Acyliminium Ions - ACS Publications - American Chemical Society

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Scaffold Diversity from N‑Acyliminium Ions Peng Wu*,†,‡,§,∥,⊥,# and Thomas E. Nielsen*,†,‡,∇ †

Department of Chemistry, Technical University of Denmark, Kongens Lyngby DK-2800, Denmark Department of Immunology and Microbiology, University of Copenhagen, Copenhagen DK-2200, Denmark § Center for the Science of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States ∥ Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, United States ⊥ Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts 02115, United States # Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States ∇ Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore 637551, Singapore ‡

ABSTRACT: N-Acyliminium ions are powerful reactive species for the formation of carbon−carbon and carbon−heteroatom bonds. Strategies relying on intramolecular reactions of N-acyliminium intermediates, also referred to as N-acyliminium ion cyclization reactions, have been employed for the construction of structurally diverse scaffolds, ranging from simple bicyclic skeletons to complex polycyclic systems and natural-product-like compounds. This review aims to provide an overview of cyclization reactions of N-acyliminium ions derived from various precursors for the assembly of structurally diverse scaffolds, covering the literature over the past 12 years (from 2004 to 2015).

CONTENTS 1. Introduction 2. N-Acyliminium Ions 2.1. Formation of N-Acyliminium Ions 2.2. Reactivity and Stereochemistry 3. Synthesis of Bicyclic Scaffolds 3.1. Bicyclic Scaffolds with Shared Bonds (or Fused Rings) 3.1.1. Heteroatom Nucleophiles 3.1.2. Alkene and Alkene-Type Nucleophiles 3.1.3. Aromatic Nucleophiles 3.1.4. Other Nucleophiles 3.2. Bicyclic Scaffolds with Multiple Shared Bonds (or Bridgehead Atoms) 3.3. Bicyclic Scaffolds with Spiro Atoms 4. Synthesis of Tricyclic Scaffolds 4.1. Linear Tricyclic Scaffolds 4.1.1. Heteroatom Nucleophiles 4.1.2. Alkene and Alkene-Type Nucleophiles 4.1.3. Indole and Heteroaromatic Nucleophiles 4.1.4. Other Aromatic Nucleophiles 4.2. Tricyclic Scaffolds with Spiro Atoms 4.2.1. Alkene and Alkene-Type Nucleophiles 4.2.2. Aromatic and Heteroaromatic Nucleophiles 4.3. Other Tricyclic Scaffolds 5. Synthesis of Tetracyclic Scaffolds 5.1. Linear Tetracyclic Scaffolds 5.1.1. Indole and Heteroaromatic Nucleophiles 5.1.2. Other Aromatic Nucleophiles 5.2. Tetracyclic Scaffolds with Spiro Atoms © 2017 American Chemical Society

5.2.1. Indole and Heteroaromatic Nucleophiles 5.2.2. Other Aromatic Nucleophiles 5.3. Other Tetracyclic Scaffolds 5.3.1. Heteroatom Nucleophiles 5.3.2. Indole Nucleophiles 6. Synthesis of Polycyclic and Miscellaneous Scaffolds 6.1. Polycyclic Scaffolds 6.1.1. Linear Polycyclic Scaffolds 6.1.2. Spiro Polycyclic Scaffolds 6.1.3. Other Polycyclic Scaffolds 6.2. Miscellaneous Scaffolds 7. Conclusions Author Information Corresponding Authors ORCID Notes Biographies Acknowledgments Abbreviations Used References Note Added after ASAP Publication

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1. INTRODUCTION N-Acyliminium ions (NAIs) are highly reactive electrophiles that have been widely applied in organic syntheses for the construction of a range of structurally diverse compounds.

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Received: December 1, 2016 Published: May 11, 2017 7811

DOI: 10.1021/acs.chemrev.6b00806 Chem. Rev. 2017, 117, 7811−7856

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sors,27−31 have been reported in the past decade. It is also noteworthy that a range of NAI cyclization reactions have been demonstrated on solid supports, especially for the synthesis of peptides and constrained peptidomimetics, but many of these reactions have been reviewed elsewhere.32−42 Within the boundaries described above, the aim of this review is to provide an overview of the literature from 2004 to 2015, with a focus on intramolecular cyclization reactions for the synthesis of chemical scaffolds containing a minimum of two fused rings. The main sections of the review comprise comprehensive summaries of reported synthetic methods and categorize all scaffolds according to the number of rings, the nature of the resulting bonds, and the different types of nucleophiles involved in cyclization.

Figure 1. Classification of iminium ion chemistry. The coverage of this review is highlighted by the purple-blue hexagon.

Scheme 1. Formation of NAIs through the Defragmentation of a Leaving Group at the α-Position of the Acyl Nitrogen in a Reversible Manner

Following early studies in the 1950s,1−4 an impressive number of synthetic examples have been reported using NAIs for the syntheses of alkaloids, natural-product-like compounds, and biologically active molecules.5,6 Among different named reactions involving NAIs, the Mannich and Pictet−Spengler reactions are the two most-studied types. Discovered by Ame Pictet and Theodor Spengler in 1911,7 the Pictet−Spengler reaction is an intramolecular version of the Mannich reaction,8 which has been extensively studied in the pursuit of alkaloids containing indole and isoquinoline scaffolds.9−12 Intermolecular addition and intramolecular cyclization are two major reaction types associated with NAI chemistry. The former type has been periodically reviewed on several occasions, for example, in early reports in the 1970s and 1980s by Zaugg13,14 and more recently in the 2000s by Yazici and Pyne.15,16 The earliest review on the latter type of cyclization was published in the 1980s by Speckamp and Hiemstra,17 and a comprehensive review covering examples of intramolecular reactions of NAIs up to 2003 was published in 2004 by Maryanoff and coauthors.5 A review on a broader topic of iminium ion cyclization, with a focus on enantioselective reaction variants, was also published in 2004.6 Since the appearance of these most recent reviews, a substantial amount of progress and a large number of valuable contributions in applying NAIs for the synthesis of diverse scaffolds through intramolecular cyclization reactions have been reported. This review systematically summarizes these novel synthetic methods. Following up on the 2004 review by Maryanoff and coauthors,5 this account focuses on the intramolecular trapping of NAIs by tethered nucleophiles that lead to cyclic αfunctionalized amido derivatives, as applied in the synthesis of diverse scaffolds embedded in natural and synthetic polycycles (Figure 1). Only cyclization steps that directly involve NAI intermediates are included in this review. Rearrangement reactions of NAIs leading to cyclized compounds of different scaffolds,18 NAI cyclizations that lead to a reduced or equivalent count of cyclic systems,19 and cyclizations involving vinylogous NAIs20−22 are not included herein. NAI chemistry has also been widely applied for the functionalization of monocyclic pyrrolidines and piperidines at the α-position;23−26 however, reactions used for the introduction of substituents on monocyclic scaffolds are also outside the scope of this review. It must be mentioned that a plethora of intermolecular NAI reactions, typically deriving from hydroxylactams or other NAI precur-

Scheme 2. Formation of NAIs through the Protonation of an Enamide

Scheme 3. Formation of NAIs through Anodic Oxidation

Figure 2. Structures of N-acyliminium ion (NAI) and structurally related chemotypes.

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Figure 3. Plethora of structurally diverse compounds prepared through the cyclization of N-acyliminium ions.

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Scheme 4

2. N-ACYLIMINIUM IONS

acids.53−55 Within this category fall examples of direct imine acylation with a wide range of activated carboxylic acids, as reported by Taylor and co-workers, to access scaffolds of various ring sizes through intramolecular reactions of the intermediate NAIs with oxygen, nitrogen, sulfur, and carbon nucleophiles.53−55

2.1. Formation of N-Acyliminium Ions

The single most widely applied method for NAI formation involves the release of a leaving group from the α-position of the acyl nitrogen under acidic reaction conditions, a process that proceeds in a reversible manner (Scheme 1). Hydroxyl compounds, such as the hydroxylated pyrrolidine, pyrrolizidine, and indolizidine alkaloids reported by Pyne and co-workers,43−45 have been commonly used as NAI precursors. A protonated hydroxyl group is the most common leaving group, but halogen, alkyloxy, aryloxy, acetoxy, alkylthio, arylthio, arylsulfonyl, carbamate, and benzotriazolyl moieties have also been utilized. Within this scope fall cyclic precursors, such as those in which the α-position of the acyl nitrogen is functionalized with an alkoxy moiety (i.e., cyclic N,O-acetal structures), which are readily cleaved in acidic medium with concomitant generation of cyclic NAIs. Both Lewis and Brønsted acids have been applied for this purpose. Stoichiometric amounts of acid are normally used, although procedures using catalytic amount of acids, such as chiral Brønsted acids, have also been developed. A wide range of Lewis acids, such as the halogenated or pseudo-halogenated Lewis acids FeCl3, SnCl4, InCl3, BF3·OEt2, Sc(OTf)3, In(OTf)3, TMSOTf, Zn(OTf)2, Cu(OTf)2, and AgOTf, have been used. Reported Brønsted acids used for NAI generation normally comprise common protic acids, such as formic acid, AcOH, H2SO4, TsOH, TFA, and CSA. Additionally, many NAI precursors are enamides, whose protonation under acidic conditions generate NAIs that are subsequently trapped by nucleophiles (Scheme 2). NAIs can be obtained through the oxidation of amides using various electrochemical technologies and techniques (Scheme 3), a type of reaction also termed the Shono oxidation.46,47 In the most common electrochemical procedure for NAI generation, the highly reactive NAI intermediate is frequently trapped with solvent nucleophiles, such as methanol, to form a N,O-acetal. The NAI is then readily formed through treatment with acid, thereby allowing an irreversible reaction with other nucleophiles, typically carbon nucleophiles.44,45 NAIs have also been obtained through direct imine acylation with acid halides,48−51 anhydrides,52 and activated carboxylic

2.2. Reactivity and Stereochemistry

As an important subfamily of the iminium ion class, NAIs are generally more reactive than other types of iminium ions because of the electron-withdrawing nature of the carbonyl group. Among numerous cyclization methods in organic synthetic chemistry, NAI-based cyclization methods have emerged as a particularly versatile approach for accessing structurally diverse scaffolds of broad biological interest. Most methods involve trapping the intermediate NAI with heteroatom nucleophiles or π-type carbon nucleophiles, including aromatic and heteroaromatic rings, as well as double and triple bonds. The viability of the intramolecular cyclization depends on both the ability to form the NAI and the reactivity of the nucleophilic species. NAI precursors come in numerous structural variations that translate into a diverse range of cyclic scaffolds. High diastereoselectivity has often been reported for intramolecular NAI cyclization, where chiral induction can stem from favorable steric interactions of appropriately substituted substrates or from auxiliaries.56 High enantiomeric selectivity has been achieved in NAI cyclizations, owing to the emergence of new chiral catalysts.57−63 Aside from NAIs, the structurally related N-alkoxycarbonyliminium, N-carbamoyliminium, N-sulfonyliminium, N-phosphoryliminium, and N,N-diacyliminium ions can also be considered in the broader interpretation of NAIs (Figure 2). A considerable number of NAIs are derived from Boc- or Cbzprotected amino substrates, which makes the N-alkoxycarbonyliminium ions common intermediates in NAI cyclization. This review focuses primarily on NAIs and N-alkoxycarbonyliminium ions, although a few carefully selected cases of N-carbamoyliminium and N-sulfonyliminium ions are included to demonstrate the diversity of accessible scaffolds. The scaffolds obtained by the cyclization of NAIs through either carbon−carbon or carbon−heteroatom bond-forming reactions can be categorized according to the number and nature 7814


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Scheme 5

of the resulting ring systems, such as bridged, spirocyclic, and “other” scaffolds, as presented in the following sections (Figure 3). In cases where a limited number of scaffolds with different numbers of rings can be obtained through the same type of

reaction, such scaffolds are grouped together, as illustrated by the

Scheme 6

all be obtained through aza-Prins cyclization under similar

examples presented in Scheme 4, where the main bicyclic products 3 are presented together with the single tricyclic compound 4 and the single tetracyclic compound 5, as they can conditions. Scaffolds of the same size are further categorized on the basis of nucleophile type (heteroatom nucleophiles, aromatic and heteroaromatic nucleophiles, alkenes and activated alkenes, etc.). Chiral substrates and products depicted in the illustrated schemes of this review indicate racemic mixtures, unless otherwise specified.

Scheme 7

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Scheme 8

Scheme 9

cyclization step in the presence of TsOH. The NAI intermediate 2 was trapped by the tethered carbamate to give funtionalized N,N-acetals 3. The methodology was extended to tricyclic scaffold 4 and tetracyclic scaffold 5, the invoked cyclization reactions being mediated by BF3·OEt2 and TFA, respectively.64 Intriguingly, the C5−C8a cis isomer being the major diastereomer (trans/cis, dr 1:80) in the case of carbon−carbon bond formation in scaffold 5 was different from all other carbon− nitrogen bond forming reactions, which predominantly led to the formation of the trans-diastereomeric product. This stereochemical discrepancy can be explained by a thermodymanically controlled carbon−nitrogen cyclization and a kinetically controlled carbon−carbon cyclization. This tandem-cyclization approach was successfully applied to the first total synthesis of the natural product (−)-dysibetaine (Scheme 4).65 Kimpe and co-workers reported a diastereoselective ring expansion of β-lactams to give γ-lactams through NAI intermediates,66 as used for the synthesis of bicyclic lactam scaffolds 8, 9, 11, and 12.67 Upon treatment with AgBF4 and pyridine in refluxing toluene, cis-4-(1-chloro-1-methylethyl)-1(ω-hydroxyalkyl)azetidin-2-ones 6, synthesized from 2-aminoethanol and 3-amino-1-propanol in four steps, were converted to ring-expanded NAI intermediates 7 through a transient silver(I)induced carbenium ion. Intermediates 7 were intramolecularly trapped by tethered hydroxyl groups to preferably form trans isomers of 1-aza-4-oxabicyclo[3.3.0]octan-8-ones and 1-aza-4oxabicyclo[3.3.0]nonan-8-ones 8. Starting from compound 10, bicyclic 1,4-diazabicyclo[3.3.0]octan-8-ones and 1,5-

Scheme 10

3. SYNTHESIS OF BICYCLIC SCAFFOLDS 3.1. Bicyclic Scaffolds with Shared Bonds (or Fused Rings)

3.1.1. Heteroatom Nucleophiles. Blaauw and co-workers reported the diastereoselective cationic tandem-cyclization strategy for the preparation of bicyclic N-heterocyclic scaffolds. Enantiomerically pure dipeptide substrates 1, readily synthesized through a coupling step between L-allysine ethylene acetal and a Cbz-protected amino acid component, underwent a double 7816


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Scheme 11

Scheme 12

diastereomer 15a, which presumably is the thermodynamically preferred diastereomer, as further indicated by DFT calculations. It is noteworthy that the acetal substrate 13b with a shorter Cbzprotected amino substituent led not to the bicyclic scaffold 15b but instead to the β-elimination product of the NAI intermediate (Scheme 6).68 3.1.2. Alkene and Alkene-Type Nucleophiles. In the presence of BF3·OEt2, NAI precursors 16 underwent endo-trig cyclization to give azabicyclic carbocation intermediates 17, which could be trapped by nitriles and hydrolyzed to generate amido-substituted azabicyclic compounds 18 through tandem aza-Prins−Ritter reactions. Carbocation intermediates 17 also underwent Friedel−Crafts-type reactions in the presence of benzene to give phenyl-substituted compounds 19. Both amidoand phenyl-substituted azabicyclic compounds could be generated in a highly diastereoselective manner with good to excellent yields.69 In most cases (18a−18h and 19a−19d), a single diastereomer was exclusively formed. The diastereomeric

Scheme 13

diazabicyclo[4.3.0]nonan-9-ones 11 and 12 were obtained with higher trans diastereoselectivity compared to 1-aza-4-oxabicyclic compounds, which can be explained by the steric hindrance imposed by the Boc group (Scheme 5).67 In a study on the synthesis of bicyclic peptidomimetics, Hruby and co-workers reported the synthesis of bicyclic benzyloctahydropyrazino[1,2-a]pyrimidin-6-one derivatives 15 through amide−aldehyde condensation followed by NAI cyclization. Carbamate-tethered acetal substrate 13a derived from phenylalanine was treated with formic acid to give a single 7817


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Scheme 14

Scheme 15

ratio was determined by 1H NMR spectroscopy, and the diastereomeric identity was confirmed by NOESY and X-ray crystallographic analysis. However, the excellent diastereoselectivity was lost when a tertiary carbocation derived from substrate 16a was used for the aza-Prins−Ritter hydrolysis sequence (Scheme 7).69 The same group reported the synthesis of tosylated bi- and tricyclic scaffolds through aza-Prins cyclization. In these reactions, the p-toluenesulfonic acid functioned as both a Brønsted acid catalyst and a reactive nucleophile.70 The Nhomoallyl hydroxylactams 21 and 23 served as NAI precursors for the tandem aza-Prins−Ritter reactions. Through this approach, hexahydroindolizin-3(2H)-ones/hexahydro-1H-quinolizin-4(6H)-ones 22 and 1,3,4,10b-tetrahydropyrido[2,1-a]isoindol-6(2H)-ones 24 were provided in moderate to high yields, notably with no apparent elimination side reactions. All cyclized and substituted products were obtained with excellent diastereoselectivity, except those derived from substrates with no substitution at the α-position to nitrogen (R = H), with dr ratios decreasing from 17:3 to 1:1. Along these lines, 5-hydroxy-1-(3methylbut-3-en-1-yl)pyrolidin-2-one failed to form a cyclized product, presumably because of steric hindrance around the tertiary carbocation intermediate during the reaction. The authors also reported Ts-deprotection through Mg/MeOH treatment to provide the corresponding alcohol, and the methodology was applied in the synthesis of indolizidine alkaloids (Scheme 8).70 Bicyclic isoindolin-1-one compounds 23 underwent similar aza-Prins−Ritter and aza-Prins/Friedel− Crafts sequences to give tricyclic amido-substituted compounds 25 and phenyl-substituted compounds 26, respectively (Scheme 9).69 Starting from acyclic precursors, Dobbs and co-workers reported the synthesis of analogous bicyclic [6,5] and [6,6] aza scaffolds relying on aza-Prins and aza-silyl-Prins reactions with concomitant incorporation of halo, phenyl, and amido substituents. Substrates 27a and 27b, containing both amide and aldehyde functional groups, the latter masked with an acetal protecting group, underwent intramolecular NAI formation and

subsequent aza-Prins (28) or aza-silyl-Prins cyclization (29). Iron chloride, indium trichloride, and indium tribromide were used as Lewis acids to promote the double cyclization process (Scheme 10).71 Hanessian and co-workers reported the synthesis of enantiopure, 6-substituted octahydroindole (31, 33) and hexahydroindole (35) 2-carboxylic acid methyl esters through N-Boc acyliminium ions derived from 4-ω-butenyl and butynyl N-Boc L-pyroglutamic acid esters.72,73 The terminal alkene tethers of 30 and 32 and the alkyne tether of 34 are potential πnucleophiles that attack the cationic NAIs formed in the presence of Lewis acids including tin(II) halides and BF3·OEt2. Intramolecular tandem Friedel−Crafts-type cyclization of the alkene substrates 30 led to the formation of a new sp3 stereogenic carbon center with an equatorially positioned aryl substituent. Under BF3·OEt2 conditions, dilution of aromatic solvents through addition of CH2Cl2 led to a progressive decrease in yields, although the main products were unaltered. The epimer of substrate 30 (substrate 32) was included to demonstrate the diastereoselective formation of compound 33 in 74% yield. The obtained 6-bromo-azabicyclic scaffolds were used as substrates for further decoration, including Pd-catalyzed Suzuki−Miyaura, Heck, and Stille reactions to give functionalized azabicyclic compounds (Scheme 11).72 Inspired by previous reports of intramolecular cyclization of allylsilane with iminium ions,5,6,74 Hong and co-workers obtained the bicyclic pyrrolo[1,2-a]azepine scaffold 37 through an intramolecular NAI cyclization of propargylsilane 36 in a bioinspired synthesis of the natural alkaloid stemoamide 38.75,76 Starting from alkynylation of 4-bromobutyraldehyde with propargyl trimethylsilane, followed by TBS protection, succinimide substitution, and reduction using NaBH4, propargylsilane 36 was obtained as the NAI precursor in 75% yield. Various reductive cyclization experiments revealed that bicyclic compound 37 could be obtained in 86% yield, with a dr ratio of 3:1 (cis/trans; the separated major isomer upon TBS removal was identified as the cis isomer by X-ray crystallographic analysis), using anhydrous FeCl3 as the catalyst. Subsequent TBS removal, 7818


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Scheme 16

isomer 42 being dominant, which was rationalized by involving steric repulsion associated with the chelated titanium enolate transition state. However, attempts to eliminate the iodo moiety and remove the oxazolidinone were unsuccessful (Scheme 14).79 3.1.3. Aromatic Nucleophiles. Tetrahydroisoquinolines represent a class of scaffolds that have frequently been synthesized through intramolecular NAI cyclization. The tetrahydroisoquinolines 46 were obtained through Pictet− Spengler-type cyclization of NAIs generated from N,O-acetalic TMS ethers 45 in the presence of BF3·OEt2 in the synthesis of calycotomine 47 (Scheme 15).80 As reported by Rutjes and coworkers, similar bicyclic tetrahydroisoquinolines with a vinyl substituent at the 1-position were obtained from linear aromatic allylic N,O-acetals in the presence of either a Lewis acid such as Sc(OTf)3 or a protic acid such as TFA/TFAA through Nsulfonyliminium ion intermediates.81 Rutjes and co-workers also reported other types of NAI-based coupling reactions for the synthesis of functionalized lactams.82,83 Bicyclic 4-amino-1,2,4-tetrahydro-2-benzazepin-3-ones 50 and 53 were synthesized according to two methods for NAI cyclization. The first method involved the synthesis of the

careful separation of the two diastereomers by silica gel chromatography, ruthenium-catalyzed CO-insertion reaction, and a final nickel-catalyzed reduction of the corresponding butenolide were pursued to construct the fused lactone ring onto an azepine to give the tricyclic scaffold of stemoamide 38 with an overall yield of 37% from the starting aldehyde component (Scheme 12).75 In a Schmidt reaction for the synthesis of tricyclic pyrrolo[1,2b]isoquinolin-3(2H)-one scaffolds reported by Gu and coworkers,77 substituted bicyclic pyrrolizine 40 was synthesized through an intramolecular Schmidt−NAI reaction using alkynesubstituted azide substrate 39 and oxalyl chloride (Scheme 13).78 Nagasaka and co-workers reported an intramolecular tandem Michael/Mannich-type reaction of α,β-unsaturated carbonyl compounds 41 for the synthesis of bicyclic indolizidines 42.79 Substrates 41, synthesized by a four-step procedure from succinimide, contain an Evans oxazolidinone moiety that was used as a chiral auxiliary for NAI cyclizations carried out in a mixed AcOEt/CH2Cl2 solvent system in the presence of TiCl/nBu4NI. The cyclized products were obtained as a mixture of the three diastereomers 42, 43, and 44, with the (7S,8R,8aS)-7,8a-cis 7819


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Scheme 17

Scheme 18

Scheme 20

benzotriazole (Bt) adducts 49, which serve as convenient NAI precursors in the presence of AlCl3. The second method provided products with additional substituents on the resulting seven-membered ring, through N-acylation of a substituted imine component 52, overall leading to densely functionalized benzazepin-3-ones 53. In both cases, activated aromatic rings, for example, methoxy-substituted benzene rings, led to products with higher yields. In terms of diastereoselectivity, only the cis product was formed using the benzotriazole method, whereas approximately 1:1 diastereomeric mixtures were obtained through imine acylation, the latter presumably originating from a similar E/Z ratio of the NAI intermediate (when R3 is not a hydrogen group; Scheme 16).84 An aza-Nazarov-type cyclization assembling a new sixmembered ring, using CF3SO3H as the acid, was reported by Klumpp and co-workers for the synthesis of polycyclic scaffolds.85−87 A study using substituted imines 54 and arylacetyl

chlorides 55 in the presence of excess amounts of CF3SO3H gave bicyclic 3-oxo-1,2,3,4-tetrahydroisoquinolines 57 in mostly good to high yields. The cyclization step occurred with modest diastereoselectivity using the optically active substrate 58 prepared from Mosher’s acid chloride, which gave the cyclization product 59 with high diastereoselectivity, albeit in low yield (Scheme 17).85 3.1.4. Other Nucleophiles. N-Malonate-5-hydroxy-γ-lactams 60 were synthesized from succinimide as precursors for NAIs. Whereas 60a was cyclized to the expected product 61a in TFA, the homologous substrate 60b led to only the dehydrated pyrroline-2-one derivative. The expected cyclized product 61b was obtained through a reductive cyclization approach using the corresponding N-bromoalkyl-5-malonate-γ-lactam substrate (Scheme 18).88

Scheme 19

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by addition of formic acid to the side chain to yield the bicyclic spiro compounds 68. Using enantiomerically pure diene substrate 69, derived from an (S)-N-Boc-2-pyrrolidinone derivative, spirocyclic formate ester 70 was obtained with complete desired stereoselectivity, although the formate substituent at the C3′ position occurred with a diastereoselective ratio of 8:5 favoring the 3′β-formate as determined by highperformance liquid chromatography (HPLC) analysis. Spirocyclic compound 70 was used as the substrate to enantioselectively give the C3′α-alcohol and C3′β-alcohol analogues of 70, which were used as starting components for the stereoselective total syntheses of various tricyclic marine alkaloids, including (−)-lepadiformine, (+)-cylindricine, and (−)-fasicularin (Scheme 21).91 Attempts to obtain spirocyclized products through sixmembered NAIs by treating N-Boc-amide ketone with acids failed to form spiro compounds. Instead, tetrahydropyridine was obtained through cleavage of the Boc group and subsequent condensation of the resulting amino ketone.92 Another study performed by the same group revealed that substrates with Ntosyl, N-benzyloxycarbonyl, and N-benzoylamide ketones failed to give the expected 1-azapiro[5.5]undecane scaffolds, whereas N-benzylamide ketone substrate 71 bearing an endocyclic carbonyl group successfully provided the bicyclic spiro product 72 in formic acid (Scheme 22).92

Scheme 21

Scheme 22

4. SYNTHESIS OF TRICYCLIC SCAFFOLDS 4.1. Linear Tricyclic Scaffolds

4.1.1. Heteroatom Nucleophiles. Tricyclic scaffolds containing a bicyclic N,N-acetal moiety were synthesized from N-substituted substrates 73,93 which were obtained through the coupling of 3-(1-ethyoxyethoxy)isoindolin-1-one and p-nitrophenylesters.94 Several acids including TfOH, BF3·OEt2, SnCl4, TMSOTf, and TFA were tested for the generation of NAIs from 73, which revealed that the use of TMSOTf was favorable, whereas TFA was shown to be ineffective in this reaction. NSulfonyl substrates with a Ts, Ms, or Ns protecting group led to tricyclic compounds 74 in good yields with high to excellent stereoselectivities, whereas substrate 73 with a Cbz group gave

3.2. Bicyclic Scaffolds with Multiple Shared Bonds (or Bridgehead Atoms)

In total synthesis studies on the alkaloids pinnamine and anatoxin-a, Tanner and co-workers reported the synthesis of key bicyclic scaffolds 63 and 64 from β-diketone substrate 62 through Lewis-acid-catalyzed NAI cyclization.89 The stereochemical outcome of the cyclization reactions depended on the choice of Lewis acids, the solvent composition, the reaction time, and the temperature, and selected examples are presented in Scheme 19. Both thermodynamic and kinetic reaction pathways were invoked to explain the product distribution, and the targets were successfully achieved in 10 steps with an overall yield of 5% (pinnamine) and in nine steps with an overall yield of 9% (anatoxin-a).89

Scheme 23

3.3. Bicyclic Scaffolds with Spiro Atoms

In explorations of synthetic routes to the spiroaminal natural compounds marineosin A and B from Streptomyces-type actinomycetes, Shi and co-workers reported the synthesis of a spiroaminal fragment through NAI cyclization.90 NAI precursor 65 was readily obtained from 4-methoxy-3-pyrrolin-2-one and upon treatment with p-TsOH·H2O in CHCl3 gave the spiro compound 66 as a single isomer in 54% yield, together with a small amount of starting compound 65. Subsequent reduction of 66 using Pd/C and Tf2O-mediated Vilsmeier−Haack reactions were also investigated in that study (Scheme 20).90 Kibayashi and co-workers reported several types of NAI spirocyclization reactions, such as formic acid-induced intramolecular aza-spirocyclization reactions of conjugated dienecontaining NAIs derived from compounds 67. Protonation of compounds 67 in the presence of formic acid yielded the corresponding NAI, which underwent cyclization with the conjugated diene through a chairlike transition state, followed 7821


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Scheme 24

Scheme 25

aniline amine. Subsequent diversification reactions through Nalkylation of the amide NH and reductive N-acylation/ sulfonation of the aromatic NO2 were also demonstrated for the obtained tricyclic scaffolds with four diversification handles (Scheme 24).95 4.1.2. Alkene and Alkene-Type Nucleophiles. In an effort to construct the tetracyclic core of lipoxygenase-inhibiting tetrapetalones,98 Hong and co-workers reported an NAI-based cyclization to construct substituted benzopyrroloazepinones 79 and 80.99 Hydroxylactam substrates 78 were tested for the NAI cyclization step, and a combination of FeCl3 and TMSCl was selected after the screening of various acidic reaction conditions, relying on formic acid, SnCl4, TiCl4, and ZnCl2. The reaction scope revealed that the stereoselectivity of the cyclization was affected by different substituents at the C-7 and C-8 positions (carbon numbering based on the benzo[f ]pyrrolo[1,2-a]azepin1-one core scaffold). For hydroxylactam substrates 78c and 78f with electron-withdrawing groups (EWGs), no diastereoselectivity was observed in the formation of the corresponding benzopyrroloazepinones, whereas for electron-donating-group(EDG-) substituted hydroxylactam substrates 78d and 78e, excellent diastereoselectivity favoring the formation of the cis isomers 79d and 79e was observed. This profound substituent

the corresponding product 74g in low yield, and substrates with Boc (74h) or Ac (74i) moieties failed to undergo cyclization (Scheme 23). The yields and high stereoselectivities of the reaction were explained by a proposed intramolecular interaction between the SO bond of the sulfonyl moiety and the iminium ion intermediate.93 An Ugi multicomponent reaction and NAI cyclization cascade was employed to synthesize tricyclic dihydropyrazino-quinazolinedinones 77,95 the core scaffold found in the marine alkaloids brevianamides and fumiquinazolines.96,97 Aryl fluoride 75 was obtained in moderate to good yields (43−82%) through a fourcomponent Ugi reaction of 2-fluoro-5-nitro-benzoic acid, (2,4dimethoxyphenyl)methanamine, 1,1-diethoxy-2-isocyanoethane, and an aldehyde (R1-CHO). A subsequent substitution reaction with a primary amine and an acid-mediated double cyclization step gave the desired tricyclic scaffold 77, the stereochemistry of which was confirmed by X-ray crystallography. It was proposed that the cyclization steps were initiated by the formation of an oxonium ion upon treatment of 76 with formic acid under MW irradiation conditions with concomitant removal of the 2,4-dimethoxybenzyl protecting group. In this cyclization step, the amide nitrogen reacted with the oxonium ion to generate the NAI, which was trapped by the nucleophilic 7822


Chemical Reviews

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Scheme 26

Scheme 27

effect on diastereoselectivity was explained by a proposed πbridged chairlike transition state of the tertiary carbocation formed by the intramolecular reaction between the alkene and NAI. An aryl group with EDGs helps to stabilize the tertiary carbocation and enhances the formation of the π-bridged transition state, leading to the generation of the cis isomers through chloride attack from the side opposite the aryl ring. A less-favored boatlike transition state was proposed in the presence of an EWG-substituted aryl group, leading to the generation of trans isomers 80 through chloride attack at the

pseudoequatorial position. The incorporation of a hydroxylactam substrate 81 with a benzyl-protected two-carbon primary alcohol at the C-5 position was successfully applied in this method to give compounds 82 and 83 containing a tetracyclic scaffold (Scheme 25).99 In a study investigating cyclization reactions of chiral allylsilanes with NAIs, Aubé and co-workers reported the synthesis of the series of tricyclic pyrrolo[1,2-c]quinazolin5(1H)-one derivatives 86−88 through N-carbamoyliminium ion intermediates 85 from enantiomerically pure components.100 7823


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Scheme 28

Scheme 31

Scheme 29

benzyloxy substituent to the silicon moiety (substrate 84b) led to a reversal in the diastereoselectivity, and the proposed mechanism involved a transient cationic five-membered oxonium ion species that led to the formation of the trans products 86. To test the generality of the influence imposed by the terminal benzyloxy substituent on the diastereoselectivity of this type of intramolecular allylsilane reaction, silane substrates

Condensation of an azide silane component and an aldehyde afforded the imine substrates 84, which were treated with TiCl4 to generate NAI intermediates 85, which were, in turn, trapped by the tethered allylsilane moiety to afford mixtures of stereoisomeric products 86−88 in high enantiomeric purity (e.g., 86a in 97:3 er, 86b in 99:1 er). It was observed that a γScheme 30

7824


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Scheme 32

Prins-type cyclization of trimethylsilylmethylallene substrates.102 Succinimide- and phthalimide-derived allenylmethylsilane hydroxylactams 94 and 96 were used as precursors for intramolecular NAI cyclization reactions in the presence of TMSOTf. Cyclization at the α-carbon position of the TMS group afforded five-membered pyrrolizidinone products 95 with an exoallene moiety, whereas 6-endo cyclization provided the six-membered indolizidinone derivatives 97 with an exo-1,3-diene unit (Scheme 27).101 Kibayashi and co-workers reported several examples of spirocyclization for the synthesis of bicyclic,91,92 tricyclic,103,104 and tetracyclic scaffolds.105 They also reported an NAI reaction using spiroindole substrate 98 for the construction of a linear tricyclic 4a,9-disubstituted octahydroacridine compound 99. The diene conjugated substrate 98 was synthesized from isatin (Scheme 28).106 4.1.3. Indole and Heteroaromatic Nucleophiles. Indole moieties display excellent reactivity as nucleophiles in Pictet− Spengler-type reactions with NAIs generated in situ to yield alkaloid-like scaffolds.57,61,62,103,107−109 An asymmetric version of the Pictet−Spengler reaction was first reported by Jacobsen and co-workers in 2004, when they showed how various Pictet− Spengler-type reactions could be catalyzed by chiral thioureas.57 Tryptamine-derived imine substrates 100 reacted with acetyl chloride in the presence of 2,6-lutidine and thiourea catalyst 101 in Et2O at −30 °C to provide N-acetyl tetrahydro-β-carbolines 102 in good yields with high enantioselectivities. Compounds 102f and 102g, bearing substituents at the 5- and 6-positions of the indole moiety, resembling the ubiquitous substitution patterns in indole alkaloids, were also within the scope of this methodology. 57 Catalyst 101 has also been used for enantioselective intermolecular Mannich reactions of Nacylisoquinolinium ions (Scheme 29).11 Compounds 105, sharing the same tetrahydro-β-carboline scaffold as 102 (Scheme 29), were synthesized from a series of bicarbonyl-substituted tryptamines 103 through chiral phosphoric acid 104 (Scheme 30).110 In addition to synthesizing various tricyclic scaffolds, Jacobsen and co-workers have synthesized tetracyclic scaffolds through Pictet−Spengler reactions catalyzed by chiral thioureas. The hydroxylactams 106 and 109 were obtained though reduction of the corresponding succinimide derivative with NaBH4 or through addition of alkyl lithium reagents to either succinimide or maleimide derivatives and were used as substrates for Pictet−

Scheme 33

89 were cyclized to give bicyclic indolizinone derivatives 91−93 as isomeric mixtures (Scheme 26). Reversal of diastereoselectivity was again observed for the indolizinones synthesized using the allylsilane substrate with a γ-benzyloxy substituent to the silicon moiety (substrate 89b).100 Cho and co-workers reported the synthesis of bicyclic and tricyclic heterocyclic scaffolds bearing an exoallene and an exo1,3-diene unit using trimethylsilylmethylallene substrates 94 and 96.101 The group previously reported the synthesis of 2,6disubstituted-3,4-dimethylidene tetrahydropyrans through 7825


Chemical Reviews

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Scheme 34

sation of aldehydes and isotryptamines to give enantiomerically enriched tetrahydro-γ-carbolines under similar chiral thiourea/ benzoic acid cocatalytic conditions.59 In addition to thioureas,114 chiral phosphoric acids have also been utilized as catalysts for intermolecular addition of indole nucleophiles to cyclic NAIs.115 A metal-catalyzed tandem isomerization/NAI cyclization sequence was developed for the synthesis of 1,2,3,4-tetrahydroβ-carbolines 116 from acylated N-allylic tryptamine substrates 114. Starting from amides 117, the structurally related 3,4dihydroisoquinolines 118 could be obtained under similar reaction conditions (Scheme 33).107 A series of hydroxamate substrates 119 were subjected to oxoNAI cyclization upon reaction with aldehyde components using TMSCl/NaI, providing tricyclic [1,2]oxazino[4,5-b]indole, [1,2]oxazepino[4,5-b]indole, and [1,2]oxazocino[4,5-b]indoles 120. This approach to N−O-containing fused indole scaffolds was shown to have a broad scope, and several types of benzaldehydes, including benzaldehydes with both EWGs and EDGs, furan-2-carbaldehyde, thiophen-2-carbaldehyde, and paraformaldehyde, were tolerated in the reaction. In the case of the aliphatic n-butyraldehyde 119a, BF3·OEt2 was found to effectively form the Boc-deprotected, cyclized product 121 (Scheme 34).116 Based on early work on furan cyclization to NAIs that revealed a dependency on the tether length, attachment, and general substitution pattern on the furan ring,117−120 Pyne and coworkers reported the acid-promoted cyclization of NAIs formed in situ from furan-tethered dihydroxy or diacetox-γ-ylactams. Substrates furan-4,5-dihydroxy-γ-lactam 122 and furan-4,5diacetoxylactam 125, both containing a two-carbon tether, were readily synthesized following a reduction approach.45,121 Lactam 122 gave both trans- and cis-diastereoisomeric products 123 and 124, respectively, in different ratios depending on the specific acidic conditions. In the case of TFA, the two diastereoisomers were formed in a ratio of 39:11 (cis/trans), which was only slightly improved to 21:4 (cis/trans) when BF3· OEt2 was employed as the acid. The preference for cis selectivity can be explained by invoking intramolecular hydrogen bonds. Lactam 125 gave the linearly fused tricyclic scaffold 126 as a single diastereoisomer with trans selectivity, which can be attributed to the formation of an acetoxonium ion intermediate that directs the nulecophilic attack of the furan ring from the opposite side of the lactam ring. Pyne and co-workers also

Scheme 35

Spengler reactions in the presence of the thiourea catalyst 107 to yield tetracyclic scaffolds 108 and 110 in high enantiomeric excess. An SN1-type mechanism involving anion binding by the thiourea catalyst and a spiroindoline intermediate was proposed for this reaction (Scheme 31).111 Thiourea catalyst 107 was also used by the Jacobsen group in NAI Pictet−Spengler reactions of pyrrole substrates 111. Regioselective cyclization of succinimide- and glutarimidederived pyrrolohydroxylactams was performed to give two types of tricyclic scaffolds. Products 112 were obtained through C2-cyclization when the pyrrole NH position was not substituted, and products 113 were predominantly formed through C4-cyclization when the sterically demanding protecting group triisoproylsilyl (TIPS) was attached to the pyrrole NH. In both cases, substituted substrates 111 (R2 = alkyl), prepared by addition of alkyllithium to imides, underwent cyclization with high enantioselectivities, whereas substrates prepared by reduction (R2 = H) led to products with only modest ee values (Scheme 32).58 Outside the scope of this review, other variations on enantioselective addition of indole nucleophiles to iminium ions that do not belong to the group of NAIs have been reported for the synthesis of tetrahydro-β-carbolines, such as chiral phosphoric acid-catalyzed synthesis of N-unsubstituted tetrahydro-β-carbolines through sulfenyliminium ions,112 one-pot imine formation and asymmetric Pictet−Spengler reactions cocatalyzed by a chiral thiourea and benzoic acid to afford Nunsubstituted tetrahydro-β-carbolines,113 and one-pot conden7826


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Scheme 36

Through careful fine-tuning of the cyclization conditions, selective formation of the kinetic product (α-epimer) or the thermodynamic product (β-epimer) could be achieved (Scheme 37).126 4.1.4. Other Aromatic Nucleophiles. Pyrrolo[2,1-a]isoquinoline scaffolds have also been constructed from LDOPA-derived substrates in a stereocontrolled manner under different acidic conditions.10 Oxoamide substrates 143 were obtained by treating L-DOPA-derived succinimides with organolithium reagents. Both BF3·OEt2 and TFA were successfully applied in the NAI cyclization step, and a general observation was that the trans product (144) was preferred when BF3·OEt2 was used as the catalyst, whereas the cis product (145) predominated under TFA conditions. It was noteworthy that the deprotection occurred prior to cyclization, that the protecting group of TBDPS or Bn had no effect on the stereochemical outcome of the reaction, and that the cis selectivity improved with decreasing size of the substituent at the α-position of the nitrogen when TFA was used as the acid (Scheme 38).10 In addition to this method, enantiomerically pure tricylic pyrrolo[2,1-a]isoquinolines were also obtained through a tandem organolithium addition/NAI cyclization approach.127 In a continuation of previous work on catalytic αamidoalkylation reactions of N,O-acetals,128−130 Comesse, ̈ and co-workers reported the Tf2NH-catalyzed Dalla, Daich, NAI cyclization of N,O-acetal substrates131 for both intramolecular and intermolecular transformations.132 As for studies on cyclization reactions, N,O-acetal 146 with a quaternary carbon flanked by two electron-withdrawing groups was readily available through a stereoselective formal [3 + 2] cycloaddition method.131 The Tf2NH-catalyzed cyclization of 146 gave tricyclic compounds 147 in good to excellent yields (Scheme 39).

investigated furan-tethered dihydroxy- and diacetoxylactams with different tether lengths.121,122 In these studies, N-(furan-2yl)methyl-4,5-dihydroxy-γ-lactam with a one-carbon tether failed to give the cyclized 5−5−5 scaffold, and instead, the dimerized compound was obtained as a single diastereoisomer in 60% yield.121 N-(Furan-2-yl)propyl-4,5-dihydroxy-δ-lactam and N(furan-2-yl)propyl-4,5-diacetoxy-δ-lactam, both having a threecarbon tether, also led to formation of the dimerized macrocyclic products through intermolecular cyclization, instead of the 5− 7−5 tricyclic scaffold.122 The dimerization of these dihydroxylactam substrates can be explained by the fact that 5−5−5 and 5−7−5 linearly fused scaffolds are sterically less favored than the 5−6−5 linear scaffold.121 Dimerization of NAIs derived from other 4,5-dihydroxy-γ-lactams has also been observed in Rittertype cascade reactions for the synthesis of arylamidopyrrolidinone libraries (Scheme 35).123 The series of N,O-acetal TMS ethers 127 were conveniently prepared as NAI precursors from the corresponding amides in the synthesis of 5,6-dihydrophenanthridines 128−130.124 Electron-rich aromatic rings (of high nucleophilicity) led to the formation of cyclized compounds in high yields, whereas less reactive rings, such as the unsubstituted benzene ring and a 3chloro derivative, failed to give the desired dihydrophenanthridines 128s and 128t (Scheme 36).124 Franzen and co-workers reported a one-pot hemiaminal formation/NAI cyclization sequence for the synthesis of a series of quinolizidine derivatives.125,126 Hemiaminal substrates 134 were formed through an enantioselective conjugate addition of aldehyde 131 and nucleophile-substituted amide 132, catalyzed by the chiral pyrrolidine derivative 133.125 The key step was the diastereodivergent intramolecular NAI cyclization, which was tested with a wide selection of substrates to give the tricyclic scaffolds 135−139 and the three tetracyclic scaffolds 140−142. 7827


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Scheme 37

Scheme 38

Lewis superacid Sn(NTf2)4 was sufficient to perform this reaction, and the tricyclic products 149 and 151 were generated in excellent yields following extensive optimization of reaction conditions (Scheme 40). It is noteworthy that several other

An earlier example from the same group was a study on triflimidate-based catalyst for the cyclization of hydroxylactam substrates 148 and 150 to afford tricyclic compounds with scaffolds similar to that of 147. A loading as low as 1 mol % of 7828


Chemical Reviews

Review

Scheme 39

Scheme 40

Scheme 43

catalyst in different solvents. Enantiomeric excess exceeding 70% was obtained using 20% of catalyst 75 in toluene, although the yield was poor (23%, Scheme 41). Hydroxylactam substrate 154 was obtained as a single diastereomer through the addition of allylmagensium chloride to the parent substituted thiazolidinedione. Thiazoloisoquinolines 155 were obtained in high yields, whereas isomerization of the allyl group at the C-10b position of the thiazole[4,3a]isoquinoline-3-one scaffold was observed for 155. Thiazoloisoquinoline 155b (R = CH3) was obtained in good yield (96%) but with a poor diastereoselectivity (dr = 70:30) (Scheme 42).136 A subsequent ring-closing metathesis (RCM) reaction converted 155 to the corresponding tetracyclic spiroisoquinoline derivatives. Compounds with the same thiazolo[4,3-a]isoquinoline scaffold substituted by two methoxy groups were obtained by the same authors in an earlier work on Parham cyclization,133 which were also used for the synthesis of pyrrolo[2,1-a]isoquinolines and isoindolo[1,2-a]isoquinolines.9,135 A highly diastereoselective NAI cycliczation step was reported in a four-step asymmetric synthesis of the pyrroloisoquinoline alkaloid (+)-crispine A 159.138 Imide substrate 156, obtained from (2S)-2-amino-3-(3,4-dimethoxyphenyl)propan-1-ol and succinic anhydride,139 was subjected to a NaBH4 reduction and acidic conditions to give the tricyclic lactam 158 through the intermediate hydroxylactam/NAI 157. A subsequent approach comprising IBX oxidation, Rh-catalyzed decarbonylation, and LAH reduction gave crispine A 159 with an excellent ee value (>95%, Scheme 43).138 Kałuża and co-workers reported the synthesis of hexahydropyrroloisoquinolines 161 and 162 substituted at the newly formed quaternary carbon stereocenter through NAI cyclization from L-tartaric acid-derived acetylated hydroxylactam substrates 160.140,141 Investigation of the reaction scope and conditions revealed that the diastereoselectivity of the acid-catalyzed NAI

Scheme 41

Scheme 42

triflimidates were tested, including Bi(NTf2)3, Cu(NTf2)2, and In(NTf2)3, and all displayed excellent catalytic efficiency.128 Lete and co-workers have reported several NAI approaches for the synthesis of heterofused compounds, typically relying on a methoxylated aryl nucleophilic substrate for the synthesis of tricyclic compounds containing isoquinoline scaffolds.9,10,56,60,127,133−137 Enantioselective intramolecular cyclization of tertiary NAIs derived from 152 with nucleophilic methoxylated benzene rings can be affected with BINOL-derived chiral Brønsted acids.60 Along these lines, pyrrolo[2,1-a]isoquinoline 153 was synthesized with various degrees of enantiomeric excess depending on the BINOL-derived acid 7829


Chemical Reviews

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Scheme 44

from the hydroxylactam 163 in the presence of Lewis acid.142 Hydroxylactam substrate 165, readily obtained from DIBAL-H reduction of the corresponding piperidine-2,6-dione substrate, was cyclized to the tricyclic compound 166 using TMSOTf as the acid to form NAIs in situ (Scheme 45).143 Compound 166 was obtained as a mixture of two diastereomers and coupled to a C28 fatty-acid chain to yield marine natural products schulzeines B and C.145 More quinolizinone scaffolds and some indolizinone scaffolds 168−172 were synthesized in moderate to high yields with poor diastereoselectivity from dibenzylamino-substituted hydroxylactams 167.144 Compounds 168−172 were converted to their corresponding cyclic enamides through Cope elimination of the dibenzylamino substituent (Scheme 46).144 As a continuation of a previous study on the Schmidt reaction of azido acyl chlorides through isocyanate ion intermediates,146 Gu and co-workers reported a new type of Schmidt reaction for the synthesis of tricyclic benzo-fused lactams 174 through NAIs. The azido acyl chloride was generated by treating the carboxylic acid substrate 173 with oxalyl chloride. A subsequent Schmidt rearrangement of the aminodiazonium ion intermediate afforded the NAIs, which were trapped by the tethered aromatic ring through an intramolecular Pictet−Spengler reaction to afford the fused tricyclic compounds 174 and tetracyclic compound 175 (Scheme 47).77 King and co-workers have described the synthesis of several polycyclic scaffolds through triflic acid-mediated NAI cyclization, with examples of the acyl group being either endocyclic or exocyclic to the cyclic NAI precursors.147−149 The study was initiated with triflic acid-mediated cyclization of biphenylacetamide 176, leading to the expected tricyclic compound 177, as well as the tetracyclic compound 178, which is a rare example of NAI cyclization of unactivated aromatic nucleophiles in the synthesis of eight-membered rings.147 A series of substituted phenylbutyramides 179 and their corresponding N-acyl-2hydroxy-pyrrolidines 181 were examined in the reaction. The resulting tricyclic compounds 180 were obtained as mixtures of isomers. Through the preformation of the intermediate 2hydroxy substrate 181, improved overall yields for products 180 with electron-withdrawing substituents were obtained (Scheme 48).147 As a complement to this exocyclic NAI cyclization approach, an endocyclic approach for the synthesis of benzo-fused eightmembered benzazocinones and dibenzazocinones was reported by the same group.149 Reduction of the succinimides 182 gave the corresponding hydroxylactams 183, which were applied in endocyclic NAI cyclization in the presence of 10 equiv of triflic acid in refluxing CHCl3, thereby generating pyrrolobenzazocin5-ones 184 from mildly deactivated or activated phenyl

Scheme 45

Scheme 46

cyclization step was strongly dependent on the size of the substituent R and the reaction conditions, including the solvent, amount of acid, temperature, and concentration of the lactam substrates. The diastereoselective outcome of the reaction was dictated by various steric interactions between the nucleophilic dimethoxyphenyl group, the R substituent, and the pendant acetoxy groups (Scheme 44).140 Kuntiyong and co-workers reported several examples of the synthesis of tricyclic quinolidizdinone scaffolds.142−144 In an effort to synthesize the tricyclic core of the marine natural products referred to as schulzeines, the tricyclic scaffold of tetrahydroisoquinoline fused with δ-lactam 164 was synthesized 7830


Chemical Reviews

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Scheme 47

Scheme 48

substrates. The cyclization did not occur for the strongly deactivated nitro derivative 184i, but even more surprisingly, the reaction also did not occur for the 4-methoxy-substituted analogue 184g. Piperidinobenzazocine 185 and pyrrolobenzazocin-5-one 186 were also obtained in good yields from the corresponding hydroxylactams. Succinimides 187 were subjected to the reduction/cyclization approach to give the “trans” isomers 188, with the R group oriented trans to the pyrrolidinone ring as the major product, together with minor amounts of the “cis” isomers 189 (Scheme 49).149 Daic̈ h and co-workers investigated the use of sulfur nucleophiles in NAI cyclization in the late 1990s,150,151 and more recent examples from the group include studies on cascade sequences, including NAI cyclization for the synthesis of tricyclic and tetracyclic compounds incorporating N,O-, N,S-, and N,Seacetal moieties.152−154 α-Hydroxy lactams 190 were synthesized from trimethylimidazolidine-2,4-dione as precursors for NAIs 191, which could be isomerized into cyclic aza-oxonium ions 192. A final intramolecular reaction of the aromatic moiety to the N-acyliminium cation 193 gave the tricyclic compound 194 in variable yields, depending on the different types of acetals and substituents around the scaffold. Direct π-cationic cyclization of the NAI 191 (X = O, R = 2-I) led to the formation of the

regioisomer 194b, which has an iodo moiety in the ortho position of the benzene ring (Scheme 50).152 The formation of products resulting from direct π-cationic cyclization and heterocyclization/transposition/cyclization was observed.154 4.2. Tricyclic Scaffolds with Spiro Atoms

4.2.1. Alkene and Alkene-Type Nucleophiles. Although indole-containing alkaloids have been synthesized by numerous variations on the Pictet−Spengler theme, few attempts have been made to synthesize 2-spiroindoline alkaloids through direct reaction of 2-substituted indoles.155 A recent example of direct transformation of 2-substituted indoles to 2-spiroindolines was reported by Abe and co-workers.103 Protonation of indole substrates 195 at the C3-position of the indole ring in formic acid yielded the corresponding NAI, which reacted with the conjugated diene through a chairlike transition state, followed by addition of formic acid to the side chain to generate tricyclic spiro compounds 196 (Scheme 51).103 Yazici and Pyne reported a sequential 1,4- and 1,2-addition of bis-nucleophiles to α,β-unsaturated NAIs for the synthesis of spiro and bridged scaffolds. (E)-Enamide substrates 197, obtained by treating the corresponding α,β-unsaturated NAI precursors with allyltrimethylsilane for 1 h at room temperature, were converted to the tricyclic spiro scaffolds 198 in the presence 7831


Chemical Reviews

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Scheme 49

Scheme 50

Scheme 52

Scheme 53

Scheme 51

7832


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spiro-1-isoindolin-3-ones 221 and 222 from oxylactams.157,158 Bicyclic oxylactam pyrrolidines and piperidines 213 were synthesized from (R)-phenylglycinol-derived NAIs through cyclization with tethered arene nucleophiles, giving mixtures of diastereoisomeric products with dr ratios of approximately 3:1.157 Other types of bicyclic oxylactams derived from N-(2hydroxy-1(R)-phenylethyl)-succinimide and tricyclic oxylactam obtained from phthalimide were cyclized to give spirocyclohexane[1,2′]-pyrrolidin-5′-ones 216 and 217 and spirocyclohexane[1,1′]isoindolin-3′-ones 218 and 219, but this method could not be extended to the corresponding spirocyclopentane compound (Scheme 56).158 Among examples of intermolecular NAI reactions for the synthesis of tricyclic scaffolds was a sequential cascade of Lewisacid-mediated ring-opening of cyclopropyl ketones with nitriles, copper-catalyzed Ritter reaction, and Lewis-acid-promoted cyclization approach to give tricyclic fused indolizinones in moderate to good yields.159 Another example was the synthesis of polycyclic spirocyclic and bridged heterocyclic scaffolds through intermolecular 1,4- and 1,2-addition reactions of bisnucleophiles to α,β-unsaturated NAIs.30

Scheme 54

Scheme 55

4.3. Other Tricyclic Scaffolds

In the study of sequential 1,4- and 1,2-addition of bisnucleophiles to α,β-unsaturated NAIs, Yazici and Pyne also reported the synthesis of bridged tricyclic scaffolds 224 and 225 from enamides 223, which were obtained as separable mixtures of 1:1 diastereomers by treating the corresponding NAI precursor with allyl- or 2-methallyltrimethylsilane in the presence of BF3·OEt2 for 1 h. Retreatment of the isolated diastereomers of 223 under the same conditions for 18 h gave pure diastereomers of tricyclic enamides 224 and 225. The alternative approach of treating the mixture of two diastereomers of 223 gave 1:1 mixtures of separable diastereomers of 224 and 225 (Scheme 57).30 Scaffolds with bridged piperidine rings, such as that of morphine, are found in various natural and biologically active compounds. Wanner and co-workers reported the synthesis of unsaturated 5-substituted 7,8-benzomorphans 227 through a cyclization step of 4,4-disubstituted N-acetyl-1,4-dihydropyridines 226 as NAI precursors. In most cases, a clean transformation in 4 M hydrochloric acid in dioxane gave the desired products in excellent yields. The obtained unsaturated tricyclic bridged scaffolds 227 could also be transformed to the corresponding saturated compounds using NaBH4 as the reductant. A concomitant cyclization, N-deprotection, and Boc-protection approach was also included in the same study, which afforded compounds containing the 5-substituted 7,8benzomorphan scaffold (Scheme 58).160 A few bispidine derivatives bearing a 3,7-diazabicyclo[3.3.1]nonane core scaffold were prepared from the amine substrate 228,161 which was obtained through a stereoselective Mannich reaction of a β,β′-diamino ketal and an aldehyde component.161,162 Amine 228 underwent a condensation step with glutaric anhydride and phthalic anhydride to give imide 229 and 230, respectively, which were reduced to the corresponding hydroxyl compounds 231 and 232. In the presence of methanesulfonic acid, the NAI cyclization of 231 gave tricyclic bispidine compound 233, and the cyclization of 232 gave a mixture of three tetracyclic compounds 234, 235, and 236 with a total yield of 75%. Following hydrogenation over palladium on charcoal, the Cbz-deprotected bispidine derivatives of 234, 235, and 236 were evaluated for their analgesic effects. In comparison

of BF3·OEt2 with the loss of the Bn group. Compounds 198 were obtained in moderate to good yields with high diastereomeric selectivity (Scheme 52).30 4.2.2. Aromatic and Heteroaromatic Nucleophiles. In addition to the tricyclic scaffolds obtained from the furantethered 4,5-dihydroxylactams,122 Pyne and co-workers also obtained compounds with spirotricyclic units when the furan-5position was substituted by a bromine (199 and 201) in the presence of TFA or Sc(OTf)3. The tricyclic compounds 200 and 202 were obtained as single diastereoisomers,122 which share the same spirocyclic butenolide core as compounds synthesized by Martin in the 1990s, through LiClO4 promoted cyclization of activated TIPS-substituted furan-tethered hydroxyl-γ-lactam substrate (Scheme 53).156 The amido ketone NAI precursor 203 contains an activated pyridine nucleophile, which undergoes cyclization and generates tricyclic spirolactams 205−207 in the presence of Brønsted acids, such as TsOH, PPTS, and CSA, at high temperature. The formation of 206 and 207 were explained as a result of rearrangement and/or Hilbert−Johnson reactions of 205. Prolonged reaction time also led to the isolation of the enamide, which can be regarded as the dehydration product of the NAI intermediate 204 (Scheme 54).104 Another activated pyridine nucleophile, embedded in amido ketone substrate 208, was applied in the synthesis of tetracyclic spirolactams 211 and 212, probably through thermally induced rearrangement of 210, with a similar type of Brønsted acidic reaction condition (Scheme 55).105 Vernon and co-workers reported the asymmetric synthesis of spiro-2-pyrrolidin-5-ones/-2-piperidin-6-ones 214 and 215 and 7833


Chemical Reviews

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Scheme 56

to that of morphine, only weak analgesic effects were observed for these compounds (Scheme 59).161

Scheme 57

5. SYNTHESIS OF TETRACYCLIC SCAFFOLDS 5.1. Linear Tetracyclic Scaffolds

5.1.1. Indole and Heteroaromatic Nucleophiles. In addition to extensive applications for the synthesis of tricyclic scaffolds, the Pictet−Spengler reaction has also been an important synthetic method for the construction of alkaloids with tetracyclic indole or isoquinoline scaffolds. Enamides generated from substrate 237 through a ruthenium-catalyzed tandem ring-closing metathesis (RCM)/isomerization sequence were isomerized to NAI intermediates 240, which underwent an intramolecular cyclization with tethered heteroatom and carbon nucleophiles to give polycyclic compounds with excellent diastereoselectivity, such as hemiaminals 241−243; tricyclic compounds 244 and 245; pyrrolo[2,1-a]isoquinolines 246 and 247;12 and tetracyclic indolizinoindole derivatives 248, 249, and analogue 250 (Scheme 60).163 In the previously mentioned ruthenium hydride/Brønstedacid-catalyzed isomerization method reported by Nielsen and coworkers, allylic amides 251 were isomerized to NAI precursors, which were trapped by a tethered indole nucleophile to afford 252 (Scheme 61).107 Scaffolds resembling that of 252 were also obtained through enantioselective BINOL phosphoric acid- (BPA-) catalyzed cascade reactions of a range of tryptamine derivatives 253 and 258 with lactones,61 ketoacids,62 or enones,63 as reported by Dixon and co-workers. In all cases, reactions of tryptamines 253 with various cyclic enolesters yielded reactive NAI intermediates,

Scheme 58

7834


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Scheme 59

Scheme 60

Scheme 61

which were attacked by pendant indole nucleophiles in an enantioselective manner, mediated by the chiral conjugate base of BPA. The reactions were generally tolerant of several substitution patterns, and the polycyclic β-carboline products 255−257 were obtained in good yields, typically with high enatioseletivity (Scheme 62).61−63 A recent computational mechanistic study involving DFT and QM/MM hybrid calculations suggested that the BINOL-derived phosphoric acid-catalyzed Pictet−Spengler reaction involves a highly ordered transition structure that accounts for the high level of enantioselectivity in this type of reaction.164 Compounds 259 sharing a similar 6−5−6−6 ring system with scaffold 256 were also obtained in earlier studies of one-pot multicomponent/ Pictet−Spengler-type reactions through N-carbamoyliminium ions derived from indole substrates 258 (Scheme 63).108 Inspired by the Ru-catalyzed tandem RCM/isomerization sequence reported by the Nielsen group,163 You and co-workers developed an RCM/isomerization Pictet−Spengler cascade based on ruthenium/chiral phosphoric acid sequential catalysis. In this approach, tetrahydro-β-carbolines 261 were obtained in high yields and enantioselectivities from substrates 260 derived from substituted allyl amine, whereas poor enantioselectivity was 7835


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Scheme 62

Scheme 64

Consecutive Sonogashira/NAI cyclization reactions were reported for the synthesis of a series of tetracyclic and pentacyclic lactams in good yields.168 Substrates 265 and 267 with either a benzofuran core or an indole core were obtained by a Sonogashira reaction between N-alkynylimides and 2-iodophenol or 2-iodo-N-tosylaniline in good yields. Selective partial reduction of 265 and 267 using LiEt3BH followed by the treatment of TsOH led to the formation of tetracyclic lactams 266 and pentacyclic lactams 268 in moderate to good yields (Scheme 66).168 5.1.2. Other Aromatic Nucleophiles. Nucleophilic substitution of unprotected N,O-acetals catalyzed by a low loading of Lewis superacidic tin(IV) triflimidate has successfully been applied to the synthesis of tetracyclic scaffolds 270 and tricyclic scaffold 272 through Friedel−Crafts-type cyclization of substrates 269 and 271, respectively, in excellent yields (Scheme 67). This method shows broad applicability using silicon-based nucleophiles and other types of carbon nucleophiles, including methylene, arenes, and ketones.128 Stepakov and co-workers examined a series of tetracyclic scaffolds prepared through intramolecular Friedel−Crafts-type reactions of racemic hydroxylactams 273, 276, 279, and 281. Because of the inductive effect of the adjacent oxygen atom, only the carbonyl group at the β-position of the dihydroisoxazole oxygen was reduced, giving the target hydroxylactams as single diastereomers in moderate to excellent yields.169 Starting from hydroxylactams 273, which were isolated as single diastereomers upon NaBH4 reduction of the corresponding pyrrolidine-2,5diones, both tetracyclic isoxazolopyrroloisoquinolines 274 and 275 were observed, typically with variable epimeric ratios as determined by NMR spectroscopic analysis (Scheme 68). It is assumed that the major diastereomer 274 was formed by nucleophilic attack on the NAI formed in situ in the presence of BF3·OEt2, from the sterically least-hindered face, opposite the dihydroisoxazole ring.170 Based on these results, a follow-up study on hydroxylactams 276 and 279 with different substituents at the N-(2-phenylethyl) fragment (Schemes 69 and 70) was reported by the same group.171

Scheme 63

obtained when unsubstituted allyl amines were used as substrates (261r, R2 = H) (Scheme 64).165 Cincinelli and co-workers reported the TFA-catalyzed cyclization reaction of indole-2-containing carboxylic acid oxoamides 262.166,167 Depending on the length of the chain between the amide and the oxo group and the substitution pattern of the amides, cyclization occurred through one of two distinct mechanisms: either a Friedel−Crafts-type pathway to form β-carbolinones and dihydro-2H-azepino[3,4-b]indol-1ones166 or an NAI pathway to give tetracyclic pyrrolizino[2,1b]-indoles 264.167 Attachment of another N substituent at the secondary amide moiety of 262 effectively blocked the formation of the hydroxylactam intermediates 263 required for the NAI pathway, thus leading to the formation of the corresponding tricyclic compounds with larger fused rings (Scheme 65).167 7836


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Scheme 65

Scheme 66

In a study on intermolecular α-amidoalkylation between various α-acetoxy lactams 285−287 and silane C-nucleophiles in the presence of a catalytic amount of bismuth triflate [Bi(OTf)3], ̈ and co-workers also performed intramolecular NAI Daich cyclization reactions of α-acetoxy lactams 285−287, which were obtained by acetylation of the corresponding hydroxylactams.172 The Bi(OTf)3-catalyzed π-cationic cyclization showed tolerance of the N,O-acetal substrates 285a−c, whereas N,S-acetal substrates 285d−f failed to give the cyclized product and instead led to the corresponding S,N,S-diacetals in low to moderate yields. Chiral trans-diacetate 286 led to the single diastereomer 289 in 73% yield, and 287 led to the dehydrated tricylic compound 290 with a newly formed double bond in conjugation with the phenyl ring (Scheme 72).172

Scheme 67

5.2. Tetracyclic Scaffolds with Spiro Atoms

5.2.1. Indole and Heteroaromatic Nucleophiles. Based on previous work on the synthesis of the hexahydroindolinnone scaffold through NAI cyclization,118 Padwa and co-workers reported an aza-Wittig/NAI approach for the synthesis of furantethered tetracyclic scaffolds.173 The hexahydroindolinone substrate 291 was obtained through an aza-Wittig reaction between an iminophosphorane and a ketoacid, and sulfoxide substrates 293 and 295 were obtained by oxidizing the corresponding aza-Wittig products with sodium periodate.

Intramolecular Friedel−Crafts-type cyclization was also performed on racemic hydroxylactams 281 to examine the effect on stereoselectivity of a substituent in the β-position of the acyl nitrogen atom. In both cases, a mixture of the three pyrroloisoquinolines 282, 283, and 284 was obtained (Scheme 71).171 The relative configurations of the diastereomers in these studies were determined by single-crystal X-ray crystallography and NOE spectroscopic analyses.170,171 7837


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Scheme 68

Scheme 69

Scheme 70

Scheme 71

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Tetracyclic scaffold 292 was obtained as a racemic mixture in more than 90% yield in the presence of TFA or TfOH. Compounds 294 were obtained as the exclusive racemic products through a Pummerer/Pictet−Spengler cyclization sequence,174 following treatment with trifluoroacetic anhydride and TFA. The comparatively low yield of 294b was explained by the entropically more demanding cyclization toward the sevenmembered ring.173 In a further expansion of the reaction scope, polycyclic compounds, such as racemic compound 296, were synthesized. This approach is analogous to procedures reported by Tu and co-workers,120 in addition to heteroaromatic systems based on tethered thiophene and pyrrole moieties (Scheme 73).119 Bosch and co-workers reported the synthesis of spiroindole3,3′-indolizidine from (S)-tryptophanol-derived lactam substrates,175 thus providing an efficient enantioselective synthesis of spiropiperidone derivatives. Lactam substrates 297 were readily accessible through a cyclocondensation approach, in which (S)-tryptophanol reacted with an appropriate prochiral or racemic δ-oxoester.176 A regio- and stereoselective intramolecular cyclization at the 2-position of the indole gave the tetracyclic indolo[2,3-α]quinolizidine 298.177 Cyclocondensation using substituted (S)-tryptophanol with reduced nucleophilicity at the 2-position of the indole moiety, for example, through N-tosylation, gave lactam substrate 299, which was subjected to acidic conditions, such as TiCl4, BF3·OEt2, or TFA, to enable electrophilic attack from the indole 3-position of the NAI formed in situ, thereby affording an intermediate spiroindoleninium cation, which was trapped to give the tetracyclic spiroindole-3,3′-indolizidines 300 (Scheme 74). The hydroxymethyl appendenage that functioned as an efficient stereocontrol substituent could be removed,109 to give the corresponding enantiopure spiroindoline compounds.175 The same group also reported the application of (S)-tryptophanol as a starting material for the synthesis of other spiro compounds, such as ent-rhynchophylline and ent-isorhynchophylline.178 This type of α-aminoalkylation reaction has also been carried out with benzylic N-thioacyliminium ions.179 5.2.2. Other Aromatic Nucleophiles. Starting from spirocyclic hydroxylactam 301, tetracyclic scaffold 302 was obtained by direct nucleophilic attack of the π-aromatic ring to the NAI formed in situ from the less-hindered isoxazole side (with the O substituent). Using naphthyl-substituted substrates 301, compounds 303a and 303b with a pentacyclic scaffold were obtained in excellent yields (Scheme 75).180 Erythrina and homoerythrina compounds are alkaloids bearing a tetracyclic core scaffold based on a spiroamine unit, such as 3-demethoxyerythratidinone 306 and erysotramidine 309.181 Among numerous methods for assembly of the erythrinane tetracyclic core,182,183 a two-step sequence comprises ketone alkylation with N-substituted iodoacetamides to give hydroxyl lactam substrates 304, 307, and 310, followed by NAI cyclization to give tetracyclic scaffolds, such as compounds 305, 308, and furan-fused compounds 311,120 which Padwa and co-workers have studied extensively (Scheme 76).119,184 A one-pot process involving Pictet−Spengler reactions of NAI precursors 312 and 315 formed from simple furan substrates has been employed in other erythrinane syntheses.185 A range of acids, including both Brønsted and Lewis acids, have been tested for the method. It was found that treatment of 312 with BF3· OEt2, from −78 °C to room temperature with a total reaction time of 16 h, afforded the tetracyclic compound 313 in 57% yield. Using AlCl3 as the Lewis acid in the reaction gave another

Scheme 72

Scheme 73

Scheme 74

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Scheme 75

Scheme 76

stereochemical outcome of the reaction, and a “syn-selective cyclization effect” of the TIPS-protected lactam was discussed in the study.187 The minor product 325 from the NAI cyclization step was used for a subsequent Wacker oxidation, reduction, Swern oxidation, and aldol cyclization to give (+)-3-demethoxyerythratidinone 326, which failed to undergo the desired ringopening/ring-closing metathesis reactions (Scheme 78).188

tetracyclic compound, namely, 314, with a double bond in one of the three nonaromatic rings of 313. With 315 as the NAI precursor, BF3·OEt2, AlCl3, and TFA led only to complex mixtures, whereas formic acid as the solvent in this reaction at room temperature for 2 h resulted in the Pictet−Spengler cyclization product 316. Reflux conditions for a prolonged period of time gave the tetracyclic compound 317 through successive acid-catalyzed electrophilic substitutions of the aromatic ring with NAI and the terminal aldehyde (Scheme 77).185 Simpkins and co-workers reported several procedures for the synthesis of erythrinane alkaloids, such as the aromatic dienoid type, erysotramidine 320, and the alkenoid type, 3-demethoxyerythratidinone 326.186−189 A common key step in the methods of Simpkins and co-workers relies on NAI cyclization. The bridged imide substrate 318 was obtained through a desymmetrization effected by a chiral bis-lithium amide base. Desilylation of 318 and TFA-assisted NAI cyclization gave 319 as a single diastereomer in excellent yield. A subsequent retro-Diels−Alder reaction, dehydrogenation, and methylation gave erysotramidine 320.186 Enantiopure hydroxylactam substrate 321 was used as an NAI precursor. The nature of the protecting groups attached to the secondary hydroxyl group of the lactam 321 determined the

5.3. Other Tetracyclic Scaffolds

5.3.1. Heteroatom Nucleophiles. Overman and coworkers reported a sequential asymmetric Heck/NAI cyclization approach for the synthesis of the tetracyclic alkaloid 330 containing a 1,2,3,4-tetrahydro-iminoethano-9H-carbazole scaffold.190 Dienyl carbamate triflate substrate 327 was synthesized as a Heck precursor and underwent an asymmetric Pd-catalyzed cyclization effected with chiral ligands developed by Pfaltz and co-workers,191 thereby generating a crude tricyclic dienyl carbamate compound that could be treated with an excess amount of TFA to give enantiopure 3,4-dihydro-9a,4a(iminoethano)-9H-carbazole 330 in 75% overall yield. Starting from said tetracyclic diydrocarbazole 330, further elaboration included seven steps as part of the first total synthesis of the pentacyclic natural alkaloid product (+)-minfiensine (331) (Scheme 79).190 7840


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336/337, respectively, in the presence of TsOH, albeit as mixtures of diastereoisomers that were separable by column chromatography (Scheme 80). The proposed mechanism involved the formation of a cyclic, six-membered NAI, which was subjected to nucleophilic attack from the amide nitrogen to afford the target product.64 The stereochemistry of the synthesized compounds was assigned through X-ray crystal structure analysis, NOESY, and circular dichroism experiments.192 A series of bridged phenylpyridines with a high degree of scaffold similarity compared to the constrained tetracyclic compounds above were synthesized through intramolecular cyclization of NAIs formed in situ from acyclic precursors 338 and 341.193 The cyclization step, also performed with TsOH· H2O as the acid, revealed that the diastereoselectivity depended on the steric effects of substituents at the chiral center of substrates 338 and 341. Benzyl substitution led to excellent diastereoselectivity, whereas smaller substituents, such as methyl and i-Bu, reduced the diastereoselecitivity significantly. Although no crystal structures were reported for the synthesized tetracyclic compounds 339, 340, 342, and 343, the absolute stereochemistry was assigned on the basis of NOESY analysis and circular dichroism measurements, as well as reported data of known analogues (Scheme 81).193 5.3.2. Indole Nucleophiles. An annulation strategy was reported by Delgado and Blakey for the construction of a tetracyclic core194 that resembles the scaffolds embedded in malagashanine and strychnine alkaloids.195 Indole aminol substrates 344 with either N-acylamide or N-tosylamide were synthesized as N-acyl-/tosyliminium ion precursors. In addition to the desired tetracyclic products 345, the tetrahydro-β-

Scheme 77

A series of conformationally constrained compounds containing a fused chiral bicyclic bridge were obtained through a cascade cyclization approach, comprising the steps of cyclic NAI intermediate formation and cyclization.192 α-Amino acids were used as chiral sources to construct biaryl substrates 332 and 335, which were cyclized to the tetracyclic compounds 333/334, and Scheme 78

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Scheme 79

tosyliminium by the appended allylsilane group whereas undesired Pictet−Spengler products were formed through competitive C3−C2 migration. The presence of a strongly electron-withdrawing group attached to the iminium ion nitrogen favored the formation of tetracyclic products 345. The presence of the electron-donating groups at the indole ring and removal of the benzyl protection group at the indole nitrogen resulted in lower yields of tetracyclic compounds, and Pictet−Spengler products were preferred (Scheme 82).194

Scheme 80

6. SYNTHESIS OF POLYCYCLIC AND MISCELLANEOUS SCAFFOLDS 6.1. Polycyclic Scaffolds

6.1.1. Linear Polycyclic Scaffolds. Meyer, Cossy, and coworkers reported the synthesis of polycyclic scaffolds based on substituted bicyclic NAI precursors.196,197 Protonation of the corresponding enamides (347) and hemiaminals (350, 353) yielded substituted bicyclic NAIs with tethered π-nucleophiles (indol-2-yl, indol-3-yl, 1-methyl-pyrrol-2-yl, and 3,5-dimethoxyphenyl), which underwent diastereodivergent Pictet−Spengler reactions to give epimeric polycyclic scaffolds, notably with good control of stereoselectivity of the quaternary stereocenter at the newly formed ring junction. NAIs with a pyrrolidinone moiety fused to three-membered (347), six-membered (350), and norbornene (353) ring systems were successfully employed in this reaction, thereby generating both kinetic and thermodynamic products, depending on the reaction conditions. Selected examples are summarized in Schemes 83 and 84.197 Cyclization under kinetic and thermodynamic control was reported by the same group, for example, in the Pictet−Spengler cyclization of bicyclic NAIs generated through protonation of the enamide substrates 356 in the presence of MsOH to afford tetracyclic 3azabicyclo[3.1.0]hexan-2-ones 357−361 with high diastereoselectivity.196 The enamide substrate 356 bearing a 3-azabicyclic[3.1.0]hexan-2-one bicyclic moiety was obtained through a Cu-free Sonogashira cross-coupling reaction between Nsubstituted cis-2-iodocyclopropanecarboxamides and terminal aryl- and heteroarylalkynes/-enynes,198 followed by 5-exo cyclization of the nitrogen amide onto the alkyne triple bond. Enamides with a nucleophilic 3,4-dimethoxyphenyl group substituted at the nitrogen position led to formation of the desired cyclization products in high yields as single diastereomers, most notably when the olefin was substituted by an aromatic group. A substrate with a dienamide moiety (356, R = prop-1-en-2yl) did not provide the desired tetracyclic product;

Scheme 81

carbolines 346 were also obtained as side products resulting from competitive Pictet−Spengler processes. These observations were explained by a proposed mechanism in which the desired product 345 was obtained through trapping of the formed N-acyl-/ 7842


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Scheme 82

Scheme 83

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Scheme 84

Scheme 85

N-aryloxymethyl-substituted hemiaminals 382 as the hydroxyl substrates, a cascade oxocyclization/exocyclic NAI formation/ arylation mechanism was proposed for the formation of the tetracyclic scaffold 383 (Scheme 88).199 6.1.2. Spiro Polycyclic Scaffolds. Among the synthetic methods reported to access spiro-oxindole scaffolds,200 a tandem halide displacement/amide coupling/spirocyclization approach ̈ and co-workers for the synthesis of spirowas used by Daich oxindole 384 with a lactam moiety.201 Regioselective reduction of 384 gave the hydroxyl-γ-lactam spiro-oxindoles 385 and 386 as NAI precursors, which, under acidic reaction conditions, yielded penta-/hexacyclic spiro-oxindoles 387−394 with high diastereoselectivity (Scheme 89).201 Dixon and co-workers reported cascade cyclization reactions of basic and acidic reagents in one pot, also referred to as site-

instead, it underwent decomposition. Enamides bearing a less nucleophilic 3-methoxyphenyl group or the 3-thienyl moiety led to the formation of Pictet−Spengler cyclization products 362− 364 in satisfying yields (Scheme 85).196 A variety of 3-substituted isoindolinone scaffolds were obtained through intramolecular cyclization of γ-hydroxylactams catalyzed by a multimetallic Ir−Sn 3 complex {[Cp*Ir(SnCl3)2SnCl2(H2O)2]}.199 Phthalimide- and succinimidederived γ-hydroxylactams 365, containing tethered aromatic nucleophiles, were cyclized to the corresponding tetra- and tricyclic scaffolds 366−372 in excellent yields in the presence of 1 mol % of the Ir−Sn3 catalyst (Scheme 86). The scope of the reaction was also tested for γ-hydroxylactams 373 with heteroatom nucleophiles, including sulfonamides, alcohols, and thiols to yield compounds 374−381 (Scheme 87). In the case of 7844


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Scheme 86

cascade toward polycyclic spiro compounds 399−405, which were obtained in moderate to excellent yields with a broad substrate scope (Scheme 90). The major products formed resulted from attack of the π-nucleophile on the face opposite the carbonyl ketone group when diastereoselectivity was observed in this SIBA-catalyzed cascade reaction.202 6.1.3. Other Polycyclic Scaffolds. Building on the azaNazarov-type reaction reported by Klumpp and co-workers,85 a follow-up study of the synthesis of various heterocyclic scaffolds extended the application scope of this aza-Nazarov-type cyclization, such as in the reactions of NAI salts 406 prepared in situ from acid chlorides and imines. In the presence of 2−5 equiv of CF3SO3H, NAI salts 406 were cyclized to give bicyclic products 407 and 408, tricyclic product 409, tetracyclic products 410 and 411, and pentacyclic products 412 and 413. The benzoylated substrate 414 preferentially cyclized at the benzyl phenyl group to give the Friedel−Crafts-type alkylation product 415 (Scheme 91).86 In a recent example from the Klumpp group, acetal-containing benzamide substrates 416 and alcohol-containing substrates 420 were utilized for the synthesis of tricyclic scaffolds 417 and 421, respectively, also using CF3SO3H. Tetracyclic compounds 418 and 419 were obtained using the benzene-fused acetal substrates, and compounds 422−424 were obtained using the corresponding alcohol substrates (Scheme 92).87 In a study of the electrophilic cyclization of carbamates and NAIs, the 4-methoxyxanthene-tethered hydroxylactam 425, prepared from commercially available 4-methoxyxanthen-9-ol in four steps, was cyclized to the pentacyclic pyrrolo[1,2a]xantheno[1,9-cd]azepine 426 in the presence of TFA in 55% yield (Scheme 93).203

Scheme 87

Scheme 88

6.2. Miscellaneous Scaffolds

isolated base- and acid- (SIBA-) catalyzed cascades. This method entails a base-catalyzed intermolecular Michael addition between substituted amide pronucelophiles 395 and α,β-unsaturated carbonyl substrates 396, followed by an acid-catalyzed intramolecular NAI cyclization of the Michael adducts 397. Polymersupported 2-tert-butyliminio-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (PS-BEMP) and Amberlyst A15 were employed as mutually compatible strongly basic and acidic reagents to facilitate the Michael-initiated NAI cyclization

NAI-based cyclization has been applied to the synthesis of more complex structures, as are typically found in natural products. Chida and co-workers reported an NAI-based strategy for the synthesis of a diazatricyclic core common to several polycyclic natural marine compounds belonging to the madangamine family. The NAI precursor 427 was synthesized through a ringclosing metathesis and palladium-catalyzed cycloisomerization sequence. A stepwise cyclization with isolated N,O-acetal 428 7845


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Scheme 89

first afforded compound 429 in 29% yield, whereas a one-step procedure gave 429 in 66% yield (Scheme 94).204 Hong and co-workers recently reported the stereoselective synthesis of scaffold 433, which contains the vicinal azacontaining quaternary−tertiary chiral center found in the 1azabicyclo[5.3.0]decane core of the cephalotaxus alkaloids. Starting from TMS substrate 430, the strategy involves a TiCl4-promoted NAI cyclization and a ruthenium-catalyzed cyclization using ruthenium catalyst 432, which shares a high degree of structural similarity with the second-generation Hoveyda−Grubbs catalyst. The NAI cyclization could be carried out in different solvents with variable yields and cis/trans ratios for the tetracyclic compound 431, and the best cis/trans ratio of 5:2 was determined by 1H NMR spectroscopic analysis, achieved in mesitylene with a combined yield of 87% (Scheme 95). The authors explained the stereoselective outcome of the NAI cyclization as resulting from the stereoelectronic effect of conjugation of the Z-/E-allylsilane with the arene in a proposed boatlike transition state.205 Employing methods for silyl enol ether formation and NAI cyclization, Delpech and co-workers synthesized a diazatricyclic core scaffold to serve as a model compound for the natural marine product sarain A, the total synthesis of which was achieved by Overman and co-workers.206 In this approach, both the NAI and silyl enol ether moieties were generated in a single step from carbamates 434 or 437 by electrophilic and nucleophilic activation using TBDMSOTf.207 Substrate 434 was obtained through selective reduction of a corresponding glutarimide substrate.208 Treatment of 437 with TBDMSOTf gave a mixture of the tricyclic product 438 (10% yield); the

further-cyclized tetracyclic compound 439 (13% yield); a Ndeprotected compound; and an unstable salt byproduct, the latter presumably formed as a result of the addition of trimethylamine onto the silyloxycarbenium ion of aldehyde 438. 2,6-Lutidine was used as a less nucleophilic, more hindered base for the NAI cyclization, which, together with a TBSdeprotection step under acidic conditions using acetic acid, transformed the cyclic carbamate 434 into the tricyclic compounds 435 and tetracyclic compound 436, which imitate the zwitterionic character of saratin A through the interaction between the tertiary amine and the aldehyde moiety. Compounds 435 and 436 were obtained as an equilibrium mixture with a combined yield of 30% (for three steps) (Scheme 96).207 Horne and co-workers reported several examples of the synthesis of spirooxindole and diketopiperazine scaffolds through an asymmetric stereocontrolled spirocyclization approach.209−211 A mixture of 2,6-dibromo- and 2,5-dibromotryptophan methyl esters 440, readily available from the dibromination of tryptophan methyl ester using 2 equiv of NBS, was condensed with prenyl aldehyde to generate the corresponding imine intermediates 441, which were activated to NAI species using N-Troc prolinyl chloride, thus affording spirocyclized mixtures of bromo-substituted oxindoles 442, in the presence of TFA. A subsequent Zn-faciliated Troc removal induced the formation of 6-bromodemethoxyspirotryprostatin 443 and 5-bromodemethoxyspirotryprostatin 444 in an overall yield of 56%. Cu-catalyzed methoxylation of 443 gave spirotryprostatin A 445.209 A similar stereoselective spirocyclization protocol starting from 2-chlorotryptophan methyl ester, 7846


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Scheme 90

Scheme 91

Scheme 92

obtained by NCS halogenation of tryptophan methyl ester, gave spirotryprostatin B 446 in four steps (Scheme 97).210 Among the many known biologically active marine alkaloids, nakadomarin A (449) bears a particularly unique 5−5−5−6−8− 15 hexacyclic scaffold, which is unprecedented in the many types of natural alkaloids identified so far.212 Synthetic approaches to generate the core of nakadomarin A were reported as early as the 1990s,213 and different total synthetic routes have been reported.214−218 For the 21-step total synthesis of (−)-nakadomarin A reported by Funk and co-workers, NAI cyclization was utilized to construct the core scaffold.216 This work was based on earlier work by the same group on the synthesis of the 5−5−5−6 tetracyclic core through stereoselective Sc(OTf)3-catalyzed Michael addition, followed by intramolecular trapping of the resulting NAI by a tethered furan nucleophile.219 To avoid partial cleavage of the TIPS group, InCl3 can be employed as the catalyst for the key NAI cyclization step from enecarbamate 447 to tetracyclic compound 448. A subsequent sequential ring-closing alkyne metathesis/semihydrogenation using Lindlar catalyst gave the 15-membered aza-ring as a single configurational isomer, and Boc deprotection, N-acylation, ring-closing meta7847


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Scheme 93

Scheme 95

Scheme 94

approaches in the past half-century. NAI-based cyclization methods typically bring a rapid increase in scaffold complexity, notably from simple building blocks, as well as easy access to natural-product-like structures. Such reactions are ideally suited for syntheses of compound collections, where NAI-based cyclization reactions have been widely pursued in both academic settings and the pharmaceutical industry. There is little doubt that NAI-based reactions will continue to substantially impact heterocyclic chemistry applied to medicinal chemistry and chemical biology in the future. This review has provided a comprehensive summary of the application of NAIs for the formation of structurally diverse scaffolds, covering the literature of the past 12 years. It is noteworthy that, in many other examples, although NAIs were not directly involved in the cyclization steps to construct key scaffolds, they were widely used to form cyclization substrates, which are beyond the scope of this review. We hope that the work summarized herein will inspire and assist chemical researchers in their pursuit of new scaffolds derived from NAIs. We expect an increased focus on more “non-flat” scaffolds enriched in sp3hydridized carbon atoms and chiral centers and the development

thesis using first-generation Grubbs catalyst, and a final lactam reduction led to (−)-nakadomarin 449 (Scheme 98).216

7. CONCLUSIONS The efficient and systematic synthesis of molecules with diverse scaffolds and functions is a prerequisite for the development of new therapeutic agents and other fine chemicals of use in the chemical, biological, and medicinal sciences. Among the numerous methods available to access such scaffolds, cyclization of NAIs has proven to be one of the most powerful and successful Scheme 96

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Scheme 97

Scheme 98

Brigham and Women’s Hospital, and Massachusetts Institute of Technology. His research interests lie in the broad fields of synthetic and bioorganic chemistry, chemical biology, and drug discovery, especially small-molecule modulators of biological macromolecules.

of corresponding asymmetric NAI cyclization reactions in the pursuit of novel scaffolds for small-molecule discovery efforts.

AUTHOR INFORMATION Corresponding Authors

Professor Thomas E. Nielsen received his Ph.D. from the Technical University of Denmark (DTU) for work in the field of natural product total synthesis under the supervision of Professor David Tanner. He then carried out postdoctoral studies at the Carlsberg Laboratory (with Professor Morten Meldal, 2003−2005), and Harvard University and the Broad Institute of Harvard and MIT (with Professor Stuart L. Schreiber, 2006−2007), working within various areas of chemical biology research. In 2008, he returned to the Department of Chemistry at DTU and cofounded the Center for Antimicrobial Research (CAR), heading the development of new synthesis methodology, bioactive materials, and assay technologies; he also joined Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University, as a visiting professor. In 2014, he became the director of Protein & Peptide Chemistry, Novo Nordisk A/S, and affiliated as a professor at the Department of Immunology and Microbiology, University of Copenhagen. A central theme in his research is the chemical synthesis of small molecules, peptides, and modified proteins to probe biological phenomena and ultimately provide the basis for the development of new medicines to treat cancer, haemophilia, diabetes, obesity, and antimicrobial infectious disease. Thomas E. Nielsen has received several national and international scientific awards and is the coauthor of more than 90 journal publications and patents.

*E-mail: [email protected] or [email protected]. *E-mail: [email protected]. ORCID

Peng Wu: 0000-0002-0186-1086 Notes

The authors declare no competing financial interest. Biographies Dr. Peng Wu performed his doctoral work in medicinal chemistry under the supervision of Professor Yongzhou Hu at Zhejiang University between 2007 and 2012, during which time he spent an Erasmus LiSUM stay at Uppsala University between 2010 and 2011. After one year as an H. C. Ørsted Postdoc guided by Professor Thomas E. Nielsen and Professor Mads H. Clausen at the Technical University of Denmark (DTU) between 2012 and 2013, he continued his stay at DTU as a researcher funded by a Lundbeck Grant until 2015, before joining the Faculty of Health and Medical Sciences at the University of Copenhagen to work with Professor Thomas E. Nielsen and Professor Michael Givskov. In 2016, he moved to Cambridge, MA, working as a Research Fellow at Harvard University, Broad Institute of MIT and Harvard, 7849


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ACKNOWLEDGMENTS Financial support from the Lundbeck Foundation (R140-201313835), Technical University of Denmark, University of Copenhagen, Broad Institute of MIT and Harvard, Brigham and Women’s Hospital, and Harvard Medical School is gratefully acknowledged. The authors thank Bennett C. Meier and Shawn D. Nelson Jr. for proofreading and discussions, and Amit Choudhary for assistance in the preparation of figures. Former Nielsen Group members contributing to N-acyliminium ion projects over the years are gratefully acknowledged and thanked for their enthusiasm and dedication.

TBME TBS Tf TFA TFAA TIPS TMS TMSOTf Troc Ts p-TsOH XPhos

ABBREVIATIONS USED Ac acetyl BEMP 1,3-dimethylperhydro-1,3,2-diazaphosphorine BINOL 1,1′-bi-2-naphthol Bn benzyl Boc tert-butyloxycarbonyl BPA BINOL phosphoric acid Bt benzotriazole i-Bu isobutyl n-Bu n-butyl Bz benzoyl Cbz carboxybenzyl CSA camphorsulfonic acid de diastereomeric excess DFT density functional theory DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine dr diastereomeric ratio EDC 1-ethyl-3-(3-dimethylamino)propyl)carbodiimide EDG electron-donating group ee enantiomeric excess Et ethyl EWG electron-withdrawing group FDA U.S. Food and Drug Administration HFIP 1,1,1,3,3,3-hexafluoroisopropanol IBX 2-iodoxybenzoic acid LAH lithium aluminium hydride Me methyl Ms methanesulfonyl MS molecular sieves MW microwave NAI N-acyliminium ion NBS N-bromosuccinimide NCS N-chlorosuccinimide NMR nuclear magnetic resonance NOESY nuclear Overhauser effect spectroscopy Ns p-nitrobenzenesulfonyl Ph phenyl PMP 1,2,2,6,6-pentamethylpiperidine PPTS pyridinium p-toluenesulfonate i-Pr isopropyl n-Pr n-propyl PS polymer-supported QM/MM quantum mechanics/molecular mechanics RCM ring-closing metathesis SN nucleophilic substitution TBAF tetra-n-butylammonium fluoride TBDMS tert-butyldimethylsilyl TBDMSOTf tert-butyldimethylsilyl trifluoromethanesulfonate

tert-butyl methyl ether tert-butyldimethylsilyl trifluoromethanesulfonyl trifluoroacetic acid trifluoroacetic anhydride triisopropylsilyl trimethylsilyl trimethylsilyl trifluoromethanesulfonate trichloroethyl chloroformate para-toluenesulfonyl para-toluenesulfonic acid 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

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NOTE ADDED AFTER ASAP PUBLICATION This paper was published to the Web on May 11, 2017, without all of the final changes incorporated. This was fixed in the version published to the Web on May 15, 2017.

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