asymmetric catalytic hydrogenation in the context of total synthesis has chiefly been used for

Figure 15.

classic alkylation of tert-butyl N-(diphenylmethylidene)glycinate. As a typical illustration, Lepine and Zhu utilized the cinchona-derived Corey catalyst 9-O-allyl-N-(9′anthracenylmethyl)cinchonidinium bromide (92-7) in the enantioselective benzylation of glycine ester 92-1 with 92-2 during the total synthesis of complex cyclic tripeptide biphenomycin A (Scheme 92a).375 The reaction afforded functionalized amino acid precursor 92-3 in 87% yield and >95% ee. The cinchona-based asymmetric phase transfer catalysis in the alkylation of glycinimine esters in the construction of functionalized amino acids has also been exploited in the total syntheses of complex bicyclic octapeptide celogentin C by Castle376 and naturally occurring aminopyrazine amino acid tetrahydrolathyrine by Dodd/Thierry377 and in the synthesis of simple pyrrolidine alkaloid (+)-hygrine by Jew/Park.378 In a creative departure from the typical glycinimine alkylation chemistry, Shibasaki and co-workers developed phase transfer

Figure 16.

the preparation of advanced amino acid intermediates by hydrogenation of dehydro amino acid precursors.380,381 A number of innovative catalyst systems have been developed or adopted toward this purpose. During the total synthesis of (−)-haoulamine, Fürstner and Ackerstaff utilized chiral ethyl-DuPhos−Rh catalyst 93-2 in the hydrogenation of dehydro amino acid derivative 93-1, which occurred in 97% yield and 96% ee (Scheme 93a).382 Notably, the aryl iodide group was fully preserved. The same catalyst was featured in the synthesis of cyclic hexapeptide longicatenamycin A, specifically for the synthesis of its 4485


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chiral ligand in the efficient reduction of a cyclic imine during the total synthesis of Aporhoedane alkaloid lennoxamine.389 The total synthesis of the naturally occurring amino sulfonic acid derivative from Chryseobacterium sp. NR 2993 sulfobactin A was accomplished by a reductive dynamic kinetic resolution of an aliphatic α-amino β-keto ester using H2 (80 bar) and Ru(SYNPHOS)Br2 as the catalyst (Scheme 93d). The reaction afforded the anti-α-amino β-hydroxy ester product in high yield (90−92%) and stereoselectivity (dr 96:4, 92% ee). The level of stereocontrol was highly sensitive to the choice of solvent.390

Scheme 93

4.8. Miscellaneous Reactions (Figure 17)

Isolated cases of other emerging asymmetric methods for C−N bond construction have been reported recently. Zeng and Chemler

Figure 17.

reported an effective Cu(II)-catalyzed alkene carboamination in the total synthesis of (+)-tylophorine (Scheme 94a).391 In this reaction, Scheme 94

subunit,383 as well as in the early stages of the synthesis of neoplastic agent cribrostatin IV.384 Evans and coworkers developed and applied sulfidophosphite−Rh catalyst 93-5 for the preparation of amino acid subunit 93-6 in the course of the total synthesis of the complex tricyclic oligopeptide teicopanin aglycon (Scheme 93b).385 The hydrogenation reaction is highly efficient (96% yield, 94% ee) and shows remarkable tolerance for the aromatic nitro group. Another common application in total synthesis is the asymmetric hydrogenation of aromatic imines and iminium ions, for example, dihydro-β-carbolines. The Noyori (S,S)-TsDPEN− Ru(II) (TsDPEN = N-p-tosyl-1,2-diphenylethylenediamine) catalyst 93-8 was used in the effective transfer hydrogenation of dihydro-β-carboline 93-7, in which the initially produced tetrahydrocarboline underwent lactamization onto a pendant methyl ester, ultimately affording the tetracyclic product 93-9 in 89% yield and 96% ee (Scheme 93c). The aryl bromide group was completely stable in this reaction. The product was advanced to complete the short enantioselective synthesis of aborescidines A, B, and C.386 A similar reaction was adopted for the synthesis of (S)-(−)-stepholidine by Cheng and Yang387 and (S)-(−)-quinolactacin B by Santos and co-workers.388 The latter group also developed an interesting variant of the Ru-catalyzed asymmetric transfer hydrogenation in which L-proline tetrazole functions as the D-chlorotryptophane

Cu(BOX)(OTf)2 (BOX = bisoxazoline) complex 94-2 mediates a ring-forming carboamination that delivers pyrrolidine 94-3 in 64% yield and >81% ee. The enantiomeric excess could only be determined after completion of the total synthesis of the alkaloid, which required two additional steps from carboamination product 94-3. This appears to be the only example of catalytic asymmetric olefin amination in total synthesis thus far. The Rovis group has developed a catalytic enantioselective [2 + 2 + 2] cycloaddition reaction that combines unsaturated 4486


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as convenient sources of N-nucleophiles that react with different types of Michael acceptors in a highly diastereoselective fashion. For example, to showcase the power of their recently developed methodology,399 Davies and co-workers reported in 2003 the total syntheses of sperabillins B and D, antibiotics isolated from the culture filtrates of Pseudomonas fluoresens YK-437 with activity against Gram-positive and Gram-negative bacteria, including antibiotic-resistant strains.400 To establish the chiral β-amino acid fragment, the authors performed a reaction between acrylate 95-1 and lithium (R)-(αmethylbenzyl)allylamide (95-2), which resulted in formation of compound 95-3 as a single diastereomer in excellent yield. The orthogonally protected amine was used for installation of the second C−N bond by means of a tandem azidation/ hydrogenation (Scheme 95). The diastereoselective conjugate

isocyanates and alkynes in a ring-forming process forging a stereogenic C−N bond. This powerful Rh-catalyzed reaction was applied in the total synthesis of quinolizine alkaloid (+)-lasubine II (Scheme 94b).392 Cycloaddition involving alkyne 94-4 and isocyanate 94-5 in the presence of 5 mol % [Rh(C2H4)2Cl]2 and a 10 mol % concentration of phosphorimidate ligand 94-6 afforded quinolizinone 94-7 in 62% yield and 98% ee. The reaction is accompanied by 20−23% amounts of pyridones arising from 2 equiv of the alkyne, suggesting that the alkene is the last 2π component in the [2 + 2 + 2] cycloaddition. Quinolizinone 94-7 was advanced to (+)-lasubine II in two steps. A similar process was used in the total synthesis of indolizine alkaloid (−)-209D, in which the product distribution in the Rh-catalyzed cycloaddition reaction was controlled by the choice of the ligand.393 La(BINOL)-catalyzed addition of 2-phenylnitroethane to an aldehyde in the synthesis of (+)-preussin is a rare example of the asymmetric catalytic Henry reaction establishing a stereogenic C−N bond in total synthesis.394 Andrews and Kwon applied an asymmetric phosphine-catalyzed [3 + 2] annulation reaction in the total synthesis of aspidospemine alkaloid (+)-ibophyllidine.395 A cinchona-derived Brønsted base served as a catalyst for the enantioselective addition of α-aryl-α-isocyanoacetates to phenyl vinyl selenone in the total synthesis of complex alkaloid trigonoliimine A.396 Catalytic asymmetric allylic alkylation forming a carbon−carbon bond bearing a nitrogen substituent was exploited in the total synthesis of sphigofungins E and F (Scheme 94c). In this application, the Trost palladium catalyst system was used for allylation of 2-phenyl-4-methyloxazolidin-5-one with 1,1-diacetoxy4-siloxy-2-butene, setting the tertiary amine stereocenter in the α-substituted α-amino acid segment of the natural products.397

Scheme 95

5. ADDITION TO CC BONDS 5.1. Conjugate Addition Reactions

Among different methods for the stereoselective addition to CC bonds encountered in total synthesis for C−N bond construction, conjugate addition (Michael reaction) is dominant. The installation of the chiral center comprising the C−N bond can be achieved by addition of either carbon or nitrogen nucleophiles.398 The typically mild conditions allow for performing transformations in the intra- or intermolecular modes. 5.1.1. Intermolecular Conjugate Addition of Chiral Amines (Figure 18). Chiral lithium amides can be considered

addition of N-benzyl(α-methylbenzyl)amine to different Michael acceptors developed by the Davies group was also used in the syntheses of pseudodistomines B and F,401 solenopsine A,402 and other alkaloids.403,404 N-Benzylamine 96-2 prepared from ketopinic acid can serve as a nucleophile for the diastereoselective Michael addition to different acrylates.405 In 2008, Hayashi et al. used this reaction in the total synthesis of negamycin, a promising chemotherapeutic agent for genetic diseases. tert-Butyl acrylate 96-1 reacted with the lithium amide generated by treatment of amine 96-2 with n-BuLi to deliver the corresponding β-amino acid in 96% yield as a single diastereomer.406 Next, the amino group was restored with NIS to deliver key intermediate 96-4 in 81% yield (Scheme 96). Subsequently, the 5-epi-(+)-negamycin was prepared using the same diastereoselective Michael reaction.407 Various chiral 5-substituted lactams were also shown to undergo conjugate addition to nitroalkenes under basic conditions with high stereocontrol. For example, nitroalkene 97-1 was treated with lactam 97-2 in the presence of t-BuOK to provide adduct 97-3 in 58% yield as a single diastereomer that was used for the formal synthesis of indolizidine 167B (Scheme 97). The authors found that it was essential to perform the reaction with 1 equiv of 18-crown-6 as well as 1 equiv of water to achieve both a high yield and a high stereoselectivity.408

Figure 18. 4487


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with a high yield and stereoselectivity, the authors conducted a sophisticated screening of conditions that resulted in several unexpected findings. Initially, the authors presumed that the formation of lithium enolate 98-2 was complete within 1.5 h at −78 °C, since quenching the reaction with a solution of NH4Cl resulted in the isolation of the conjugate addition product in 89% yield and 97% ee. However, an attempt to perform diastereoselective alkylation of enolate 98-2, formed under these conditions, with 3-iodo-1-propyl silyl ether 98-3 afforded the product in 70% yield and 86% ee. To explain the lower yield and selectivity, a quench with HCl in MeOH instead of aqueous NH4Cl was performed, which is homogeneous in comparison to the NH4Cl quench as it freezes instantaneously upon addition at −78 °C, allowing conjugate addition to continue. Indeed, with the HCl/MeOH quench, the addition product was produced in only 54% yield and 97% ee. On the basis of these observations, the authors explained the initially low enantioselectivity and yield were due to the disruption of the reactive chiral aggregate upon premature addition of DMPU required for the subsequent alkylation. Indeed, if the conjugate addition is allowed to continue for 16 h at −65 °C before alkylation at −40 °C and protodesilylation, amino ester 98-4 was isolated in 89% yield and 98% ee. 5.1.2. Intermolecular Conjugate Addition Forming C−C Bonds (Figure 19). Simple amines can participate in

Scheme 96

Scheme 97

Recently, Tomioka and co-workers described a formal synthesis of (−)-kopsinine asymmetric conjugate addition of lithium N-(trimethylsilyl)-N-benzylamide to 3-(N-Boc-indol3-yl)propenoate 98-1 mediated by a chiral 1,2-diether (Scheme 98).409 It was shown that the initially formed Scheme 98

Figure 19.

diastereoselective intermolecular conjugate additions to chiral Michael acceptors with stereogenic centers in close proximity to the reactive double bond, leading to a new C−N bond with useful levels of stereocontrol. In 2000, the Fukuyama group reported the enantioselective synthesis of gelsemine, in which the pyrrolidine ring of the core structure was assembled by two separate Michael addition reactions (Scheme 99a). First, bicyclo[3.2.1]octa-2,6-diene 99-1 reacted with methylamine in MeOH to exclusively provide adduct 99-2, which was transformed to 2-aminoacetonitrile 99-3. To accomplish the cyclization, the latter was treated with KN(SiMe3)2 to trigger an intramolecular conjugate addition, furnishing advanced intermediate 99-4 in 62% yield.410 The double intermolecular azaMichael reaction between benzylamine and divinyl ketone 99-5 was used as a key step for the synthesis of alkaloid lentiginosine (Scheme 99b). After careful screening of the conditions, the desired adduct was obtained in 75% yield and moderate diastereoselectivity using CH2Cl2 as a solvent in the presence of a catalytic amount of CF3CO2H.411 Dodd and co-workers disclosed a straightforward approach to 2,3-aziridino-γ-lactones from vinyl triflates412 and

aggregate between the lithium amide and (1R,2R)-1,2dimethoxy-1,2-diphenylethane reacts with propenoate 98-1 to form a chelated amino enolate intermediate that can be alkylated in the presence of N,N′-dimethylpropyleneurea (DMPU) with 3-iodo-1-propyl silyl ether 98-3 with high diastereoselectivity. To perform this two-step transformation 4488


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Scheme 99

Scheme 101

5.1.3. Intramolecular Conjugate Addition Reactions (Figure 20). Intramolecular Michael-type reactions have been implemented with both carbon and nitrogen nucleophiles and have been known to proceed through a well-defined highly ordered transition state with a predictable stereochemical outcome. As a result, among different types of conjugate addition reactions, these transformations are the most prevalent for the stereoselective formation of C−N bonds in total synthesis. In 2003, the Shishido group reported the synthesis of aspidospermine utilizing a Bronsted acid-catalyzed intramolecular aza-Michael reaction (Scheme 102a).416 Cyclohexenone 102-1 comprising an amide group was treated with p-toluenesulfonic acid in benzene followed by ketalization of the adduct and hydrogenation, giving rise to lactam 102-2 in 86% yield as a single diastereomer. A similar approach with different nitrogen nucleophiles was also adopted for the syntheses of narseronine,417 powelline,418 strychnine,419 and mesembrine.420 Hale et al. prepared (−)-agelastatin A by intramolecular addition of pyrrole to a cyclopenten-2-one unit.421 Ma and co-workers reported an application of azaMichael addition to α,β-unsaturated sulfone 102-5 during the course of the total synthesis of clavepictines A and B (Scheme 102b).422 The starting material was prepared from L-alanine in several steps that included a diastereoselective reduction of enamine 102-3 with NaBH3CN under acidic conditions. The cyclization commenced with AlCl3-mediated cleavage of the Boc group followed by treatment with aqueous sodium bicarbonate, giving rise to the bicyclic product 102-6 in excellent yield and diastereoselectivity. On the basis of computational analysis, the authors concluded that the isolated diastereomer 102-6 is favored thermodynamically. A late-stage formal [1,8]-conjugate addition was employed by Eichberg and Vollhardt in the total synthesis of racemic strychnine.423 Starting cobalt complex 102-7 comprising an amino group gave pentacyclic product 102-8 in 77% yield upon oxidative demetalation promoted by iron(III) nitrate (Scheme 102c). Acid-catalyzed transannular aza-Michael addition was employed by the Fürstner group during the course of the total synthesis of lythranidine (Scheme 103).424 Contrary to the original expectations, macrocyclic enone 103-1 did not spontaneously cyclize, likely due to an unfavorable positioning of the reacting groups. Moreover, the incipient piperidine proved to be unstable under harsh conditions. Nevertheless, after a systematic screening, the authors discovered that the cyclization could be promoted with a catalytic amount of p-toluenesulfonic acid in 1,2-dichloroethane at 45 °C, giving rise to products 103-2 and 103-3 as a mixture of trans and cis isomers in favor of the requisite trans isomer. A double diastereoselective aza-Michael addition strategy can be advantageous for the natural product synthesis, especially when applied in a bidirectional functionalization. An example was reported by Stockman and co-workers.425 To rapidly assemble alkaloid cis-223B, the authors applied the

Scheme 100

demonstrated its utility in the synthesis of polyoxamic acid (Scheme 100).413 γ-Lactone 100-1 was treated with (2,4dimethoxybenzyl)amine to provide 2,3-aziridino-γ-lactone 1002 in 64% yield as a single diastereomer. The synthesis was completed in several steps that included regioselective ring opening of the aziridine at the C3 position and hydrolysis of the γ-lactone to the acyclic product. Synthetic equivalents of ammonia are an important class of nucleophiles for the stereoselective construction of C−N bonds via the intermolecular aza-Michael reaction. Conjugate addition of the azide anion to a 2(5H)-furanone derivative was used at an early stage of the total synthesis of bacilosarcins A and B.414 Phthalimide is another well-known equivalent of ammonia; however, its application in the synthesis of structurally complex alkaloids is limited by its low nucleophilicity combined with drastic activation conditions. In the course of sphingofungin F total synthesis by Li and Wu, a diastereoselective Lewis acidcatalyzed conjugate addition of phthalimide to methyl acrylate 101-1 resulted in the formation of the β-amino acid derivative 101-2 as a single diastereomer in 73% yield (Scheme 101). It was proposed that the observed excellent stereoselectivity was a result of the steric hindrance from the cis-fused dioxolane.415 The phthalimide proved to be an excellent protecting group and was removed in the last step of the synthesis. 4489


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Figure 20.

to perform isomerization of the undesired isomer via a retroMichael reaction. Indeed, treatment of exo-105-3 with methanolic HCl produced the desired isomer endo-105-3 in 87% yield. The overall yield of compound endo-105-3 was increased using a methanolic solution of HCl for the cyclization step, producing a mixture of methyl esters 105-7 and 105-8 in 52% yield and a 1.8:1 ratio (path b).428 An analogous isomerization was utilized by the same group for the readily scalable total synthesis of Lycopodium alkaloid (−)-cermizine B.429 The synthesis commenced with enantioselective 1,4-addition of keto ester 106-1 to crotonaldehyde in the presence of Hayashi’s catalyst (Scheme 106). The reaction solvent was then changed to i-PrOH/H2O, and tandem aldol condensation/conjugate addition mediated by LiOH was accomplished, which delivered cis-decahydroquinoline 106-4 in 75% yield and 90% ee. Of note, the proline-based catalyst was completely recovered using an ion-exchange resin extraction. In the following one-pot sequence, compound 106-4 was first decarboxylated under acidic conditions, and after the solvent was replaced again, a base-promoted retroMichael/1,4-addition isomerization was initiated to afford an equilibrium mixture of diastereomers 106-5 and 106-7, along with ring-opened product 106-6 in a 1:4.5:4.5 ratio. However, it was observed that only the more stable diastereomer 106-5 reacted with phosphate 106-8, shifting the equilibrium toward the desired isomer. The developed method allowed for the preparation of 0.96 g of cermizine B starting from 5 g of keto ester 106-1 in a single pass. Analogously, Kündig and co-workers accomplished the synthesis of quinolizidinecontaining alkaloid vertine using 1,4-conjugate addition of piperidine nitrogen to the vinyl ketone moiety.430 Fuestro and Pozo demonstrated that deprotonated chiral sulfinamides could serve as a convenient source of nitrogen for

cross-metathesis/conjugate addition cascade transformation (Scheme 104a). The 1,8-diene bearing a tert-butyl carbamate group was first combined with ethyl vinyl ketone in the classic cross-metathesis reaction, furnishing a mixture of the expected product 104-3 and pyrrolidine 104-2 in an excellent combined yield. Next, this mixture was submitted to the CF3CO2Hmediated Boc cleavage/cyclization reaction, resulting in formation of hexahydro-1H-pyrrolizine 104-4 in 75% yield, with the relative stereochemistry matching that of the natural product. Trost and Rudd also utilized a double conjugate addition in the synthesis of cylindricines C, D, and E, alkaloids from the marine benthic invertebrate Clavelina cylindrical found off the coast of Tasmania (Scheme 104b).426 In this case, the Boc group was first removed from divinyl ketone 104-5 and the resulting amine cyclized under basic conditions. Cleavage of the silyl ether resulted in formation of cylindricine C in 90% yield over three steps. Cylindricines D and E were obtained by simple O-methylation or -acylation of cylindricine C, respectively. In 2000, Bonjoch and co-workers utilized diastereoselective aza-Michael addition for the construction of the 6-hydroxyoctahydroindole-2-carboxylic acid unit of the peptidic active-site protease inhibitors aeruginosins 298-A and -B (Scheme 105).427 The construction of this unit was initiated by Birch reduction of O-methyltyrosine, furnishing the lithium salt 105-2. Treatment with 3 N aqueous HCl induced hydrolysis and isomerization of dihydroanisole followed by diastereoselective cyclization (path a) to give cis compound 105-3 as a mixture of exo and endo isomers. After N-benzylation, products 105-5 and 105-5 were isolated in 44% yield and a 1:1 ratio, and could be readily converted to methyl esters 105-7 and 105-8. Since only one diastereomer was suitable for the aeruginosin synthesis, the authors attempted 4490


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Scheme 102

Scheme 104

Scheme 105

Scheme 103

PdCl2/CuCl2-catalyzed intramolecular aminomethoxycarbonylation, the trans-2,6-disubstituted piperidine readily underwent epimerization to the thermodynamically more stable cis product under basic conditions. This process was rationalized in terms of the retro-aza-Michael-type transformation. During the course of the total synthesis of tetrodotoxin, Isobe and co-workers successfully applied 1,4-conjugate addition of a carbamate to an unsaturated ester (Scheme 108).433 The cyclization of highly constrained carbamate 108-1 took

diastereoselective intramolecular 1,4-addition reactions, as illustrated in the total synthesis of pinidinol and its CF3 analogue (Scheme 107).431 The aza-Michael cyclization of 107-1 was carried out upon deprotonation with t-BuOK, producing the thermodynamic product exclusively in 61% yield. Of note, the thermodynamic stability of the cis isomer was further demonstrated by Szolcsányi and co-workers in the synthesis of pinidinone.432 Initially obtained by 4491


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Scheme 106

Scheme 107

amide group in 109-1 that preceded the intramolecular 1,4-addition to cyclohexeneone followed by intramolecular chloride displacement. After Pd-catalyzed unsaturation, advanced tricyclic intermediate 109-2 was isolated in 69% yield. Next, the Boc groups in the aniline fragment were cleaved under acidic conditions to initiate a simultaneous diastereoselective Michael-type cyclization, giving rise to pentacyclic intermediate 109-3, which comprises a complete ring system of the alkaloid. The same sequence was later applied by this group in the synthesis of aspidophytine.435 As mentioned previously, intramolecular conjugate addition of N-substituted carbon nucleophiles is another mode for the stereoselective construction of C−N bonds by conjugate addition in natural product synthesis. For example, in the total synthesis of (+)-α-lycorane, Peng and Shao demonstrated the potential of aliphatic nitro compounds in the stereoselective formation of C−N bonds by the diastereoselective Michael reaction (Scheme 110a).436,437 Substrate 110-1 upon deprotonation with tetramethylguanidine (TMG) underwent cyclization to diastereomeric nitrocyclohexanes 110-2 and 110-3 in a 6:1 ratio. The predominant formation of diastereomer 110-2 might be explained by the more favored chairlike transition state with the nitro group occupying an equatorial position. It is also a thermodynamically preferred isomer. The total synthesis of kainic acid reported by Fukuyama and co-workers demonstrated that enolates derived from glycine esters are also effective Michael donors (Scheme 110b).438 In this way, compound 110-6 was cyclized upon deprotonation with LiN(SiMe3)2 to produce L-proline derivative 110-7 as a major diastereomer in 95% yield. 5.1.4. C−N Bond Formation via Dearomatization (Figure 21). Conjugate additions of nitrogen nucleophiles to polysubstituted benzoquinones generated from phenol derivatives via oxidative dearomatization found creative applications in total synthesis. Wipf and Spencer applied this strategy in the synthesis of Stemona alkaloids, specifically tuberostemonine, didehydrotuberostemonine, and 13-epituberostemonine (Scheme 111). After oxidation with PhI(OAc)2, initial spirocyclization of phenol 111-1 produced lactone 111-2, which reacted with methanol to release the ester. The following aza-Michael cyclization furnished cis-indolinone 111-3. In the first report, the authors described a one-pot oxidative spirocyclization/ring opening and recyclization with limited

Scheme 108

Scheme 109

place upon deprotonation with t-BuOK and produced cyclic carbamate 108-2 in 90% yield. A tandem process integrating a diastereoselective azaMichael addition and intramolecular alkylation was a key transformation in the synthesis of (+)-aspidospermidine reported by Marino and co-workers in 2002 (Scheme 109).434 The tandem reaction was triggered by deprotonation of the 4492


Chemical Reviews

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Scheme 110

Scheme 111

Scheme 112

Figure 21.

scalability, with the highest yield of 54% achieved on a 0.50 g scale.439 The next-generation synthesis was conducted in two steps, after nitromethane proved to be the best solvent for the oxidative spirocyclization on a large scale (100 g) and at higher concentrations.440 Fan and co-workers recently reported a bioinspired construction of a challenging 5,11-methanomorphanthridine core of montanine-type Amaryllidaceae alkaloids based on tandem oxidative dearomatization/intramolecular aza-Michael addition as a key step (Scheme 112).441 Compound 112-1 was subjected to optimized oxidative dearomatization conditions with PhI(OAc)2 and CF3CO2H in CH3OH to generate the corresponding o-quinone monoketal intermediate. Without isolation, the intermediate smoothly cyclized with high stereoselectivity (99% ee) via conjugate addition. The observed stereochemistry was rationalized on the basis of 1,3-allylic strain arguments. Two main conformers, 112-3 and 112-4, were proposed for the transition state of the process. Since the latter one had an energetically unfavorable 1,3-allylic strain, the reaction occurred through Si face attack of the enone group via the kinetically accessible conformer 112-4.

disclosed a total synthesis of (+)-ent-clividine,444 a natural product that was originally isolated from the bush lily Clivia miniata Regel (Scheme 113a). The rhizome extracts of this plant have been used in traditional Zulu medicine for a broad variety of indications. After the authors established the complete carbon skeleton of the natural product, amine 113-1 was converted to chloramine 113-2, which underwent radical cyclization upon treatment with n-Bu3SnH and azobisisobutyronitrile (AIBN), furnishing silylated clividine in 83% yield. Zard and Sharp applied similar conditions for the generation of the amidyl radical from hydroxylamine O-benzoate 113-4 during the synthesis of aspidospermidine (Scheme 113b).445 The cascade radical cyclization proceeded with high diastereoselectivity, resulting in a mixture of the key tricyclic intermediate 113-5 (53% yield) and

5.2. Radical Reactions (Figure 22)

Diastereoselective intramolecular reactions involving nitrogen442 and carbon443 radicals for the stereoselective construction of C−N bonds have also found application in the total synthesis of alkaloids. In 2011, Banwell and co-workers 4493


Chemical Reviews

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Figure 22.

Scheme 113

Scheme 114

Another mild reductive method for the generation of nitrogen-centered radicals uses acyl azides such as 115-1, as illustrated by Yoshimitsu and Tanaka during the preparation of agelastatin A (Scheme 115).457 The transformation of acyl Scheme 115

azide 115-1 to cyclic bromide 115-4 was a crucial step, placing both nitrogen and bromine atoms on the same side of the double bond, thereby setting the required stereochemistry for nucleophilic SN2-type displacement of the bromide in the following step. The stereochemical outcome of the reaction presumably results from the initial formation of radical 115-3 and intramolecular delivery of bromine from the iron center. In 2010, Tokuyama reported the total synthesis of racemic lepadiformine using the radical translocation−cyclization approach as a key step (Scheme 116).458 The reaction was initiated by the generation of an sp2-type radical and its translocation to a more stable N-substituted sp3 radical, which underwent a diastereoselective 6-exo cyclization, producing 116-2 in 67% yield. The high degree of stereocontrol was rationalized by a transition state minimizing the steric repulsion between the vinylsulfonyl and benzylic CH2 groups.

bicyclic product 113-6 (29% yield). Incorporation of the chlorine atom at the double bond prior to cyclization was essential to disfavor a 5-exo ring closure in the second act of the cyclization. The amidyl radical cascade cyclization approach was extended to the synthesis of 13-deoxyserratine446 and fortucine.447,448 Hudlicky and Varghese employed a nitrogen-centered radical cyclization for the construction of the ethylamino bridge of ent-hydromorphone (Scheme 114). In this case, the nitrogen radical was generated from compound 114-1 via single-electron transfer (SET) reduction of the tosyl amide group. The presented strategy was adopted from previous reports on the synthesis of morphine alkaloids via radical anion closure of the piperidine ring used previously by Parker,449,450 Mulzer,451−453 Ogasawara,454,455 and Chida.456 4494


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Scheme 116

Scheme 118

In 2005, Renaud and co-workers reported the total synthesis of polyhydroxylated pyrrolizidine alkaloid hyacinthacine A1, an effective inhibitor of rat intestinal lactase. The synthesis was based on a free radical carboazidation of a chiral allylsilane developed earlier by the same group (Scheme 117)459−461

diastereomer 118-5 in moderate yield by means of sequential 7endo and 5-endo cyclizations (Scheme 118b).464 Subsequently, this approach was also extended to another member of this family of alkaloids, cephalezomine H.465 Ressig and co-workers reported an elegant formal synthesis of strychnine using a cascade radical reaction for the construction of the advanced tetracyclic intermediate 119-2 (Scheme 119).466 Starting material 119-1, available in multigram

Scheme 117

Scheme 119

Compounds 117-1 and 117-2 reacted in the presence of (Bu3Sn)2 and 3-pyridylsulfonyl azide to provide 117-3 in 74% yield, predominantly as the syn isomer.462 Notably, the silicon group was incorporated into starting material 117-1 to ensure high diastereoselectivity and to serve as a latent hydroxy group. In 2011, Curan and Zhang reported a short total synthesis of meloscines in which the B and C rings were assembled in one step using cascade radical annulation of divinylcyclopropane initiated by the Bu3SnH/AIBN system (Scheme 118a).463 Originally, the reaction was performed using N-benzyl amide, which predominantly exists as the (E)-rotamer more suitable for the cyclization, resulting in a 55% yield of 118-3 as a single diastereomer. However, the necessity of subsequent benzyl group removal prompted the authors to test amide 118-2 as the substrate. Although the yield dropped to 38%, this approach was considered superior since no additional steps to add and remove the benzyl group were necessary. Ishibashi and co-workers reported a classic radical cascade reaction for the construction of the pentacyclic core of natural product cephalotaxine, which was isolated from the Asian plum yews Cephalotaxus drupacea and Cephalotaxus fortunei. The radical reaction was triggered by Bu3 SnH/1,1′-azobis(cyclohexanecarbonitrile) (ACCN) to produce the desired

scale, reacted with an excess of SmI2 in the presence of hexamethylphosphoramide (HMPA), triggering sequential ketyl radical generation, cyclization, and acylation in one pot. To convert byproduct 119-3, resulting from the reductive fragmentation, to the requisite nitrile, and thereby to increase 4495


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exo attack by the acyl radical upon the more substituted carbon of the enamide followed by elimination of the phenylthiyl radical.

Scheme 120

5.3. Additions of Nitrogen and Heteroatoms across CC Bonds (Figure 23)

The addition of nitrogen nucleophiles to the double bond activated by electrophilic reagents is a powerful strategy for the simultaneous installation of a stereogenic C−N bond and a different functional group at the β-position. Electrophilic agents such as I2, NIS, and t-BuOCl are the most used activators and have been shown to be compatible with several nitrogen nucleophiles. Kang and Lee used the intramolecular iodoamination for the formal synthesis of the amino acid natural product dysiherbaine, a neurotoxin isolated from the Micronesian sponge Dysidea herbacea (Scheme 121a). To establish the cis-1,2-amino alcohol unit, benzoate 121-1 was converted to carboimidothiolate 121-2 using a two-step protocol. The compound reacted with NIS to produce oxazolidinone 121-3 in 51% yield over three steps as a single diastereomer.470 Trichloroacetimidates are also suitable nucleophiles for iodoamination of double bonds, as illustrated by Kim and coworkers in the synthesis of polyoxamic acid (Scheme 121b).471 Trichloroacetimidate 121-4 obtained from the corresponding alcohol was reacted with I2 in THF, providing the product of 5-exo cyclization exclusively in 75% yield. Transannular formal aminobromination was recently reported by Trauner and co-workers as a key step for the synthesis of several loline alkaloids (Scheme 121c).472 In that transformation, azocine 121-6 was exposed to Br2 in MeOH,

the overall yield, the reaction mixture was treated with bromoacetonitrile prior to isolation. Two other byproducts, 119-4 from reduction and 119-5 from CN group elimination, were isolated in 5% yield each. A remarkable synthesis of the complex alkaloid stephacidin B is the only example of the application of acyl radicals for the diastereoselective construction of C−N bonds in total synthesis (Scheme 120).467 In this example, the authors used the (1-methyl-2,5-cyclohexadien-1-yl)carbonyl group introduced by Jackson and Walton as a convenient acyl radical precursor.468,469 Amide 120-1 reacted with tert-amyl peroxybenzoate in tert-butylbenzene to generate a formamidyl radical that smoothly cyclized to produce bridged diketopiperazine 120-2 in 62% yield. The reaction is believed to proceed through an

Figure 23. 4496


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CF3SO2NH2 appeared to be unclear as no formation of CF3SO2NHCl was observed on the basis of 19F NMR measurements. Nevertheless, the additive had a strong effect on the course of the reaction since no product was isolated in its absence. Looper and Bhonde recently accomplished the synthesis of the densely functionalized paralytic shellfish toxin saxitoxin.474 The assembly of the crucial bicyclic guanidine structure was initiated by a clean Ag(I)-catalyzed 5-exo-dig cyclization of 123-1 to ene−guanidine product 123-2 in excellent yield. The second diastereoselective cyclization was performed using I2/AgOAc activation, since attempts to effect epoxidation with reagents such as DMDO or m-chloroperoxybenzoic acid (MCPBA) were unproductive. After iodocyclization, the product 123-3 was obtained as a single diastereomer. Displacement of the iodine group was achieved by a procedure similar to Woodward dihydroxylation, resulting in the formation of tricyclic oxazolidinone 123-4 (Scheme 123).

Scheme 121

Scheme 123

resulting in a simultaneous removal of the Cbz group and diastereoselective transannular cyclization to bromopyrrolizidine hydrobromide 121-7 in excellent yield. It should be mentioned that the authors did not discuss whether the reaction proceeds through a sequential addition of bromine cation and nitrogen across the double bond or it is a stepwise process including the classic dibromination followed by nucleophilic substitution. The cyclic guanidines of axinellamines A and B were assembled by a haloamination strategy developed by Baran and co-workers.473 Initially, several chlorinated reagents displayed inconsistent performance in the crucial cyclization step forming guanidine 122-2 (Scheme 122), depending on the batch of the Scheme 122 Notably, this three-step transformation was also performed in one pot, producing two new C−N bonds and one C−O bond in advanced intermediate 123-4 in 57−67% yield, thereby shortening the synthesis. The iodine-induced sequential diastereoselective cycloamination and lactonization reactions were employed by Williams and co-workers in the synthesis of structurally related Stemona alkaloids stemospironine475 and stemonine.476 For example, the azepine 124-1 was treated with iodine in the last step of the stemospironine total synthesis, producing the target molecule in moderate yield (Scheme 124). The reaction commenced with formation of the trans-2,5-disubstituted pyrrolidino iodide followed by the aziridinium cation, which controlled the stereochemistry of the ensuing lactonization step. The low reaction yield was attributed to facile overoxidation of the pyrrolidine product. Several aminometalation reactions have been employed for the stereoselective construction of C−N bonds in natural products. An example of the diastereoselective aminomercuration

starting material. Ultimately, it was discovered that, upon reaction of the guanidine 122-1 with t-BuOCl in the presence of CF3SO2NH2, spirocyclic product 122-3 was reproducibly isolated in 81% yield as a single diastereomer after oxidation by Dess−Martin periodonane. The role of the catalytic amounts of 4497


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Scheme 124

Scheme 126

1-Aminobicyclo[3.3.1]nonan-9-one product 126-2 was isolated in 63% after oxidation with tetrapropylammonium perruthenate (TPAP)−N-methylmorpholine N-oxide (NMO), and the synthesis of (−)-huperzine was completed in three additional steps. Another application of diastereoselective Heck cyclization with an N-acyl enamine as the acceptor is found in the total synthesis of (±)-lycodine by Tsukano and coworkers.480 Several examples of natural product syntheses with an application of aminopalladation reactions were reported. Wolfe and Babij described the total synthesis of the polycyclic guanidine natural product merobatzelladine B where two of the three rings of the molecule were assembled by Pd-catalyzed diastereoselective alkene carboamination.481 The starting γ-aminoalkene 127-1 was prepared using the diastereoselective Mannich reaction between the corresponding chiral sulfinylimine and heptan-2-one followed by reduction and refunctionalization. Cyclization of 127-1 to cis-2,5-disubstituted pyrrolidine 127-2 was accomplished using the Pd2(dba)3/P(2-furyl)3 catalytic system with NaO-t-Bu in refluxing xylenes, producing 127-2 in 68% yield with diastereoselectivity greater than 20:1 (Scheme 127). Next, pyrrolidine 127-2 was converted to urea 127-3, and the second Pd-catalyzed alkene carboamination was tested. The bicyclic product 127-4 was obtained using the Pd2(dba)3/P(Cy)3 precatalyst in 91% yield and excellent diastereoselectivity. The observed stereochemistry probably resulted from the boatlike transition state 127-5. Several indole alkaloids with a broad spectrum of biological activity, including (+)-lysergic acid, (+)-lysergol, and (+)-isolysergol, were prepared by Fujii, Ohno, and co-workers by a Pdcatalyzed domino cycloamination of a distal double bond (Scheme 128).482 Diastereomeric allenic amides 128-1 and 128-2 were subjected to the cyclization using 5 mol % Pd(PPh3)4 and potassium carbonate in DMF, furnishing, in the first case, the tetracyclic product 128-3 almost exclusively. However, the cyclization of allenic amide 128-2 resulted in a mixture of diastereomers 128-3 and 128-4 in a 31:69 ratio. Mechanism studies of this domino transformation based on the cyclization results with diastereomers 128-1 and 128-2 were also described. Initially, the authors proposed that the cyclization could occur through aminopalladation or carbopalladation of the allene double bond. However, the different cyclization outcomes from 128-1 and 128-2 support the aminopalladation pathway. For the diastereomer 128-1, the reaction occurred via oxidative insertion of the palladium catalyst into the 4-bromoindole unit (intermediate 128-5) followed by coordination of Pd(II) to the allene. Alkenylpalladium(II) intermediate 128-7, produced via transition state 128-6, exclusively produced the product 128-3 after reductive elimination. In a similar manner, cyclization of 128-2 proceeded through oxidative insertion (intermediate 128-8); however, transition state 128-9 is destabilized by steric repulsion between the tosyl amide group and methylene protons, both located on the same side, infuencing the diastereoselectivity of the transformation.

reaction was reported by Chida and co-workers during the enantioselective syntheses of Amaryllidaceae alkaloids vittatine and hemeanthamine.477 The construction of the perhydroindole skeleton of vittatine was accomplished by an intramolecular cyclization of carbamate 125-1 mediated by mercury(II) trifluoroacetate in THF followed by reduction with NaBH4, producing product 125-2 in 75% yield (Scheme 125a). The Scheme 125

same procedure was used for the hemeanthamine synthesis, in which the corresponding product was isolated in 53% yield. Another aminomercuration reaction was employed by Meyer and Bouillon in the synthesis of morusimic acid B, an alkaloid isolated from the ripened fruits of the white mulberry tree Morus alba L., Moracae, in 2002 (Scheme 125b).478 Oxazole 125-3 was treated with Hg(OAc)2 to induce cyclization to cis2,5-disubstituted pyrrolidine 125-4 in 74% yield. The observed stereochemistry was rationalized by the initial formation of the cyclic mercuronium ion followed by SN2-type ring opening by nitrogen and bond rotation, which brings the side chain into the sterically disfavored endo position. Intramolecular diastereoslective Heck cyclization of an alkenyl carbamate was developed to construct the tertiary bridgehead amino group of (−)-huperzine A, a Lycopodium alkaloid and potent reversible acetylcholine inhibitor isolated from the club moss Huperzia serrata (Scheme 126).479 Carbamate 126-1 with a pendant 3-bromopyridine group was a carefully chosen substrate for the challenging Heck cyclization, achieved with Pd(PPh3)4 at 130 °C in DMF. 4498


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Scheme 127

Scheme 129

Reisman and co-workers recently described Cu-catalyzed electrophilic aromatic arylation of tryptophan derivatives followed by intramolecular diastereoselective cyclization leading to functionalized indoles such as 129-3 (Scheme 129).483 According to the proposed mechanism, Cu(III)−aryl complex 129-4 with bidentate coordination to the substrate undergoes reductive elimination to form the C−aryl bond concomitant with cyclization of the diketopiperazine nitrogen onto the indolinium cation. The versatility of the methodology was demonstrated by its application in the total synthesis of bisindole alkaloids naseseazine A and B. Trost and Tang reported the preparation of two benzomorphanes via a very unusual aminolithiation protocol

(Scheme 130).484 An initial effort to perform the cyclization of amino alkene 130-1 with LDA resulted in a complete recovery of the starting material, presumably due to the difficulty of isomerization of the exocyclic olefin. The isomerization was successfully performed under acidic conditions, furnishing the product 130-2 in excellent yield. Indeed, 130-2 smoothly reacted with LDA, producing advanced intermediate 130-3 in quantitative yield. This synthesis intermediate was transformed to (−)-matazocine upon demethylation with BBr3. Moreover, the authors were able to develop a one-pot procedure for the cyclization of exocyclic alkene 130-1 producing the desired product in 98% yield by simply using a stronger base (LDA/ tetramethylethylenediamine (TMEDA)) capable of isomerization of the double bond. The observed stereochemistry was

Scheme 128

4499


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Scheme 130

Figure 24.

conditions488 and the opportunity to further transform constrained aziridines into valuable intermediates by a variety of ring-opening transformations.489,490 A powerful example of such a transformation was demonstrated by Banwell and Lupton in the synthesis of racemic aspidospermidine (Scheme 132a).491 For the installation of the quinolizidine fragment, azide 132-1 was first exposed to heating in benzene for 3 days, producing aziridine 132-2 as a single diastereomer in 72% yield. The regioselective ring opening of the aziridine ring was achieved by the treatment of 132-2 with a 1 M HCl solution in Et2O. The resulting unstable α-chloro β-amino ketone was immediately subjected to reduction with TiCl3·THF, leading to the tetracyclic indole derivative 132-4 in 46% yield. The trans-1,2-diamine unit of agelastatin A was also created through an aziridination pathway (Scheme 132b).492 Azidoformate 132-5 was first heated in a sealed tube, producing constrained tricyclic compound 132-6, which was treated with sodium azide to induce regio- and streoselective aziridine ring opening to 132-7. Hudlicly et al. also reported that chiral aziridines could serve as electrophiles in Fridel−Crafts alkylation of sesamol during the preparation of 7-deoxypancratistatin.493 Photoinduced intermolecular aziridination of cis-disubstituted dihydrofuran was adopted by Williams for the preparation of the antibiotic lankacyclinol (Scheme 133).494 Generation of the nitrene from benzyl azidoformate resulted in its insertion into the double bond of dihydrofuran 133-1 followed by hydrolysis, producing aminofuranose 133-2 in 87% yield. The stereochemical outcome of the aziridination was explained by the stereodirecting inflence of the dihydrofuran substituents. Liu and co-workers applied a rhodium-catalyzed diastereofacial aziridination reaction for the preparation of N-acetylneuraminic acid, an aminoglycoside antibiotic active against both Gram-positive and Gram-negative pathogens. Sulfamate 134-1 was treated with PhIO and MgO in the presence of rhodium(II) trifluoroacetamide to produce aziridine 134-2 as a sole product. The product was trapped using Barbier allylation under optimized conditions (Scheme 134).495 The configuration of the sulfamate tether dictates the stereochemistry of nitrene addition to the double bond.

explained by intramolecular protonation of allylic anion 130-4 from the α-face of an almost flat six-membered ring. All the aforementioned examples of N−X addition to double bonds used nitrogen as a nucleophile. Wardrop and co-workers developed highly electrophilic acylnitrenium ions able to react with unactivated double bonds and utilized this unusual reaction for the preparation of α-hydroxyalkyl lactams.485 To further demonstrate the advantages of this substrate-controlled nitrenium ion oxamidation reaction, the authors chose the polyhydroxylated indolizine alkaloid castanospermine as a target for the total synthesis (Scheme 131).486 N-Hydroxamide Scheme 131

131-1, derived from a corresponding α-D-xylopyranoside, reacted with PhI(O2CCF3)2 in the presence of CF3CO2H to generate a nitrenium ion that after intramolecular cyclization produced aziridinium intermediate 131-3. This intermediate reacted with the trifluoroacetate anion from the less hindered side. The resulting α-trifluoroacetate was hydrolyzed, giving advanced intermediate 131-2 in 56% yield and excellent diastereoselectivity. This unusual transformation was subsequently applied for the preparation of the azasaccharide alkaloid swainsonine.487

6. CYCLOADDITION REACTIONS (FIGURE 25)

5.4. Stereoselective Aziridination of the CC Bond (Figure 24)

6.1. [4 + 2] Cycloadditions

Aziridination is an effective transformation for the simultaneous construction of two C−N bonds during the synthesis of alkaloids. The benefits include relatively mild reaction

Implementation of [4 + 2] annulation with the construction of stereogenic C−N bonds in alkaloid synthesis can be divided 4500


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Scheme 132

Scheme 134

A unique and unusual intramolecular [4 + 2] cycloaddition was adopted for the construction of the cyclic guanidine segment of the hepatotoxic algal metabolite 7-epi-cylindrospermopsin (Scheme 135b).498 Urea precursor 135-5 was converted to N-sulfinylurea heterodienophile 135-6 upon treatment with thionyl chloride and imidazole at −78 °C. The resultant transient intermediate gives rise to a [4 + 2] cycloadduct, dihydrothiazine oxide 135-7, upon warming to room temperature. The cycloaddition occurs in high yield and very high stereoselectivity, affording 135-7 in 81% yield as a single isomer. Martin and Vanderwal included an intramolecular [4 + 2] annulation of an indole dienophile in the context of a beautifully designed and masterfully executed six-step total synthesis of the polycyclic indole alkaloid strychnine (Scheme 135c).499 Ionization of the functionalized indole precursor with potassium tert-butoxide effected a diastereoselective cyclization setting three stereogenic centers of strychnine in one effective step. It is most likely that the cycloaddition takes place by a stepwise mechanism involving a Michael addition of the indole anion to the dienal followed by a Mannich-type reaction. Despite the relatively harsh reaction conditions, aldehyde 135-9 was isolated in 64% yield and advanced to strychnine in only four additional steps.500 Other applications of intramolecular [4 + 2] cycloadditions for the construction of stereogenic C−N bonds can be found in the total synthesis of (±)-β-erythroidine and (±)-8-oxo-βerythroidine (an enamide as the dienophile)501 and the vindoline domain of (+)-vinblastine (an imine as the dienophile, 2-(2-indolyl)acrylate as the diene).502 Intermolecular [4 + 2] cycloadditions have been applied in the total synthesis of quinolizidine nupharamine alkaloids from castroleum (3-furanaldimine as the dienophile),503 the dihydroquinoline alkaloid (±)-martinelline from the tropical plants Martinella (dihydropyrrolidine as the dienophile),504 and benzodioxazine alkaloids phellodonin and sarcodonin ε from the fungus Phellodonin niger, which possess a truly bizarre molecular functionalization (piperazine N,N′-dioxide as the heterodienophile).505 An application where the nitrogen atom is a part of a heterodyne system is featured in the asymmetric total synthesis of (+)-lepadine B, a decahydroquinoline alkaloid from the tunicate Clavelina lepadiformis (Scheme 135d).506 The first steps of the synthesis utilized a BF3-mediated hetero-Diels− Alder cycloaddition of methyl acrylate with dihydropyridine 135-10, prepared from pyridine and N-benzoyl-O-L-methylvalinol in two steps. The stereochemistry is controlled effectively by the chiral auxiliary present in the heterodiene, affording the cycloadduct with a 92:8 dr. This reaction sets four

Scheme 133

into three groups of roughly equal size: (1) the nitrogen atom is a part of the dienophile (an imine or an enamine), (2) the nitrogen atom is a part of the diene (again, an imine or dienamine), and (3) [4 + 2] cycloaddition of nitroso compounds. We chose to separate the third group from the first two because of the number of applications and a special reactivity of nitroso compounds. One of the most spectacular examples of [4 + 2] annulation involving imines as the 2π components in total synthesis was described by Gin and co-workers.496 (−)-Batzelladines are marine polycyclic guanidine alkaloids from the Crambe genus. At the early stages of the total synthesis of (−)-batzelladine D, a [4 + 2] annulation between carbodiimide 135-2 and imine 135-3 afforded cyclic guanidine 135-4 in high yield (Scheme 135a). Both (E)- and (Z)-isomers of 135-2 provided the same product with high stereocontrol dictated by the configuration of cyclic imine 135-3. The authors considered three alternative pathways for the ring-forming process, including a polar concerted [4 + 2] cycloaddition as an alternative to stepwise pathways. This innovative transformation was a critical component in establishing the polycyclic structure of several batzelladine alkaloids.497 4501


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Figure 25.

out of five stereogenic centers of (+)-lepadine B. The azabicyclo[2.2.2]octene ring system effectively translated to

the requisite substituted decahydroquinoline ring system using olefin metathesis chemistry. 4502


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Scheme 135

cycloaddition with the heterodienophile in intermediate 135-16 (Scheme 135f). In a related effort directed at the synthesis of several unique spiroquinazoline alkaloids, this type of intermediate is formed and isolated in a separate step.516 In this case, however, it is produced in situ by deprotonation (H) of 135-15 with aqueous potassium hydroxide and then 1,5-tautomerization (H). The [4 + 2] cycloaddition was complete within 12 h at room temperature, affording the products in 78% yield as a 1.4:1 mixture of diastereomers at C3. As anticipated on the basis of computational predictions, complete anti selectivity between the 2π and 4π components was observed in the [4 + 2] cycloaddition reaction. Nitroso compounds are excellent dienophiles in [4 + 2] cycloaddition reactions for the stereoselective C−N bond construction in natural product synthesis. Both inter- and intramolecular versions have been used, but in all examples the nitroso [4 + 2] cycloaddition is featured at the early stages of total synthesis applications. Hudlicky and co-workers described an intermolecular cycloaddition of the transient methyl nitrosoformate to dihydroxydibromocyclohexadiene derivative 136-1 in the course of the total synthesis of Amaryllidaceae alkaloids such as (+)-narciclasine (Scheme 136a).517 Substrate 136-1 was produced in two steps via the enzymatic oxidation of 1,3-dibromobenzene. The [4 + 2] cyclization occurred in 60% yield, affording the bicyclic product 136-2 as a sole diastereomer. The stereogenic C−N bond established in this reaction was carried through to (+)-narciclasine unchanged. An intramolecular variant of the diastereoselective nitroso [4 + 2] cycloaddition was adopted in the synthesis of

Zhao, Andrade, and co-workers described a [4 + 2] annulation in the total synthesis of three Aspidosperma alkaloids in which the N-tert-butylsulfinyl auxiliary directs the stereochemical course of the reaction (Scheme 135e).507 Lithium dienamide 135-13 was generated by deprotonation of indolederived N-tert-butylsulfinylimine 135-12 by lithium bis(trimethysilyl)amide at low temperature. The lithium dienamide reacted with methyl 2-ethylacrylate to provide the cycloaddition product, which was N-allylated with allyl bromide in situ. The key synthesis intermediate 135-14 was isolated in 81−90% yield with an excellent dr of 11:1. The annulation occurred by a domino Michael/Mannich addition sequence rather than a concerted polar cycloaddition process. This common intermediate was subsequently advanced to complete the synthesis of (−)-tabersonine, (−)-vincadifformine, and (−)-aspidospermidine. Other examples in which dienamides are 4π components in a [4 + 2] annulation process include the total synthesis of the iboga-type indole alkaloid voacangalactone508 and several Aspidosperma alkaloids.509 As a part of a combined synthetic/biosynthetic program aimed at pursuing Diels−Alder-ase, an elusive putative enzyme catalyzing biosynthetic Diels−Alder reactions, the Williams group described a series of total synthesis accomplishments in the area of prenylated indole alkaloids containing a bicyclo[2.2.2]diazaoctane core.510−514 This diverse group of alkaloids is isolated from both terrestrial and marine fungi. The total synthesis of (+)- and (−)-versicolamides B from fungi of the Aspergillus genus serve as an example.515 Two stereogenic C−N bonds are established by a biomimetic [4 + 2] 4503


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6.2. [3 + 2] Cycloadditions

(−)-lepadines A, B, and C, a group of decahydroquinoline alkaloids from the North Sea tunicate Clavelina lepadiformis (Scheme 136b).518 Hydroxamic acid 136-3 served as an early

Application of dipolar, or [3 + 2], cycloadditions for the stereoselective C−N bond construction in natural product synthesis526 are dominated by addition of nitrones to dienes, either inter- or intramolecularly. The second most used transformation is the cycloaddition involving azomethine ylides. Together, these processes constitute over 85% of the applications since 2000; some unusual examples of creative chemistry that fall outside the scope of these two types of reactions will be highlighted at the end of this section. The synthesis of (S)-(+)-cocaine by Davis and co-workers exemplifies a stereoselective intramolecular [3 + 2] cycloaddition between nitrone and methyl enoate groups in substrate 137-2 (Scheme 137a), which, after N-methylation, affords key tricyclic intermediate 137-3 with all the stereogenic centers of the alkaloid.527 The nitrone was prepared by Recatalyzed oxidation of imine 137-1, and the [3 + 2] annulation required Lewis acid activation in addition to heating and prolonged reaction times. Due to the structural constraints in the substrate, the polycyclic product was formed with complete stereocontrol, and isolated in 49% yield over the three steps. A similar reaction was exploited in a more complex system at the concluding stages of the total synthesis of virosaine A (Scheme 137b).528 A different method for the generation of the reactive nitrone was used. Treatment of cyclic hydroxylamine 137-4 with N-tert-butylbenzenesulfinimidoyl chloride in the presence of DBU resulted in complete regioselective formation of nitrone 137-5. The authors rationalized the observed regioselectivity in the nitrone formation on the basis of steric grounds. In contrast to the previous example, the nitrone was much more reactive and the cycloaddition occurred rapidly upon warming to 0 °C. Desilylation with n-Bu4NF (tetra-nbutylammonium fluoride, TBAF) afforded virosaine A in 81% overall yield. Stable nitrone 137-6 derived in seven steps from the diethyl ester of L-malic acid has been used as a starting material in the synthesis of several complex alkaloids. The synthesis of (−)-batzelladine D, a polycyclic guanidine alkaloid from Bahamian marine sponges, started from [3 + 2] cycloadduct 137-7 obtained from nitrone 137-6 and 1-undecene in 75% yield with high regio- and stereocontrol (Scheme 137c).529 The left-hand section of the related alkaloid batzelladine A, which contains another cyclic guanidine, was prepared by a similar reaction using an α,β-unsaturated ester as a dipolarophile; this type of alkene displays similar reactivity.530 The cyclic guanidine alkaloids (+)-saxitoxin and (+)- and (−)-decarbamoylsaxitoxin were prepared by a similar cycloaddition as the first step of their synthesis.531,532 Intermolecular nitrone [3 + 2] cycloadditions with a variety of functionalized alkenes have also been used in the total syntheses of the pyrrolizine alkaloid casuarine from the bark of Casuarina equisetifolia L.,533 the central amino acid portion of the complex tetrapeptide alkaloids tubulysins,534 and the complex fungal alkaloid citrinadine, in which the [3 + 2] reaction with an enantioenriched nitrone was used for diastereotopic selection of a racemic dipolarophile.535 An intricate intramolecular [3 + 2] annulation forming a bridged heterotricyclic product is a highlight in the total synthesis of the freshwater toxins cylindrospermopsin and 7-epi-cylindrospermopsin (Scheme 137d).536,537 Nitrone 137-9 was prepared early on in 84% yield by oxidation of oxazine 137-8 with MCPBA at −78 °C. The intramolecular cycloaddition required significant thermal activation at 200 °C.

Scheme 136

intermediate, which was oxidized to acylnitroso intermediate 136-4 upon treatment with tetra-n-propylammonium periodate under optimized conditions in aqueous DMF. Diastereoselective cyclization of this transient intermediate was governed by the configuration of the benzyloxy substituent, presumably via a boatlike endo transition state that optimized stereoelectronic interactions. The cyclic product 136-5 was isolated in 90% yield as a 6.6:1 mixture of diastereomers, and advanced to complete the synthesis of the lepadines. A very closely related approach was also used in the total synthesis of macrolactone alkaloids (+)-azimine and (+)-carpaine,519 as well as two other alkaloids from a tunicate of the Clavelina genus, tricyclic (±)-fasicularin and (±)-lepadiformine,520 and in the total synthesis of the bridged tricyclic plant alkaloid from the rye grass Lolium cuneatum, (+)-loline.521 A combination of the nitroso-Diels−Alder reaction and enzymatic resolution was developed as the source of the starting material for the total synthesis of a diverse group of bioactive alkaloids.522−525 In the synthesis of (+)-streptazoline,522 a tricyclic nitrogen-containing metabolite from Streptomyces viridochromogenes, bicyclic cycloadduct 136-7 was formed by oxidation of tert-butyl hydroxycarbamate with sodium periodate in the presence of cyclopentadiene (Scheme 136c). Reduction of 136-7 could be achieved with 0.2 equiv of Mo(CO)6 and sodium borohydride, affording 136-8 in 60% overall yield. Its enzymatic resolution with Candida antartica and vinyl acetate in organic solvents then afforded 1-hydroxy-4-amino-2-cyclopentene derivatives in a highly enantioenriched form. The C−N bond in 136-7 was preserved throughout the synthetic route to (+)-streptazoline. 4504


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Scheme 137

(−)-quinocarcin via a subsequent aryne annulation. Another synthesis that exploits an early-stage intermolecular azomethine [3 + 2] cycloaddition is the asymmetric total synthesis of the fungal antimitotic alkaloid spirotryptostatin A.545 All other total synthesis applications in our survey utilize intramolecular [3 + 2] cycloaddition of azomethine ylides. These include the total syntheses of Aspidosperma alkaloids aspidospermine, aspidospermidine, and quebrachamine,546 the Martinella alkaloid (−)-martinellic acid,547 the Kopsia lapidilecta alkaloid (±)-lapidilectine B,548,549 and the C20 diterpenoid alkaloid nominine550 and the synthesis of (−)-tetrazomine.551 Padwa and Mejia-Oneto described several applications of oxonium ylides formed by Rh-catalyzed fragmentation of a diazo compound in the synthesis of alkaloids. As a typical example, ylide 138-2 was formed from diazo ester 138-1 in the presence of rhodium acetate as a transient intermediate in the formation of [3 + 2] cycloadduct 138-3 (Scheme 138a).552 The exo selectivity is believed to be governed by the bulky tert-butyl ester substituent, in contrast to previous findings that favor the endo selectivity in the absence of such substitution. The annulation product established two stereogenic C−N bonds found in the synthesis target aspidophytine. Kerr and Leduc reported a [3 + 2] annulation of activated cyclopropanes and oximes catalyzed by ytterbium triflate and its application in the synthesis of alkaloids. In the synthesis of the Securinega alkaloid (−)-allosecurinine (Scheme 138b),553 condensation of 5-[(3-methoxybenzyl)oxy]pentanal (138-4) with hydroxylamine 138-5 afforded oxime 138-6, and its annulation under the reaction conditions gave pyrroloisoxazolidine 138-7 in 88% yield as a single isomer. This reaction established two stereogenic C−N bonds of (−)-allosecurinine. A similar cyclization was utilized in the total synthesis of FR901483, an immunosuppressive alkaloid from the fermentation broth of

Polycyclic substituted hydroxylamine 137-10 was isolated in 78% yield and subsequently advanced to complete the synthesis of cylindrospermopsin and 7-epi-cylindrospermopsin. Other applications of intramolecular [3 + 2] cycloaddition of nitrones can be found in the total synthesis of Amaryllidaceae alkaloids (−)-hemeanthidine, (+)-pretazettine, and (+)-tazettine,538 the Iboga alkaloid (−)-(19R)-ibogamin-19-ol,539 and the spirobicyclic frog skin alkaloid DL-histrionicotoxin.540−542 An effective application of a potentially biomimetic [3 + 2] cycloaddition of azomethine ylide for the stereoselective construction of C−N bonds was realized during the total synthesis of the pentacyclic alkaloid gracilamine (Scheme 137e).543 Gracilamine is a plant alkaloid isolated from Galanthus gracilis, an Amaryllidaceae species, collected from a Turkish mountain. What is interesting in this example is that an uncharged imine is used as the substrate. The imine is generated by condensation of aldehyde 137-11 and a leucine ester hydrochloride in the presence of triethylamine and magnesium sulfate. Heating of the imine in toluene at reflux presumably results in its tautomerization to azomethine ylide 137-12, which undergoes cyclization to afford the diastereomers 137-13 and 137-14 in 55% and 11% yield, respectively. Complete selectivity was achieved with the corresponding tert-butyl ester. Because gracilamine is an ethyl ester, ester 137-13 was advanced to complete the synthesis to avoid refunctionalization. In a more classical, early-stage implementation of the azomethine ylide cycloaddition, reactive zwitterion 137-15 and acrylate afforded the bicyclic adduct at −20 °C (Scheme 137f).544 The stereoselectivity was defined by Oppolzer’s sultam auxiliary, reaching the level of 11:1. Methanolysis to remove the sultam auxiliary resulted in the formation of methyl ester 137-17 in 74% yield over the two steps. This bicyclic product was advanced further to complete the concise total synthesis of 4505


Chemical Reviews

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acetate in the presence of sodium sulfate as a dehydrating agent upon heating in ethyl acetate in a sealed tube at 150 °C. The product was isolated in good yield and diastereocontrol of 9:1, and advanced further to complete the synthesis of (−)-cylidricine C. An intriguing stereoselective [5 + 2] cycloaddition was used to establish the stereogenic C−N bond of (−)-Bao Gong Teng A, a tropane alkaloid from the Chinese herb Erycibe obtusifolia (Scheme 139b).561 A rapid (0 °C, 1 min) addition of methyl vinyl ketone to chiral enantiopure TpMo(CO)2(η3-pyridinyl) complex 139-3 (>99% ee) in the presence of ethylaluminum dichloride afforded bicyclic Mo complexes exo-139-4 and endo139-5 in 89% yield and very good diastereocontrol (7:1). The minor endo isomer could be equilibrated to exo-139-4 under basic conditions. Molybdenum complex 139-3 can be prepared on a large scale in enantiomerically pure form by resolution of diastereomeric intermediates using crystallization. From exo139-4, the synthesis of (−)-Bao Gong Teng A was completed in six steps. A stepwise 1,5-“Michael-like” annulation with a related chiral η 3-oxopyridinylmolybdenum complex was exploited in the construction of the azabicyclo[3.3.1]nonane ring system of the plant alkaloid (−)-adaline.562 The group of Bach utilized [2 + 2] photocycloadditions between cyclic enamides and ketenes in the synthesis of alkaloids. Specifically, the total synthesis of the simple antifungal pyrrolidine alkaloid (+)-preussin from Presussia sp. is based on a diastereoselective Paternò−Büchi reaction of chiral 2-substituted 2,3-dihydropyrroles and aromatic aldehydes. Interestingly, a similar [2 + 2] photocycloaddition with tetrahydropyridine substrates occurs in substantially lower yields.563

Scheme 138

Cladobotrium sp.554 The synthesis of (±)-peduncularine, a bridged bicyclic tryptamine-derived alkaloid from the Tasmanian shrub Aristotelia peduncularis, was accomplished by a unique [3 + 2] annulation between specially designed allylic silanes and chlorosulfonyl isocyanate.555 6.3. Other Cycloadditions

An intramolecular ytterbium triflate-catalyzed [3 + 3] annulation of an acyclic nitrone generated in situ and an activated cyclopropane akin to that mentioned iat the end of preceding subsection 6.2 was adopted in the synthesis of another securinega alkaloid, (+)-phyllantidine.556 In a different approach, Hsung and co-workers developed a [3 + 3] annulation reaction, inter- or intramolecular, between vinylogous amides and vinyliminium ions and applied it in the stereoselective synthesis of several alkaloids.557−560 For example, in the synthesis of cylindricines Scheme 139a),557

7. NITRENOID REARRANGEMENTS The rearrangement of nitrenoid intermediates is a powerful approach for the construction of stereogenic C−N bonds, featuring a stereospecific migration from carbon to an electrondeficient nitrogen atom with predictable regioselectivity and retention of configuration. In this section, recent applications of four prominent name reactions, namely, Curtius rearrangement, Beckmann rearrangement, Hoffmann rearrangement, and Schmidt reaction, in complex molecule synthesis will be compiled.

Scheme 139

7.1. Curtius Rearrangement (Figure 26)

alkaloids from the marine ascidian Clavelina cylindrica, [3 + 3] cyclization of substrate 139-1 was effected with piperidinium

The Curtius rearrangement is a classic method for stereoselective formation of C−N bonds involving degradation of acyl azides into isocyanates, which could be trapped with various nucleophiles.564,565 Starting from readily available chiral carboxylic acids or their derivatives, acyl azides generated under mild conditions undergo a facile rearrangement with retention of configuration at the migrating carbon. Thus, it is not surprising that the Curtius rearrangement is used frequently in total synthesis. In the synthesis of Amaryllidaceae alkaloid (−)-lycorine, the requisite nitrogen was introduced as carbamate 140-5 from carboxylic acid 140-4 using diphenylphosphoryl azide (DPPA) together with tert-butyl alcohol (Scheme 140).566 Notably, precursor cyclohexane 140-3 bearing three adjacent stereogenic centers was accessed by a chiral ligand-controlled asymmetric cascade conjugate addition. Related strategies for the construction of stereogenic C−N bonds was also applied in the total syntheses of other alkaloids, including pancratistatin,567−569 4506


Chemical Reviews

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Figure 26.

material). Upon treatment with lithium hydroxide, (+)-mycalamide B was isolated in 64% yield. The Curtius rearrangement was strategically applied to access the N-acyl hemiaminal group from the corresponding hydroxy acid by Crimmins,579 Hong,580 and Smith581−583 in the syntheses of two potent cytotoxins, (+)-irciniastatin A (psymberin) and (−)-irciniastatin B, isolated from the IndoPacific marine sponge Ircinia ramose. This strategy was adopted to install the hemiaminal side chain in the synthesis of (+)-zampanolide.584,585 The Curtius rearrangement was demonstrated to be a powerful method for the asymmetric synthesis of complex tertiary alkylamine derivatives. In 2014, Kan and co-workers disclosed an enantioselective synthesis of alkaloid SB-203207 (Scheme 142).586 Cyclopentane 142-1, bearing four contiguous chiral centers, was treated with silica gel to afford the bicyclic enesulfonamide, which was subsequently converted to cyclic carbamate 142-2 under Curtius rearrangement conditions in 71% overall yield. Fukuyama and co-workers also utilized the Curtius rearrangement to furnish the tertiary alkyl carbamate in the syntheses of (−)-huperzine A587 and (−)-histrionicotoxin.588 In the synthesis of sorbicillactone A, Harned and co-workers synthesized tertiary alkylamine 143-2 from the corresponding acyl azide under microwave irradiation (Scheme 143).589 Subsequent acylation of crude amine 143-2 with fumaric acid chloride mono-tert-butyl ester provided amide 143-3 in 49% combined yield. In the formal synthesis of the marine diterpenoid diisocyanoadociane, Mander and Fairweather used a closely related strategy to install a tertiary alkylamine group.590 In addition, the requisite isocyano group was installed by reduction and dehydration of the Curtius rearrangement product in the total synthesis of the marine sesquiterpene 10-isocyano-4-cadinene.591

Scheme 140

trans-dihydronarciclasine,570 (+)-belactosin A,571 (±)-gelsemine,572 (−)-gelsemoxonine,573 and (+)-hapalindole Q.574 In the syntheses of marine natural products mycalamides A575−577 and B,578 the Curtius rearrangement was chosen as a key step to introduce the requisite nitrogen moiety (Scheme 141a). The judicious choice of the nucleophile, specifically an alcohol, greatly improved the synthetic efficiency. Roush and Pfeifer synthesized the mycalamine unit 141-2 from carboxylic acid 141-1 with external 2-(trimethylsilyl)ethanol as the trapping nucleophile.575 Due to the steric congestion of carbamate 141-2, the direct acylation reaction with pederic acid failed. In turn, the authors had to use a longer stepwise reaction sequence to complete the synthesis of mycalamide A. In 2010, Rawal and Jewett reported a remarkable convergent synthesis of mycalamide B.576 The isocyanate intermediate generated from ester 141-6 by a three-step sequence was trapped with an internal primary alcohol, resulting in a 10-membered cyclic carbamate, 141-7, in 44% overall yield (Scheme 141b). Remarkably, the design of carbamate 141-7 succeeded in overcoming the steric congestion (cf. 141-2) and efficiently coupled with the pederic acid component 141-8 to provide 141-10 in 45% yield (73% based on recovered starting

7.2. Beckmann Rearrangement (Figure 27)

The Beckmann rearrangement, named after the German chemist Ernst Otto Beckmann, is a rearrangement of oximes 4507


Chemical Reviews

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Scheme 141

Figure 27.

converts cyclohexanone to the nylon-6 precursor caprolactam.594 The Beckmann rearrangement of ketoximes is stereospecific, with the stereogenic carbon migrating anti to the leaving group on the oxime nitrogen. Recent applications using Beckmann rearrangement of ketoximes in total synthesis are summarized in this section. In the syntheses of two alkaloids, (−)-swainsonine595 and (+)-amphorogynine A,596 a stereoselective Beckmann rearrangement of α,α-dichlorocyclobutanone 144-2 driven by strain release smoothly yielded lactam 144-3 upon treatment with O-(mesitylenesulfonyl)hydroxylamine (MSH) and Zn−Cu (Scheme 144). Electronic effects associated with the Scheme 144

Scheme 142

α,α-dichloro substituent governed the regioselectivity of both the [2 + 2] cycloaddition and ring expansion by Beckmann rearrangement. The polyhydroxylated indolizidine (+)-6-epicastanospermine595 was also assembled by the same strategy from the enantiomer of cyclobutanone 144-2. In 2013, Shenvi and Jansen reported an elegantly executed eight-step asymmetric synthesis of (−)-neothiobinupharidine, utilizing an early stereoselective Beckmann rearrangement to build the lactam segment of the alkaloid (Scheme 145).597

Scheme 143

Scheme 145

to amides or lactams.592,593 The importance of the Beckmann rearrangement is exemplified by an industrial process that 4508


Chemical Reviews

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In 2003, Romo and Poullennec reported an enantioselective total synthesis of the marine alkaloid (+)-dibromophakellstatin, isolated from the Phakellia mauritiana sponge in the Indian Ocean (Scheme 147).604 Starting from hydroxamate

An asymmetric vicinal difunctionalization of 3-methyl-2-cyclopentenone and subsequent oxime formation afforded oxime 145-2 in 42% yield over the two steps. Upon treatment with TsCl and pyridine, lactam 145-3 was obtained in 69% yield and 95% ee on a multigram scale. Related Beckmann rearrangements were also utilized to form lactams during the syntheses of pinnaic acid,598 (−)-ibogamine,599 (±)-cis-195A, and (±)-trans-195A.600 The lupidine alkaloid (+)-sparteine is naturally occurring but less abundant compared to its (−)-enantiomer. In 2002, Aubé and co-workers completed the first asymmetric synthesis of (+)-sparteine, featuring two ring-expansion reactions, namely, an intramolecular Schmidt reaction and a photo-Beckmann rearrangement (Scheme 146).601 Irradiation of nitrone 146-2 at

Scheme 147

Scheme 146

147-1, sequential intramolecular Mitsunobu reaction, aminolysis, and N−O bond cleavage delivered amide 147-3 in 53% combined yield. Upon treatment with hypervalent iodine reagent PhI(O2CCF3)2 (phenyliodine bis(trifluoroacetate), PIFA), the Hoffmann rearrangement of amide 147-3, followed by in situ intramolecular cyclization and hydrogenolysis, provided cyclic urea (−)-phakellstatin in 50% overall yield. Bromination with N-bromosuccinimide (NBS) completed the synthesis of (+)-dibromophakellstatin in 69% yield. A similar strategy was utilized in the total syntheses of (−)-epibatidine,605 (±)-indatraline,606 and (−)-myriocin607 to establish the requisite stereogenic C−N bonds from amide groups. The precursor amides can be prepared from the corresponding nitriles under mild hydrolysis conditions with a Pt complex. In the remarkable recent total syntheses of cyclopiamine B and ent-citrinalins B, Sarpong and co-workers converted cyanoenone 148-1 to the corresponding amide with the assistance of the platinum catalyst HPt[(PMe2OH)(PMe2O)2H] (148-3) (Scheme 148a).608 A subsequent Hoffmann reaction was effected with PIFA to provide carbamate 148-2 in 70% yield. Further elaborations led to completion of the synthesis efficiently. In 2011, Herzon and co-workers reported a robust synthesis of (−)-huperzine A (Scheme 148b).609 Oxidative desilylation, dehydration, and platinum-catalyzed nitrile hydration of advanced intermediate 148-5 afforded amide 148-6. Treatment of amide 148-6 with PIFA and subsequent global deprotection provided (−)-huperzine A on a gram scale in 56% overall yield over four steps.

254 nm in benzene provided lactam 146-4 in 76% yield via putative oxaziridine intermediate 146-3. Of note, construction of the lactam skeleton by intramolecular Schmidt rearrangement of azidocarbonyl compound 146-5 and its analogues failed, presumably due to the low reactivity of the ketone toward the weakly nucleophilic azide. In 2004, Fleming and Buttler used a Beckmann rearrangement of bis(oxime methanesulfonate) to prepare the advanced bislactam as an intermediate in the synthesis of (±)-sparteine.602 7.3. Hofmann Rearrangement (Figure 28)

The Hofmann rearrangement, named after German chemist August Wilhelm von Hofmann, is a reaction converting primary amides to primary amines via isocyanates.603 As with the

7.4. Schmidt Reaction (Figure 29)

The Schmidt reaction involves the initial nucleophilic attack of hydrazoic acids or related azide species onto electrophiles, such as carboxylic acids, ketones, and/or transient carbocation intermediates.603 In recent years, the studies on azidocarbonyl compounds have greatly expanded the versatility of the Schmidt reaction,610 and related applications in total synthesis are complied in this subsection. Since the 1990s, the Aubé group has extensively studied the intramolecular Schmidt reaction as a key step to construct nitrogen-containing heterocycles and applied it in several distinctive total syntheses, including those targeting alkaloids 223A,611 251F,612,613 and lepadiformine C.614 In 2005,

Figure 28.

aforementioned nitrenoid rearrangements, retention of configuration is also observed in Hofmann rearrangement. In this section, the compiled examples showcase the power of the Hofmann rearrangement to construct chiral amine derivatives within the setting of complex molecular synthesis. 4509


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Scheme 148

Scheme 149

Scheme 150

Figure 29.

Aubé and Zeng reported a concise synthesis of (±)-stenine in nine steps from commercially available compounds (Scheme 149a).615 Treatment of (trimethylsilyl)oxy diene 149-1 with cyclohexenone in the presence of SnCl2 afforded exo-Diels−Alder intermediate 149-2, which underwent an intramolecular Schmidt reaction to furnish tricyclic lactam 149-3 in high yield with a 3:1 diastereomeric ratio. In 2013, Tu and coworkers disclosed the divergent syntheses of Lycopodium alkaloids (−)-lycojaponicumin C, (−)-8-deoxyserratinine, (+)-fawcettimine, and (+)-fawcettidine from a versatile common tricyclic azidotrione intermediate (Scheme 149b).616 The tin(IV) chloride-mediated intramolecular Schmidt reaction of advanced intermediate 149-4 afforded the requisite skeleton in moderate yield with high chemoselectivity (46% yield, dr 9:1). Thiolactam formation with Lawesson’s reagent (LR) and subsequent reduction with Raney nickel led to the common intermediate 149-7, which underwent one further simple transformation to complete the syntheses of the latter three alkaloids. Incorporation of the Schmidt reaction into a cascade process was exploited recently in total synthesis. In the total synthesis

of (±)-stemonamine, the Tu group utilized a tandem rearrangement of epoxy azides (Scheme 150).617 Treatment of advanced intermediate 150-1 with TiCl4 generated keto azide intermediate 150-4, and the subsequent intramolecular Schmidt reaction afforded lactam 150-2 in 68% yield. In addition, Wang and co-workers reported an enantioselective synthesis of (S)-tylophorine utilizing a tandem intramolecular Schmidt/Bischler−Napieralski/imine reduction reaction cascade.618 7.5. Miscellaneous Reactions

In a process reminiscent of the Schmidt reaction, the Baskaran group developed an interesting method to prepare 5-hydroxymethyl azabicyclic compounds from epoxide-initiated cationic cyclization of azides. This method was further applied to the enantioselective syntheses of indolizidine alkaloids 167B and 209D as shown in Scheme 151.619 4510


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mine,631 (+)-deoxocassine,632 and (+)-dihydropinidine and (−)-pinidinone.633 In 2012, Yao and co-workers completed a protecting-groupfree synthesis of the Lycopodium alkaloid (−)-lannotinidine B in 10 steps and 23% overall yield (Scheme 153a).634 The synthesis was characterized with three reductive amination events to furnish the desired molecular skeleton. Commencing with advanced diketo aldehyde 153-1, intermolecular reaction with benzylamine and sodium tris(acetoxy)hydroborate under acidic conditions gave intermediate 153-2, which underwent regioselective iminium cation formation and stereoselective reduction, thus providing bicyclic amine 153-4. The authors suggested that the excellent selectivity of the intramolecular reductive amination was due to a steric bias during the second reductive amination. A subsequent two-step oxidative cleavage of the terminal alkene and a third reductive amination led to the required azepine 153-5 in 64% combined yield. In 2014, Dai and co-workers reported the concise total syntheses of two Lycopodium alkaloids, lyconadins A and C, featuring a tandem reductive amination/formal [4 + 2] cycloaddition (Scheme 153b).635 Ketone 153-6 was treated with ammonium acetate and sodium cyanoborohydride to afford the primary amine, which was subsequently reacted with formaldehyde under acidic conditions to provide polycyclic ketone 153-9 in 68% yield. A stepwise approach to ketone 153-9 from 153-6 was pursued to probe the mechanism of this cascade reaction. Interestingly, a tandem reductive aminiation/aza-Michael reaction of ketone 153-6 did give amine 153-10 in 53% yield. However, starting from amine 153-10, the formation of ketone 153-9 was not observed under the Mannich reaction conditions. Thus, a concerted Diels−Alder cycloaddition or a stepwise Mannich/aza-Michael process was suggested for this transformation by the authors. Aside from direct reductive amination, reduction of preformed ketimines was also frequently employed in complex molecule synthesis. In the synthesis of hispidospermidin, the Danishefsky group performed a reduction of ketimine 154-2, generated from ketone 154-1 and N1-(3-(dimethylamino)propyl)-N1-methylbutane-1,4-diamine, to construct the requisite secondary amine (Scheme 154a).636 In the total synthesis of (±)-spisulosine (ES285), a similar transformation was applied at a late stage as well.637 In addition, reduction of cyclic ketimines generated by a two-step sequence was exploited to install the cyclic amine derivative in the total synthesis of (±)-crinine.638 In 2013, the Ma group reported an enantioselective synthesis of indole alkaloid (+)-methyl N-decarbomethocychanofruticosinate, characterized by an intramolecular oxidative coupling (Scheme 154b).639 Nitrile 154-3 was reduced by nickel boride, generated in situ, and the ensuing amine was spontaneously condensed with the ketone to afford the cyclic ketimine. Subsequent selective reduction led to tetracyclic amine 154-4 in 88% yield over two steps. In the synthesis of (−)-pinnaic acid, nitroketone 154-5 was converted to bicyclic spirobicyclic amine 154-6 in 91% overall yield by a two-step sequence (Scheme 154c).640 A close strategy using a reduction/reductive amination protocol to generate the chiral amine derivative was applied in the total syntheses of adenophorine641 and quinine.642 In 2004, Molinski and co-workers reported an enantioselective total synthesis of (+)-milnamide A utilizing a diastereoselective reduction of a preformed ketimine (Scheme 155).643 Oxidation of oxazoline 155-1 and concurrent rearrangement of

Scheme 151

8. REDUCTION OF IMINES AND ENAMINES (FIGURE 30) The stereoselective reduction of imines and enamines has provided another powerful method for the stereoselective construction of stereogenic C−N bonds. In this section, synthetic applications in total synthesis have been divided into two categories, substrate-directed reductions and auxiliarydirected reactions. Applications of the catalytic asymmetric reduction in total synthesis can be found in section 4. 8.1. Substrate-Directed Reduction

In complex molecule synthesis, reduction of imines and enamines bearing a stereodirecting group is the most frequently used variant, according to our literature survey. Owing to preexisting geometric and electronic biases in the substrate en route to a complex target molecule, one diastereomer would be formed in preference to the other(s) in the reduction process. In this subsection, reductive amination, involving direct conversion of ketones or aldehydes to amines, will be discussed first, followed by reduction of preformed ketimines, enamines, imidates, and oximes. Of note, due to the often facile tautomerization between the imine and enamine forms during the reduction reaction, we do not make a clear distinction between the two and provide the reported structure of the isolated precursor or assign it arbitrarily between the two tautomeric forms. In 2004, Baran and Richter reported a concise six-step synthesis of (+)-hapalindole Q, featuring a direct coupling of indole with (R)-carvone (Scheme 152a).620 Upon treatment of advanced intermediate 152-1 with ammonium acetate and sodium cyanoborohydride under microwave irradiation conditions, the primary amine 152-2 was obtained as a major product in 63% yield with a 6:1 diastereomeric ratio. Notably, when conducted at 25 °C without irradiation, the same reductive amination required 7 days to reach completion and displayed a 3:1 diastereomeric ratio at a higher yield.621 Subsequent isothiocyante formation with thiocarbonyldiimidazole completed the synthesis. A similar diastereoselective reductive amination was applied to install the nitrogen functionality in the syntheses of indole alkaloids (−)-12-epifischerindole U isothiocyanate,620 (−)-fischerindole G,209 and hapalindoles J and U,622 the Lycopodium alkaloids (±)-nankakurines A and B623 and (−)-lyconadin C,624 pamamycin-607,625 and FR901464 and spliceostatin A.626 In addition, intramolecular reductive amination was employed to form cyclic amines in the syntheses of (−)-hyacinthacine A5,627 (+)-hyacinthacine A6,628 and lead compound (+)-(2S,3S)-CP-99,994.629 The one-pot intramolecular amine generation/reductive amination was also employed by Renaud and co-workers in a concise 10-step synthesis of the marine alkaloid lepadiformine in 15% overall yield from cyclohexanone (Scheme 152b).630 Under hydrogenation conditions, azide 152-3 was reduced to a primary amine, and a consecutive stereoselective reductive amination afforded bicyclic compound 152-4. Subsequent lactam formation gave 152-5 in 72% overall yield. This onepot reductive amination strategy was also employed in the syntheses of (−)-lycojaponicumin C,616 (+)-1-epi-castanosper4511


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Figure 30.

synthesis. In 2009, Baudoin and co-workers reported a concise synthesis of (±)-coralydine featuring a C(sp3)−H activation/ electrocyclization strategy (Scheme 156).644 The imine formed by condensation of benzocyclobutylamine 156-1 and aldehyde 156-2 underwent a cascade tandem electrocyclic ring opening/ 6π-electrocyclization to afford cyclic imine 156-4. Selective

the resulting ketone provided dihydrooxazinone 155-2 in 90% yield. Subsequent hydrogenation with PtO2 and H2 afforded amine 155-3 in high yield with an excellent diastereoselectivity (90% yield, dr 70:1). Stereoselective reduction of imine intermediates generated by other means was also exploited in complex molecule 4512


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Scheme 152

Scheme 154

Scheme 153

Scheme 155

Scheme 156

reduction using sodium borohydride provided cyclic amine 156-5 in 68% yield with a 6:1 diastereomeric ratio. In the total synthesis of chaetominine, Evano and co-workers employed a selective reduction of the imine intermediate, which was accessed by isomerization of an amino epoxide.645 In 2012, the Mann group disclosed an interesting total synthesis of pyrrolizidine alkaloid amphorogynine C, featuring an intramolecular azide−olefin cycloaddition/imine formation via a nitrogen extrusion/selective reduction sequence.646 The diastereoselective reduction of iminium ions generated in situ has complemented the reduction of preformed imines as a means of C−N bond construction in total synthesis. In the synthesis of (+)-kopsihainanine A, advanced intermediate 157-1 was cyclized to iminium salt 157-2 under Bischler−Napieralski conditions (Scheme 157a).647 Subsequent stereoselective reduction of 157-2 provided cyclic amine 157-3 in 82% yield over two steps. A close strategy using a

Bischler−Napieralski reaction/reduction sequence was applied in the synthesis of dihydrocorynantheol.648 In the synthesis of the Lycopodium alkaloid (+)-serratezomine A, Johnston and coworkers employed a reduction of the iminiun ion to install the required C−N bond (Scheme 157b).649,650 Starting from imino alcohol 167-4, mesylation and spontaneous cyclization gave iminium ion 157-5, which was reduced to tricyclic amine 4513


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Scheme 157

Scheme 158

157-6/157-7 in 98% yield. However, the broad NMR peaks of 157-6/157-7 precluded a reliable measurement of the diastereoselectivity. A subsequent two-step sequence (NaOH, TBAF) led to (+)-serratezomine A in 33% overall yield, along with a 22% yield of lactone 157-8 generated from the diastereomer of 157-7. To complete the total synthesis of (−)-cermizine C from (−)-senepodine G, Snider and coworkers utilized a selective reduction of the iminium ion generated by addition of MeMgBr to the lactam followed by acidic treatment.651 The Galbulimima alkaloids are a family of structurally fascinating polycyclic compounds. The total synthesis of these alkaloids by the Movassaghi and Evans groups highlighted the power of enamine/imine (iminium) chemistry to construct C−N bonds in the following two examples (Scheme 158). The Movassaghi group reported a biomimetic syntheses of two members, (−)-GB 13652 and (−)-himandrine,653 featuring an intramolecular imine/enamine aldol cyclization. In the synthesis of GB 13, a copper-promoted conjugate addition of iminium chloride 158-1 and enone 158-2 afforded imino ketone intermediate 158-3. Concurrent tautomerization of 158-3 to enamine 158-4 enabled an intramolecular aldol reaction to provide imino alcohol 158-5. Subsequent selective reduction and carbamate formation provided the polycyclic product 158-3 in 50% yield over three steps. In 2012, Evans and co-workers reported the total syntheses of (+)-GB 13 and (+)-himgaline utilizing a similar concept.654 Commencing with triketone 158-7, removal of the Boc group, condensation, and dehydration afforded the imine intermediate, which underwent intramolecular aldol reaction to give 158-8 under acidic conditions. Subsequent reduction, oxidation, and carbamation gave polycyclic intermediate 158-9 in 39% yield over six steps. Maloney and Danheiser used α-aminonitriles as precursors of iminium ions in the total synthesis of quinolizidine alkaloid (−)-217A (Scheme 159).655 Treatment of advanced intermediate 159-1 with LiN(SiMe3)2 and allylic bromide 159-2 afforded the alkylation product, which underwent reductive decyanation via iminium ion 159-3 to give tertiary amine 159-4 in 74−77% yield over two steps. The stereocontrolled reductive decyanation was also employed in the synthesis of (±)-alkaloid 241D.656

Scheme 159

Selective reduction of an enamine was performed to generate a stereogenic C−N bond in the total synthesis of Aconite alkaloid (±)-nominine (Scheme 160a).657 Protection of ketone 160-1 as a silyl enol ether and subsequent treatment with lithium aluminum hydride afforded the enamine intermediate, which was elaborated to carbamate 160-2 in 63% overall yield. Under acidic conditions, reduction of 160-2 with NaBH3CN provided polycyclic carbamate 160-3 as a single diastereomer in 90% yield. In 2005, Magnus and Matthews reported the syntheses of tetrahydroisoquinoline alkaloid (±)-renieramycin G and (±)-lemonomycinone amide involving a nucleophilic addition of an organolithium reagent to unactivated isoquinoline and a selective reduction of the enamine (Scheme 160b).658 Upon treatment with [(benzyloxy)methyl]lithium, isoquinoline 160-4 was converted to 1,2-dihydroisoquinoline 160-5 after acylation. To circumvent elimination of the O-triisopropylsilyl (O-TIPS) group in direct reduction of 160-5, oxazolidinone 160-6 was prepared by desilyation in 91% yield. Subsequent stereoselective reduction of ene carbamate 160-6 took place cleanly in the presence of triethylsilane and trifluoroacetic acid, and the following hydrazinolysis provided cis-tetrahydroisoquinoline 160-7 in 86% yield over the two steps. The structure of 160-7 was unambiguously determined by an X-ray diffraction study. The stereoselective reduction of enamine bearing an electron-withdrawing group at the β-position has frequently 4514


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stabilized enamide was applied in the syntheses of Rauwolfia alkaloids suaveoline and norsuaveoline661 as well as lepadins A−E and H.662,663 In 2005, the De Brabander group completed the total synthesis and stereochemical assignment of irciniastatin A (psymberin) utilizing a selective reduction of a methyl imidate to build the requisite stereogenic C−N bond (Scheme 162).664

Scheme 160

Scheme 162

Advanced imtermediate 162-1 was treated with Me3OBF4 in the presence of immobilized poly(vinylpyridine) to provide imidate 162-2. Subsequent acylation, reduction, and saponification gave irciniastatin A in 56% yield with a 2.4:1 diastereomeric ratio. In 2003, the Mander group exploited an interesting cyclization of bisoxime and subsequent stereoselective reduction in the first racemic synthesis of the Galbulimima alkaloid GB 13 (Scheme 163).665 Treatment of bis(ketoxime) 163-1

been utilized in total synthesis. The Kouklovsky group accomplished the synthesis of the antipsychotic compound nemonapride in nine steps from D-alanine using a selective Birch reduction of a cyclic enamino ester (Scheme 161a).659 Exposure of enamide 161-1 to sodium and ammonia in THF, followed by saponification with an aqueous sodium hydroxide solution, afforded carboxylic acid 161-3 in 66% yield, together with a 14% yield of the overreduction product 161-3. En route to the synthesis of (±)-cycloclavine, Petronijevic and Wipf found that hydrogenation of enone 161-4 took place exclusively from the α-face to afford cis-fused hydroindole 161-5 after pyridinium chlorochromate (PCC) oxidation (Scheme 161b).

Scheme 163

Scheme 161

with zirconium tetrachloride and sodium borohydride gave N-hydroxypiperidine 163-2 via a putative imtermediate, 163-4.666 Reduction of hydroxylamine 163-2 followed by amide formation provided polycyclic trifluoroacetamide 163-3 in 34% overall yield. Reduction of a ketoxime to amine was also applied in the synthesis of (+)-deoxoprosophylline.667 8.2. Auxiliary-Directed Reduction

Auxiliaries are typically introduced at an early stage of synthesis to impose stereochemical biases. An important requirement placed on chiral auxiliaries is the ease of attachment and

Further elaborations led to completion of (±)-5-epi-cycloclavine.660 In addition, a similar stereoselective reduction of the 4515


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removal during complex molecule synthesis. Recent examples using auxiliary-directed reduction of imines and enamines will be cataloged in this subsection. In the synthesis of (−)-isooncinotine, the Fürstner group employed a traceless asymmetric hydrogenation to introduce the requisite C−N bond (Scheme 164).668 Pyridine derivative

Scheme 165

Scheme 164

164-1 bearing a chiral oxazolidinone was treated with Pearlman’s catalyst in a mixture of methanol and acetic acid to provide amino alcohol 164-5 in 78% yield and 94% ee. Protonation of the pyridine enhanced the reactivity of the heterocyclic ring toward hydrogenation. In addition, effective hydrogen bonding between the pyridinium ion and oxazolidinone resulted a more rigid conformation and enhanced facial selectivity. Concurrent release of the auxiliary led to the imine and/or enamine intermediate, which underwent further hydrogenation to afford amino alcohol 164-5. According to our review of the literature since 2000, (α-methylbenzyl)amine is a frequently used auxiliary to direct stereoselectivity in the reduction of iminium ions or enamines. For instance, a creative desymmetrization of an achiral precursor via reductive amination of a 2,2-disubstituted 1,3cyclohexanedione derivative was developed for the synthesis of (−)-strychnine (Scheme 165a).669 Ozonolysis of alkene 165-1 and subsequent treatment of the ensuing diketo aldehyde with [(S)-α-methylbenzyl]amine in the presence of sodium cyanoborohydride resulted in the tertiary amine 165-2 in moderate yield (37%). Dealkylaiton of the tertiary amine was achieved by its transformation to carbamate 165-3 with α-chloroethyl chloroformate in 72% yield, and after three additional steps, a smooth thermal fragmentation of the 1-chloroethyl carbamate provided the unmasked amine.670 In the synthesis of (−)-corytenchine A, Georghiou and co-workers also employed [(S)-α-methylbenzyl]amine as a chiral auxiliary (Scheme 165b).671 The Bischler−Napieralski reaction of amide 165-4 provided the iminium ion intermediate, which was subjected to selective reduction with sodium borohydride followed by hydrogenation to chiral amine 165-5 in 72% overall yield. In the synthesis of quinolizidine (−)-217A, [(R)-αmethylbenzyl]amine was used as a chiral auxiliary to induce the diastereoselective reduction of a piperidine derivative (Scheme 165c).672 Treatment of alkyne 165-6 with sodium iodide followed by a sequential substitution and cyclization gave enamine 165-7. Diastereoselective reduction was achieved with sodium borohydride, and subsequent alkylation afforded piperidine 165-8 in 63% overall yield from 165-6. A facile hydrogenolysis removed the (R)-α-methylbenzyl group in high yield at a late stage. In 2010, the Rychnovsky group reported a concise synthesis of (−)-lycoperine A, featuring a desymmetrization reaction and

Scheme 166

a double reductive amination (Scheme 166).673 Commencing with 5-methylcyclohexane-1,3-dione derivative 166-1, a coppermediated condensation with an amino alcohol auxiliary afforded enamine 166-2 in 96% yield. Under Palmieri’s conditions using sodium and 2-propanol, reduction of 166-2 produced alcohol 166-3 in 67% yield. Subsequent hydrogenolysis and acetylation 4516


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simplicity, typically high reaction rate at moderate temperatures, high stereoselectivity, and predictable stereochemical outcome. The Ireland−Claisen rearrangement of chiral allylic esters of N-protected amino acids provides a facile access to an enantiopure γ,δ-unsaturated amino acid via a chairlike transition state. This strategy was widely utilized in the synthesis of complex molecules. In 2012, Kim and co-workers performed the Ireland−Claisen rearrangement with allylgylcine ester to build the stereogenic C−N bond in (+)-trans-dihydronarciclasine, an alkaloid isolated from the Chinese medical plant Zephyranthes candida (Scheme 167a).678 Treatment of ester

delivered acetamide 166-4 in 70% overall yield. At a late stage, a double alkylation provided dicyanopiperidine 166-7. Hydrolysis of the 2,6-dicyanopiperidine promoted by silver nitrate delivered the 1,5-diketone, which was treated under reductive amination conditions using ammonium trifluoroacetate and sodium triacetoxyborohydride to complete the synthesis in moderate yield. A chiral sulfoxide was used as a directing group in the reduction of an enamine en route to (+)-swainsonine, and removal of the auxiliary was achieved by pyrolysis at a late stage.674

9. SIGMATROPIC REARRANGEMENTS Sigmatropic rearrangements are among the most fundamental chemical transformations in organic synthesis and offer rapid access to stereogenic carbon−carbon or carbon−heteroatom bonds. They are especially effective in the construction of congested chiral centers in complex molecule synthesis.675 A review of the literature since 2000 revealed that [3,3]sigmatropic rearrangements were the most used class of rearrangements for the construction of stereogenic C−N bonds in total synthesis, followed by [1,2]- or [2,3]-Stevenstype rearrangements of ammonium salts.

Scheme 167

9.1. [3,3]-Sigmatropic Rearrangements

In this subsection, the selected applications of [3,3]-sigmatropic rearrangement will be divided into four parts, i.e., four name reactions, Claisen rearrangement, aza-Cope rearrangement, Overman rearrangement, and Ichikawa rearrangement. In each section, the substrate-controlled diastereoselective reactions will be discussed first, followed by auxiliary-directed [3,3]-sigmatropic rearrangements. 9.1.1. Claisen Rearrangement (Figure 31). In this section, applications of Claisen rearrangement and its variations

167-1 with LiN(SiMe3)2 and (TBS)Cl led to a (Z)-silyl ketene acetal intermediate, which sequentially underwent the rearrangement and esterification to α-amino ester 167-2 as a single stereoisomer in 93% overall yield. The Takayama group utilized Ireland−Claisen rearrangement to install the requisite α-quaternary amino acid derivative in the first enantioselective synthesis of a trimeric tryptamine-related alkaloid psychotrimine (Scheme 167b).679 Zinc iodide was employed as an additive to achieve chelation between the nitrogen of the indoline and the oxygen of the enolate. Upon treatment with KN(SiMe3)2, ZnI2, and Me3SiCl, ester 167-3 provided the desired amino acid, which was further converted to amide 167-4 in 79% overall yield and 74% ee. The enantiomeric excess of 167-4 could be enhanced to 95% ee by a single crystallization from ethyl acetate. A close strategy using Ireland−Claisen rearrangement as a key step was applied in other natural products, e.g., arabino-phytosphingosine,680 2-amino-3-cyclopropylbutanoic acid,681 and (−)-amathaspiramide F,682,683 as well as the putative structure of lucentamycin A.684 Morpholinone derivatives have also been used in the Ireland−Claisen rearrangement. In 2007, the Angle group reported an enantioselective synthesis of (−)-indolizidine 195B in 13 steps from L-glutamic acid. (Scheme 168a).685 The rearragement of 5,6-cis-disubstituted morpholinone 168-1 took place at 200 °C to afford trans-piperidine 168-3 in 47% yield. The trans isomer 168-4 gave cis-piperidine 168-6 after rearrangement at room temperature, giving the product in 56% overall yield after reduction. The authors suggested that the rearrangement of morpholinones proceeded through a boatlike transition state, and attibuted the slow rate in the rearrangement of 168-1 to a significant steric interaction between the alkyl and vinyl substituents.

Figure 31.

in total synthesis will be discussed.676,677 The Ireland− Claisen rearrangement is one of the most frequently used variants of Claisen rearrangement due to its experimental 4517


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tions and, therefore, useful applications in alkaloid synthesis. The facile nature of this rearrangement is attributed to the formation of a charged iminium ion, which greatly lowers the activation barrier of rearrangement. The following two examples showcase recent applications in total synthesis. In 2004, Brummond and Hong completed a formal total synthesis of the immunosuppressant alkaloid FR901483 featuring a tandem aza-Cope rearrangement/Mannich cyclization (Scheme 170).688 Starting from cyclohexanone 170-1,

Scheme 168

Scheme 170

An auxiliary-directed aza-Claisen rearrangemnt was utilized in the total sythesis of cyclic depsipeptide halipeptin A (Scheme 169).686 Exposure of amide 169-1 to LiN(SiMe3)2 Scheme 169

intramolecular condensation followed by a [3,3]-sigmatropic rearrangement and Mannich reaction provided pyrrolidine 170-4 in 71% yield with a 2:1 diastereomeric ratio. Auxiliary-directed aza-Cope rearrangement was employed to access chiral amines at early stages in complex molecule synthesis. In 2008, Fürstner reported a concise synthesis of the pyrrolizidine alkaloid epohelmin B and its analogues using this strategy (Scheme 171).689 Upon treatment of aldehyde 171-1 Scheme 171 provided the aza-Claisen rearrangement products with a 3:1 diastereomeric ratio. Subsequent amide formation with CbzCl gave 169-2 in 52% overall yield. Removal of the Cbz group under acidic conditions provided the carboxylic acid, which, after esterification with diazomethane, afforded methyl ester 169-3 in 76% yield. 9.1.2. Aza-Cope Rearrangement (Figure 32). The azaCope/Mannich reaction involves the transformation of an

with (1S)-(+)-camphorquinone-derived amine 171-2 under acidic conditions, a [3,3]-sigmatropic rearrangement of the resultant imine took place to afford imine 171-4. Cleavage of the auxiliary was achieved by a hydrolytic workup to afford amine 171-5 in 80% combined yield and 94% ee on a multigram scale. 9.1.3. Overman Rearrangement (Figure 33). The Overman rearrangement is a [3,3]-rearrangement of allylic trichloroacetimidates readily prepared by nucleophilic addition of allylic alcohols to trichloroacetonitrile.690,691 In 2008, Banwell and co-workers reported an enantioselective total synthesis of the purported structure of (+)-montauphine from cis-3-chloro-1,2-dihydrocatechol (Scheme 172a).692 Advanced intermediate 172-1 was treated with trichloroacetonitrile and

Figure 32.

unsaturated iminium ion to an acyl-substituted pyrrolidine via sequential cation-accelerated [3,3]-sigmatropic rearrangement followed by irreversible Mannich cyclization.687 It is characterized by a skeletal rearrangement under mild reaction conditions that allow for nonobvious retrosynthetic disconnec4518


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Scheme 172

Scheme 173

Figure 33.

sodium hydride to afford a trichloroacetimidate intermediate, which was exposed to microwave irradiation in the presence of potassium carbonate to afford the rearrangement product 172-2 in 88% overall yield. The same group completed the synthesis of ent-narciclasine utilizing a closely related Overman rearrangement of a 1,2-dihydrocatechol derivative.693 In 2009, Wardrop and Dickson reported a racemic synthesis of agelastatin A, a potent cytotoxin and powerful antimetastatic agent, featuring an effective application of Overman rearrangement combined with an extended utility of the trichloroacetamide group as a protecting group, a pendant nucleophile, and a latent urea (Scheme 172b).694 Commencing with cis-3-acetoxy-5-hydroxycyclopent-1-ene (172-3), Overman rearrangement provided amide 172-4 as a single diastereomer in 78% yield. Subsequent exposure to N-bromoacetamide in refluxing dichloromethane afforded cyclic imidate 172-5 in 76% yield. Further elaborations led to completion of the synthesis. Acyclic allylic alcohols were also effectively engaged in Overman rearrangement to establish stereogenic C−N bonds. Incorporation of several [3,3]-sigmatropic rearrangements into cascade sequences of reactions to build the requisite functionalization has also been featured prominently in complex molecule synthesis. For example, Chida and coworkers developed a sequential double Overman/Mislow− Evans rearrangement to install two stereogenic C−N bonds in the synthesis of (−)-agelastatin A (Scheme 173a).695 Starting from diol 173-1, a sequential imidate formation and thermal rearrangement afforded bis(amide) 173-2 in 58% yield over two steps. Subsequent oxidation with m-CPBA to sulfoxide, which was treated with trimethyl phosphite in refluxing MeOH, initiated a Mislow−Evans rearrangement to provide allylic alcohol 173-4 with a 1:1 diastereomeric ratio. Ring-closing metathesis and cyclization furnished oxazoline 173-5 in 56% overall yield over four steps. In the synthesis of (−)-kainic acid, the Chida group designed a sequential Eschenmoser−Claisen/ Overman rearrangement to introduce the required stereogenic centers (Scheme 173b).696 Amide 173-7 could be prepared in 50% overall yield from allylic alcohol 173-6 after two sequential sigmatropic rearrangements. Of note, in the above two

examples, the inorganic base was used to avoid decomposition of the imidates by neutralizing acidic byproducts generated under the thermal conditions.697 Other syntheses based on Overman rearrangement accomplished by the Chida group as a key step include the syntheses of (+)-myriocin (single Overman rearrangement),698 mycestericin A (single Overman rearrangement),699,700 A-315675 (double Overman rearrangement),701 and broussonetine F (orthoamide Overman rearrangement).702 The Kim group completed the asymmetric total syntheses of (−)-antofine and (−)-cryptopleurine by applying an Overman rearrangement of an acyclic allylic alcohol as a key step to stereoselectively install a C−N bond.703 At an early stage in the synthesis of tetrodotoxin and 11-deoxytetrodotoxin,704−707 the Isobe group prepared a tertiary alkyl amide, 174-2, on a multigram scale relying on Overman rearrangement (Scheme 174). Trichloroacetimidate 174-3, prepared from allylic alcohol 174-1 with Cl3CCN and DBU, underwent a smooth thermal rearrangement to afford 4519


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Scheme 174

Figure 34.

amide 174-2 as a single stereoisomer in 92% yield on a 20 g scale. The authors proposed the preferred conformation shown in Scheme 174 to explain the observed stereoselectivity. In this low-energy conformer, the acetonide side chain occupies the pseudoaxial position to minimize the allylic strain with the exo-alkene substituent. Nagasawa and co-workers employed Overman rearrangement as a key step for the installation of N-tert-alkyl amide 175-3 in the synthesis of (+)-dibromophakellin (Scheme 175).708,709

carbamates to allylic cyanates, which readily undergo a sigmatropic rearrangement to allylic isocyanates.710 Notably, Ichikawa rearrangement usually takes place at a much lower temperature (less than 0 °C) compared to Overman rearrangement. Recent applications in the total synthesis will be summarized in this subsection. In the synthesis of (+)-blasticidin S, Ickikawa and co-workers utilized the [3,3]-rearrangement of allylic cyanates to install a stereogenic C−N bond (Scheme 176).711 Treatment of

Scheme 175

Scheme 176

Upon exposure to CCl3CN and DBU, allylic alcohol 175-1 (dr 1:1) was converted to the expected amide 175-3 in 48% yield together with a 50% yield of pyrrole 175-2. It was found that the configuration of the C6 center in 175-1 had a significant impact on the product distribution in this reaction. Pure cis-175-1 gave the expected amide 175-3 in only 21% yield, while the same amide was obtained in 70% yield from trans-175-1. The different reactivities originated from steric hindrance between the acetyl group at C6 and the imidate group in 175-8. Meanwhile, an isomerization pathway via iminium cation intermediate 175-10 was proposed to explain the interconversion between isomeric cis- and trans-imidates 175-8 and 175-9. 9.1.4. Ichikawa Rearrangement (Figure 34). Ichikawa rearrangement commences with a facile dehydration of allylic

advanced intermediate 176-1 with trichloroacetyl isocyanate followed by hydrolysis provided allylic carbamate 176-2. Dehydration under Appel’s conditions (CBr4, PPh3, Et3N, CH2Cl2, −10 °C) afforded the allylic cyanate, which underwent an instantaneous rearrangement and a subsequent trapping with trichloroethanol to produce carbamate 176-5 in 75% overall yield over four steps. The Ichikawa group also used a similar approach to introduce the C−N bond at an early stage in the synthesis of glycocinnasperimicin D.712,713 In 2007, the Ichikawa group reported an enantioselective synthesis of (−)-agelastatin A from L-arabitol featuring the stereoselective preparation of a vicinal diamine moiety by two 4520


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Scheme 177

Scheme 179

allylic cyanate rearrangements (Scheme 177).714 In the first, allylic alcohol 177-1 was converted to carbamate 177-2 in 85% overall yield using a four-step protocol. At a later stage, advanced cyclic intermediate 177-3 was elaborated to carbamate 177-4 in 95% overall yield after four steps under similar conditions. In the synthesis of (+)-manzamine A, the Fukuyama group employed Ichikawa rearrangement as a key step to introduce the nitrogen functionality at a congested position (Scheme 178).715 Advanced intermediate 178-1 was dehy-

afford isothiocyanate 179-3 in 96% yield with a 5.6:1 diastereomeric ratio. In contrast, Overman rearrangement of imidate 179-4 gave the corresponding amide 179-5 in 81% yield with a nearly 1:1 diastereomeric ratio. 9.2. [1,2]- and [2,3]-Sigmatropic Rearrangements (Figure 35)

In addition to the widely used [3,3]-sigmatropic rearrangement, [1,2]- and [2,3]-sigmatropic rearrangements of quaternary

Scheme 178

Figure 35.

ammonium salts have also been employed to assemble stereogenic C−N bonds in complex molecule synthesis.718 In 2005, Myers and co-workers reported a convergent synthesis of (−)-tetracycline and its analogues from the common intermediate 180-4 (Scheme 180).719,720 Starting Scheme 180

drated with trifluoroacetic anhydride and triethylamine to afford the allylic cyanate, which spontaneously underwent rearrangement at 0 °C to provide the isocyanate with complete control of the stereoselectivity. The resultant isocyanate was converted to imine 178-2 under optimized conditions (HOAc, magnesium perchlorate, 4 Å molecular sieves (MS)). Subsequent stereoselective reduction and amide formation gave amide 178-3 in 80% overall yield. The same group employed a similar strategy based on Ichikawa rearrangement as a key step to install the C−N bond in the synthesis of lysergic acid.716 Martinková and co-workers reported an enantioselective synthesis of (−)-jaspine B from D-xylose (Scheme 179).717 The synthesis was designed with a [3,3]-heterosigmatropic rearrangement of allylic thiocyanate to isothiocyanate as a key feature. Allylic thiocyanate 179-2, prepared by substitution from 179-1, underwent a thermal rearrangement (heptane, 90 °C) to

from epoxide 180-1, amine 180-4 was prepared in 62% yield by treatment with lithium triflate and subsequent selective desilylation. The authors indicated that this stereoselective transformation began with an intramolecular SN′ attack of the amine on the allylic epoxide followed by ammonium ylide formation and [2,3]-sigmatropic rearrangement. In the formal synthesis of (±)-amathaspiramide F, Soheili and Tambar developed a tandem palladium-catalyzed allylic 4521


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route to the synthesis of platynecine (Scheme 182b).723 Using a Ru−porphyrin catalyst, diazo ketone 182-5 was converted to 3-pyrrolidinone 182-7 in 85% yield and 71% dr.

Scheme 181

10. C−N BOND FORMATION BY REACTIONS OF ENOLATES In the context of total synthesis applications since 2000, there have been two principal variants of stereoselective C−N formation with enolate intermediates: (1) aldol or aza-aldol reactions, in some cases with enolates derived from α-amino esters, and (2) alkylation of enolates generated from α-amino esters. Other, less general approaches for C−N construction based on enolate chemistry are also reviewed in this section. 10.1. Aldol and Aza-Aldol Reactions (Figure 36)

As one of the most important transformations in organic synthesis, asymmetric aldol reactions provide a rapid access to

amination/[2,3]-Stevens rearrangement to install the tertalkylamine moiety of the alkaloid (Scheme 181).721 The palladium-catalyzed reaction of enantiopure amino ester 181-1 and allyl carbonate 181-2 afforded tert-alkylamine 181-5 in 70% yield as a 3.5:1 mixture of diastereomers. The authors proposed that the exo transition state 181-3 was favored to minimize the steric interaction between the aryl and the tert-butyl ester groups. Interestingly, the endo transition state is preferred with the ortho-substituted aryl group in the substrate. Although transition-metal-catalyzed sigmatropic rearrangements of ammonium ylides were employed in the alkaloid synthesis, the diastereoselectivity of these reactions was moderate. The West group completed the syntheses of racemic turnedorcidine and platynecine based on [1,2]-Stevens-type rearrangement (Scheme 182a). Treatment of azetidine 182-1 Scheme 182 Figure 36.

up to two stereogenic carbon−carbon bonds. In this subsection, recent examples utilizing the diastereoselective aldol reaction that result in stereoselective C−N bond formation in total synthesis will be compiled. Herein, the stereochemistry of the aldol reaction was controlled by the chirality of the aldehyde, the enol substrate, or a chiral auxiliary. In the synthesis of 1-deoxy-7,8-di-epi-castanospermine, an asymmetric vinylogous Mukaiyama aldol reaction was exploited to construct vicinal C−N and C−O bonds (Scheme 183). The reaction of pyrrole derivative 183-1 and 2,3-O-isopropylideneD-glyceraldehyde (183-2) in the presence of tin tetrachloride provided lactam 183-3 as a single isomer in 80% yield.724 The lactam was advanced to complete the synthesis in 10 additional steps. A similar diastereoselective aldol reaction of aldehyde 183-2 and a hydantoin derivative was adopted in the synthesis of D-ribo-configured ureido sugars.725 In 2011, the Hanessian group reported the first total synthesis of pactamycin, the most densely functionalized naturally occurring aminocyclopentitol, utilizing a chiral enolate

with catalytic Cu(acac)2 afforded a mixture of diastereomers 182-3 and 182-4 in 82% yield with a 3.6:1 diastereomeric ratio.722 A ruthenium-catalyzed tandem ammonium ylide formation/[2,3]-sigmatropic rearrangement was studied en 4522


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Scheme 183

Scheme 186

Scheme 184

the titanium enolate derived from ethyl (+)-(1R,2R,5R)-2hydroxypinan-3-iminoglycinate (186-1) was coupled with aldehyde 186-2, affording anti-aldol product 186-3 in 75% yield and 94% de. Subsequently, the auxiliary was cleanly removed under acidic conditions to provide amino ester 186-4 in quantitative yield. Xu and co-workers utilized an asymmetric aldol reaction as a key step to introduce the requisite stereogenic centers in the synthesis of sphingofungin F (Scheme 187a).731 Treatment of oxazinone 187-1 with KN(SiMe3)2 followed by sequential addition of BF3·Et2O and aldehyde 187-2 resulted in the aldol product 187-3 in 65% yield with a 3:1 diastereomeric ratio. Subsequent exposure of 187-3 to aqueous hydrochloric acid led to the release of the chiral auxiliary and lactone formation. The lactone was further hydrolyzed to the natural product sphingofungin F. In the synthesis of (+)-castanospermine, the Huang group employed a highly diastereoselective vinylogous Mukaiyamatype aldol reaction to install the stereogenic C−N and C−O bonds (Scheme 187b).732 Enolization of pyrrolinone 187-5 bearing a prolinol substituent with LDA and trapping the lithium enolate with Me3SiCl generated the silyl enol ether, which reacted with aldehyde 187-6 in the presence of tin tetrachloride to furnish adduct 187-8 in 65% yield with 99% de. The stereochemical outcome of the aldol reaction was explained by transition state 187-7 as shown in Scheme 187. The auxiliary was subsequently removed under acidic conditions to give the corresponding ketone, which was reduced under Luche conditions before completion of the synthesis of (+)-castanospermine. A novel copper-catalyzed aldol reaction of an α-isocyano amide bearing (R)-camphorsultam as the chiral auxiliary was developed en route to the synthesis of manzacidin B (Scheme 187c).733 The aldol reaction of aldehyde 187-10 and amide 187-11 catalyzed by Cu(t-ButSal)2 and triethylamine gave syn product 187-12 in 84% yield with a 13:1 diastereomeric ratio. The camphorsultam group was smoothly removed with lithium hydroxide in high yield.

in the diastereoselective aldol reaction at the early stage of the synthesis (Scheme 184a).726,727 Deprotonation of oxazoline 184-1 with LiN(SiMe3)2, followed by condensation with enal 184-2 and O-silylation of the product with (TES)OTf (TES = triethylsilyl), afforded 184-3 as a single diastereomer in 67% combined yield. The stereochemical outcome of this aldol reaction was rationalized by a Zimmerman−Traxler chairlike transition-state model. In the synthesis of (−)-kaitocephalin, installation of a stereogenic tetrasubstituted carbon center bearing a nitrogen substituent was required (Scheme 184b).728 To this end, the diastereoselective aldol reaction of proline ester 184-4 and (R)-serine-derived aldehyde 184-5 mediated by LDA provided 184-6 in 69% yield. In 2006, Danishefsky and Lambert reported the concise synthesis of UCS1025A, a unique alkaloid possessing antiproliferative activity against human cancer cell lines.729 The synthesis featured a desymmetrization of C2 symmetric imide 185-1 via the methyl ester silyl enolate (Scheme 185). Scheme 185

10.2. Alkylation of α-Amino Acid Derivatives (Figure 37)

The diastereoselective alkylation reaction of α-amino acid derivatives offers a straightforward solution to the problem of stereoselective C−N bond construction. In this subsection, examples of the chiral-auxiliary-directed alkylation will be discussed first, followed by substrate-controlled reactions. In the synthesis of the teicoplanin aglycon, the Boger group utilized the Schöllkopf alkylation via the copper amide734 to construct the desired amino ester subunit (Scheme 188a).735 The bis(imidate) 188-2 was lithiated with n-BuLi and treated

Under soft enolization conditions ((TBS)OTf, NEt3), imide 185-1 underwent intramolecular cyclization, resulting in azabicyclo[3.3]octan-2-one 185-2 as a 10:1 mixture of diastereomers in 79% yield. The chiral auxiliary approach has also been used to direct the stereochemical outcome of the aldol reaction for the construction of C−N bonds. In 2004, the Boger group completed a highly divergent total synthesis of the ristocetin aglycon (Scheme 186).730 At the early stage of the synthesis, 4523


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Scheme 187

Scheme 188

an alternative approach to build the requisite chiral C−N bond in the synthesis of (−)-aphanorphine (Scheme 188b).736 In addition, at an early stage of the syntheses of (−)-jorumycin and (−)-renieramycin G, the Williams group utilized an asymmetric alkylation of a chiral oxazinone, which served as a glycine template, with a benzylic iodide to furnish the requisite α-amino acid derivative with high stereocontrol.737 Among methods for stereoselective alkylation of amino acids, the stereoselective alkylation of proline derivatives is another common operation in the synthesis of alkaloids. In 2000, the Williams group reported the asymmetric total synthesis of paraherquamide A, a potent anthelmintic agent isolated from varoius Penicilium species (Scheme 189a).738,739 The synthesis featured stereocontrolled intermolecular and intramolecular alkylations to furnish the two requisite tetrasubstituted centers. Alkylation of the dianion derived from amino ester 189-1 with allylic iodide 189-2 provided the product 189-3 in good yield (58−70%). Notably, for reasons unclear, the amount of HMPA required for this reaction was variable for every batch of 189-1. At the late stage of synthesis, advanced intermediate 189-4 used as a mixture of isomers was treated with sodium hydride in THF to afford the bicyclo[2.2.2]diazaoctane product 189-6 in 50−87% yield. The authors proposed that this intramolecular SN2′ cyclization proceeded via a tight ion pair intermediate as shown in Scheme 189a. In 2007, the Williams group reported the asymmetric total synthesis of the fungal metabolites (−)-stephacidin A, (+)-stephacidin B, and (+)-notamide B, characterized by two related stereocontrolled alkylations to install two tetrasubstituted carbon centers (Scheme 189b).740 The synthesis commenced with a gram-scale asymmetric allylation of a proline derivative. The allylation of commercially available trichloro oxazolinone 189-7 using LDA afforded the product as a single diastereomer. Sequential hydrolysis and esterification provided 189-8 in 77% yield over two steps on a 20 g scale. At a later stage, the bicyclo[2.2.2]diazaoctane 18910 was prepared as a single diastereomer upon treatment of advanced intermediate 189-9 with sodium hydride. Of note, this reaction was conducted in a sealed tube at 130 °C for 9 h with benzene as the solvent. The authors attributed the higher rate of the reaction to a pressure factor compared with the normal thermal conditions (NaH, THF, reflux, 30 h). A similar “self-replication of chirality” strategy in the intermolecular enolate alkylation was applied in the total synthesis of (−)-conagenin as well.741

Figure 37.

with copper(I) cyanide to afford the corresponding copper amide, which reacted with benzylic bromide 188-1 to provide amino ester 188-3 in 70% overall yield after acidic hydrolysis. A highly diastereoselective Myers alkylation of N-methylglycine derivative 188-4 with benzylic bromide 188-5 was exploited as

10.3. Miscellaneous Reactions (Figure 38)

In 2005, Endo and Danishefsky completed the total synthesis of salinosporamide A, a very potent cytotoxin found in bacteria 4524


Chemical Reviews

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Scheme 189

Scheme 190

system (Scheme 190b).743 Advanced intermediate 190-3 was treated with LDA, and the resulting anion was oxidized with Fe(acac)3 to provide 190-5 as a single diastereomer on a gram scale in 61% yield. To rationalize the observed excellent stereocontrol in the oxidative coupling, the authors proposed a chelated transition state, consistent with Williams’s hypothesis advanced during the synthesis of paraherquamide A (vide supra).738,739 In 2011, the Nicolaou group completed an enantioselective total synthesis of epicoccin G (Scheme 191), which was Scheme 191

isolated from the endophytic fungus Epicoccum nigrum and exhibited anti-HIV activity in C8166 cells (IC50 = 13.5 μM).744 To achieve the direct two-directional sulfenylation of diketopiperazine 191-1, the classical approach employing enolization of the diketopiperazine substrate and addition of S8 to the enolate failed. Upon an extensive study, the authors found that addition of a mixture of 191-1 and 2 equiv of NaN(SiMe3)2 to a freshly prepared solution of S8 with another 3 equiv of NaN(SiMe3)2 at ambient temperature provided a mixture of oligosulfenylated compounds 191-2. Reduction and subsequent methylation gave bis(methyldithiodiketopiperazine) 191-3 in 58% overall yield with a 1.4:1 diastereoselectivity. Analysis of the crude mixture of NaN(SiMe3)2 and S8 exhibited the mass spectrometric signature consistent with (Me3Si)2N−(S)3−5−N(SiMe3)2 generated by nucleophlic ring

Figure 38.

from ocean sediment, featuring an intramolecualr acylation to install a stereogenic tetrasubstituted carbon center.742 Treatment of lactam 190-1 with Meerwein reagent Et3O·BF4 gave the corresponding imidate, which provided lactone 190-2 as a single isomer in 72% overall yield upon exposure to LiN(SiMe3)2 (Scheme 190a). In the enantioselective syntheses of (−)-stephacidin A, (+)-stephacidin B, and (+)-avrainvillamide, the Baran group utilized an intramolecular oxidative coupling to furnish the requisite bicyclo[2.2.2]diazaoctane ring 4525


Chemical Reviews

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opening of the eight-membered cyclic S8 with hexamethyldisilazide.745 In the synthesis of microcin SF608, the Carreira group utilized an efficient azidation reaction to install the stereogenic C−N bond (Scheme 192).746 Upon treatment with

Scheme 193

Scheme 192

and (+)-astrophylline749 from readily available, enantiomerically pure (+)-(1R,4S)-4-hydroxycyclopent-2-enyl acetate to introduce the stereogenic carbon−nitrogen bond. In 2011, the Comins group reported a stereoselective and protecting-group-free synthesis of (−)-205B employing a diastereoselective Tsuji−Trost allylic amination to install the key pyrrolidine ring (Scheme 194a).750 Under the catalysis with LiN(SiMe3)2, azidation of lactone 192-1 with trisyl azide (192-2) afforded a mixture of diastereomeric azidolactones 192-3 in 58% yield (1.2:1 dr). Subsequent lactone opening, reduction, and amide formation led to α-amino amide 192-5 in 83% overall yield.

Scheme 194

11. DIASTEREOSELECTIVE METAL-CATALYZED ALLYLIC N-ALKYLATION (FIGURE 39) A few applications of diastereoselective catalytic allylic amination in the total synthesis of alkaloids have been reported.

[Pd2(dba)3]·CHCl3 and t-Bu3P, intramolecular amination of 194-1 afforded pyrrolidine 194-2 in 80% yield and 95% de. Notably, the bulky phosphine ligand and a mild base (Cs2CO3) were crucial for this transformation. Replacement of the bulky ligand with n-Bu3P gave a mixture of diastereomers (dr 1:1.5), and a switch from Cs2CO3 to a stronger base led to substantial decomposition. In the synthesis of (+)-dienomycin C, Hirai and co-workers utilized a direct palladium-catalyzed intramolecular amination of an allylic alcohol to furnish the requisite piperidine skeleton (Scheme 194b).751 Treatment of 194-3 with PdCl2(CH3CN)2 afforded piperidine 194-5 as a single isomer in 82% yield. It was postulated that the stereochemical outcome was controlled through the chair transition state 194-4 to minimize steric repulsion between the carbamate and the π-allyloxy−palladium complex. In 2007, Evans and co-workers accomplished the enantioselective total synthesis of the polycyclic guanidine-containing marine alkaloid (−)-batzelladine D, featuring a stereospecific rhodium-catalyzed allylic amination (Scheme 195).752 The reaction of the lithium anion generated from 195-1, bearing a (1S)-(+)-10-camphorsulfonyl group as a chiral auxiliary, with cyclic carbonate 195-2 in the presence of a rhodium catalyst

Figure 39.

In the convergent syntheses of (+)-aristeromycin and (+)-carbovir, Brown and Hegedus performed a palladiumcatalyzed allylic N-alkylation of a cyclopentenol derivative to assemble the required structure (Scheme 193a).747 Amination of allylic carbonate 193-1 with adenine (193-2) in the presence of Pd(PPh3)4 provided the product 193-3 in 65% yield together with a 19% yield of the N7-regioisomer. Further elaborations led to the completion of the synthesis of (+)-aristeromycin. The same strategy was applied to synthesize (+)-carbovir using 2-amino-6-chloropurine (193-4) as the amination reagent (Scheme 193b). In addition, the Blechert group employed a closely related approach in the syntheses of (+)-dumetorine748 4526


Chemical Reviews

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Scheme 195

Scheme 196

structural complexity of amide 196-1. In addition, the rhodiumcatalyzed oxidative insertion of a carbamate nitrogen to form an oxazolidinone was employed at a late stage of the syntheses of methyl-L-callipeltose757 and pachastrissamine.758 In 2012, Hatakeyama and co-workers accomplished the total synthesis of (−)-kaitocephalin, an ionotropic glutamate receptor antagonist, employing rhodium-catalyzed benzylic C−H and allylic C−H amination reactions as the key steps (Scheme 197).759 Cyclic sulfamate 197-2 was prepared by a

furnished intermediate 195-3 in 84% yield with excellent regioand diastereoselectivity.

Scheme 197

12. DIASTEREOSELECTIVE C−H INSERTION REACTIONS (FIGURE 40) In the past decade, C−H functionalization has been an area of focused growth. This section will catalog applications of distereoslective C−H insertion reactions to install stereogenic C−N bonds in complex molecule synthesis.753,754 Perhaps not surprisingly, catalytic C−H functionalization by insertion of nitrenoid intermediates was the most used method in total synthesis, according to our literature review, followed by substrate-controlled C−H insertion reactions of in-situgenerated carbenes into α-C−H bonds of amines. The palladium-catalyzed C−H activation reaction is emerging as an alternative method for building stereogenic C−N bonds in organic synthesis. The Du Bois group has developed a chemoselective and diastereoselective nitrogen atom transfer methodology using transition-metal (rhodium or ruthenium) catalysis.755 In 2003, Du Bois and Hinman reported the asymmetric synthesis of (−)-tetrodoxin to showcase the power of C−H amination to assemble complex molecular structures (Scheme 196).756 At a late stage of the synthesis, advanced intermediate 196-1 was converted to oxazolidinone 196-2 in 77% yield under optimized conditions (10 mol % Rh2(NHCOCF3)4 and PhI(OAc)2). This transformation was remarkable, given the

diastereoselective rhodium-catalyzed C−H amination of sulfamate 197-1 in 74% yield using 2 mol % Rh2(OAc)4, PhI(OAc)2, and MgO. A three-step transformation led to carbamate 197-3, which underwent the allylic C−H amination to afford cyclic carbamate 197-4 in 86% yield upon treatment with 10 mol % Rh2(esp)2. A similar strategy using rhodiumcatalyzed nitrene C−H insertion of a sulfamate as a key step was applied in the total synthesis of (−)-muraymycin D2.760 Garg and co-workers employed C−H amination to install a quaternary center at a late stage in the synthesis of several

Figure 40. 4527


Chemical Reviews

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five-membered carbo- and heterocycles. In the synthesis of (−)-agelastatin A, the Feldman group exploited a stereospecific 1,5-insertion reaction of an alkylidenecarbene generated from an alkynyliodonium salt to assemble the bicyclic scaffold (Scheme 199a).764,765 Treatment of alkynylstannane 199-1

members of the welwitindolinone family of alkaloids possessing a common bicyclo[4.3.1]decane ring system within a densely functionalized tetracyclic scaffold (Scheme 198).761−763 In the Scheme 198

Scheme 199

first-generation synthesis of (−)-N-methylwelwitindolinone C isothiocyanate, advanced intermediate 198-1 was reduced with i-Bu2AlH followed by carbamate installation to provide 198-2 in 86% yield over two steps.761 A silver-catalyzed nitrene insertion reaction with 198-2 took place to deliver the requisite oxazolidinone 198-3 in 33% yield, together with a 25% yield of recovered ketone 198-1. It is assumed that regioisomeric 1,3oxazetidin-2-one 198-3 was formed during the nitrene insertion step, which subsequently fragmented to the starting ketone 198-1. Of note, the rhodium-catalyzed reaction of 198-1 gave only the recovered starting material. In the second-generation synthesis, the Garg group cleverly utilized the deuterium kinetic isotope effect to overcome the undesired regioselectivity in the nitrene insertion step.762 Deuterated substrate 198-5 was prepared by a two-step sequence involving reduction with LiBDEt3 and subsequent carbamoylation. Remarkably, under the same conditions, the silver-catalyzed reaction of 198-5 gave 198-6 in 60% yield, and ketone 198-1 was recovered in 8% yield. Both carbamates 198-4 and 198-6 could be converted to the same amino ketone after hydrolysis and oxidation of the secondary alcohol. Further elaboration led to completion of the synthesis of several welwitindolinone natural products, including N-methylwelwitindolinone C isothiocyanate, N-methylwelwitindolinone C isonitrile, C3-hydroxy-N-methylwelwitindolinone C isothiocyanate, and C3-hydroxy-N-methylwelwitindolinone C isonitrile.762 The silver-catalyzed nitrene insertion reaction for conversion of a carbamate to oxazolidinone was also employed in the synthesis of N-methylwelwitindolinone D isonitrile.763 The C−H insertion reaction of alkylidenecarbenes has been used as an efficient strategy for the construction of

with Stang’s reagent (PhI(CN)OTf) at −42 °C provided alkynyliodonium salt 199-2, which after conjugate addition of TolSO2Na afforded carbene intermediate 199-3. Subsequent 1,5-insertion reaction furnished cyclopentene 199-5 as a single diastereomer in 34% yield, along with a 41% yield of a carbine 1,2-rearrangement product, alkyne 199-4. In 2006, the Hayes group reported the enantioselective total synthesis of (−)-omuralide and its C7-epimer featuring an alkylidene 1,5C−H insertion as a key step to install the 3-pyrroline motif (Scheme 199b).766 Exposure of vinyl bromide 199-6 to KN(SiMe3)2 gave the alkylidenecarbene, which underwent a smooth C−H insertion to furnish azaspirocycle 199-8 in 83% yield, along with alkyne 199-7 in 13% yield. In addition, in the formal synthesis of (−)-cephalotaxine, Hayes and co-workers utilized a 1,5-C−H insertion reaction of a carbene to establish the requisite tetrasubstituted stereocenter (Scheme 199c).767 Peterson-type alkenation of ketone 199-9 with Me3SiCLiN2 afforded 1-diazoalkene 199-10, which rapidly fragmented to alkylidenecarbene 199-11. Facile 1,5-C−H insertion of the carbene afforded spirocyclic product 199-12 in 74% yield. 4528


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In 2009, White and co-workers completed an enantioslective total synthesis of (+)-allosedridine to showcase a method of the preparation of syn-1,3-amino alcohols via a palladium-catalyzed allylic C−H amination (Scheme 200).768 Commencing with

Scheme 201

Scheme 200

commercially available enantiopure alcohol 200-1, addition of 4-nitrobenzenesulfonyl isocyanate afforded carbamate 200-2. Allylic C−H amination in the presence of palladium catalyst provided oxazinone 200-3 in 79% yield and 81% dr. The syn diastereomer 200-3, after separation by flash column chromatography, was advanced to complete the synthesis of (+)-allosedridine in a few steps.

diastereoselectivity (dr 33:1). Subsequent reduction with LiAlH4 gave (−)-hygroline in 90% yield. In 2014, Wang and co-workers utilized the aldol reaction of the chiral organolithium reagent with an aldehyde to couple the pyrrolidine with phenanthrene moieties in the synthesis of two typical phenanthroindolizidine alkaloids, 14-hydroxyantofine and antofine (Scheme 201b).771 Upon treatment with (+)-sparteine and s-BuLi, addition of N-Boc-pyrrolidine to aldehyde 201-4 gave amino alcohol derivative 201-5 in 87% yield and 96−97% ee as a 2.3:1 mixture of diastereomers. In the synthesis of (+)-elaeokanine A, the Dieter group exploited the coupling reaction of α-(N-carbamoyl)alkylcuprate generated from N-Boc-pyrrolidine with iodoalkene 202-2 to introduce the requisite stereogenic C−N bond (Scheme 202a).772

13. METHODS BASED ON CHIRAL ORGANOMETALLIC REAGENTS (FIGURE 41) Enantioenriched organometallic reagents with a general formal structure of M−C−N provide another powerful platform for

Scheme 202

Figure 41.

the stereoselective synthesis of nitrogen-containing natural products. In this section, examples of this approach in natural product synthesis are presented. Applications fall into two general categories: (1) asymmetric metalation of prochiral amine derivatives using chiral enantiopure reagents and 2) metalation of enantioenriched substrates, typically with simple achiral organolithium reagents. Enantioselective α-lithiation of N-Boc-pyrrolidine with the s-BuLi/sparteine reagent system pioneered by Beak769 offers a reliable access to the enantioenriched 2-lithio-N-Boc-pyrrolidine/sparteine aggregate. In a two-step synthesis of all four diastereomeric hygrolines, Altmann and co-workers utilized a direct epoxide-opening reaction with the 2-lithio-N-Bocpyrrolidine rea gent to build the requisite amino alcohol motif.770 In the synthesis of (−)-hygroline (Scheme 201a), the chiral organolithium reagent, generated from (+)-sparteine surrogate-mediated lithiation of N-Boc-pyrrolidine 201-1, was treated with (S)-propylene oxide in the presence of BF3·Et2O to give alcohol 201-3 in 49% yield with excellent

After an extensive study, the authors found that mixed cuprates containing sterically hindered nontransferable ligands were critical for successful coupling reaction with the iodoalkene. (2-Methyl-2-phenylpropyl)lithium was added to a solution of the chiral lithium reagent in Et2O, followed by addition of n-Bu3P·CuCN to generate the dilithium dialkylcyanocuprate, which underwent a smooth coupling reaction with iodoalkene 202-2, resulting in the formation of 202-3 in 45% yield and 90% ee. In 2011, O’Brien and co-workers reported the concise syntheses of (R)-crispine A, (S)-nicotine, (S)-SIB-1508Y, and (R)-maackiamine using the asymmetric lithiation−transmetalation−Negishi coupling strategy.773 In the case of (R)-maackiamine, (−)-sparteine-mediated lithiation of N-Boc-pyrrolidine 4529


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Treatment of 204-4 with Freeman’s reagent (lithium 4,4′-ditert-butylbiphenylide, LiDBB) produced the cyclic product 2048 as a single isomer in 81% yield. The authors presumed that the cyclization takes place via an SEinv pathway involving lithium intermediate 204-7 stabilized by Li chelation to the Boc group.

followed by transmetalation with ZnCl2 and Negishi coupling with bromoalkene 202-4 afforded substituted pyrrolidine 202-5 in 56% yield and 90% ee (Scheme 202b). Chemoselective removal of the Boc group under mild electrophilic conditions furnished (R)-maackiamine in 54% overall yield with no loss of enantioselectivity. In 2014, Snyder and co-workers reported the concise unified syntheses of ten alkaloids from the coccinellid family, including eight monomers and two dimeric members, from a common intermediate.774 The syntheses commenced with silylation of commercially available piperidine 203-1 followed by diasteroeselective deprotonation with s-BuLi, transmetalation with copper cyanide, and allyllation of the resulting cuprate with 203-3 to afford the trans product 203-5 in 84% overall yield (Scheme 203). Further elaborations led to completion of eight

14. DESYMMETRIZATION REACTIONS (FIGURE 42) A literature search provided four examples utilizing desymmetrization to introduce stereogenic C−N bonds during the

Scheme 203

Figure 42.

synthesis of nitrogen-containing natural products. In the synthesis of salinosporamide A, an enzymatic desymmetrization of 1,3-diol 205-1 using the lipase from Pseudomonas sp. and vinyl acetate was used to introduce a chiral tertiary amine (Scheme 205). monomeric members of the coccinellid family. Meanwhile, allylation of the cuprate with allyl bromide gave the trans product 203-4 in 91% combined yield. Starting form piperidines 203-4 and 203-5, the dimeric member psylloborine A was completed through an intriguing sequence of two cascade reactions (vide infra). In the synthesis of lepadiformines A−C, alkaloids isolated from the marine tunicates Clavelina lepadiformis and Clavelina moluccensis, the Rychnovsky group exploited a reductive cyclization of an α-heteronitrile as a key step to construct the spirocyclic framework (Scheme 204).775,776 Double alkylation

Scheme 205

Subsequent silylation of the remaining hydroxy group afforded intermediate 205-2 in 94% yield and 97% ee.777 The use of chiral lithium amides for enolization of prochiral cyclic ketones provided another strategy for introduction of the stereogenic C−N bond in the synthesis of (−)-epibatidine (Scheme 206). In 2005, the Aggarwal group described an

Scheme 204

Scheme 206

enantioselective α-arylation of N,N-di-Boc-4-aminocyclohexanone. Its asymmetric enolization with lithium (R,R)-bis(1phenylethyl)amine followed by treatment with diaryliodonium salt 206-2 afforded the arylation product 206-3 in 41% yield and an impressive 94% ee.778 This product was advanced to complete a short synthesis of (−)-epibatidine. The Hatakeyama group utilized a desymmetrization by dihydroxylation/lactonization to install three contiguous stereogenic carbon centers, including one tetrasubstituted carbon center in the syntheses of neoxazolomycin779 and oxazolomycin A (Scheme 207).780 Substrate-controlled dihydroxylation of

of α-aminonitrile 204-2 with dibromide 204-1 using LDA in a mixture of DMPU−THF gave piperidine 204-3 in 82% yield. Of note, addition of LDA at −78 °C and warming the reaction mixture to 0 °C were critical for the high yield in this transformation. A subsequent two-step sequence led to nitrile 204-4, which set the stage for the reductive cyclization. 4530


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Scheme 207

Scheme 208

alkene 207-1 with OsO4, followed by lactone formation, led to synthesis intermediate 207-2 in quantitative yield. This central synthesis intermediate was diverted to complete the synthesis of both natural products.

15. MISCELLANEOUS METHODS There are a number of creative strategies for the construction of C−N bonds in total synthesis that either belong to a smaller group of examples or are not easily categorized into the aforementioned groups, and thus will be described in this section. 15.1. Electrocyclizations

Electrocyclizations constitute a powerful yet underexplored method for the asymmetric C−N bond formation in the synthesis of alkaloids. Agelastatin A, a popular synthesis target already mentioned on several occasions in this review, has been prepared by a Nazarov-type [4π] electrocyclization of zwitterionic intermediate 208-3 formed by condensation of 2 equiv of diallylamine and furfuraldehyde as shown in Scheme 208a.781 Conrotatory electrocyclization catalyzed by dysprosium triflate affords trans-1,2-diaminocyclopentenone 208-4, an early intermediate in the synthesis of (±)-agelastatin A, in 82% yield (dr >95:5). The group of Katsumura utilized diastereoselective aza-[6π]-electrocyclizations directed by aminoindanol derivatives in the synthesis of several alkaloids, namely, Rubiaceae alkaloid (−)-corynantheidol,782 Strychnostype alkaloid (−)-20-epiuleine,783 and (−)-hippodamine, an azaphenalene alkaloid isolated from ladybird beetles.784 In the latter application (Scheme 208b), the aza 6π system 208-8 was constructed in situ by a three-component cross-coupling of alkenylstannane 208-7, iodoaldehyde 208-6, and aminoindanol 208-5, which donates the nitrogen atom. Upon heating in DMF at 80 °C, the final product 208-10 forms in situ within 20 min in 81% yield as a single stereoisomer. The electron-withdrawing ethoxycarbonyl group at C4 was demonstrated to be critical for the success of the electrocyclization reaction. The resulting substituted piperidine is advanced to (−)-hippodamine.

cyclization of acetamide 209-3, which took place in 88% yield and 2.5:1 diastereoselectivity favoring the natural M atropisomer (Scheme 209).785 The natural product itself was Scheme 209

15.2. Atroposelective Reactions

Ancistrocladiniums A and B are naphthylisoquinoline plant alkaloids from the Acistrocladaceae and Dioncophylaceae genera that possess a rare rotationally hindered stereogenic N,C-axis. While ancistrocladinium A is configurationally stable, atropisomers of ancistrocladinium B slowly interconvert at room temperature. Ancistrocladinium A in the form of its trifluoroacetate salt was prepared by Bischler−Napieralski

isolated as a 10:1 mixture of M and P diastereomers. Murrastifoline F is another example of an axially chiral, configurationally stable alkaloid with an N,C-axis, which is the 4531


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(Scheme 211a). After systematic screening of different Brønsted and Lewis acids, cyclization of acetal 211-1 with Nd(OTf)3 produced spirocyclic hemiaminal 211-2 in 81% yield. In 2006, the Evans group also reported the total synthesis of azaspiracid-1. In that synthesis, a structurally similar cyclic hemiacetal comprising an azido group spontaneously cyclized upon hydrogenolysis with Pd/C, producing the thermodynamically favored HI-spiroaminal as a single diastereomer.798 In 2012, Trauner and co-workers disclosed the total synthesis of herbicidin C and aureonuclemycin, important natural products belonging to the class of undecose nucleoside antibiotics isolated from different strains of Streptomyces.799 A late-stage glycosylation of the unusual carbohydrate 211-3 was performed using Me3SiOTf to generate the oxonium cation that reacted with adenine, producing key glucoside intermediate 211-4 in 55% yield (Scheme 211b). The stereochemistry of glycosylation was controlled by the position of the benzoate group at C2. In 2013, the Overman group reported the total synthesis of Lycopodium alkaloid sieboldine A using macrocyclization with stereoselective hemiaminal formation (Scheme 211c).800 After an extensive search for reagents to generate the oxonium cation from thioglycoside 211-5, it was found that application of dimethyl(methylthio)sulfonium triflate (DMTST) with 2,6-di-tert-butyl-4-methylpyridine (DTBMP) at −20 °C afforded advanced cyclic N-hydroxyhemiaminal 211-6 in 51% yield. Kan et al. recently accomplished the total synthesis of the antitumor antibiotic UCS1025A, an alkaloid from Acremonium sp. KY4917, using an interesting strategy for the installation of the chiral hemiaminal group (Scheme 212).801 The hydroxy group of macrolactam 212-1 was initially oxidized, which prompted a spontaneous transannular cyclization to give bicyclic aminal 212-2 as a 1:1 mixture of diastereomers after protecting group exchange. However, the diastereomer ratio was improved after treatment of 212-2 with CSA and an alcohol in toluene, producing hemiaminal 212-4 as a single diatereomer. The observed stereochemistry was rationalized by kinetic control through the formation of cyclic N-acyliminium intermediate 212-3 stabilized by anchimeric assitance with the carbonyl oxygen of the benzoate, forcing the alcohol to attack from the less hindered β-face. Interestingly, when a similar tertbutyldiphenylsilyl (TBDPS) ether was submitted to the same conditions instead of the benzoate, the diastereomer with the opposite configuration was produced exclusively. The synthesis of a series of Lycopodonium alkaloids containing a chiral hemiaminal moiety by a late-stage diastereoselective addition of amines to ketones was recently reported. For example, Lei and co-workers described an interesting tautomer-locking strategy for the preparation of lycojapodine A and four other alkaloids (Scheme 213a).802 Removal of acetonide and tert-butyl carbamate in intermediate 213-1 provided carbinolammonium trifluoroacetate 213-2 in quantitative yield. Importantly, the protonated aminocarbinol serves as a lock for the amino group, thereby precluding its interference with the subsequent oxidative cleavage of the diol with 2-iodoxybenzoic acid (IBX). Indeed, when 213-2 was then treated with IBX in CF3CO2H, diol cleavage and lactonization furnished lycojapodine A in 54% yield. Another lycojapodine A synthesis was also reported by Tu and Wang using a similar strategy.803 An example of late-stage aminocarbenol formation was disclosed by Takayama and co-workers during the course of the total synthesis of hyperzine Q (Scheme 213b).804 After cleavage of sulfonamide and acetate groups in tricyclic substrate

only stereogenic element in its structure. This unsymmetric biscarbazole alkaloid is isolated from plant species Murraya euchrestifolia and Murraya koenigii as a 56:44 mixture, showing a slight preference for the M enantiomer. The enantiomers can be separated and do not racemize at ambient temperature.786 No enantioselective synthesis of murrastifoline F has been reported.786,787 Angle and co-workers reported the total synthesis of indolizidine and pyrrolizidine alkaloids based on the method for the diastereoselective preparation of 3-hydroxyproline benzyl esters reported by the same group previously.788 The key proline intermediate was prepared as a single diastereomer by the reaction between protected α-hydroxy-β-aminoaldehyde 210-1 with benzyl diazoacetate in the presence of Lewis acid (BF3·Et2O) (Scheme 210). The transformation is believed to Scheme 210

proceed through the initial addition of the diazo ester to the aldehyde via a nucleophilic attack or [3 + 2] cycloaddition. Subsequent nucleophilic cyclization (pathway a) produced the desired intermediate, 210-3 in 65% yield along with ketone 210-2 in 24% yield, resulting from a [1,2]-hydrogen shift in intermediate 210-4 or 210-5 (pathway b).789 15.3. Formation of Aminals and Hemiaminals (Figure 43)

Stereogenic C−N bonds at a more oxidized carbon atom as a part of hemiamimal or aminal groups have been found in many complex natural products. Generally, these groups are embedded within polycyclic ring systems, and their formation requires the intermediacy of oxonium or iminium cations from appropriate ketones, acetals, or hemiaminals. Usually, these reactions are initiated by acidic reagents, and the stereochemistry is a result of thermodynamic control. Several procedures dealing with epimeric mixtures of acetals or hemiacetals as precursors for chiral hemiaminals have been described. For example, during the period from 2001 to 2006, Nicolaou and co-workers reported systematic studies directed at the synthesis of azaspiracid-1, a potent marine toxin isolated from the mussel Mytilus edulis in Killary Harbor, Ireland. This molecule represented an entirely new class of marine toxins unrelated to known diarrhetic shellfish poisoning. Its extremely complex structure along with low quantities isolated from nature resulted in an incorrect structural assignment, as was evidenced by chemical synthesis.790−794 Subsequent spectroscopic analysis of degradation products from the natural material enabled the authors to propose a corrected structure, which was corroborated by another total synthesis.795−797 The FHI ring system of azaspiacid-1 was assembled by Lewis acidcatalyzed spirocyclization for the installation of the I-ring 4532


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Figure 43.

resulting guanidine 214-3 was subjected to hemiaminal formation by treatment with CF3CO2H, giving rise to monanchorin trifluoroacetate. Another impressive example of preparation of chiral hemiaminals from ketones is the total synthesis of the heptacyclic marine alkaloid norzoanthamine, accomplished for the first time by Miyashita807,808 followed by a report by Kobayashi.809 This type of natural products was isolated from colonial zoanthids of the genus Zoanthus and attracted significant attention from the synthetic community because of promising biological profile for both osteoporosis and leukemia, but mostly due to an extremely complex molecular architecture (Scheme 215). Both groups used the same approach for installation of the hemiacetal groups of the natural product, starting from the corresponding ketones, which, upon exposure to acidic conditions, proceed to cyclization. In this manner, alkyne 215-1 was hydrogenated and then subjected to a tandem

213-3 with thiophenol, hemiaminal 213-4 was isolated in an excellent yield as a single diastereomer. The synthesis was completed by treatment of 213-4 with (+)-camphorsulfonic acid, providing the polycyclic natural product in 86% yield. Similarly, Zhao and co-workers completed the total synthesis of lycopladine D (Scheme 213c).805 After sequential double bond reduction and Ts group removal, the crude product was submitted to acid-mediated cyclization, giving the target molecule in good overall yield. In some cases, diastereoselective formation of cyclic hemiaminals can be achieved by a one-pot intramolecular cyclization between aldehyde, alcohol, and amine derivatives. This approach was recently illustrated by Hale and Wang in the synthesis of the potent antitumor guanidine alkaloid monanchorin.806 Key aldehyde 214-3 was prepared in several steps concluding with nucleophilic substitution of cyclic sulfate 214-1 with azide (Scheme 214). After further functionalization, the 4533


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Scheme 211

Scheme 212

Scheme 213

acetonide removal and cyclization, providing hemiaminal 215-2. This intermediate was transformed to triketone 215-3 suitable for the final cyclization. First, treatment of 215-3 with acetic acid gave iminium acetate 215-4, which was cyclized upon ester hydrolysis mediated by CF3CO2H in water, providing free norzoanthamine after treatment with basic Al2O3. Later, Miyashita and Tanino prepared zoanthenol, another alkaloid from the zoanthamine family.810 Several indole natural products comprising an aminal moiety have been synthesized in the past 15 years. In 2006, Kawasaki and co-workers reported the total synthesis of the brominated hexahydropyrrolo[2,3-b]indole alkaloids flustramines A and B and flustramides A and B (Scheme 216a).811 These natural products were isolated from the marine bryozoan Flustra foliacea, and some of them were shown to exhibit skeletal and smooth muscle relaxant activities, as well as blocking activity on a voltage-activated potassium channel. A late-stage assembly of the aminal unit was completed by treatment of 2-indolone 216-1 with the aluminum hydride/N,N-dimethylethylamine complex at −15 °C, producing flustramides A and B in excellent

Scheme 214

yields. Flustramines A and B were prepared using the same reagent at room temperature. The same chemistry was also reported by Nakazaki and Kobayashi for the synthesis of debromoflustramine B.812 An analogous reduction/cyclization pathway was applied by Weinreb and co-workers for the 4534


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Zhou and Jia recently accomplished the total synthesis of another indole alkaloid, goniomitine, isolated from the root bark of Gonioma malagasy (Scheme 216c).818 In this case, simultaneous reduction of azide and lactam groups in 216-5 mediated by LiAlH4 gave rise to a hemiaminal intermediate that was subsequently cyclized with acetic acid, producing the desired product in 60% yield. An elegant sequence for the construction of the core structure of the indole alkaloid scholarisine G was described by the Zhu group starting from the acyclic precursor 217-1 (Scheme 217).819 Upon reduction in the presence of acetic

Scheme 215

Scheme 217

construction of the lower aminal unit of communesin F, in which a regioselective partial reduction of the indolone group by the aluminum hydride/N,N-dimethylethylamine complex triggered cyclization to the hexahydropyrido[2,3-b]indole fragment (Scheme 216b).813,814 Similar chemistry was reported for the synthesis of perophoramidene815 and esermethole.816,817 Scheme 216

anhydride, 217-1 was converted to indolone 217-4, bearing an acetamido group on the side chain, thus precluding its condensation onto the oxindole. Next, the reaction mixture was purged with oxygen, producing unstable imine 217-3, which was trapped by sodium ethoxide to afford a mixture of diastereomeric hemiaminals 217-4 in a 2:1 ratio. Treatment of this mixture with CF3CO2H resulted in the initial generation of an N-acyliminium ion followed by intramolecular diastereoselective cyclization, producing tetracyclic product 217-6 in 73% yield. To complete the synthesis, the authors performed an intramolecular aldol reaction with t-BuOK that was quenched with acetic acid at −78 °C due to significant degradation observed using other common quenching reagents such as water, methanol, or NH4Cl. An analogous approach was employed by Overman and coworkers for the construction of epipolythiodioxopiperazine toxins gliocladine C820 (Scheme 218) and plectosphaeroic acid B,821 whereby indole hemiaminal 218-1 was treated with BF3· Scheme 218

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Et2O to form an N-acyliminium cation, which underwent intramolecular cyclization to pyrroloindole intermediate 218-2 in 80% yield. The acetal group may also serve as a convenient precursor to stereogenic aminals upon condensation with two different amide groups, as was demonstrated by Blaauw et al. during the total synthesis of dysibetaine PP (Scheme 219a).822

Scheme 220

Scheme 219

16. CONCLUSION Even recognizing the undeniably dramatic progress in the field of total synthesis of natural products over the past several decades, it was still astonishing to discover over 800 reports focused on completed synthesis of alkaloids with stereogenic C−N bonds since the turn of the century. The synthesis targets have varied in complexity from rather simple pyrrolidine or piperidine alkaloids to extremely complex, highly functionalized molecular structures. As became evident during the preparation of this review, and perhaps not surprisingly, the majority of applications rely on century-old chemistry, such as iminium ion interconversions (Pictet−Spengler reaction, Mannich reaction, Bischler−Naperalski/reduction) or nuchleophilic substitution. Of course, many modernized versions of these important fundamental transformations have been developed in the process. On the other hand, the most powerful advances in efficiency, as measured by both brevity and overall yield, were realized by applications of new methods for stereocontrolled synthesis, either catalytic or noncatalytic, and continued innovations in synthesis design. On a related note, just as synthetic methods are often evaluated by their ability to deliver, we venture to predict that the impact of total synthesis in the future will be increasingly dependent on its ability to deliver the desired materials on scale and in a practical manner, taking the next step beyond proof-of-principle accomplishments.

A solution of dipeptide 219-1 in toluene was heated at reflux with p-toluenesulfonic acid, providing aminal 219-2 in 92% yield with good stereoselectivity. Porco and co-workers reported diastereoselective intermolecular aminal formation upon cyclization of dimethyl acetal 219-2 in the presence of tigloyl amide and 50 mol % CSA in the last step of the total synthesis of elliptifoline, a secondary metabolite from the Aglaia genus plant (Scheme 219b). 823 The reaction proceeded through the initial formation of acyliminium ion 219-5, which reacted with the N-nucleophile from the side opposite the tertiary hydroxy group. However, on the basis of quantum mechanical calculations, the authors hypothesized that the conformation with the 6-methoxy group proximal to C13 is stabilized by a favorable n → π* interaction, and the nucleophilic attack could only occur from the opposite side of the acyliminium cation. Tokuyama and co-workers employed a late-stage autoxidation of tetracyclic azepinoindole 220-1 for the stereoselective synthesis of indole alkaloid mersicarpine (Scheme 220).824 After the Cbz group was removed by hydrogenation with palladium on carbon, the resulting reaction mixture was purged with air to accomplish a diastereoselective peroxide formation. The peroxide was reduced with dimethyl sulfide in situ to furnish the desired product in 91% overall yield.

ASSOCIATED CONTENT Special Issue Paper

This paper is an additional review for Chem. Rev. 2015, 115, issue 11, “Frontiers in Organic Synthesis”.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Artur K. Mailyan was born in Moscow, Russia, in 1986. He earned his B.Sc. (2007) and M.Sc. (2009) degrees from the Higher Chemical College of the Russian Academy of Sciences. While studying, he had a rare opportunity to participate in research activities toward the development of novel photochromic organic compounds at the N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, under the supervision of Dr. V. Z. Shirinian. In 2012, he earned his Ph.D. from the A.N. Nesmeyanov Institute of Organoelement Compounds under the direction of Prof. S. N. Osipov, working on 4536


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REFERENCES

the development of new synthetic methodology utilizing the chemistry of CF3-substituted diazocarbonyl compounds. Soon after that, he moved to the University of California, Santa Barbara, where he is performing postdoctoral studies in Prof. Zakarian’s group. His research interests are focused on the development of new methodology as well as the synthesis of complex natural products.

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John A. Eickhoff was born in St. Cloud, MN, in 1985. He joined the U.S. Army as a medic at the age of 18 and deployed to Eastern Afghanistan in 2009. After he returned, he finished his B.S. in chemistry in 2011 at the University of Nevada, Reno, where he contributed to studying the reactivity of novel azaoxyallylic cations in aza [4 + 3] cyloadditions in the laboratory of Prof. Christopher Jeffrey. In 2012, John joined Prof. Armen Zakarian's group at the University of California, Santa Barbara, where his research interests are focused on C−C cross-coupling toward heterocycles in the context of natural product synthesis. Anastasiia S. Minakova was born in Moscow, Russia, in 1986. She obtained her B.Sc. (2007) and M.Sc. (2009) degrees from the Moscow State University of Environmental Engineering. In 2014, she moved with her husband to Santa Barbara, CA, and will commence her graduate studies at the University of California, Santa Barbara, in 2016. Zhenhua Gu studied chemistry at Nanjing University and received his Ph.D. degree from the Shanghai Institute of Organic Chemistry in 2007 with Professor Shengming Ma. He conducted his postdoctoral research with Professor K. Peter C. Vollhardt (University of California, Berkeley) and Professor Armen Zakarian (University of California, Santa Barbara). In 2012, he began his independent academic career at the Department of Chemistry, University of Science and Technology of China, with support from the Thousand Talents Plan. Research in his group is mainly focused on the development of new methods and strategies for organic synthesis, including asymmetric catalysis and natural and unnatural bioactive molecule synthesis. Ping Lu was born in Wuxi, China. He obtained his B.S. degree from the University of Science and Technology of China in 2004. He then moved to the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and received his Ph.D. degree under the supervision of Prof. Shengming Ma in 2009. He joined Prof. Thorsten Bach’s group at the Technischen Universität München, Germany, as a postdoctoral fellow of the Alexander von Humboldt Foundation in 2010. Currently, he works in Prof. Armen Zakarian’s laboratory at the University of California, Santa Barbara. His research is focused on the total synthesis of natural products and related methodology development. Armen Zakarian received his Ph.D. in Florida under the supervision of Professor Robert A. Holton. After postdoctoral studies with Professor Larry E. Overman at the University of California, Irvine, he started his independent academic position in 2004. Since 2008, his research group has been located at the University of California, Santa Barbara. Research in the Zakarian group combines the areas of reaction development, complex molecule synthesis, natural product chemistry, bioorganic chemistry, and medicinal chemistry.

ACKNOWLEDGMENTS We are grateful to Naoko Gresback for invaluable help in the preparation of this manuscript. This work was supported by the National Institutes of Health (NIH) (National Institute of Environmental Health Sciences (NIEHS) Grant R03 ES025345 and National Institute of General Medical Sciences (NIGMS) Grant R01 077379) and National Science Foundation (NSF) (Grant CHE 1463819). J.A.E. thanks the NSF Graduate Fellowship Program for support. 4537


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Review

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