A Longitudinal Study of Alkaloid Synthesis Reveals Functional Group

Review pubs.acs.org/CR

A Longitudinal Study of Alkaloid Synthesis Reveals Functional Group Interconversions as Bad Actors Steven W. M. Crossley and Ryan A. Shenvi* Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States 3.2.6. Hsung’s Formal Synthesis of (+)-Gephyrotoxin 278C (2001) (Scheme 17) 3.2.7. Lhommet’s Formal Synthesis of (+)-Gephyrotoxin 278C (2008) (Scheme 18) 3.2.8. Trudell’s Formal Synthesis of (+)-Gephyrotoxin 278C (2010) (Scheme 19) 3.2.9. Spino’s Formal Synthesis of (−)-Gephyrotoxin 278C (2010) (Scheme 20) 3.2.10. Sato and Chida’s Synthesis of (±)-Gephyrotoxin 287C (2014) (Scheme 21) 3.2.11. Smith’s Synthesis of (−)-Gephyrotoxin 287C (2014) (Scheme 22) 3.2.12. Gephyrotoxin 287C Conclusion 3.3. Agelastatin A 3.3.1. Weinreb’s Synthesis of (±)-Agelastatin A (1999) (Scheme 23) 3.3.2. Feldman’s Synthesis of (−)-Agelastatin A (2002) (Scheme 24) 3.3.3. Hale’s Synthesis of (−)-Agelastatin A (2004) (Scheme 25) 3.3.4. Davis’s Synthesis of (−)-Agelastatin A (2005/2009) (Scheme 26) 3.3.5. Trost’s Synthesis of (+)-Agelastatin A and Formal Synthesis of (−)-Agelastatin A (2006/2009) (Scheme 27) 3.3.6. Ichikawa’s Synthesis of (−)-Agelastatin A (2007) (Scheme 28) 3.3.7. Yoshimitsu and Tanaka’s Synthesis of (−)-Agelastatin A (2008) (Scheme 29) 3.3.8. Wardrop’s Synthesis of (±)-Agelastatin A (2009) (Scheme 30) 3.3.9. Du Bois’s Synthesis of (−)-Agelastatin A (2009) (Scheme 31) 3.3.10. Chida’s Synthesis of (−)-Agelastatin A (2009) (Scheme 32) 3.3.11. Movassaghi’s Synthesis of (−)-Agelastatin A (2010) (Scheme 33) 3.3.12. Romo’s Synthesis of (±)-Agelastatin A (2012) 3.3.13. Batey’s Synthesis of (±)-Agelastatin A (2013) (Scheme 36) 3.3.14. Agelastatin A Conclusion 3.4. Citrinadin B 3.4.1. Wood’s Synthesis of (+)-Citrinadin B (2013) (Scheme 37)

CONTENTS 1. Introduction 2. General Strategies: Historical Threads 2.1. General Strategies. Reduction (Scheme 2) 2.2. General Strategies. Mannich Reactions/Cascades (Scheme 3) 2.3. General Strategies. Radical Amination of C−H Bonds (Scheme 4) 2.4. General Strategies. Pericyclic Reactions (Scheme 5) 2.5. General Strategies. Hydroamination (Scheme 6) 2.6. General Strategies. Rearrangements (Scheme 7) 3. Syntheses 3.1. Loline 3.1.1. Tufariello’s Synthesis of (±)-Loline (1986) (Scheme 8) 3.1.2. White’s Synthesis of (+)-Loline (2000/ 2001) (Scheme 9) 3.1.3. Scheerer’s Synthesis of (±)-Acetylnorloline (2011) (Scheme 10) 3.1.4. Trauner’s Synthesis of (+)-Loline (2011) (Scheme 11) 3.1.5. Loline Conclusion 3.2. Gephyrotoxin 287C 3.2.1. Kishi’s Synthesis of (±)-Gephyrotoxin 287C (1980) (Scheme 12) 3.2.2. Hart’s Synthesis of (±)-Gephyrotoxin 287C (1981/1983) (Scheme 13) 3.2.3. Overman’s Synthesis of (±)-Gephyrotoxin 287C (1983) (Scheme 14) 3.2.4. Saegusa’s Formal Synthesis of (±)-Gephyrotoxin 287C (1983) (Scheme 15) 3.2.5. Pearson’s Formal Synthesis of (±)-Gephyrotoxin 278C (2000) (Scheme 16) © XXXX American Chemical Society

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Received: March 16, 2015

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DOI: 10.1021/acs.chemrev.5b00154 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 3.4.2. Martin’s Synthesis of (+)-Citrinadin B (2013/2014) (Scheme 38) 3.4.3. Citrinadin B Conclusion 3.5. Rhazinilam 3.5.1. Smith’s Synthesis of (±)-Rhazinilam (1973) (Scheme 39) 3.5.2. Sames’s Synthesis of (±)-Rhazinilam and (−)-Rhazinilam (2000/2002) (Schemes 40 and 41) 3.5.3. Magnus’s Synthesis of (±)-Rhazinilam (2001) (Scheme 42) 3.5.4. Trauner’s Synthesis of (±)-Rhazinilam (2005) (Scheme 43) 3.5.5. Nelson’s Synthesis of (−)-Rhazinilam (2006) (Scheme 44) 3.5.6. Banwell’s Synthesis of (−)-Rhazinilam (2006) (Scheme 45) 3.5.7. Zakarian’s Synthesis of (−)-Rhazinilam (2010) (Scheme 46) 3.5.8. Gaunt’s Synthesis of (±)-Rhazinilam (2012) (Scheme 47) 3.5.9. Tokuyama’s Synthesis of (−)-Rhazinilam (2013) (Scheme 48) 3.5.10. Zhu’s Synthesis of (−)-Rhazinilam (2014) (Scheme 49) 3.5.11. Lin and Yao’s Synthesis of (±)-Rhazinilam (2014) (Scheme 50) 3.5.12. Dai’s Synthesis of (±)-Rhazinilam (2014) (Scheme 51) 3.5.13. Tokuyama’s Synthesis of (−)-Rhazinilam (2015) (Scheme 52) 3.5.14. Rhazinilam Conclusion 3.6. Massadine and Massadine Chloride 3.6.1. Baran’s Synthesis of (−)-Massadine and (−)-Massadine Chloride (2008/2011) (Schemes 53 and 54) 3.6.2. Chen’s Synthesis of Massadine (2014) (Schemes 56 and 57) 3.6.3. Massadine and Massadine Chloride Conclusion 3.7. Hapalindole Q 3.7.1. Albizati’s Synthesis of (+)-Hapalindole Q (1993) (Scheme 58) 3.7.2. Kerr’s Synthesis of (±)-Hapalindole Q and (+)-Hapalindole Q (2001) (Scheme 59) 3.7.3. Baran’s Synthesis of (+)-Hapalindole Q (2004/2008) (Scheme 60) 3.7.4. Li’s Synthesis of (±)-Hapalindole Q (2014) (Scheme 61) 3.7.5. Hapalindole Q Conclusion 3.8. Akuammiline Alkaloids: Vincorine and Scholarisine A 3.8.1. Vincorine 3.8.2. Scholarisine A 4. Conclusion Author Information Corresponding Author Notes Biographies Acknowledgments References

Review

1. INTRODUCTION The roots of the pharmaceutical industry can be traced to multiple sources, including Perkins’s dyeworks, Erlich’s ideas of chemotherapy and the “magic bullet”, or the widespread distribution of Aspirin by Baeyer. A strong case can also be made for the isolation in 1804 of morphine (morphium, “the soporific principle”) from opium by Sertürner as a watershed event in the history of drug development, particularly his recognition in 1816 of its basic character “associated with ammonia”.1 The apothecary and the chemist of the 17th−19th centuries partly occupied themselves with the isolation of active principles from medicinal plants, and the advance of these substances to market for access by the consumer, similar to the pharmaceutical companies of today, with obvious differences. The identification of morphine, a carbon- and hydrogencontaining plant substance with basic properties, garnered great attention from the chemistry community since much effort had been spent in the early 19th century on the isolation and characterization of plant acids instead. Consequently, the years after Sertürner’s discovery saw a flurry of new disclosures on plant bases,1 including xanthine (Marcet, 1817),2 emetine (Pelletier and Magendie, 1817),3 strychnine (Pelletier and Caventou, 1818),4 piperidine (Oersted, 1819),5 atropine (Runge, 1819), quinine (Pelletier and Caventou, 1820),6,7 and caffeine (Runge, 1820).8 The Merck pharmacy (now Merck KGaA and Merck & Co.), originating from the Engel-Apotheke purchased in 1668 by the apothecary Friedrich Jacob Merck, was responsible for the first large-scale manufacture of morphine by isolation and its sale in the global marketplace. The ease with which these basic substances were separated from extraneous plant material by reaction with mineral acids, and further purified by crystallization as their salts, allowed many new, bioactive substances to be characterized, studied, or sold to the consumer. This sudden expansion of investigations into medicinal plant bases also required new language to describe the findings. The extraction of basic material from plants was not itself new: “alkali” is derived from the Arabic al-qualja (plant ashes), and in the 18th century the flourishing European glass and textile industry obtained lye from the ashes of plants steeped in pots of water (hence potash, potassium). In 1819, Meissner proposed the term alkaloid, for the newly identified plant bases due to their reactivity with acids but differing “in some of their properties ... from alkalis considerably.” So “oid,” related to the Greek ειδω “to appear”, was appended to “alkali.” Many of these alkaloids have since found a place in our homes (caffeine, quinine, codeine), in our language (“pipe dream” from smoking an opium pipe; Tom Lehrer’s Poisoning Pidgeons in the Park where he remarks “...my pulse will be quickenin’ with each drop of strych’nine...”), and especially on the drug market, where morphine is now the gold standard among analgesics. The name alkaloid has stuck, which is unfortunate, since modern chemistry is organized around structure, not reactivity, and the alkaloid family now contains over 27 000 members, many of which are completely unrelated structurally and only distantly related biosynthetically.35 In contrast to structurally defined classes such as steroids and flavinoids, or modular classes such as polysaccharides and polypeptides, alkaloids are all lumped together as molecules containing a “basic” nitrogen atom (which of course depends on an arbitrary threshold for basicityusually the ability to form stable salts with mineral acids) and even biosynthetically related members are constitutionally dissimilar (Scheme 1). For example, alkaloid members

AJ AJ AK AL

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Scheme 1. Alkaloid Biosynthetic Origins Are Diverse

derived from the canonical amino acids ornithine (1) (see 2 and 3), lysine (4) (see 5 and 6), tyrosine (7) (see 8 and 9), tryptophan (10), and histidine (11) (see 12 and 13) have relatively little in common except their requisite alkylamine functional group.35 Remarkably, nitrogenous terpenes 16−19, force-fit into the alkaloid family with 2−3, 5−6, 8−9, and 12−13, are only related to one another by virtue of a single atom of nitrogen! And in the case of marine isocyanoterpene-derived alkaloid 20, even the source of nitrogen is distinct: cyanide delivers the nitrogen of 20,9−12 whereas amino acids donate their nitrogen to 2−3, 5−6, 8−9, 12−13, and 16−19. As a consequence of their structural differences, unique building blocks, and in many cases early biosynthetic divergency, the alkaloids obviously defy unification via a single, best chemical synthesis strategy. However, whereas it may not be possible to make a blanket statement about the “best” way to access all alkaloids, there are common threads of strategies that weave the patchwork history of alkaloid synthesis into recognizable

reactivity patterns. Appropriate to the reactivity-based framework imposed upon their classification, synthesis approaches to alkaloids can also be arranged according to reactivity, not structure. Below, we broadly characterize five approaches to alkaloid synthesis according to the “key” step or series of steps around which the synthesis is assembled, specifically formation of the amine-containing bond framework. Within each of these reaction strategies, we highlight specific examples ranging from early or the earliest work to recent applications that best illustrate the benefits of each strategy. Reference to these strategies will provide one framework from which to analyze syntheses of molecules covered in this review.

2. GENERAL STRATEGIES: HISTORICAL THREADS 2.1. General Strategies. Reduction (Scheme 2)

The oldest strategy to synthesize alkaloids derives, by definition, from the first synthesis of an alkaloid, (+)-coniine (21), by C


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Scheme 2. Reduction of Polyunsaturated or Aromatic Heterocycles

Ladenburg in 1886.13 In this synthesis, Ladenburg reduces an unsaturated heteroaromatic molecule to arrive at a saturated, stereogenic piperidine: the strategy of heterocycle reduction is the first strategy we will briefly consider. Traversing a short three to four steps (depending on how a “step” is defined), the synthesis begins with the condensation of 2-methylpyridine (αpicoline (22)) and acetaldehyde trimer (paraldehyde) at 250− 260 °C in a sealed vessel to deliver 23 in 9% yield, and only after many failures in attempts to alkylate pyridine directly at C2. Complete reduction of unsaturation in 23 is accomplished by sodium in refluxing ethanol, delivering 2-propylpiperidine (24, i.e., rac-coniine). The identity of this material was verified by smell, chemical degradation, and administration to white mice: coniine is a neurotoxic constituent of hemlock and has been responsible for the death of many persons, accidental or deliberate, including Socrates, who was executed with draft of hemlock in 399 BC.1 Resolution of the racemate (24) into its enantiomers was accomplished by crystallization of the corresponding tartrate salts, separation, and distillation from potash to return the neutral alkaloid (21). Even though the target molecule is simple and the overall yield low, there is much to commend Ladenburg’s synthesis to the modern chemist’s preferences. There are no protecting groups. The synthesis begins with a chemical feedstock, α-picoline (22), and the

product is obtained as a single enantiomer. Relative stereocontrol is absent (there is only one stereocenter),14 but this strategy can be adopted for the simultaneous formation of multiple stereocenters, as shown below. Three examples from the more recent literature showcase this ability to rapidly increase stereochemical complexity within an alkaloid framework by reduction. The first two, both from 1985, utilize pyrrole reduction to generate fused, stereogenic ring systems. For example, Urbach synthesizes the cyclopentapyrrolidine15 subunit of ACE-inhibitor Hoe-498 (25) via pyrrole 27, itself formed via annulation of N-benzyl,O-ethyl-glycine onto aldehyde 26. Hydrogenation of the pyrrole in the presence of strong acids results in delivery of hydrogen onto one face of the molecule, concomitant with removal of the benzyl group to produce saturated heterocycle 28 in moderate yield.16 Similarly, Greenhouse and co-workers reported in the same year the synthesis of fused pyrrole 32 from pyrrole itself (30) through the intermediacy of sulfonyl pyrrole 31.17 Reduction of 32 is accomplished with hydrogen over rhodium on alumina to deliver racemic isoretronecanol (29) as a single diastereomer. The third example highlights the dramatic simplification to synthesis design imparted by the gross reduction approach. Barluenga’s concise synthesis of racemic tetraponerine-8 (33) relies on stereochemical control of hydride delivery by ring D


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Scheme 3. Mannich Reactions/Cascades en Route to Alkaloids

(synthesis of the substance “amarine” by Laurent21−27), C−H functionalization in 1878 (Hofmann’s work on coniine degradation), or Mannich reactions28,29 (reported originally by Tollens,30,31 explained and formalized by Mannich32 in 1912 and subsequent years) all laid the groundwork for widespread strategies toward alkaloid synthesis. However, these latter reactions to form Mannich bases are probably best to describe first, since they represent the earliest broadly employed general strategies to access alkaloids and in some sense encapsulate the related reactivity of the Pictet−Spengler and Bichler−Napieralksi reactions, i.e., the chemistry of iminium ions. The alcohol adduct corresponding to a Mannich base is a simple “aldol”, discovered by composer and occasional chemist Borodin in 1864,33,34 thus providing these reactions further historical depth. Also, it should be noted that Mannich reactions are extensive in biosynthetic pathways and therefore predate the other strategies by thousands of thousands of millennia.35 It is this aspect of “biomimicry” that distinguishes Mannich reaction based strategies from most other approaches, and usually renders them substantially more efficient for three main reasons. First, the chemistry of imines and iminium ions are well understood, predictable, and easy to implement, sometimes even in the presence of water and oxygen, which mitigates the tyranny of good technique. Second, because alkaloids are constructed primarily through the chemistry of imines, retrosynthetic disconnections of the target molecule can be identified with little to no perturbation of the existing functional groups, which minimizes functional group interconversion (FGI) steps (vide infra). Third, application of Mannich transforms to the target frequently arrives at the same or similar building blocks as used in the biosynthetic pathways, and these molecules are usually

topology.18 The intermediate pyrimidinine 35 is easily synthesized by alkylation of cyclic imine 34 with hexanenitrile at low temperature to prevent competitive proton transfer, followed by condensation and alkylation with 4-bromobutyraldehyde to form iminium 36. Low temperature, in situ reduction of 36 with sodium borohydride delivers the target molecule (33) in this remarkable three step synthesis. In a recent synthesis, Glorius and Fürstner demonstrated the power of modern techniques applied to this old strategy of heterocycle reduction in their synthesis of (−)-isooncinotine (37).19 The Glorius lab had previously developed a highly practical method for the asymmetric reduction of substituted pyridines to piperidines using an Evans oxazolidinone auxiliary, which can be appended to a 2-halopyridine and is expelled in the final stage of reduction.20 The synthesis of 37 begins with the elaboration of 2,6-dichloropyridine (38) to the substituted derivative 39 via Fürstner’s application of Kochi coupling to pyridine substitution, followed by copper-catalyzed C−N bond formation to install the Evans auxiliary. Hydrogenation of 39 is achieved in the presence of acid and catalytic palladium hydroxide over carbon to deliver the piperidine alcohol 40 in good yield and excellent enantioselectivity (94% enantiomeric excess (ee)). This chiral building block can be carried forward over five steps, which includes a useful tandem cross-metathesis/ hydrogenation, to arrive at (−)-isooncinotine (37) in only eight steps and 18% overall yield. 2.2. General Strategies. Mannich Reactions/Cascades (Scheme 3)

Identification of the next-earliest historical thread to follow is more challenging, since execution of pericyclic reactions in 1841 E


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Scheme 4. Radical Amination of C−H Bonds en Route to Alkaloids

these Mannich reactions and the related aldol reaction formed the general basis of alkaloid biosynthesis,45 including this specific sequence of reactions to yield tropinone. This remarkable insight can be applied to many subclasses of alkaloids, as we will see in the subsequent examples. These reactions have been reinvented46 in the past 15 years to include catalytic asymmetric variants, some of which will be discussed below and dramatically improve the chemical synthesis of certain alkaloids. A seminal report by Corey in the 1970s captures the dramatic simplifications to alkaloid synthesis imparted by the identification of multiple-Mannich disconnections. Porantherine (46), a plant alkaloid, probably arises from the scaffolds similar to the coccinellid insect alkaloids, and can be synthesized from a symmetrical intermediate (47) in a series of condensations and Mannich reactions.47 The order of events probably differs between the biosynthesis and this chemical synthesis, but the reactivity and the principles are the same: Mannich reactivity is a path of least resistance to construct alkaloids of high complexity. Lycopodine (49), a plant alkaloid representative of the vast (200+ members) lycopodium alkaloid subclass, has seen a spate of synthetic approaches. While some members such as huperzine A possess compelling biological profiles, the basis for most chemical syntheses has been structural, and led to general strategies to access the broadly distributed structural motifs embedded within lycopodine (49). Not surprisingly, the generally accepted best approach48 to 49 relies on a Mannich cascade to forge the bridging tricyclic core, which probably overlaps substantially with the biosynthesis. Heathcock’s

commercially available since they are produced as bulk starting materials for and from abundant natural sources. William Bradbury Robinson, the father of Sir Robert Robinson, supported his substantial family of 15 children through his manufacturing firm, whose primary business was the automated manufacture of surgical dressings.36 It is probably then no coincidence that one of the more famous contributions of the younger Robinson was justified on the basis of its “great value in the practice of medicine and surgery.” This classic, early example of Mannich reactions in alkaloid synthesis is the oftencited synthesis of tropinone (41),37 executed by Robinson but conceived jointly by Robinson and his friend and colleague Arthur Lapworth,38 who considered the viability of chemical reactions according to the reactants’ “alternating polarities.”39,40 The polarizations of a carbon framework by heteroatoms and especially carbonyls41 lend Mannich disconnections of alkaloids a predictability and ease of identification not found in most strategies. Application to the structure of tropinone reveals that the molecule can be dissected into succinaldehyde (42), methylamine, and acetone or a synthetic equivalent, acetonedicarboxylate, which possesses a much higher equilibrium ratio of nucleophilic enol tautomer (44) than acetone itself but will expel carbon dioxide upon acidification. This inexpensive, eventually high-yielding42 and aesthetically appealing synthesis solves the practical problem of procuring large amounts of tropinone (41) and its derivatives from nonplant sources. However, the more influential result of this work was the hypothesispartly confirmed in the 1950s43 and further in later decades44that F


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Scheme 5. Pericyclic Reactions en Route to Alkaloids

route49,50 intercepts easily synthesized cyclohexene ketal 50 (available in six steps), which when refluxed in methanolic hydrochloric acid undergoes sequential double deprotection, iminium formation, and Mannich reaction to form the tricyclic core. Conversion of pendent methyl ether to the corresponding alkyl bromide is accomplished with hydrogen bromide, and potassium carbonate effects alkylation of the amine to produce 49. A Mannich-based strategy was recently reported by Shair and co-workers to access the related, but structurally rearranged seven-membered Lycopodium alkaloids, including fastigiatine 53.51,52 These molecules represent a challenge to synthesis because although multiple aldol/Mannich (consonant) disconnections can be easily identified, a key dissonant bond between the two nitrogen atoms (Scheme 3, highlighted in red), confounds simple reactivity and would require an oxidative enamine coupling. Shair and Liau solve this problem by generating the dissonant bond first, and then forming the simpler bonds intramolecularly. Treatment of cyclohexene ketal 54 (available in 14 steps from (S)-epichlorohydrin) with aqueous hydrochloric acid liberates the enone, which is captured in an enamine Michael reaction to forge an initial seven-membered

ring, which undergoes a transannular enamine aldol to generate the final ring. Upon superficial analysis, the tertiary alcohol might seem like the dead end of an otherwise efficient strategy. However, the observation of a dehydration ion in the electrospray mass spectrum of the already strongly ionizable enamine 55 provided some hope that water was being lost by an equilibrating retro-aldol/Mannich sequence. Indeed, methylation, removal of the nosyl group, and heating with trifluoroethanol effected a facile replacement of the tertiary alcohol with the pendent secondary amine (56). Decarboxylation and acetylation complete the synthesis of fastigiatine 53. 2.3. General Strategies. Radical Amination of C−H Bonds (Scheme 4)

Although C−H functionalization has gained remarkable traction within the past decade due to innovations in transition metal catalyzed oxidations and couplings, methods for the directed functionalization of C−H bonds distant to an activating functional group can be traced all the way back to the work of Hofmann in 1878. Hofmann had been studying the effects of acid and base on N-halo-amines, which had been accidently synthesized during the course of structural assignment studies of piperidine.53 Treatment of N-bromo-coniine (57), for G


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Scheme 6. Hydroamination of Alkenes en Route to Alkaloids

group addition (FGA) or functional group interconversion (FGI), which increase or leave unchanged the complexity of a target, C−H functionalization involves functional group removal (FGR), and therefore represents a high-priority transform that decreases the complexity of a target. Finally, in a recent synthesis of (−)-isoatisine (69),61 the abundant diterpene steviol (70) (available by degradation of its glycosides, which can be purchased as the artificial sweetener, Stevia) can be processed over nine steps, mostly involving rearrangement of the ent-kaurane C/D rings to the ent-atisane skeleton, to phosphoramidate 71. The unique phosphoryl group on nitrogen proved crucial for effecting a high-yielding HLF reaction using Suárez conditions,62 which also afforded concomitant oxidation to phosphoimine 72, thus securing an additional oxidation state of isoatisine 69. Three additional steps are necessary to access the target.

example, with hot sulfuric acid produced a tertiary amine, shown later to be indolizidine (58).54 While not a naturally occurring alkaloid itself, a series of simple, polyalkyl-substituted indolizidines (59−61) have been isolated as the neurotoxic constituents of dart frog poison.55 Furthermore, what has now become known as the Hofmann−Löffler−Freytag (HLF) reaction embodies a useful mechanistic paradigm for C−N bond formation, i.e., hydrogen atom transfer from a proximal C−H to a reactive heteroatom-centered radical, followed by capture of the newly formed carbon-centered radical with an electrophile or counter radical. A seminal example of the utility of this reaction in steroidal alkaloid synthesis was published simultaneously by the groups of Corey56,57 and Arigoni/Jeger,58 who showed that an easily installed C20 amine of 63 could, through the HLF reaction, functionalize the proximal, angular C18 methyl to give 64 and cyclize to the pyrrolidine heterocycle of the conessines, such as dihydroconessine (62). The power of these remote functionalizations to simplify the retrosynthetic analysis of canonical amino acid derived alkaloids can be seen in the classic synthesis of perhydrohistrionicotoxin (65).59 In this case, use of the Barton nitrite ester photolysis60 stereoselectively desymmetrizes the spirocyclopentane ring (66) and installs the requisite oxime functionality for a Beckmann rearrangement of 67 to the spiro-lactam 68, which can be carried forward to the target (65). This remarkable sequence does not occur in high yield, but represents an striking proof-of-principle for C−H functionalization to aid the installation of skeletal C−N bonds in alkaloids, and to simplify the synthesis of a molecule at the stereochemical and functional group levels. Whereas most retrosynthetic transforms that consume steps involve functional

2.4. General Strategies. Pericyclic Reactions (Scheme 5)

Although not recognized as a pericyclic reaction in 1841,21−26 the condensation of three equivalents of benzaldehyde (74) and two equivalents of ammonia resulted in the formation of a new basic substance called “amarine”, which was subsequently shown by Corey27 to have the structure 73, resulting from disrotatory electrocyclization of an intermediate five-atom, six-electron carbanion (76). This early example of a pericyclic reaction to stereoselectively form alkaloid-like motifs presaged their utility in synthetic chemistry. Pericyclic reactions in general benefit from stereochemical predictability according to the Woodward− Hoffmann rules, and cycloadditions in particular generate a high degree of complexityC−C bonds, stereocenters, and H


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utility in the synthesis of the heterocyclic building blocks of the cyclic hexapeptide echinocandin D (17) by Evans.77 α-Bromoimide 89 can be generated from a nonchelating syn-aldol reaction. Azide displacement of the bromide, and methoxide displacement of the oxazolidine, provides ester 90, where the azide is a stand-in for the requisite amine in a hydroamination. Treatment of 90 with dicyclohexylborane effects a tandem hydroboration/amination to close the pyrrolidine ring and generate 91, which can be advanced to the macrocyclic peptide target (88). Hydroamination via protonation of an alkene using Brønsted acid is frustrated by the more facile protonation of the amine reactant, rendering it unreactive as a nucleophile. However, in situ derivatization of the amine to a less Brønsted basic functional group can facilitate these reactions. For example, Heathcock showed that the homosecodaphniphyllate skeleton 93 can be converted to homodaphniphyllate 92 using a highly effective intramolecular hydroamination reaction.67 93 is reductively fragmented with DIBALH to cycloheptene 94. After conversion of the alcohol to methyl ester 95, this secondary amine is reacted first with phenylisocyanate to generate the phenylurea, which is not isolated, but instead heated in refluxing formic acid to effect hydroamination and deacylation of the ammonium urea to yield 92. More mild conditions for hydroamination have been extensively sought by the chemical community given the power of these reactions in both fine chemical synthesis and bulk production. The Marks lab has developed transition metal catalysts that effect hydroamination through the intermediacy of only weakly basic lanthanide amides at room temperature or slightly higher, albeit under rigorously oxygen free, conditions in the glovebox. Using a samarium amide catalyst, the Marks group executed an exceptional synthesis of (+)-xenovenine (96) from chiral amine 97 via sequential double-hydroamination onto a pendant allene and terminal alkene to yield allyl pyrrolizidine 99. Hydrogenation of the remaining alkene yields (+)-96.78 Hydroamination of alkenes using alkali metal salts of amines was reported as early as 1954 by Howk and co-workers,76,79 and saw subsequent expansion to styrenes,80 which are more effective acceptors of anions. Application to complex molecules is generally frustrated by unpredictability and chemoselectivity: polysubstituted styrenes embedded in complex architecture do not react similarly to styrene itself, and the high basicity and high temperature of these hydroamination reactions cause competitive reaction of other functional groups. In particular, application to morphine required the use of sulfonamides instead of amines, to promote radical ring closure under dissolving metal conditions.81−86 While effective, the method requires prior installation of a sulfonamide, rather than an amine, which can be limiting given the number of methods for amine synthesis (reduction, reductive amination, alkylation) that exist. Trost observed that whereas hydroamination of 103 with the corresponding lithium amide is ineffective, irradiation of the reaction with light emitted from a simple incandescent tungsten bulb effects intramolecular hydroamination, suggesting a charge transfer complex prior to ring closure.87 While hydroamination constitutes an important transform in the history of alkaloid synthesis, current methods still suffer from narrow substrate scope and generally poor chemoselectivity. Therefore, while greatly simplifying as a broad strategy, hydroamination remains limited in its application.

ringsby combining simpler precursors. Among the earliest examples of cycloadditions in alkaloid synthesis include Woodward’s classic synthesis of resperpine (1958),63−65 which utilized a Diels−Alder reaction of benzoquinone to generate three proximal stereocenters en route to the E ring of the target. However, cycloadditions are found among approaches to all the families of secondary metabolites. What makes alkaloids special is the potential inclusion of a nitrogen atom in the reacting components of a cycloaddition. Scheme 5 displays important examples along this historic thread of cycloaddition approaches to alkaloid synthesis. For example, the Boger lab pioneered the use of diazenes, triazenes, and tetrazines as precursors to aromatic or polyunsaturated rings in alkaloids. In the case of streptonigrin (77), this approach allows two relatively simple components to be assembled via a Diels−Alder cycloaddition/retro-cycloaddition sequence, generating the core of the target with remarkable speed (five steps to 79).66 Here four nitrogen atoms are involved as components of the reaction partners, but three are lost in the process, highlighting the dual role of nitrogen in molecular construction as both nail and hammer. A classic application of the imino-diene Diels−Alder reaction can be found in the biomimetic synthesis of methyl homosecodaphniphyllate (80) by Heathcock.67 Here, the Michael adduct of a truncated squalene dialdehyde undergoes condensation with methylamine to iminium 82, which undergoes a tandem cycloaddition, aza-Prins addition, and hydride transfer to generate bridging pentacycle 83, core of the daphniphyllines, which is elaborated to the target 80. In this case, a high-risk biomimetic plan provides a concise, high yielding, and beautiful solution to the synthesis of 80, whereas the more conventional, and more reliable route originally planned in the Heathcock lab was discarded. Biomimicry is not always the “best” solution. The synthesis of (+)-nominine (84) by Gin demonstrates that a completely abiotic strategy can yield highly effective routes.68 In this now well-known work, the oxy-quinolinium nitrile 85 can be rapidly assembled in asymmetric fashion and coaxed with heating to undergo a reversible and equilibrating [5 + 2] cycloaddition to yield diastereomers 86 and 87 in a 3.8:1 ratio. Since the stereochemistry of 87 corresponds to that of the target 84, the major diastereomer 86 can be equilibrated with heating to the same thermodynamic ratio of diastereomers87 is obtained in 38% yield after four cycles of heating and separation. A series of FGIs and another cycloaddition convert 87 to (−)-nominine 84. 2.5. General Strategies. Hydroamination (Scheme 6)

Alkene hydroamination, while not unprecedented in biosynthetic pathways, is an uncommon reaction in the cell, and also in the reaction flask. Although this powerful reaction has the potential to form skeletal C−N bonds and two stereocenters via net isomerization of bonding, it represents an underutilized approach toward alkaloid synthesis (not considering amine conjugate addition), due mainly to the insufficiency of tools available to the synthetic chemist in this area, especially compatibility with functional groups.69,70 For example, the earliest reactions involved heating alkali metal salts of ammonia with alkenes to form alkylamines.71−76 However, formal equivalents of hydroamination are reasonably chemoselective and include the Ritter reaction (nitrile as amine equivalent), aminomercuration (mercury as proton equivalent), and hydroboration/amination (chloramine or azide as amine equivalent).69 This latter reaction has found I


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Scheme 7. Rearrangements To Install Skeletal C−N Bonds

2.6. General Strategies. Rearrangements (Scheme 7)

tandem with a Lewis acid catalyzed, exo-selective Diels−Alder reaction, assembling the entire core (115) in this cascade sequence. This tricycle 115 is a mere five steps away from the targeted alkaloid. While not comprehensive, these six categories of globally simplifying strategies for disconnecting the heterocyclic skeletons of alkaloids characterize a vast swath of the literature. Other C−N skeletal disconnectionsnitrogen nucleophile SN2; epoxide, halonium, metal-π-allyl capture; or conjugate additionfall within the criteria of “tactical” maneuvers in the context of strategies that focus on an all-carbon skeleton or other structural features, with a few exceptions (see Trauner’s loline synthesis below, section 3.1.4). In this review, as part of a thematic series on Frontiers in Chemical Synthesis, we survey alkaloids that have been synthesized multiple times in the past 10 years. Restricting the discussion to multiply synthesized alkaloids allows a comparison of strategies and their practical outcomes. Where possible, we couch these recent syntheses in the historic threads of alkaloid synthesis and try to make didactic points about choice of strategy. If a single, take-home message can be extracted from this survey, it is the importance of minimizing the addition of extraneous functional groups and especially their interconversions within a synthetic sequence, and instead utilizing chemoselective reactions of functionality present in both feedstock starting materials and the target. If one considers terpenes, the challenge of this class is the lack of functional groupsparent terpene scaffolds are hydrocarbons with minimal unsaturation. If one considers alkaloids, the challenge is the functional group that defines the class and its reactivity as a Lewis base, which challenges both chemical reactivity and purification on silica gel. Therefore, the most efficient syntheses across this class avail themselves of the inherent reactivity of the target and its synthetic intermediates, by careful choreography of steps, choice of chemoselective reactions, and/or strategy level decisions about the pernicious nitrogen atom(s). The ability to install skeletal C−N bonds and manipulate functional groups in the presence of the Lewis basic nitrogens without multiple protecting group operations, zero-sum redox maneuvers, or

In general, rearrangements of bond networks do not necessarily increase the complexity of an intermediate en route to a target molecule. Used judiciously, however, a rearrangement can result in the retrosynthetic conversion of an unorthodox scaffold into better precedented architecture that might be easily disconnected. In the case of alkaloids, rearrangements that incorporate nitrogen atoms can be used to establish a challenging C−N skeleton, as well as establish at a late stage a Lewis basic amine that would otherwise be difficult to carry through multiple operations. For example, use of a Beckmann rearrangement in the synthesis of multiply substituted piperidine, pyrrolidine, and polycyclic alkaloids transforms a heterocycle synthesis into a carbocycle synthesis.88 In the synthesis of anhydronupharamine (104), the Beckmann rearrangement of 106 to 107 allows the establishment of two stereocenters in the ring from a disubstituted enone (105).89 Dissolving metal reduction of 105 leads to the trans-relationship of 106 with high selectivity,90 and this relationship is maintained via the highly stereospecific Beckmann rearrangement of the oxime derived from ketone 106. Overman has developed many sequences that rely on a cascade sequence of a charge-accelerated aza-Cope rearrangement, followed by intramolecular Mannich reaction. In the case of 16-methoxytabersonine (108), this sequence retrosynthetically rearranges the tricyclic indolizidine core to a simpler, fused piperidine 111.91 The result is a remarkably concise synthesis (109 is synthesized in only seven linear steps) of 108, a representative member of the vast Aspidosperma indole alkaloid class. The Schmidt reaction, while not strictly a rearrangement (loss of N2 occurs), is a frequently employed transform that, like the Beckmann rearrangement, allows the incorporation of a skeletal C−N bond from a carbonyl. In other words, it allows a heterocyclic framework to be derived from a carbocycle, and one of the best examples of this maneuver is found in Aubé’s synthesis of stenine (112).92 In this now classic synthesis, the complex fused heterocyclic core is accessed in only nine steps and 14% overall yield. The Schmidt reaction of 114 to 115 is effected in J


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other lateral functional group interconversions (FGIs)93 represents the main challenge in alkaloid synthesis. For the chemical synthesis of alkaloids to be of continued relevance in the modern era, consideration must be given to the practicality of synthesisnot just its proof-of-principle. Minimization of FGIs that do not form skeletal bonds is the most straightforward way to achieve this goal.

Since its 1955 isolation, interest in the biological activity of the loline alkaloids has spurred synthetic studies, although only two unsuccessful routes104,105 to loline were published prior to 1986. Structurally, loline possesses a strained heterotricyclic molecular skeleton and oxygen and nitrogen atom substituents that lie in close proximity to each other, endowing it with a structure that appears simpler to build than it may actually be. 3.1.1. Tufariello’s Synthesis of (±)-Loline (1986) (Scheme 8). Nonetheless, Joseph Tufariello and his group were able to succeed where others had failed and published the first synthesis of (±)-loline (116) in 1986106 using a [3 + 2] cycloaddition as a key step in their 18 step and 18.2% (from 118) yielding route. Tufariello’s synthesis began with conversion of N-ethylpyrrolindin-3-one (117) to dimethyl ketal nitrone (118) via a known procedure involving ketal formation, N-oxidation, and Cope elimination.107 Next, the team reacted nitrone dipole 118 with dipolarophile methyl 4-hydroxycrotonate (119) to form intermediate 120, in which the relative stereochemistry of three carbon centered stereogenic centers was set, though not in the final arrangement. Next, the free primary alcohol of 120 was mesylated to activate it for displacement by the nitrogen atom, an event that occurred after hydrogenolytic cleavage of the N−O bond over Pd/C in MeOH to give pyrrolizidine 121. With the pyrrolizidine core formed, the team sought to set all stereocenters correctly and then close the ether linkage of loline (116). To this end, the C1 stereocenter of 121, which was generated in the initial [3 + 2] cycloaddition, required epimerization to match that of loline (116). Tufariello and coworkers used NaOMe to successfully enact this epimerization. Subsequent reduction of the methyl ester to the free alcohol with LiAlH4 and acetate protection of both this primary alcohol and the C2 secondary alcohol gave diacetate 122. The C2 secondary alcohol was protected to prevent premature ring closure onto C7 after conversion of the C7 ketal to the ketone. Practically, trifluoroacetic acid (TFA) facilitated ketal deprotection, and hydrogenation with Adam’s catalyst in glacial acetic acid occurred

3. SYNTHESES 3.1. Loline

Loline (116) and related compounds are norpyrrolizidine alkaloids that all possess an oxygen bridge. Although first isolated in 1955,94 loline was not assigned its correct structure until 1965.95 Interest in these alkaloids arose out of the observation that cattle grazing on tall fescue grass (Festica arundinacea) were known to develop a foot lameness known as “fescue foot”.96,97 Others have reported increased respiration98 and abdominal fat necrosis99,100 among these same cattle. Subsequent investigation of the alkaloid content of tall fescue revealed a number of structurally similar alkaloids of which loline (116) is the eponymous member. However, the negative effects of tall fescue consumption on cattle were traced to ergot alkaloids.101 Loline alkaloids, produced by endophytic fungi, were shown to provide chemoprotection for their plant hosts against certain types of insects and aphids but had little negative effect on mammalian systems.102 More recently, biologists have studied the biosynthetic pathways of the loline alkaloids and have managed to clone the gene cluster responsible for their production.103

Scheme 8. Tufariello’s Synthesis of (±)-Loline (1986)

K


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Scheme 9. White’s Synthesis of (+)-Loline (2000/2001)

reduced both carboxylic acids to their corresponding alcohols. Subsequent acid catalyzed acetalization of the intermediate 1,3diol with PMPCH2(OMe)2 selectively produced dioxane 128 as a single diastereomer in 64% yield over two steps. Swern oxidation of the remaining free alcohol generated an unstable aldehyde that was therefore immediately reacted with allylidene triphenylphosphorane to yield a 3:7 mixture of E:Z alkenes 129. No epimerization of the stereogenic ethereal carbon proximal to the aldehyde was observed in this reaction. Treatment of 129 with excess DIBALH reduced the less sterically hindered acetal C−O bond of 129 selectively to give a primary alcohol with concomitant formation of an internal p-methoxybenzyl ether (PMB−). To improve the E:Z ratio, the previously formed alcohol was catalytically photoisomerized in the presence of 1% molecular iodine. This resulted in the conversion from a 3:7 to a 95:5 E:Z ratio of 130. With diene 130 in hand, the group proceeded to elaborate the molecule to the requisite bicycle 133. Accordingly, a Swern and a Pinnick oxidation transformed the alcohol of 130 to the carboxylic acid 131, which was in turn converted to an activated O-succinimidyl ester and then further amidated with hydroxylamine to yield hydroxamic acid 132 in 75% yield from 130. Initial studies of the key hetero-Diels−Alder reaction on a model system led the team to settle on the use of NaIO4 in chloroform as the optimal condition. When applied to hydroxamic acid 132, cycloadduct 133 was obtained in 87% yield as a separable 57:43 mixture of the desired cis to undesired trans isomer. During optimization studies, selectivity was never more than moderate. Temperature had little effect on the reaction; benzene increased the yield at the cost of cis selectivity;

from the more sterically accessible convex face to give the secondary alcohol 123. Next, the C7 alcohol was converted to the stereochemically inverted chloride 124 through the action of thionyl chloride in DMF. Heating 124 in a NaOMe/MeOH solution at reflux removed the acetate protecting groups and induced the generated C2 alkoxide to displace the chloride and form the targeted ether linkage of 125. To complete the synthesis, Tufariello and his team needed to convert the C3 hydroxmethyl functionality to an N-methylamine. Therefore, the primary alcohol of 125 was oxidized to a carboxylic acid via a Jones oxidation, esterified to the methyl ester, and converted to the hydrazide by refluxing with hydrazine hydrate. Under the action of isoamyl nitrite and ethanolic hydrogen chloride, the hydrazide was oxidized and underwent a subsequent Curtius rearrangement to give the desired carbamate 126 as a 3:1 mixture with a methyl ester, which was chromatographically removed. Finally, LiAlH4 reduced the carbamate to give the desired N-methylamine 116 in a remarkable18.2% yield from nitrone 118. 3.1.2. White’s Synthesis of (+)-Loline (2000/2001) (Scheme 9). The second synthesis of loline (116) and first asymmetric synthesis was completed in 2000 by James White and his team at Oregon State University.108,109 White accomplished this feat in 20 steps and ∼0.4% yield from (−)-malic acid 127 via a route incorporating an intramolecular hetero-Diels−Alder cycloaddition of an acylnitrosodiene as a key reaction. White’s team began with the synthesis of diene 129, a known compound available in six steps from (−)-malic acid (127) according to a route established by Kibayashi.110 Specifically, the activity of BH3·SMe2 and B(OMe)3 in THF on malic acid (127) L


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Scheme 10. Scheer’s Synthesis of (±)-Acetylnorloline (2011)

reason for the inclusion of acetylnorloline in this discussion. Scheerer and his team capitalize upon a stereoselective tethered aminohydroxylation of a homoallylic carbamate to set key stereocenters en route to their 19 step synthesis with an overall yield of ∼3% from 139. Scheerer’s synthesis began from protected 3-oxo-proline (141), which can be prepared in three steps (up to 48% overall yield) from glycine ethyl ester114,115 or in two steps from N-Boc2-azetidinone (139) by the author’s route.116 With respect to the latter, lithiation of ethyl diazoacetate in the presence of azetidinone (139) resulted in the Claisen condensation product 140. Insertion of the carbamate nitrogen into the carbenoid generated upon exposure of 140 to (Rh)2(OAc)4 quantitatively delivered β-ketoester 141. At this point, the team attempted to render the route enantioselective by setting two of the four contiguous stereocenters of loline (116) with a bioreduction of 141 with Baker’s yeast, but their attempts were unsuccessful because of poor scalability and difficulties with isolation. Nonetheless, they decided to continue with a racemic synthesis. Sodium borohydride reduced the ketone of 141 and generated a cis relative stereochemistry, and acetate formation gave 142. Next, a kinetically controlled deprotonation effected a Dieckmann condensation to deliver cyclized product 143 in 69% yield along with 95% diastereoselectivity. A further seven steps were required to convert 204 to Kishi’s intermediate (+)-165. 3.2.8. Trudell’s Formal Synthesis of (+)-Gephyrotoxin 278C (2010) (Scheme 19). The fifth formal synthesis of gephyrotoxin 278C (160) was achieved by Trudell and coworkers of the University of New Orleans in 2010.133 Trudell’s route capitalized upon the stereochemistry embedded within the structure of cocaine (205) to form the pyrrolidine core of gephyrotoxin 278C. Previous work by the authors had revealed that cocaine (205) could be degraded in three steps and good yield to the corresponding ketone of 206, which the team then converted to 206 by treatment with TBSCl under basic conditions.140,141 With the electron-rich silyl enol ether in place, ozonolytic cleavage, reduction, and methylation of the intermediate carboxylic acid gave the desired pyrrolidine 207. A further six steps were required to obtain Kishi’s intermediate (+)-165.

(198) and chiral diol 199, which could be made in four steps from ethyl 3-oxo-8-tert-butyldimethylsilyl-oxy-6-octenoate. Initial attempts to effect ring-forming transformation on a nonTBDPS protected 200 gave 50% yield of product in >93:7 diastereoselectivity, but favoring the wrong diastereoisomer. The authors attributed this effect to a hydrogen bonding interaction of the alcohol with the nitrogen atom. Indeed, the team found that when they protected the alcohol with a TBDPS group they were able to obtain the correct diastereomer in a 3:2 ratio with the undesired isomer. The team was not able to further improve this diastereomeric ratio, however. From a mechanistic standpoint, the authors propose that the formal [3 + 3] cycloaddition reaction proceeds through a two-step Knoevenagel condensation, 6π electrocyclic ring closure. To complete the formal synthesis, in situ hydrogenation delivered pyrrolidine 201 and treatment with TBAF delivered Kishi’s intermediate 165. 3.2.7. Lhommet’s Formal Synthesis of (+)-Gephyrotoxin 278C (2008) (Scheme 18). Lhommet and co-workers published the fourth formal synthesis of gephyrotoxin 287C (160) in 2008.132 The team’s route relies on a diastereoselective reduction of a chiral pyrrolidine β-enamino ester (203) to set the two stereocenters adjacent to the pyrrolidine nitrogen of gephyrotoxin 287C. Lhommet’s route began with the synthesis of chiral 203, which was accomplished in three steps via addition of acetoacetic acid S


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Scheme 21. Sato and Chida’s Synthesis of (±)-Gephyrotoxin 287C (2014)

3.2.9. Spino’s Formal Synthesis of (−)-Gephyrotoxin 278C (2010) (Scheme 20). The most recent formal synthesis of gephyrotoxin 287C (160) was published by the group of Claude Spino of Sherbrooke University in 2013.134 Spino’s route featured a Beckmann ring expansion/photochemical ringontraction sequence to form the pyrrolidine ring from a cyclopentanone starting material and required 13 steps to reach (−)-165, an intermediate in Kishi’s synthesis (Scheme 12), in 1.1% yield. The synthesis began with a [4 + 3] cycloaddition between 1,3butadiene and the Favorskii intermediate generated from 2chlorocyclopentanone (208) according to a procedure of Föhlisch and Joachimi142 to give ketone 209 in 87% yield. The double rearrangement sequence was next. A one-pot Beckmann rearrangement of ketone 209 occurred in the presence of hydroxylamine-O-sulfonic acid and formic acid. This was followed by N-chlorination with NCS to give 210, substrate for the photochemical ring contraction, which occurred upon irradiation with 254 nm light. A solvent swap and treatment with benzyl alcohol furnished 211 in 55% (65% brsm) yield, which the authors note was one of the highest obtained for the ring contraction of an N-chlorolactam. A six step sequence elaborated 211 to Kishi’s intermediate 165. The authors employed enzymatic desymmetrization in this latter sequence to obtain their enantioenriched material. 3.2.10. Sato and Chida’s Synthesis of (±)-Gephyrotoxin 287C (2014) (Scheme 21). Following the Kishi, Hart, and Overman syntheses of the 1980s, it was not until 2014 that a

fourth total synthesis of (±)-gephyrotoxin 287C was published, fruit of a collaboration between the Sato and Chida groups at Keio University.143 Their route utilized N-methoxyamides to directly couple an amide with an aldehyde, and chemoselective nucleophilic addition to an amide as key steps to forge the target alkaloid in 14 steps and 9.4% overall yield. This synthesis commenced from penten-4-oic acid (212). Conversion of the carboxylic acid moiety of 212 to the Weinreib amide, followed by Grubbs’s olefin metathesis with allyltrimethylsilane, gave 213. In a key step, condensation of the Weinreib amide with 4-bromobutanal generated N-oxyiminium ion intermediate 214, which underwent an intramolecular cyclization/allylation to the cis-fused compound 215. Secondary amides are normally not nucleophilic enough to undergo condensation reactions with aldehydes, but the N-methoxy group of the Weinreib amide increases the nucleophilicity of the nitrogen atom, permitting it to undergo condensation. Ozonolysis of 215 followed by an HWE reaction provided 216 as the Z-isomer. Some trans-halogenation of bromide to iodide was observed; however, the exchange was inconsequential to the next reaction, a radical addition into the α,β-unsaturated ester initiated by AIBN and Bu3SnH. Use of the Z-isomer was crucial though, as the opposite stereochemistry for 217 was obtained from the E-isomer. This radical cyclization occurred flawlessly, giving 217 as a sole isomer in excellent yield. The key step involving reductive allylation of the Weinreib amide in the presence of an ester was next. Monoreduction of the N-methoxyamide with the Schwartz reagent formed an iminium/ T


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Scheme 22. Smith’s Synthesis of (−)-Gephyrotoxin 287C (2014)

workers at the University of Oxford in 2014.144 The efficiency of Smith’s synthesis is due in large part to masterful implementation of a diastereoselective intramolecular enamine/Michael cascade reaction to forge two bonds and three stereocenters in one step. Smith’s synthesis started with Boc protection of the amide nitrogen and O-TBS protection of the chiral pool material, Lpyroglutaminol (221). These protections were followed by alkylGrignard addition to the amide and subsequent reduction of the less sterically hindered face of the intermediate N-Boc-iminium with L-selectride in the presence of BF3·OEt2 to give 3,6-cissubstituted-pyrrolidine 222. The cyclopentene moiety of 222 was then unmasked to the dicarbonyl intermediate 223 by ozonolysis, and the resultant terminal aldehyde was homologated in situ with 1-(triphenylphosphoranylidene)-2-propanone to generate α,β-unsaturated ketone 224. This key substrate for the cyclization cascade was first deprotected with TFA and then allowed to stir for 72 h with warming at 40 °C. The liberated secondary amine 225 condensed with the ketone to form a six-membered iminiumcontaining ring, which tautomerized to an enamine and then added from the carbon into the α,β-unsaturated ketone to give iminium 226. A reduction of the iminium 226 with sodium cyanoborohydride, directed via the primary alcohol, resulted in cis-aza-decalin 227. When reductions were attempted without use of the alcohol-directing group, the opposite stereochemistry was obtained. Swern oxidation of the primary alcohol of 227 and subsequent Wittig olefination gave methyoxy vinyl ether 228. Another functional group interconversion transformed the ketone of 228

hemiaminal, which was allylated upon the addition of allyl tributylstannane in the presence of catalytic scandium triflate. The optimized reaction gave a 4.6:1 diastereomeric mixture of 218 in 84% yield. The chemoselectivity of this reaction finds its basis in the higher Lewis basicity of the N-methoxyamide compared to the ester. Coordination of the Lewis acidic zirconium hydride to the more basic functionality results in selective reduction of the Weinreib amide over the ester. Conversion of the nascent zirconium hemiaminal to the N-OMe iminium is effected by catalytic Sc(OTf)3, inducing attack by allyltributylstannane. Hydroboration, Parikh−Doering oxidation, and Wittig olefination provided 219. Reductive cleavage of the N-OMe bond with zinc and acetic acid liberated the secondary amine to undergo an intramolecular Michael addition to form the pyrrolidine ring of (±)-gephyrotoxin (160). Reduction of the northern methyl ester to an aldehyde was enabled by use of the bulky reducing agent, NaAlH(OtBu)iBu2 at 0 °C, which successfully differentiated the two esters on the basis of sterics without over-reduction. Subsequent Wittig olefination gave Ziodoalkene 220. Finally, Sonogashira coupling and reduction of the tert-butyl ester to the alcohol oxidation state gave (±)-gephyrotoxin 278C (160) in 14 steps, five steps shorter than the Overman synthesis, and nine steps shorter than Kishi’s, beginning to approach an ideal solution. 3.2.11. Smith’s Synthesis of (−)-Gephyrotoxin 287C (2014) (Scheme 22). The most concise synthesis of (−)-gephyroxtoxin 287C (160) was accomplished in a nine step sequence with a 14% overall yield by Martin Smith and coU


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Scheme 23. Weinreb’s Synthesis of (±)-Agelastatin A (1999)

and antiangiogenic,148 antidiabetic,151 and insecticidal properties.152 The promise of its bioactivity and thought-provoking structure have prompted no less than 13 total syntheses and six formal syntheses153−158 of agelastatin A. The following discussion will focus entirely on the total syntheses.

into alkyne 229 under basic conditions with the dehydrating agent diethyl phosphoryl chloride. At this point, methoxy vinyl ether of 229 was protonated and hydrolyzed under acidic conditions to the corresponding aldehyde, which was then reduced to give the free alcohol 230. The last C−C bond of the synthesis was formed through a hydrometalation/cross-coupling strategy. Dichloroindium hydride hydrometalated the alkyne in the presence of triethylborane to generate a vinyl indium species, which was cross-coupled with trimethylsilyl-protected iodoacetylene under palladium catalysis to give (−)-gephyrotoxin 287C (160) after TMS removal. 3.2.12. Gephyrotoxin 287C Conclusion. The efficiency of Smith’s synthesis, both in yield and in overall step count, derives from not only good design, but also a sensibility about telescoping certain steps that do not require intervening purification. Obviously, the key Mannich cascade occurs without intervening isolation and purification, but other steps that normally would have been subjected to aqueous workup and chromatography are instead collapsed together with no apparent harm to yield. Although it can be debated whether earlier syntheses of gephyrotoxin 287C (160) might also appear more efficient were their steps similarly telescoped, certainly the outcome for Smith’s synthesis is a high overall yield with remarkably reduced labor and materials, which illustrates the practicality of alkaloid chemical synthesis in the modern era.

The sheer number of syntheses of agelastatin A provides the opportunities both to marvel at the myriad ways to dissect even a medium-size alkaloid, and to identify features of the most efficient syntheses of agelastatin A that might dictate how syntheses of other alkaloids are planned. In other words, mimicry of the best syntheses aid the synthetic chemist in pruning off unpromising branches from their retrosynthetic (EXTGT) tree. The features common to the most efficient syntheses of agelastatin A (231) are (1) minimization of functional group interconversions (FGIs), which consume labor (steps), but do not increase complexity toward the final target; (2) maximization of steps that build skeletal bonds, stereocenters, or functional groups found in the target; and (3) high yields (essentially the syntheses conform to the precepts of transform hierarchies in ref 93). 3.3.1. Weinreb’s Synthesis of (±)-Agelastatin A (1999) (Scheme 23). Steven Weinreb and his group at Pennsylvania State University completed the first total synthesis of agelastatin A in 1999 in 14 steps with an overall yield of 7%.159,160 The key strategy of this synthesis entailed functionalization of cyclopentadiene’s two alkenes to introduce the nitrogens and four stereocenters of the target. In order to accomplish this task,

3.3. Agelastatin A

Agelastatin A (231) is a tetracyclic member of the growing family of pyrrole-2-aminoimidazole alkaloids (PAIs). It is a marine alkaloid, first isolated in 1993 by Pietra and co-workers from the axinellid sponge Agelas dendromorpha.145−147 Agelastatin A has shown cytotoxicity against a panel of human-cancer cell lines (IC50’s 97−703 nM),148,149 potent inhibition of osteopontin (OPN)-mediated neoplastic transformation and metastasis,150 V


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Scheme 24. Feldman’s Synthesis of (−)-Agelastatin A (2002)

unsaturated enone was induced in methanol under mildly basic conditions to give annulated intermediate 243. In the final sequence, the pyrrole moiety of 243 was brominated with NBS, which replaced the TMS group with a bromine atom. Subsequent loss of isobutene from the Boc group was promoted by reaction of the bromide of 243 with TMSI, and subsequent treatment with methyl isocyanate under basic conditions gave the desired product, (±)-agelastatin A (231), in 7% overall yield. Use of TMSI was needed because full deprotection of the nitrogen resulted in dimerization by pyrazine formation. The basic conditions of the methyl isocyanate installation were sufficient to remove the TMS-carbamate. 3.3.2. Feldman’s Synthesis of (−)-Agelastatin A (2002) (Scheme 24). The second total synthesis of (−)-agelastatin A (231) also came out of Pennsylvania State University, from the laboratories of Ken Feldman.163,164 Feldman’s route features the conversion of an alkynyliodonium salt into an alkylidenecarbene, which undergoes a C−H bond insertion to form a C−C bond in a cyclopentene ring as a showcase step. Feldman’s team completed this synthesis of (−)-agelastatin A (231) from epichlorohydrin in 14 steps and 3.5% overall yield. The synthesis began with the addition of LiCCTMS to (S)epichlorohydrin (244) with assistance from BF3·OEt2 to form chiral epoxide 245. The team envisioned the conversion of the epoxide to the oxazolidinone 246 via Vilarrasa’s oxazolidinone synthesis.165 Accordingly, the epoxide was opened with sodium azide, treated with butyllithium and then carbon dioxide and trimethylphosphine. A sequence of functional group interconversions (carbamate nitrogen protection, TMS deprotection, and stannylation) yielded 247. Treatment of 247 with Stang’s

Weinreb’s team employed as key steps a hetero-Diels−Alder reaction, a Mislow−Evans rearrangement, and a Sharpless/ Kresze amination. Weinreb began his synthesis with a [4 + 2] hetero-Diels−Alder reaction between cyclopentadiene (232) and N-sulfinyl methyl carbamate (233). The cycloaddition product 234 was treated with phenyl magnesium bromide, which attacked the electrophilic sulfur atom to cleave the S−N bond. Upon heating in HMPT and ethanol, a Mislow−Evans [2,3]-sigmatropic rearrangement occurred, and after cleavage of the S−O bond with HMPT, cis-functionalized cyclopentenes 235 and 236 were formed as a ∼1:1 mixture. Fortunately, 235 could be efficiently converted to 236 by treatment with KOtBu in THF. N-Boc protection of the carbamate of 236 preceded a Sharpless/Kresze amination161,162an ene reaction/[2,3]-sigmatropic rearrangement sequencewith di-SES (β-trimethylsilylethansulfonyl) sulfodiimide to give 237, in which a second nitrogen atom was installed, as a single isomer. Reductive cleavage of the S−N bond with sodium borohydride or trimethyl phosphite gave 238. NBoc protection of the carbamate of 236 was found to improve the reliability and scalability of the Sharpless/Kresze amination. Subsequent acylation of 238 with pyrrole 239 resulted in quantitative formation of the N-acylsulfonamide 240. Selective removal of the SES protecting group in the presence of the TMS group was ensured by use of TBAF in THF giving 241. Hydrolysis of 241 with lithium hydroxide gave pyrrole 242 as the major product in a 4:1 ratio with a Boc-deprotected compound, which would be recycled. Oxidation of the free alcohol to the ketone was accomplished with a pyridinium dichromate (PDC) oxidation. Michael addition of the pyrrole into the α,βW


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Scheme 25. Hale’s Synthesis of (−)-Agelastatin A (2004)

iodonium reagent166 at −42 °C gave 248, precursor for the key step. Addition of a chilled solution (0 °C) of 248 to a refluxing solution of TolSO2Na in DME led to isolation of the desired product (250) (34%) and a Ts-terminated alkyne (41%). Both products likely arise from intermediate 249. In the case of the desired product 250, the authors speculate that 1,5-C−H insertion occurs, while a 1,2-shift of the TolSO2 group occurs to give the Ts-terminated alkyne. Subsequent conjugate addition of o-nitrobenzylamine to the unsaturated sulfone moiety within 250 followed by acylation with pyrrole 2-carboxylic acid gave 251 with the requisite trans geometry. The net effect of this sequence was stereoselective formation of requisite C−N bond of agelastatin A (231). Facile oxazolidinone hydrolysis occurred upon treatment of 251 with cesium carbonate in methanol and water. When alcohol 252 was subjected to Swern oxidation conditions, 253 was formed as the sole product. This third C−N bond formation presumably proceeds though conjugate addition to an unobserved cyclopentenone intermediate, which arises from Ts-H elimination. To complete the synthesis, the o-nitrobenzylamine protecting groups were photolytically removed, and upon annulation to form the fourth and final C−N bond about the cyclopentane core, debromoagelastatin was obtained. Finally,

bromination of debromoagelastatin with NBS in methanol/ tetrahydrofuran gave (−)-agelastatin A (231). 3.3.3. Hale’s Synthesis of (−)-Agelastatin A (2004) (Scheme 25). In 2004, a group from University College London led by Karl Hale published a third synthesis of (−)-agelastatin A (231) in 26 steps from aminoglycoside 254.167,168 In their initial publication, Hale’s team completed a formal synthesis of Weinreib’s intermediate 238 but later developed a total synthesis based on the same initial route.167,168 The following discussion is restricted to Hale’s total synthesis. Hale and his team began their synthesis from aziridine 255, available in five steps from aminoglycoside 254 via a procedure of Hough and Richardson.169,170 Ring opening of the aziridine and three functional group interconversion/protection steps gave diamine 256, which was modified to iodide 257 in four more steps. Vasella’s reductive ring cleavage171,172reductive cleavage of iodide 257 with zinc and acetic acidfurnished linear 258. Another three steps involving methenylation, RCM, TES deprotection, and carbamate formation gave (−)-238, the seventh intermediate in Weinreib’s synthesis, in 17 steps overall. From (−)-238, consecutive N-acylations, first with benzyl(methyl)carbamic chloride (to give 259) and then with 5(trimethylsilyl)-1H-pyrrole-2-carbonyl chloride, gave 260. In a noteworthy step, Hale’s team found that radical deprotection of X


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Scheme 26. Davis’s Synthesis of (−)-Agelastatin A (2005/2009)

Scheme 27. Trost’s Synthesis of (+)-Agelastatin A and Formal Synthesis of (−)-Agelastatin A (2006/2009)

the N-SES (β-trimethylsilylethansulfonyl) protecting group of 260 was more effective than any fluoride-based method they tried. Up to 7% of the TMS-deprotected product was also produced under radical conditions. Hydrolysis of the oxazolidinone with LiOH produced urea 261. A PDC oxidation afforded the enone 262. Unlike Weinreb’s bromination of the less electron rich pyrrole 243 (cf. Scheme 23), bromination of 262 gave a mixture of mono-, di-, and tribrominated products. Rather than purify these, addition of Hünig’s base promoted the desired conjugate addition, and a hydrogenolysis step removed all the

bromine atoms to give 263. Finally, a hyrogenolysis/ring closure and monobromination sequence, following the method of Feldman (Scheme 24), gave the targeted (−)-agelastatin A (231). 3.3.4. Davis’s Synthesis of (−)-Agelastatin A (2005/ 2009) (Scheme 26). A fourth total synthesis of (−)-agelastatin A was published by Franklin Davis and his team at Temple University in Philadephia in 2005173 and with an optimized route in 2009,174 using Davis’s sulfinime technology as a key part of Y


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Scheme 28. Ichikawa’s Synthesis of (−)-Agelastatin A (2007)

their strategy. Davis’s route builds the molecule in 11 steps with an impressive 23% yield overall. Davis’s primary aim was to synthesize biorelevant nitrogen compounds in an asymmetric fashion via sulfinimine-based technology, a goal which the team attained in short order. Specifically, aminoester (264) was deprotonated with LDA and to this solution was added an excess of sulfinimine 265, resulting in the formation of a separable 18:5:1 diastereomeric mixture favoring the major syn isomer. Two functional group manipulations (Weinreib amide formation and N-sulfinyl amino group removal) preceded coupling with pyrrole-2carboxylic acid to give the intermediate 267. Allyl addition to the Weinreib amide was followed by base catalyzed isomerization to the α,β-unsaturated ketone 268, which was treated with Grubbs’s second generation catalyst to effect ring closing metathesis and form the cyclopentenone 269.

With the key cyclopentenone 269 in hand, construction of the rest of the molecule followed the general strategy of the Weinreib, Feldman, and Hale syntheses. A conjugate addition of the pyrrole moiety was followed by hydrogenolysis of the Nbenzyl protecting groups and carbamate formation upon addition of methyl isocyanate to give debromoagelastatin 270. Finally, bromination of the pyrrole portion of 270 with NBS or dibromatin provided (−)-agelastatin A (231). 3.3.5. Trost’s Synthesis of (+)-Agelastatin A and Formal Synthesis of (−)-Agelastatin A (2006/2009) (Scheme 27). The fifth total synthesis of agelastatin A was completed by Trost and Dong of Stanford University in 2006,175 with a full report appearing 3 years later.176 Trost completed a formal synthesis of natural (−)-agelastatin A and a total synthesis of its unnatural enantiomer, (+)-agelastatin A, in eight steps from 271 and 10 steps overall from commercially available starting material using a Z


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Scheme 29. Yoshimitsu and Tanaka’s Synthesis of (−)-Agelastatin A (2008)

Envisioning that aziridine 280 could be elaborated to the product, the group discovered that use of the copper carbene complex 279 in conjunction with PhINTs could effect the transformation, with the conformation of 276 dictating aziridination from the more accessible convex face of the molecule. Heating N-tosyl aziridine 280 in DMSO with In(OTf)3 as a Lewis acid provided α-amino ketone 281 in 91% yield, a method developed in house by the Trost group. Finally, addition of methyl isocyanate gave 282, and SmI2 cleaved the NOMe bond and removed the N-tosyl protecting group to furnish (+)-agelastatin A (231). The (−)-enantiomer of agelastatin A (231) could be obtained simply by using (S,S)-273. 3.3.6. Ichikawa’s Synthesis of (−)-Agelastatin A (2007) (Scheme 28). A sixth total synthesis of (−)-agelastatin A (231) was published by the Ichikawa group of Kochi University in 2007.177 This synthesis required 23 steps from 283 and featured a [3,3]-sigmatropic rearrangement of an allyl cyanate as the key step. The synthesis began with benzoyl and bis-acetonide protected L-arabitol derivative 283, which could be prepared in two steps from L-arabitol. This compound 283 was treated with aqueous acetic acid to remove the terminal acetonide, and the resulting diol was then bis-mesylated. In a useful reductive elimination, the bis-mesylate produced the alkene 284 after being heated in 2butanone with sodium iodide and tetra-n-butylammonium iodide for 2 h. This reaction involves displacement of one or both mesylates by an iodide in a Finkelstein-like manner, formation of an iodonium ring, and reversion to I2 and the alkene. Benzoate 284 was hydrolyzed to a primary alcohol, and then successively oxidized and homologated to an α,β-unsaturated methyl ester with (carbethoxymethylene)-triphenylphosphorane in a two step, one pot sequence. This methyl ester was reduced down to the alcohol oxidation state with DIBALH, which was

palladium-catalyzed asymmetric allylic alkylation (AAA) strategy to form the molecule’s core. Trost began his synthesis with a screen of palladium source and loading, base and base loading, solvent, and concentration to find conditions sufficient to join Boc-activated cyclopentene-1,4diol 271 and 5-bromopyrrole-2-carboxylate 272. The team found that use of [Pd(C3H5)Cl]2 source in DCM with Cs2CO3 as the base and ligand (R,R)-273 gave the best result, 83% yield and 92% ee, of the adduct 274. With 274 in hand, saponification of the methyl ester followed by an oxalyl chloride mediated coupling gave Weinreib amide 275, substrate for the second palladium-catalyzed allylation reaction. For the second coupling, use of Pd2(dba)3·CHCl3 as the palladium source proved to be more effective than [Pd(C3H5)Cl]2 and delivered cyclized compound 276 in 91% yield. With the success of these two reactions individually, the team attempted to make these reactions into a cascade sequence by directly coupling pyrroloamide 277 with 271 to form 276 in one step. Yet when the reaction was attempted under basic conditions, almost no reaction occurred. Trost reasoned that pyrroloamide 277 serves as a good bidentate ligand upon deprotonation, effectively chelating the palladium and quenching its reactivity. When the group attempted the cascade reaction with Pd2(dba)3·CHCl3 as the palladium source under acidic conditions to avoid this detrimental chelation, compound 278 was obtained in 51% yield. Piperazinone 278 is an isomer of the desired compound 276. Thus, while either enantiomer of 276 could be obtained by switching between (R,R)-273 and (S,S)273, the desired isomer 276 for the agelastatin A synthesis required an iterative route. Trost pointed out though that compound 278, after it was subjected to a Sharpless/Kresze allylic amination, could be elaborated to agelastatin A by analogy with Weinreib’s synthesis (Scheme 23). AA


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Scheme 30. Wardrop’s Synthesis of (±)-Agelastatin A (2009)

then reoxidized to give aldehyde 285. Alkylation of 285 with diethyl zinc proceeded smoothly in the presence of the Soai catalyst, (S)-diphenylprolinol, to give enantioenriched alcohol 286 in 92% yield and as an inseparable 92:8 diasteromeric mixture. Alcohol 286 was converted to allyl carbamate 287 by reaction with trichloroacetyl isocyanate followed by base hydrolysis. In the key step of the synthesis, triphenylphosphine, carbon tetrabromide, and triethylamine in DCM at −10 °C dehydrated the carbamate to the corresponding cyanate, which then underwent a [3,3]-sigmatropic rearrangement to form the C− N bond of 288 with [1,3]-chirality transfer. To avoid partial hydrolysis of the isocyanate function during aqueous workup, the reaction mixture was treated with tributyltin benzyl alkoxide, which yielded benzylcarbamate 288. Removal of the acetonide in refluxing MeOH over Dowex 50 W gave the diol 289. Grubbs’s ring closing metathesis of 289 formed a cyclopentene, which upon treatment with 2,2dimethoxypropane in camphorsulfonic acid (CSA) afforded 290 along with a 1-methyl-1-methoxyethyl ether of 290. Hydrolysis of this side product on wet silica removed this unwanted methoxyethyl ether to return allylic alcohol 290, substrate for the second [1,3]-chirality transfer. As before, the alcohol of 290 was transformed into an allyl carbamate, induced to undergo a [3,3]-sigmatropic rearrangement, and after trapping of the resultant isocyanate moiety with 2,2,2-trichloroethanol, Ntrichloroethoxyl (Troc)-protected carbamate 291 was obtained. The Troc group of 291 was reductively removed with zinc in acetic acid, and the liberated allyl primary amine was acylated to give pyrrole-containing compound 292. Removal of the acetonide was followed by an IBX oxidation to furnish an α,βunsaturated enone, and under basic conditions the dibromopyrrole moiety of 292 cyclized in a conjugate addition fashion onto the enone, providing 293. Finally, (−)-agelastatin (231)

was obtained by hydrogenolysis of the Cbz protecting group of 293, which occurred with debromination of the pyrrole moiety; reaction of the amine with methyl isocyanate and subsequent cyclization to form the hemiaminal portion of 231; and bromination of debromoagelatstatin with NBS following the protocol of Feldman. Ichikawa and co-workers completed their synthesis in 23 steps and 7.7% yield overall. 3.3.7. Yoshimitsu and Tanaka’s Synthesis of (−)-Agelastatin A (2008) (Scheme 29). In 2008, Yoshimitsu, Ino, and Tanaka published a seventh total synthesis of (−)-agelastatin A (231) in 16 steps with an 8% yield overall.178 The reaction sequence features an intramolecular aziridination of an azidoformate and subsequent regioselective azidination to effect a net trans-diamination of a double bond as the key step. In addition, this route demonstates two new protocols for the preparation of an imidazolidinone hemiaminal motif from an oxazolidinone intermediate. This synthesis was initiated with known Boc-protected 4aminocyclopentene-1-ol ((+)-294), which could be prepared from cyclopentadiene (232) and resolved by acetylation with the enzyme Lipase PS-C Amano II in 42% yield and >99% ee after recrystallization. A Mitsunobu reaction on (+)-294 with 4nitrobenzoic acid inverted the alcohol stereochemistry, and a deprotection of the N-Boc group with TFA occurred prior to a Paal−Knorr pyrrole synthesis to give 295. Next, carbamoylation of the pyrrole with trichloroacetyl isocyanate and subsequent dehydration of the carbamate with POCl3 furnished the cyanide of 296. Base mediated hydrolysis of the 4-nitrobenzoate gave 296 itself. Azidoformate (297) was successfully formed by a CDI coupling with TMSN3, from which HN3 was presumably generated in situ by aqueous hydrolysis. In the first part of the key step, high temperature/pressure conditions resulted in aziridination of the π-bond to give 298. Next, the strained AB


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Scheme 31. Du Bois’s Synthesis of (−)-Agelastatin A (2009)

aziridine was opened with sodium azide in DMF to give trans299 selectively as the sole regioisomer. It is worth noting that other nitrogen nucleophiles such as benzylamine and aqueous ammonia exclusively added to the oxazolidinone moiety, giving urea derivatives rather than the desired aziridine ring opened product. Difficulty with lactamization of 299 led the authors to convert the nitrile of 299 to the amide 300 with hydrogen peroxide in aqueous sodium hydroxide. Hydrogenolysis of the azide generated a free amine which lactamized to 301 upon heating in MeNH2 in DMSO at 130 °C. To complete the synthesis, a Ley oxidation of the southern alcohol to a ketone preceded hemiaminal formationan overall oxidative cyclization, and treatment of the intermediate with NBS yielded the desired product, (±)-agelastatin A (231). 3.3.8. Wardrop’s Synthesis of (±)-Agelastatin A (2009) (Scheme 30). David Dickson and Duncan Wardrop of the University of Illinois at Chigago published an eighth total synthesis of (±)-agelastatin A in 2009.179 This synthesis, which proceeded in 14 steps and 8% overall yield, features as a central idea the use of a trichloroacetamide functionality to mediate cyclofunctionalization. The sequence commenced from known cis-3-acetoxy-5hydroxy-cyclopentadiene 302, which can be prepared in two steps from cyclpentadiene via a peracetic acid epoxidation and subsequent Pd(0)-catalyzed syn-1,4-addition of acetic acid.180,181 Trichloroacetamide 303 was formed in a two step sequence involving imidate formation followed by an Overman rearrangement. Bromination of the olefin of 303 with bromoacetamide induced ring closure, and refluxing the resultant intermediate with DBU in toluene eliminated the bromide to give cis-fused dihydrooxazole bicycle 304. Subsequent hydrolysis regenerated the trichloroacetamide group to give 305.

A Mitsunobu reaction of 305 with phthalimide provided a requisite C−N bond in a trans-orientation to the already present trichloroacetamide in 305. Subsequent heating in DMF under basic conditions in the presence of N-(methyl)benzylamine gave compound 306, thereby unmasking the latent urea functionality present in the trichloroacetamide. Decomposition of the phthalimide to the primary amide and subsequent EDC coupling with pyrrole-2-carboxylic acid yielded 307. Hydrolysis of the acetate of 307 gave a free allylic alcohol that was subsequently oxidized with IBX to form α,β-unsaturated enone 308. Heating 308 under basic conditions promoted an intramolecular conjugate addition to form 309, which upon hydrogenolysis of the N-benzyl protecting group cyclized to form hemiaminal 270. Finally, bromination of 270 under Feldman’s conditions163 furnished the desired target, (±)-agelastatin A (231). 3.3.9. Du Bois’s Synthesis of (−)-Agelastatin A (2009) (Scheme 31). Paul Wehn and Justin Du Bois of Stanford University completed a ninth total synthesis of (−)-agelastatin A (231) in 2009.182 Du Bois made use of a rhodium-catalyzed aziridination as a key step en route to his 11 step synthesis of this molecule, which was obtained in 15% overall yield. Optically enriched lactam (−)-310 is commercially available and can be converted into 311 in three steps: N-Boc protection, reduction to an alcohol (also commercially available), and sulfamoylation of the primary alcohol. In the key step of this reaction, 311 was converted to aziridine 312 by treatment with catalytic [Rh2(esp)2], PhI(OAc)2, and MgO in excellent yield (95%) as a single diastereomer. With a remarkable catalyst loading of just 0.06%, over 1500 turnovers occur for this reaction. Reacting 312 with sodium azide in aqueous isopropanol opened up the aziridine in a regioselective fashion to give 313 as a 9:1 mixture of regioisomers. In the next step, oxathiazepane 313 AC


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Scheme 32. Chida’s Synthesis of (−)-Agelastatin A (2009)

was first N-acylated with diethyl pyrocarbonate, which rendered the C−O bond of the sulfamate more electrophilic, and then in the same pot was treated with sodium selenophenol, prepared separately, to cleave the C−O bond and form a Se−C bond. 314 was obtained as a result of this sequence. Next, the N-Boc protecting group was removed under acidic conditions to give a secondary amine. This amine was then converted to the pyrrole of 315 via a Paal−Knorr pyrrole synthesis. The azide of compound 315 was converted to an amine with trimethylphosphine via a Staudinger reduction and reacted with methyl isocyanate to form a methylated carbamide. The selenide was oxidized to the selenoxide with mCPBA and eliminated to give the exocyclic methylene 316. Notably, if the elimination of the selenoxide occurred before Staudinger reduction, then the allylazide underwent a [3,3] rearrangement to the more substituted alkene. For this reason, the azide was first reduced to the amine before elimination. Johnson−Lemieux oxidation of the newly formed methylene furnished a ketone, onto which the carbamide cyclized to form the hemiaminal 317. With the formation of cyclic hemiaminal 317, all that remained to complete the synthesis was formation of the six-membered lactam and bromination of the pyrrole. Accordingly, the N-carbamate protecting group was removed

concomitant with cyclization to form the lactam 270 in the presence of KOtBu in tert-amyl alcohol. Finally, the pyrrole moiety was brominated according to Feldman’s procedure163 to give (−)-agelastatin A (231). 3.3.10. Chida’s Synthesis of (−)-Agelastatin A (2009) (Scheme 32). Also in 2009, Chida’s group of Keio University in Japan published a tenth total synthesis of (−)-agelastatin A in 21 steps and 1.2% overall yield from 318.183 The route features a sequential Overman/Mislow−Evans rearrangement of an allylic bistrichloroimidate intermediate to install a diaminohydroxy group as its key step. Chida began his synthesis from enantiomerically pure (−)-2,3O-isopropylidene-D-threitol 318, which is derived from D-tartaric acid. Monotosylation of 318 was followed by thiophenol alkylation to form desymmetrized 319. A Swern oxidation of the remaining primary alcohol to the aldehyde followed by a Wittig reaction produced diene 320 as a 1:5 ratio of the E:Z alkenes. Since the E alkene was needed to obtain the correct stereochemistry in the key pericyclic cascade, the team then isomerized 320 using thiophenol and AIBN under radical conditions to obtain a 10:1 E:Z ratio. Removal of the acetonide in aqueous acetic acid gave diol 321. AD


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Scheme 33. Movassaghi’s Synthesis of (−)-Agelastatin A (2010)

This sequence set the requisite functionality and stereochemistry for the key sequential sigmatropic rearrangement. Treatment of diol 321 with trichloroacetonitrile and DBU in DCM gave the corresponding allylic bistrichloroacetimidate, which then underwent two sequential Overman rearrangement reactions to form two C−N bonds in 322 stereoselectively. Next, oxidation of the sulfide with mCPBA generated a sulfoxide, which underwent a Mislow−Evans rearrangement to give alcohol 323 as an inconsequential 1:1 mixture of diastereomers after cleavage of the S−O bond with trimethylphosphite. Ring closing metathesis of 323 resulted in formation of the corresponding cyclopentene. Mesylation of the alcohol resulted in ring closure to a single oxazoline 324 by displacement of the nascent mesylate with the oxygen atom of the trichloroacetimidate, thereby converging the two alcohol diastereomers to a single product. The two trichloracetamides on the carbocyclic ring were also successfully differentiated by the ring closure. Next, the remaining trichloroamidate group in 324 was removed by a DIBALH reduction, and an EDCI coupling was employed to install the pyrrole moiety of agelastatin A, giving 325. With 325 in hand, acid hydrolysis of the oxazoline moiety regenerated a trichloroacetamide and liberated a secondary alcohol, which was protected as a THP acetal (326). The final sequence of this synthesis followed the conjugate addition strategy previously utilized by the Weinreib, Feldman, Hale, Davis, Ichikawa, Wardrop, and Chida syntheses. In order to enable this transformation, the trichloroamidate group of 327 was converted to an DMB(Me)-amidate group which would tolerate basic conditions. The THP acetal protecting group was then removed and the resultant alcohol was oxidized to an α,βunsaturated enone 328. Treatment of 328 with triethylamine was

sufficient to effect cyclization, and after removal of the DMB protecting group with CAN, (−)-agelastatin (231) was obtained. 3.3.11. Movassaghi’s Synthesis of (−)-Agelastatin A (2010) (Scheme 33). Interestingly, all of the preceding syntheses have in common an early introduction of the cyclopentane C-ring of agelastatin A (231) followed by further elaboration of the B- and D-rings to the final target. Instead of this approach, the Movassaghi group opted for a biomimetic strategy.184 This strategy proved highly effective. The MIT team completed their synthesis in 2010 and it is among the most concise syntheses of (−)-agelastatin A to date, requiring only seven steps. The team developed an imidazolone-forming annulation reaction and a carbohydroxylative trapping of imidazolones as part of their efficient synthesis, which yielded the final product in 12% (7 steps) or 22% (8 steps) overall yield from chiral pool material O,O-dimethyl aspartate 330. The Movassaghi group followed up on this initial communication and the 11th total synthesis of ageslastatin A with a full paper in 2013.185 Movassaghi’s synthesis commenced with a Paal−Knorr pyrrole reaction between D-aspartic acid dimethyl ester (330) and the masked 1,4-dialdehyde 329. The resultant pyrrole 331 was obtained in 84% yield and 99% ee. 331 was then brominated with NBS in THF with 2,6-di-tert-butyl-4-methylpyridine (DTBMP) as a base. The resultant bromopyrrole was further functionalized to the corresponding amide 332 in 82% yield by treatment with chlorosulfonyl isocyanate followed by reductive removal of the sulfone from the amine. Next, addition of sodium borohydride followed by TsOH to a methanolic solution of 332 generated bicycle 333 as a single diastereomer in 90% yield and AE


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Scheme 34. Biosynthetic Basis of Romo’s Disconnections of (±)-Agelastatin A

Scheme 35. Romo’s Synthesis of (±)-Agelastatin A (2012)

carboxylate (CuTC) to give 336. Subsequent treatment with methanol hydrogen chloride unveiled the triazone of 336 to reveal a keto-urea, which underwent spontaneous cyclization to form compound 337. Alternatively, thioester 334 could be converted to 337 in a one pot process involving a stannyl urea under the CuTC mediated conditions followed by HCl addition. The yield for the two-step process, however, was better than that

99% ee. No epimerization of the stereocenters was observed for this reaction. The next part of the synthesis required a general strategy for the introduction of the imidazolone substructure present in agelastatin A. After some experimentation, the authors found that thioester 334 could be coupled with readily available triazone 335 in the presence of stoichiometric copper(I)-thiophene-2AF


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Scheme 36. Batey’s Synthesis of (±)-Agelastatin A (2013)

the otherwise unreactive amide, and the N-OMe bond was reductively cleaved with samarium iodide after successful coupling. Subsequent hydrogenation with Lindlar’s catalyst furnished intermediate 347, the key cyclization precursor. Romo’s team found that the showcase cyclization step occurred best in TFA at low temperatures. Under acidic conditions, the hemiaminal was converted to an iminium ion (348) that cyclized to form intermediate 349 either through a Nazarov 4π-electrocyclization or a polar 5-exo-trig cyclization. Cationic intermediate 349 was trapped upon addition of water to form hemiaminal 350. Despite their best efforts, 350 could not be taken directly to agelastatin A. Instead, removal of the Tse protecting group to give 351 was required before cyclization to form the B-ring would occur. Yet cyclization to form a 68:13 mixture of (±)-agelastatin A (231) and its diastereomer 388 did occur easily on silica gel once the Tse group had been removed. 3.3.13. Batey’s Synthesis of (±)-Agelastatin A (2013) (Scheme 36). In 2013, Duspara and Batey completed the 13th and most recent total synthesis of (±)-agelastatin A via a sequence which proceeded in only seven steps with a 14% overall yield.188 Batey’s route capitalized upon a 4π conrotatory electrocylization to set a trans relative relationship between two of the amines on the C-ring and leveraged those stereocenters to set the remaining stereocenters in the molecule. Duspara and Batey insightfully saw that the trans-diamine relationship in the C-ring could be installed via a 4π-suprafacial conrotatory electrocyclization and designed an appropriate substrate to realize this transformation. Accordingly, in the presence of catalytic dysprosium(III) triflate, furfuraldehyde (352) reacted with two equivalents of the bis-allylated amine (353) to generate intermediate 354 via a domino condensation/ ring opening sequence, and 345 then underwent a Nazarov-like π4a electrocyclization to obtain diamino cyclopentenone (355). Next, 1,2-reduction of the cyclopentenone 355 gave inter-

of this one pot operation. Finally, 337 was converted to (−)-agelastatin A (231) and its diastereomer (338) in a 2:1 mixture upon treatment with methanesulfonic acid with heating. 3.3.12. Romo’s Synthesis of (±)-Agelastatin A (2012). In 2012, Reyes and Romo at Texas A&M completed a 12th total synthesis of (±)-agelastatin A.186 As with Movassaghi, Romo elected to proceed using an approach inspired by biosynthetic reasoning. The end result of Romo’s insights led to a 12 step and 1% overall yielding route. Romo, however, utilized a different biogenetic model than Movassaghi, basing his analysis on the structures of related pyrrole-2-aminoimidazole alkaloids, nagelamide J (339), cyclooroidin (340), and kermadine (341), which are plausible biosynthetic precursors of the agelastatins (Scheme 34). Romo envisioned that agelastatin A could arise from a precursor resembling kermadine (341) which may cyclize first to form the C-ring, as in the case of nagelamide J (339), or to form the B-ring first, as in the case of cyclooroidin (340). Developing this idea further with insights from known reactivity of PAI’s and their own experience,187 the team elected to form the C-ring first and the B-ring last, though also in a cascade sequence. Romo’s synthesis commenced with the synthesis of known imidazolone 343 from tartaric acid 342 and N-methylurea via an acid promoted condensation (Scheme 35). Several lateral transformations involving O-methylation and N-p-toluenesulfonylethyl (Tse) protection, followed by an ester reduction and an alcohol oxidation, gave aldehyde 344. Next, the authors installed the alkynyl acetal 345 via use of the Ohira−Bestmann modification of the Seyferth−Gilbert homologation followed by zinc(II) mediated acetalization. The ethoxy carbinolamide 346 was obtained from the key coupling of alkynyl acetal 345 with N-methoxy amido pyrrole, a process which was mediated by tin(IV) chloride. The use of an N-methoxy amide was crucial for this coupling as it increased the nucleophilicity of AG


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Scheme 37. Wood’s Synthesis of (+)-Citirinadin B (2013)

mediate 356 after TBDPS protection. Removal of all four N-allyl protecting groups under the conditions of Guibé and co-workers occurred smoothly,189 and an acid wash (to facilitate handling) generated the HCl salt 357. The electrocyclization worked best with N-allyl protecting groups, but no reaction was observed when protecting groups were absent. The next step involved differential functionalization of the N3 and N9 amines. Although it would have been simplest to employ a syn-1,2-protection of the amino alcohol, the team wished to avoid further protecting group chemistry and instead sought conditions that would allow differential acylation of the amines on the basis of steric encumbrance, i.e., proximity to the bulky OTBDPS protecting group. Indeed, after optimization, the team found a one-pot procedure that could effect the transformation to bis-acylated compound 358. The team found that 2-(2pyridon-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate

(TPTU) gave the best selectivity for N9 over N3 with the lithium 5-bromo-1H-pyrrole-2-carboxylate salt. The team was able to obtain at best a 54% isolated yield. Rather than use toxic methyl isocyanate, Batey used a carbamoylimidazole-based equivalent to acylate the N3 amine. This reagent was easy to use and gave excellent selectivity for amines in the presence of free alcohols, so removal of the TBDPS protecting group with cesium fluoride could be performed in the same pot. These two reactions led to intermediate 358. From 358, IBX oxidation of the alcohol resulted in a 14:86 mixture of 360:359, which were found to not interconvert under the oxidative conditions of their formation from 358. In support of this conclusion, Batey notes that treatment of 360 to the reaction conditions did not lead to formation of 231. Addition of acidic trifluoroethanol to the solution after IBX oxidation along with mild heating led finally to formation of the desired AH


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Scheme 38. Martin’s Synthesis of (+)-Citrinadin B (2013/2014)

N059. It was isolated by Kobayashi and co-workers in 2005, following the isolation of citrinadin A in 2004.190−192 The citrinadins exhibit activity against murine leukemia L1210 (citrinadin A, IC50 6.2 μg/mL; citrinadin B, 10 μg/mL) and human epidermoid carcinoma KB cells (citrinadin A, IC50 10 μg/ mL). Intrigued by their biological activity and structural complexity, Martin and Wood independently reported total syntheses of these molecules in 2013 and 2014 publications.193−195 (The groups published A and B, respectively, in back-to-back 2013 reports, but we will compare only syntheses of citirinadin B.)

agelastatin A (231) in 48% yield along with 12% 360. This last reaction proceeds through an intramolecular aza-Michael addition of the pyrrole nitrogen into the enone of intermediate 359, followed by hemiaminal formation. 3.3.14. Agelastatin A Conclusion. What can be learned from this dizzying array of syntheses? The first obvious trend is that the later syntheses are more efficient. The basis for this trend can likely be found in three places. First, better or more powerful analytical tools can direct syntheses toward efficiency by detecting trace products in risky reactions that might be optimized but are initially inefficient. Second, total synthesis as a field has faced very recent pressure to prove itself practical and meaningful, which usually translates into providing significant amounts of material for further study at reasonable cost, instead of proof-of-principle exercises. Third, later syntheses must be more efficient or risk irrelevancywhy do worse what has been done well? Whereas there is always excitement in tackling an alkaloid that has yet to succumb to chemical synthesis, the revisitation of old but important targets drives innovation by requiring practicality. 3.4. Citrinadin B

3.4.1. Wood’s Synthesis of (+)-Citrinadin B (2013) (Scheme 37). John Wood’s synthesis of (+)-citrinadin B (361)

Citrinadin B (361) is a spirooxindole alkaloid secondary metabolite of the marine-derived fungus Penicillium citrinum AI


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Martin’s synthesis began with 1,3-diketone 376. Monoketalization, Claisen condensation, vinyl triflate formation, and conjugate methyl addition with concomitant triflate elimination transformed 376 to vinyl ester 377. In the key step, the team first generated an extended zinc(II) enolate with LDA in the presence of ZnCl2. The addition of the chiral pyridinium salt 378 to the enolate of 377 gave the chiral adduct 379 with 92:8 diastereoselectivity after workup. Methanolysis of the (+)-TCC chiral auxiliary under basic conditions generated a vinylogous amide in situ, which then underwent an intramolecular lactamiztion to give 380 in 80% yield and 84% ee. This chiral compound 380 could be further enriched to >98% ee by recrystallization. The next few steps of the synthesis involved manipulation of the northern ring of 380. Five steps were required to obtain xanthate 381 from vinylogous lactam 380. In the first step, the TIPS group was removed with TBAF. This deprotection reduced steric encumbrance around the vinylogous amide, thereby facilitating organocuprate mediated conjugate addition of a methyl equivalent in the second step. The cuprate addition also required assistance of a Lewis acid (BF3·OEt2) because of the decreased electrophilicity of vinylogous amides compared to enones. The bulky PhMe2SiCH2 group (the methyl surrogate) was employed to increase diastereoselectivity of the conjugate addition; simple methyl group addition gave low (99% ee through use of Pd[PPh3]4 (10 mol %) in ACN with NEt3 as a AP


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Scheme 48. Tokuyama’s Synthesis of (−)-Rhazinilam (2013)

macrocycle was formed upon treatment of 456 with Mukaiyama’s reagent to give (±)-rhazinilam (386) in 11 steps with 15% overall yield. 3.5.9. Tokuyama’s Synthesis of (−)-Rhazinilam (2013) (Scheme 48). In 2013, Tokuyama and his team published a ninth total synthesis of (−)-rhazinilam (386). In this synthesis, the authors made use of a gold-catalyzed cascade cyclization to form two rings in one step as the key step in their 16 step synthesis.235 Tokuyama’s team elected to construct the chiral quaternary carbon center at the start of their synthesis via a diastereoselective Michael reaction as reported by d’Angelo et al.236 Accordingly, 2ethylcyclohexan-1-one (457) was condensed with (S)-1phenethylamine to form the corresponding tetrasubstituted enamine. This chiral enamine added to methyl acrylate in a 1,4fashion with a remarkable 83% yield and >99% enantiomeric excess after 7 days. Subsequent acid hydrolysis of the intermediate imine yielded the chiral ketone 458. Silyl enol ether formation followed by DDQ oxidation produced the α,β-unsaturated ketone 459 from 458. A nondiastereoselective epoxidation of 459 in a basic solution of H2O2 yielded diastereomeric epoxyketones 460. The lack of selectivity in the epoxidation step was inconsequential though because the next step, an Eschenmoser−Tanabe fragmentation, eliminated both stereocenters generated in this epoxidation. The Eschenmoser−Tanabe fragmentation was effected by conversion of epoxyketone 460 into a semicarbazone, followed by oxidative fragmentation under Warkentin’s procedure239 to give 461. To obtain substrate 462 for the key cyclization reaction, several more steps were required. The aldehyde was oxidized to a carboxylic acid via a Pinnick oxidation. This carboxylic acid was then coupled with aminoacetoaldehyde diisopropylacetal using

steric and electronic effects. A subsequent in situ Suzuki coupling reaction of 2-iodonitrobenzene in the presence of catalytic Pd(OAc)2, S-Phos ligand, and K3PO4 in n-BuOH delivered the desired biaryl compound 453 in 63% yield from 452. The N-Boc protecting group was also removed in this process and the reaction could be conducted on a multigram scale. Iodoolefin 451 was separately prepared following a procedure from Gaunt’s rhazinicine192 synthesis in five steps from diester 449. Specifically, Wittig olefination, global hydrolysis, and monoesterification with 2-(TMS)ethanol generated 450 in 81% yield as a mixture of geometrical isomers. Selective reduction of the remaining carboxylic acid of 450 to the alcohol oxidation state and Appel-type iodination yielded iodoolefin 451. Union of the two fragments, iodoolefin 451 and pyrrole 453, under basic conditions furnished 454. The next part of this synthesis necessitated “zipping up” the linear substrate 454 to form rhazinilam (386). Gaunt and coworkers envisioned this occurring in a two step process involving first a Pd(II)-catalyzed C−H bond alkenylation followed by macrolactamization. This strategy was ultimately successful. The team found that they could optimize the conditions of Liégault and Fagnou234 for the Pd(II)-catalyzed alkylation of pyrroles to form the quaternary carbon bond of 455 in 60% yield. Specifically, 10 mol % Pd(OAc)2, 20 mol % NaOtBu, and 10 mol % DMF in pivalic acid at 110 °C under a balloon of oxygen afforded the desired product in 60% yield (78% brsm). The use of oxygen at the terminal oxidant reinforced the efficiency of this C−H alkenylation process through which was introduced the sterically congested sole quaternary carbon bond of rhazinilam (386). Hydrogenation of the nitro group to the amine and conversion of the TSE ester of 455 to the corresponding carboxylic acid yielded the aniline acid 456. Finally, the desired AQ


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Scheme 49. Zhu’s Synthesis of (−)-Rhazinilam (2014)

reaction.240 Finally, the ester of 465 was hydrolyzed to a carboxylic acid and intramolecularly coupled with the aniline nitrogen via EDCI and HOBt in DCM to furnish (−)-rhazinilam (386) in 7.6% overall yield. 3.5.10. Zhu’s Synthesis of (−)-Rhazinilam (2014) (Scheme 49). In 2014, a team led by Jieping Zhu of Ecole Polytechnique Fédérale de Lausanne published the 10th total synthesis of rhazinilam (386).237 Zhu’s synthesis features use of a chiral imidodiphosphoric acid to catalytically and enantioselectively desymmetrize a bicyclic bislactone, bearing an all-carbon stereogenic center, as the key step en route to their 14-step synthesis of (−)-rhazinilam. At the project’s genesis, the authors aimed to desymmetrize 4,4-disubstituted pimelate, but eventually settled on the more comformationally rigid bicyclic derivative 467 as a better substrate. Meso-bicycle 467 could be obtained in one step from Kuehne’s aldehyde 466 via hydrolysis and treatment with acetic anhydride. Initial experiments on the desymmetrization of 467 in the presence of methanol and a chiral phosphoric acid showed promise. The team optimized chiral phosphoric acid, solvent, nucleophile, solvent, and temperature parameters to settle on imidodiphosphoric acid 468, methanol, and 1,4-dioxane at room temperature as the optimal combination. Under these conditions, bicycle 467 was desymmetrized to 469 in 95% yield and 92:8 enantioselectivity. With a satisfactorily enantioenriched starting material in hand, the next part of the synthesis involved differentially functionalizing the three carbonyls of 469. Thus, the aldehyde of 469 was protected as a thiolane, the methyl ester was then reduced to the alcohol oxidation state with lithium borohydride, and the carboxylic acid was converted to a methyl ester with diazomethane to give compound 470. Mesylation of 470’s alcohol

HOBt and EDCI to form the amide linkage of 462. Finally, a Sonogashira coupling was employed to join the terminal acetylene with 2-bromoiodobenzene. These three reactions produced 462, substrate for the key double cyclization cascade. To obtain the desired intermediate 463 in an optimized 65% yield, the team found that use of [Au(PPh3)]NTf2 (30 mol %), KHSO4 (30 mol %) in iPrOH/1,4-dioxane with microwave irradiation and heating at 80 °C was most effective. The use of microwave irradiation was employed to improve upon the disappointing 28% yield obtained when the optimized conditions from the initial model system optimization were applied to the actual system under standard thermal conditions. In their initial screening on a model system, the team found that, of the carbophilic transition metal sources, CuI, PdCl2, AuCl, AuCl3, [Au(PPh3)Cl], and AuCl/AgOTf gave no desired product. However, [Au(PPh3 )Cl]/AgOTf, [Au(PPh3 )Cl]/AgNTf2, [(Cy-JohnPhos)Au]NTf2, and [Au(PPh3)]NTf2 gave yields from 20 to 69% and improved in the order listed. Mechanistically speaking, Au(I) activates the alkyne to electrophilic attack by the amide nitrogen, which occurs to form a six-membered lactam. Protonolysis of the intermediate gold−carbon bond gives an enamine, and decomposition of the acetal gives the corresponding aldehyde. Enamine addition to the aldehyde then results, and dehydration of the intermediate alcohol gives the pyrrole moiety of 463. Several functional group interconversions and a macrolactamization were required to complete the synthesis of rhazinilam (386). Accordingly, the pyrrole-amide of 463 was reduced to hemiaminal 464 under Luche reduction conditions and then further reduced with NaBH3CN in acidic media. Conversion of the aryl bromide moiety into the aniline 465 was accomplished via an aryl azide in a one-pot copper-mediation AR


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Scheme 50. Lin and Yao’s Synthesis of (±)-Rhazinilam (2014)

give the N-alkylated pyrrole 477, substrate for the showcase reaction. When 477 was subjected to the optimized regioselective C5 alkenylation conditions (Pd(OAc)2, AgOAc, DMF, and DMSO at 80 °C) a 12:1 ratio of desired C5:C2 alkylated products was obtained in 56% yield. The C5 alkylated products formed as a 7:4 diastereomeric mixture of rotamers. An especially remarkable aspect of this reaction is the capacity for the reaction to differentiate between the C5 and C2 positions of the pyrrole moiety of 477. During their development of this reaction on a model system, the team noticed that the role of the solvent had a major effect on the regioselectivity of the reaction, with DMF/DMSO preferentially forming bonds at the C5 position and toluene, mesitylene, DCE, 1,4-dioxane, and acetone forming bonds at the C2 position. The authors proposed that, in noncoordinating solvents, the C2 palladation is directed by chelation of the adjacent C3 ester. In noncoordinating solvents, the solvent coordinates to palladium and prevents coordination of the C3 ester, resulting in electrophilic palladation at the more electron rich C5 carbon. To complete the synthesis, the alkene of 478A was hydrogenated with Wilkinson’s catalyst, giving 479. Both esters of 479 were hydrolyzed, and the methyl ester hydrolysis occurred with decarboxylation. The nitro group was then hydrogenated to the corresponding aniline, and finally coupled with the carboxylic acid to yield (±)-rhazininlam (386) in 2.4% overall yield. 3.5.12. Dai’s Synthesis of (±)-Rhazinilam (2014) (Scheme 51). The Dai group of Purdue University published the 12th total synthesis of rhazinilam (386) in 2014.242 The team completed their synthesis in 14 steps and ∼3.7% overall yield.

preceded displacement of the mesylate with sodium azide in DMF at 80 °C to give azide 471. The thiolane was then oxidatively cleaved with IBX/TBAB to reveal the aldehyde, and a subsequent Staudinger reaction preceded an aza-Wittig reaction with the aldehyde to form imine 472. The final sequence of this synthesis required pyrrole formation. To accomplish this, Zhu and co-workers alkylated chiral imine 472 with the bromide 397 by heating at 100 °C in DMF. Treatment of the intermediate iminium bromide salt with Ag2CO3 effected a 1,5-Grigg’s216 electrocyclization at 110 °C in toluene to give pyrrole 473. This cyclization required the exclusion of oxygen because of the sensitivity of the product pyrrole 473 to oxygen. Hydrogenation of the nitro group to an amine and hydrolysis of the methyl ester gave the precursor 474 for the final coupling reaction, a reaction that proceeded upon exposure of 474 to EDC, DMAP, NEt3, and DCM. These last three steps completed Zhu’s synthesis of (−)-rhazinilam (386). Zhu conducted his synthesis with an impressive 19.5% overall yield. 3.5.11. Lin and Yao’s Synthesis of (±)-Rhazinilam (2014) (Scheme 50). A team led by Lin and Yao of China Pharmaceutical University in 2014 achieved the 11th total synthesis of rhazinilam (386).238 In the interest of advancing metal catalyzed direct C−H activation chemistry, the team developed a C−H alkenylation as a key step in their seven step synthesis. Lin and Yao’s team began their synthesis with a van Leusen241 reaction of phenyl acrylate 475 and TosMIC to form pyrrole 476. The pyrrole 476 was then alkylated with iodoolefin 477, synthesized according to Zakarian’s method (see Scheme 46), to AS


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Scheme 51. Dai’s Synthesis of (±)-Rhazinilam (2014)

Scheme 52. Tokuyama’s Synthesis of (−)-Rhazinilam (2015)

They utilized a biosynthetically inspired divergent approach to access not only rhazinilam, but also the related natural products: mersicarpine, leuconodines B and D, melodinine E, and leuconolam, all monoterpene indole alkaloids. In the specific case of rhazinilam (386), the Dai group employed a Witkop− Winterfeldt oxidative indole cleavage followed by transannular cyclization as the key step. The synthesis began from the commercially available ketone 480, which was advanced to racemic allyl ketocarboxylate 481 in three high yielding steps via a N-Boc-protection, α-carboxylation,

and ethylation. Treatment of 481 with Pd2(dba)3 and DPPE ligand effected a decarboxylative allylation, while TFA removed the N-Boc protecting group to yield 482, in which the quaternary carbon center of rhazinilam (386) was now established. Next, the terminal alkene was hydroborated with 9-BBN and oxidized with NaBO3 to give an alcohol. This nascent alcohol was then mesylated and displaced with NaN3 to deliver azidoketone 483. The next step entailed a substantial skeletal rearrangement, the key transformation of this synthesis. First to occur was a Witkop−Winterfeldt243,244 oxidative indole cleavage to rearAT


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stage formation of the pyrrole mitigates competitive reactivity of this electron-rich heterocycle with other functional groups in synthetic intermediates. On the other hand, installation of the functional groups necessary for such an end-game pyrrole synthesis often requires many functional group interconversions, which decreases overall efficiency. Heterocycle functionalization to build the ring system around the pyrrole has the potential to increase efficiency, but then must rely on highly chemoselective reactions, protection of the pyrrole (e.g., as the 2- or 3carboxylate ester), and careful choreography of steps to avoid side reactions, low yields, or dead ends. Clearly, the ability execute low-FGI syntheses relies on the development of new, chemoselective methods, as demonstrated in the syntheses of the massadines in section 3.6.

range the carbon skeleton of 483. Dai’s team found that freshly purified mCPBA under anhydrous conditions effected this transformation, successfully cleaving the indole ring to the intermediate nine-membered lactam 484, which underwent spontaneous cyclization to form tricyclic hemiaminal 485. The azide moiety of 485 was reduced over Pd/C with hydrogen to unmask a primary amine and subsequently formed the acetamide 485 in situ in the presence of acetic anhydride. Next, the addition of TFA dehydrated the hemiaminal of 486 to form a transient iminium cation into which the amide nitrogen of the acetamide added, thereby providing the rearranged intermediate 487 in 30% yield over three steps. The addition of tBuOK followed by an acetic acid quench promoted an aldol addition of the acetamide into the ketone of 487 to give 488, which happens to be the natural product leuconodine B. To complete the synthesis, the alcohol of leuconodine B (488) was mesylated and eliminated to give the unsaturated compound 489, also known as the natural product melodinine E. The aminal substructure of 489 was induced to fragment upon exposure to sulfuric acid, providing the natural product leuconolam (490). Finally, chemoselective DIBALH reduction of the 5-hydroxy-pyrrolone 490 and aromatization by elimination of two equivalents of water occurred to give racemic rhazinilam (386). 3.5.13. Tokuyama’s Synthesis of (−)-Rhazinilam (2015) (Scheme 52). The 14th and most recent synthesis of rhazinilam (386) was published in 2015 by Tokuyama and co-workers.245 This was also the group’s second total synthesis of this molecule, but is sufficiently different in approach to merit discussion here. As the key step in their 14 step (7.1% overall yield) synthesis, the Tokuyama group made use of a [3 + 2] cycloaddition between a Münchnone dipole and a phenylacetylene dipolarophile to form a substituted pyrrole which could be elaborated to (−)-rhazinilam. The synthesis commenced from the known chiral amine 492, which bears an optically pure quaternary center. 492 is available in five steps from D-aspartic acid (491) according to a procedure of Feldman and co-workers.246 Activation of formic acid with acetic anhydride facilitated N-formylation of 492, while chemoselective hydrolysis of the diester with KOH in MeOH/THF yielded N-acyl pipecolinic acid 493, precursor for the key [3 + 2] cycloaddition reaction. As expected from their initial studies, when 493 was heated at reflux with (2-nitrophenyl)acetylene in acetic anhydride, the pyrrole 495 was obtained. The reaction proceeds via condensation of 493 into the Münchnone 494, which as a dipole then undergoes a [3 + 2] cycloaddition with the dipolarophile (2-nitrophenyl)acetylene. Subsequent loss of carbon dioxide generates the aromatic pyrrole 495. To complete the synthesis, the team needed to homologate the ester and forge the macrolactam ring. Therefore, the ester of 495 was reduced to the alcohol with LiBHEt3 in THF at −40 °C and then reoxidized to the aldehyde 496 using Parikh−Doering oxidation. A Horner−Wadsworth−Emmons olefination effected the homologation and the nascent alkene and nitro group were both reduced with H2 over Pd/C in ethyl acetate to furnish 465. Finally, the ester of 465 was hydrolyzed and coupled with the aniline nitrogen through the activity of EDCI and DMAP in DCM to give the desired product, (−)-rhazinilam (386) in 7.1% overall yield from D-aspartic acid (491). 3.5.14. Rhazinilam Conclusion. Rhazinilam, and especially its pyrrole nucleus, provides a useful study in the pros and cons of heterocycle synthesis versus heterocycle functionalization. Late

3.6. Massadine and Massadine Chloride

The massadines are marine pyrrole−imidazole alkaloids that are remarkable for their structural complexity. Along with the palau’amines, axinellamines, and tetrameric stylissadine, massadines are among the most complex members of their family.247 The complexity of massadine (497) and related members is due to a confluence of factors, including a dense and diverse arrangement of functional groups, numerous contiguous stereocenters, and varying degrees of halogenation. Massadine itself was first isolated in 2003 from the marine sponge Stylissa aff. Massa, while massidine chloride was reported in 2007.248,249 Beyond structural complexity, members of the pyrrole− imidazole alkaloids, which include palau’amine, axinellamines, and the tetrameric stylissidines, are known to possess a variety of biological activities, including immunosuppressant,250 cytotoxic,250 anti-inflammatory,251 and antifungal activities.248 With this combination of a difficult structure and promise of intriguing biological activity, it is unsurprising that these molecules generally, and massadine in particular, have captured the imagination of a number of synthetic laboratories.

3.6.1. Baran’s Synthesis of (−)-Massadine and (−)-Massadine Chloride (2008/2011) (Schemes 53 and 54). The first synthesis of massadine (497) and massadine chloride (498) was accomplished by the Baran lab in 2008, with a full report detailing an enantioselective route published in 2011.247,252 This discussion will focus on Baran’s 2011 enantioselective route to massadine (497) and massadine chloride (498). In the interest of improving the practicality of the synthesis, the team also published a more concise racemic route to a key intermediate (512) of Baran’s route to the massadines, axinellamines, and palau’amine in 2011, discussed below.253 Baran’s enantioselective synthesis of massadine (497) featured use of an enantioselective Diels−Alder reaction and a late stage silver(II) oxidation as key steps. AU


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Scheme 53. Baran’s Synthesis of (−)-Massadine and (−)-Massadine Chloride (2008/2011)

Scheme 54. Baran’s Synthesis of (−)-Massadine and (−)-Massadine Chloride (2008/2011), Continued

minor decrease in yield and enantiomeric excess (84%, 89% ee on 19.2 g scale). The reduction of (+)-502 to remove the oxazolidinone proved remarkably difficult because the oxazolidinone carbonyl tended to be reduced more easily than the imide carbonyl. Nonetheless a two-step process involving thioesterification with dodecanethiol to form (+)-503, followed by reduction with LiAlH4, proved effective. LiAlH4 reduced both the ester and the thioester to their corresponding alcohols. These nascent alcohols were then mesylated and displaced with sodium azide. TBAF-mediated

The enantioselective synthesis of massadine (497) and massadine chloride (498) began with an enantioselective Diels−Alder reaction between the TIPS-protected diene 499 and oxazolidinone dienophile 500 to set three stereocenters and two C−C bonds of 502. After much optimization the team found that Ishihara’s bis-sulfonamide bis(oxazoline) (BOX) ligand254 (501) in combination with copper(II) triflate in nitromethane at −20 °C gave the desired adduct (+)-502 in 97% yield and 95% ee. The reaction was also amenable to scale-up albeit with a AV


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Scheme 55. Baran’s Improved Synthesis of Common Intermediate 512 (2011)

removal of the TIPS protecting group gave the bis-azido alcohol (+)-504. The liberated secondary alcohol of (+)-504 was reprotected with a PMB protecting group and the olefin was oxidatively cleaved with ozone to generate diketone (+)-505. The protecting group interchange of PMB for TIPS was necessary because the subsequent intramolecular aldol and bromination reactions gave very poor yields when the TIPS group was present, probably due to steric hindrance of the TIPS group. With the PMB protecting group in place, enol silane bromination occurred readily and intramolecular aldol addition was promoted on silica gel to deliver (+)-506. Two more stereocenters were formed in the cyclization Conditions to effect chlorination and dehydration of (+)-506 to obtain (+)-508 were elusive. For example, use of Brønsted and Lewis acids did not give the dehydrated product, basic conditions led to epoxide formation, and use of the Burgess reagent formed a sulfamidate. Ultimately, the team found that displacement of the α-bromide of (+)-506 with chloride tempered the reactivity of that position so that after PMB removal with TFA to give the diol (+)-507, treatment with sulfuryl chloride formed the allyl chloride (+)-508, thereby effecting dehydration and chlorination with inversion of stereochemistry in one step. The five electrophilic sites of trihalo compound (+)-508 made it highly sensitive to various reaction conditions. Baran’s team was forced to reduce the enone under Luche conditions and thereby mitigate three of the electrophilic sites in order to obtain (Boc)2guanylated (−)-509. Next, this alcohol of (−)-509 was oxidized back to the enone with IBX. This oxidation also induced a cyclization of the enone with diastereoselectivity initially favoring the undesired diasteromer via an intramolecular azaMichael addition. Over 50 conditions were tried at room temperature or below to reverse this selectivity, but in each case selectivity for the wrong diastereomer was obtained. At higher temperatures the team was able to overcome the bias of this cyclization somewhat to obtain a 1.3:1 diastereomeric ratio. Conversion to α-amino-ketone (−)-511 was accomplished in two steps by exposure of the diastereomeric mixture of (+)-510 and (−)-511 to sodium diformylamide followed by hydrolysis and deprotection of the BOC groups with TFA. The next step of this synthesis required oxidation at C20 of (−)-511 to the proper oxidation state. It was discovered that oxidation of the C20 position could be effected with silver(II) picolate in 10% TFA to deliver (−)-512 in 69% yield. TFA protonated the primary amine and thereby ensured that

oxidation at C20 occurred preferentially to amine oxidation. With the C20 alcohol in place, (−)-513 was formed by reaction of (−)-512 with cyanamide in brine at pH 5 (Scheme 54). Brine was thought to improve the yield by minimizing the amount of Cl−OH exchange at C17. Next, oxidation in TFA/H2O with DMDO followed by an acid-induced cyclization yielded a diastereomeric mixture of αand β-(−)-514 in 15 and 56% yields, respectively. To complete the synthesis, all that remained was to reduce and acylate the azide of (−)-514. Accordingly, hydrogenation over platinum oxide provided the corresponding amines and acylation with 515 in DMF and with DIPEA gave a mixture of 6,10-epi-massadine (516) and its chloride (517) and (−)-massadine (497) and its chloride (498). Massadine chloride (498) could be converted into massadine (497) by heating in water at 60 °C. Compound 512 served as a common precursor for the Baran lab to access not only massadine (497) but also other members of the dimeric pyrrole−imidazole alkaloids, particularly palau’amine and the axinellamines. Although it was enantioselective, Baran’s initial route (Scheme 53) to 512 was 20 steps with a 1% overall yield. In order to provide a greater supply of material for biological studies of the axinellamines, palau’amine and massadines, Baran and his team devised an improved synthesis.253 Although racemic, the second generation route reaches 512 in merely eight steps and 13% yield from 518 (Scheme 55). The route features an ethylene glycol assisted Pauson−Khand cycloaddition reaction, a Zn/In-mediated Barbier-type reaction, and a TfNH2-assisted chlorination−spirocyclization as key steps. Synthesis of intermediate 512 commenced with a Pauson− Khand reaction between propargyl Boc-protected amine 519 and bis-allylic trimethylsilyl ether 518 in which Co2(CO)10 was used as the metal carbonyl source and NMO served as the oxidant. Optimization of this reaction revealed that ethylene glycol was a necessary additive, significantly improving the yield of 520 to a satisfactory 46−58%. With functionalized cyclopententenone 520 in hand, the team reduced the ketone and deprotected the secondary alcohols under Luche reduction conditions. The resulting crude triol was converted to an inconsequential 2:1 mixture of diastereomeric chlorides (521) by the action of NCS and PPh3 in DCM. Then, without chromatographic purification, the secondary chloride of 521 was converted to an organometallic Barbier reaction by the action of a zinc/indium mixture, which reacted with amino aldehyde 522 to generate amino alcohol 523 stereoselectively. It AW


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Scheme 56. Chen’s Synthesis of Massadine (2014)

Scheme 57. Chen’s Synthesis of Massidine (2014), Continued

AX


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removed the Boc and acetonide protecting groups with TFA to give 532. Interestingly, the triphenylphosphine imide 532 of aminoimidazole was quite stable to hydrolysis and thereby served as a protecting group in subsequent steps. The pyrrole 533 was installed on both primary amines of 532 with good regioselectivity to give 534 in 66% yield over three steps. Introduction of the second aminoimidazole group into 534 was next. The team found a method involving guanidine formation via use of 535, oxidation of the hydroxyl group to an aldehyde, and acid induced condensation to be the most efficient and reliable method to effect the transformation to 536. At this stage, the C9′ epimerization could be easily accomplished under acidic conditions (diastereomeric ratio >10:1 in TFA in DCM) (Scheme 56). Boc removal from the second aminoimidazole also occurred under these conditions, giving 537 as a result. 537 is an intermediate in Chen’s synthesis of ageliferin, but at this point the route diverges to massadine.256 In order to obtain massadine (497), the cyclohexenone core needed to undergo a ring contraction. In practice, Chen found that alcohol 538 (obtained by a lithium triethylborohydride reduction of 537) was able to effectively direct a Sharpless type Ti(IV)-promoted oxidation of the BOM-protected 2-aminoimidazole unit, which furthermore underwent a Scheuer250 ring contraction to give the desired iminohydantoin 539 with the desired stereochemistry (Scheme 57). Aside from its stereoselectivity, this reaction occurs in a highly chemoselective manner, not touching the less electron rich unprotected aminoimidazole or the two dibromopyrroles. Without chromatographic purification 539 was treated with calcium borohydride to afford hemiaminal 540, and subsequent removal of the protecting groups gave premassadine 541. To complete the synthesis, the team needed to oxidize the aminoimidazole group of 541 and promote the intramolecular cyclization to form the ether linkage of massadine (497). This process was pH-sensitive and undesired N-cyclization also occurred spontaneously. Eventually, the team found that the use of NBS in methanol at neutral pH proceeded cleanly to give a disastereomeric mixture of massadine−methanol adducts which was easily converted to a mixture of nat-massadine (497) (0.014% yield from L-serine) and 3,7-epi-massadine upon treatment with aqueous HCl. 3.6.3. Massadine and Massadine Chloride Conclusion. Similar to syntheses of citrinadin B (361), these syntheses of the massadines are the first but probably not the last, especially should the alkaloids prove therapeutically valuable.258 Clearly the ease with which (±)-512 can be synthesized is grossly simplifying for the synthesis of the massadines, and the simplicity of Chen’s intermediate 537 may lead to a greater material throughput if a more concise route is invented. In any case, future contributions need to address stereocontrol and chemoselectivity in the final sequence to 497 and related alkaloids. In a broader sense, the lessons learned from the syntheses of these highly complex alkaloids may be relevant to future explorations in medicinal chemistry campaigns as more complex architecture is explored in drug design.

was found that using either Zn, In, Sn, or Fe under anhydrous conditions gave no product; rather, only a mixture of zinc and indium in the presence of NH4Cl furnished the desired product in acceptable yields. Next, two steps were employed to convert the primary chlorides to azides, deprotect the Boc-protected amine, and install the guanidine of 524, all in order to enable the key chlorination−spirocyclization step. Extensive studies were required to carry out this spirocyclization in an effective manner, in part due to variability of results depending on the batch quality of 524. Eventually the team found that TfNH2 from the preceding steps played a beneficial role in the reaction. Thus, catalytic amounts of TfNH2 with tBuOCl delivered a single diastereomer of the spirocycle. Finally, DMP oxidation and treatment with TFA furnished the desired intermediate 512 in 13% yield over eight steps. 3.6.2. Chen’s Synthesis of Massadine (2014) (Schemes 56 and 57). Recently, the Chen group of UT Southwestern, published a second synthesis of massadine (497) alongside a synthesis of sceptrin.255 The Chen group had previously published an asymmetric synthesis of ageliferin256,257 in which they utilized a biogenic Mn(III)-mediated oxidative radical cyclization to effect a formal [4 + 2] dimerization to construct the core of ageliferin. In their 2014 report, the authors elaborate an intermediate from this route to complete massadine (497). Moreover, they use their interesting resultsthe ability to promote cycloaddition reactions via single electron oxidation to shed light on plausible biosynthetic pathways for the construction of these remarkable alkaloids: sceptrin, ageliferin, and massadine. Aside from their complexity-building oxidative cyclization, the team also employs a Scheuer ring contraction250 to effect a crucial rearrangement en route to massadine. Chen’s synthesis of massadine (497) proceeds in 22 linear steps from 527 and 0.014% yield from L-serine. Chen’s route to massadine (497) began with synthesis of 526 and 528 as components of a linear precursor en route to the polysubstituted core. A DCC-mediated esterification of Boc-βAla-OH with homoallylic alcohol 525 (derived from Garner’s aldehyde) gave 526. Chlorination of BOM-protected imidazole (527) and then Vilsmeier−Haack formylation and nucleophilic aromatic substitution of the previously formed aryl chloride with sodium azide furnished 528. The BOM group of 528 served as a directing group for these lithiations, providing good regioselectivity. The coupling partners 526 and 528 in crude form were then linked via an aldol addition, and a Dess−Martin periodinane oxidation furnished β-ketoester 529. With the construction of 529, the team was set for the key step: a single electron oxidation promoted [4 + 2] cyclization. The team found that radical generation and cyclization of 529 was enabled by use of Mn(OAc)3 in acetic acid at 50−60 °C or Mn(picolinate)3 in methanol at 90 °C and produced 530 as a 2.5−3:1 mixture of diastereomers (epimeric at C9′) in 36% yield over four steps from homoallylic alcohol 525. The mixture was inconsequential because a subsequent decarboxylation with lithium hydroxide generated a single diastereomer, albeit with the undesired stereochemistry. The strong preference of the system for the incorrect stereoisomer convinced the authors that it would be best to epimerize the stereocenter of 530 at a later step. Next, the sterically congested position of the liberated alcohol underwent a three-step sequence involving mesylation, Finkelstein-like iodination, and azidation to install the azide of 531. Chen’s next task was to install the pyrrole side chains. To do this, his team first reduced the azides by a Staudinger reaction and

3.7. Hapalindole Q

In the late 1960s and early 1970s the algal species Hapalosiphon intricatus and H. fontinalis were reported to produce substance(s) capable of inhibiting the growth of other blue-green algae, Anabaena sp. and A. oscillarioides respectively, but the active principles were unknown.259 Piqued by these observations, Moore and co-workers cultured H. fontinalis samples isolated from soil of the Marshall Islands.259 Their subsequent isolation AY


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coupling reaction to link functionalized camphor derivative 544 with indole moiety 546 and capitalized on the rigid and stereodefined features of the camphor bicycle 547 for stereocontrol of substituents about the cyclohexane ring. To make the precursors for the key coupling reaction, (+)-(1R)-9-bromocamphor (543) was acylated to give the corresponding enol acetate (544) and indole 545 was silylated and brominated to yield 546. The authors initially attempted this coupling via displacement of an α-keto halide with an aryl cuprate,263 but this strategy failed due to the thermal instability of 3-indoyl cuprates. Exploration of palladium catalysis, however, eventually revealed that Cl2Pd[P(o-tol)3]2 could join the tin enolate of 544 (generated in situ) with the N-TIPS-protected bromoindole (546) to give the desired endo intermediate (547) in 51% yield alongside the undesired exo product in up to 10% yield. Treatment of 547 with sodium naphthalide accomplished reductive cleavage of the bicycle to generate an alkene and an enolate, the latter of which was trapped with acetylaldehyde exclusively on the face of the cyclohexanone ring trans to the indole moiety to form diastereomeric alcohols (548). Nonetheless, this diastereomeric mixture was inconsequential since mesylation of the alcohol followed by elimination to generate the requisite alkene occurred subsequently. The action of sodium iodide in HMPA removed the N-TIPS protecting group to yield ketone 549. Finally, reductive amination and treatment of the resultant amine with 1,1′-thiocarbonyldiimidazole (TCDI) furnished an isothiocyanate in an ∼3:1 diastereomeric mixture and completed the final sequence to (+)-hapalindole (542) in eight steps with an overall 8% yield. 3.7.2. Kerr’s Synthesis of (±)-Hapalindole Q and (+)-Hapalindole Q (2001) (Scheme 59). Kinsman and Kerr accomplished a second total synthesis of (±)-hapalindole Q in 2001264 and rendered their route enantioselective in 2003.265 The authors completed their racemic synthesis in eight steps with a 12.4% overall yield while their enantioselective version was longer, proceeding in 12 steps with 93% enantiomeric excess and 1.7% overall yield. Both feature a Diels−Alder reaction as the key step, but the enantioselective version utilizes one of MacMillan’s

and characterization work revealed the active secondary metabolites to be the first members of the thereafter-named hapaloindole-type alkaloids. Subsequent work has since named 63 members to this family, which include the hapalindoles, fisherindoles, welwitindolinones, ambiguines, hapalindolinones, hapaloxindoles, and fontanamides.260 Aside from the aforementioned antialgal activity of the hapalindoles, insecticidal (hapalindoles and welwitindolinones), antimycotic (hapalindoles, welwitindolinones, and ambiguines), antibacterial (hapalindoles and ambiguines), and antineoplastic (welwitindolinones) activities have been reported for various members of this family.260 Structurally, the hapalindole-type alkaloids are indoloterpenes, products of the formal coupling of a tryptamine with a monoterpene (geranyl) chain at the C3 position of the indole moiety. Of these alkaloids, hapalindole Q (542) is among the simpler members of the family and possesses antibacterial and antimycotic activity.259,261 The indole moiety of hapalindole Q (542) is unfunctionalized except at the C3 position, where it is linked to an isothiocyanate-containing monoterpene unit. Four groups have accomplished total synthesis of hapalindole Q (542) to date, with the shortest requiring only five steps and the longest 12. The primary challenge surmounted by each of the following syntheses entails the achievement of stereocontrol over the four stereogenic centers present in the molecule.

3.7.1. Albizati’s Synthesis of (+)-Hapalindole Q (1993) (Scheme 58). The first synthesis of hapaindole Q (542) was achieved in 1993 by Vaillancourt and Albizati via an eight step route from (+)-(1R)-9-bromocamphor (543).262 Albizati’s synthesis of hapalindole Q featured a palladium-catalyzed Scheme 58. Albizati’s Synthesis of (+)-Hapalindole Q (1993)

AZ


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Scheme 59. Kerr’s Synthesis of (+)-Hapalindole Q (2001)

amine catalysts. The routes are similar enough that only the enantioselective version will be discussed here. Kerr sets all four of the hapalindole Q stereocenters in one step with his asymmetric Diels−Alder reaction, and only requires functional group interconversions (FGIs) to elaborate the Diels−Alder adduct to the final product. Kerr’s synthesis commenced with a four-step sequence to prepare the indole-containing dienophile 551 for the key Diels− Alder cycloaddition. Knoevenagel condensation of N-tosyl protected 1H-indole-3-carboxaldehyde (550) with malonic acid was followed by sulfuric acid promoted esterification, reduction of the resultant α,β-unsaturated ester to the corresponding alcohol, and then oxidation with Dess−Martin periodinane (DMP) to give dienophile (551). In the key step, an asymmetric Diels−Alder reaction, condensation of aldehyde 551 with MacMillan’s imidazolidinone 552 first gave an imimium dienophile intermediate. This in turn reacted with cyclohexadiene 553 to furnish intermediate 554 in an 85:15 ratio of endo to exo isomers and in 93% enantiomeric excess. The high degree of complexity installed in this steptwo bonds and four stereocentersarguably offsets the low yield (35%) for this reaction. Substrate 554, as a mixture of endo and exo isomers, was then oxidized to a carboxylic acid under Pinnick oxidation conditions and converted to an acyl azide with the reagent diphenylphosphorylazide (DPPA). The resulting acyl azide underwent a thermally induced Curtius rearrangement to

yield the methyl carbamate (555) upon addition of methanol to the intermediate isocyanate. Notably, the Curtius rearrangement occurred without skeletal rearrangements of the [2.2.2]-bicycle, an event that the authors had feared might occur but were relieved did not. The authors do not mention a precedent that may have incited their initial fear. Dihydroxylation of 555 produced a 3:1 diastereomeric mixture of diols. Fortuitously, the minor exo isomer of 555 was dihydroxylated more slowly than the endo isomer of 555, enabling purification of the endo product through kinetic resolution of these diastereomers. The relatively low diastereoselectivity observed in this dihydroxylation reaction is explained by a hydrogen-bonding pathway between the osmium species and the carbamate (minor pathway) that competes with the steric repulsion of the carbamate (major pathway). Nonetheless, after oxidative cleavage of the diol mixture with sodium periodate, the carbinol stereocenters generated in the dihydroxylation step were lost, rendering the low diastereoselectivty inconsequential. Methylenation of the carbonyls of 556 proved difficult. Low yields, monomethylenation, and aldol condensation products were all observed under various conditions. The authors eventually settled on a sequential Wittig olefination procedure as the most efficient means to install the desired methylene groups of 557. Finally, a double deprotection of the secondary amine and indole with TBAF followed by application of Albizati’s BA


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Scheme 60. Baran’s Synthesis of (+)-Hapalindole Q (2004/2008)

Scheme 61. Li’s Synthesis of (±)-Hapalindole Q (2014)

conditions262 for the formation of the isocyanate gave (+)-hapalindole Q (542) in 93% ee, the same enantiomeric excess obtained in the key enantioselective Diels−Alder reaction. 3.7.3. Baran’s Synthesis of (+)-Hapalindole Q (2004/ 2008) (Scheme 60). In a 2004 communication and in a 2008 full paper, the Baran lab at The Scripps Research Institute detailed their synthesis of (+)-hapalindole Q (542), alongside other members of the family.266,267 Baran’s efficient route utilized a direct oxidative coupling of an indole with an enolate as their key reaction and ultimately forged the molecule in five steps with an overall 22% yield. The team took full advantage of the enone functional group and carbogenic stereocenter of (S)-carvone, a chiral pool monoterpene, to install the additional functionality and set the three remaining stereocenters present in hapalindole Q. Starting with (S)-carvone (558) and simple indole, addition of LHMDS to a mixture of the two compounds effected formation of the indole anion and the kinetic carvone enolate, which upon addition of a soluble copper(II) source, copper(II) 2-ethylhexanoate, resulted in oxidative radical formation and subsequent coupling to form 559 as a single trans diastereomer. Baran and team developed this oxidative radical coupling method inhouse. They found that other oxidants (hypervalent iodine reagents, FeCl3, various cupric species, etc.) gave lower yields. A major byproduct of the oxidative coupling was a carvone dimer, but indole dimers were not observed. As is often the case in synthesis, this direct oxidative coupling was not the first approach attempted by Baran. Rather, an approach involving an aldol addition reaction of the carvone enolate to a N-MOM-protected isatin was pursued first. This bond formation was successful, but difficulty in reducing the resultant alcohol prompted development of another strategy. An oxidative enolate oxindole coupling was then pursued, and successfully so, but once again a subsequent reduction proved obstinate and led finally to development of the successful oxidative enolate−indole coupling reaction.

Reductive alkylation to form 560 commenced with a conjugate reduction of the enone of 559 by L-selectride. Aldol addition of the nascent enolate to acetylaldehyde gave a mixture of secondary alcohols, which after dehydration with Martin’s sulfurane resulted in formation of 560 with excellent diastereoselectivity (>20:1). LHMDS was added to deprotonate the indole nitrogen prior to reduction because excess L-selectride engaged in 1,4-hydride addition competitively with indole N−H deprotonation. When conjugate reduction occurred before deprotonation, the resulting enolate could be quenched by the proton of another indole molecule, thereby quenching the kinetic enolate. Microwave-enhanced reductive amination followed by isothiocyanate formation with thiocarbonyl diimidazole (TCDI) yielded (+)-hapalindole (542) with 6:1 diastereoselectivity at the newly formed stereocenters and in 22% overall yield. Intermediate 549 was also encountered in Albizati’s synthesis,262 but Baran’s use of microwave irradiation reduced the time of the reductive amination from 7 days to a mere 2 min, occurred with an increased diastereomeric ratio (6:1 vs 3:1), and proceeded with identical yield. 3.7.4. Li’s Synthesis of (±)-Hapalindole Q (2014) (Scheme 61). Most recently in 2014, Ang Li and his group at the Shanghai Institute of Organic Chemistry (SIOC) enlisted an oxidative cyclization strategy to make hapalindole Q along with five other members of the family, an approach that was inspired by a plausible biosynthetic proposal.268 Li’s route resulted in synthesis of (±)-hapalindole Q (542) in five steps from nerol and 22% overall yield from 560. Li’s approach commenced from the boronic acid of nerol 560, available in one step from nerol, and the commercially available indole aldehyde 561. Condensation of the aldehyde of 561 with liquid ammonia at −78 °C was followed by the addition of nerol boronic acid 560. Upon warming to room temperature and appropriate workup, adduct 562 was produced in moderate yield with 10:1 diastereoselectivity. This diastereomer 562 results from a chairlike transition state in which steric interactions are minimized. After reductive removal of the sulfone protecting BB


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3.8.1.1. Qin’s Synthesis of (±)-Vincorine (2009) (Scheme 62). In 2008, Qin and his group had detailed a synthesis of the Strychnos alkaloid (±)-minfiensine286 in which they assembled the core using a copper(I) carbenoid cyclopropanation/ring opening/ring closing cascade. In the interest of demonstrating that akuammiline alkaloids could also be obtained from a route incorporating this reaction and in order to publish the first synthesis of an akuammiline alkaloid, the team designed a synthesis of (±)-vincorine (565) using this same methodology.283 The diazo precursor 567 for the key reaction was formed in five steps from 586 in a sequence that involved cleavage of a C− N double bond, addition of a methyl acetate unit, and diazotization. With 567 in hand, treatment of the substrate with copper(I) triflate resulted in formation of the copper carbenoid and subsequent cyclopropanation to form 569. Subsequent ring opening generated zwitterionic intermediate 570. The tosyl protected secondary amine could then add back onto the imine to form an aminal, and proton transfer resulted in the key intermediate 571. Installing the final five carbon atoms and setting the remaining four stereocenters proved difficult for the team; however, they were eventually able to reach their target 564 in a 25-step sequence with a 1% overall yield from tetrahydrocarboline 571. 3.8.1.2. Ma’s Synthesis of (−)-Vincorine (2012) (Scheme 63). Dawei Ma’s group at SIOC completed a second total synthesis of (−)-vincorine (565) in 2012.284 The 18 step route commenced from 5-methoxyltryptamine with a 5% overall yield and 64% ee. Key steps include a palladium-catalyzed direct C−H functionalization of indole derivatives, organocatalyzed asymmetric Michael addition of an aldehyde to an alkylidene malonate, and an oxidative intramolecular coupling between an indole and malonate moiety. To obtain 573, 5-methoxytryptamine (572) was protected with a Boc group and the resultant indole was functionalized at the C(2) position with ethyl acrylate via a palladium-catalyzed alkenylation. A four-step sequence involving hydrogenation, reduction, oxidation, and Knoevenagel condensation furnished Michael acceptor (574), precursor for the key stereodetermining step. Under the catalysis of O-trimethylsilyl (TMS)-protected diphenylprolinol, the selenide aldehyde 575 reacted with intermediate 574 to form Michael adduct 576 in 75% yield and as a 5:1 diastereomeric mixture. Further optimization could not improve on this result. A five-step sequence entailing oxidation and elimination of the aryl selenide, photochemical alkene isomerization, aldehyde reduction, and TBS protection of the resultant alcohol transformed 576 to 577 with an overall enantiomeric excess of 64% and 58% yield. In the showcase step, treatment of 577 with LiHMDS presumably formed the dianionic compound 578. The action of iodine resulted in the oxidative coupling to form to the geminal quaternary stereocenters of 579. The Boc-protected secondary imine of 579 then cyclized onto the imine of 579 to give aminal 580 after proton transfer. Remarkably, only one isomer was obtained from this reaction, presumably a result of minimization of steric interactions in the six-membered transition state of the initial ring closure. The overall transformation formed two bonds and two stereocenters. Ma’s final five-step sequence to give (−)-vincorine (564) involved a Krapcho decarboxylation, closure of the final sevenmembered ring via a formal swapping of the O-TBS group with a

group and conversion of the secondary amine into the isocyanate with TCDI to yield 563, the stage was set for the key cyclization. The use of DDQ as an oxidant alongside the Lewis acid, Sc(OTf)3, formed hapalindole Q (542) in one step and 48% yield. DDQ dehydrogenates the benzylic position to form an unsaturated imine, and the authors propose that the scandium(III) Lewis acid coordinates the intermediate indole imine, activating it and thereby increasing electrophilicity at the benzylic position. Cyclization of the alkene onto the benzylic position then occurred in a Prins-like manner via an all-equatorial chairlike transition state. This transition state also exclusively gave the trans orientation between the two newly formed stereocenters, while their absolute orientation was set by the isocyanate and quaternary carbon stereocenters. 3.7.5. Hapalindole Q Conclusion. Syntheses of hapalindole Q (542) present an interesting study in modular/cyclic versus linear/chain alkaloid synthesis. Although many polycyclic alkaloids benefit from a dissection of rings into simple linear motifs, the simplification offered by this approach depends on the extent to which the rings themselves are the main elements of complexity. Modular routes can be more efficient if the rings are simple, but then the chemical reactions that connect them must be efficient and selective. Consideration of which approach is optimal for a given molecule must take into account these different structural features. The efficiency of both the Baran and Li routes derives from the vertical productivity of almost every single synthetic step; lateral FGIs are almost absent. 3.8. Akuammiline Alkaloids: Vincorine and Scholarisine A

The first akuammiline alkaloids were isolated in Ghana by Henry in 1927 from seed samples of the Picralima klaineana tree, which was known by the Ghanan natives as “akuamma” and used by them as an antipyretic medication for malaria.269,270 Consequently, these and related alkaloids became known as “akaummiline” alkaloids. Studies concerning the biological activity of these alkaloids have shown them to possess anticancer, antibacterial, anti-inflammatory, and antitussive to antimalarial actvitivity.271−278 Both vincorine (564), isolated in 1962 from Vinca minor,279 and scholarisine A (565), isolated in 2008 from Alstonia scholaris, a plant used to treat several respiratory diseases in traditional Chinese medicine,280 are members of this family which have received attention from several synthesis groups.

Garg and co-workers recently reviewed these syntheses as part of a discussion of cascade reactions in akuammiline alkaloid total synthesis.281 Similarly, Gaich and co-workers have also recently reviewed vincorine and scholarisine A in the context of a discussion of the akuammiline alkaloids.282 Consequently, the following discussion will focus primarily on the overall strategy of each group to these molecules. 3.8.1. Vincorine. Total synthesis of vincorine (564), an akuammiline alkaloid, has been achieved three times since its isolation279 in 1962 from Vinca minor: in a 2009 racemic 31 step sequence by Qin and co-workers;283 in 2012 by Ma and team in an 18 step sequence (64% ee);284 and beautifully in 2013 by Horning and MacMillan in a nine step route.285 BC


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Scheme 62. Qin’s Synthesis of (±)-Vincorine (2009)

Scheme 63. Ma’s Synthesis of (−)-Vincorine (2012)

radical cyclization.285 Their synthesis was completed in nine steps with an overall yield of 9% (95% ee). A key Diels−Alder/ iminium cascade to build the core of the moleculeforming three bonds and four stereocentersis a particularly impressive feature, and their 7-exo-dig radical cyclization is also noteworthy.

chloride, subsequent N-alkylation, and a formal indole methylation. 3.8.1.3. MacMillan’s Synthesis of (−)-Vincorine (2013) (Scheme 64). Horning and MacMillan’s beautiful 2013 enantioselective synthesis of (−)-vincorine (565) features an organocatalytic Diels−Alder/iminium cyclization cascade and a BD


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Scheme 64. MacMillan’s Synthesis of (−)-Vincorine (2013)

allene yielded (−)-vincorine (564) in 80% yield. Only the terminal unsaturation was hydrogenated under these conditions, and the correct geometrical isomer was obtained through hydrogenation of the convex face. 3.8.1.4. Vincorine Conclusion. As demonstrated in the previous sections, indole alkaloids are often best synthesized by purchase of the indole nucleus (as indole itself, tryptamine, or tryptophan) followed by chemoselective functionalization by annulation, oxidation, or rearrangement. In this case, the ability to minimize the appendage and interconversion of functional groups depends on the competitive reactivity of the Lewis basic indole and indoline heterocycle, other Lewis basic alkaloid components (amines, other heterocycles), and the intermediate functional groups necessary for skeletal bond formation. The synthesis of vincorine by MacMillan and Horning is efficient because (1) the functional group interconversions applied to the target and its indole intermediates enable grossly simplifying skeletal bond-forming steps, and (2) the chemoselectivity of these key steps spares existing functional groups or requires minimal application of protecting group chemistry. While desperation to finish a molecule might encourage more bruteforce strategies, with patience and a little bit of luck, highly efficient syntheses of complex indole alkaloids can become the norm. 3.8.2. Scholarisine A. Total synthesis of (+)-scholarisine A (566) has been achieved twice since its isolation280 in 2008 from Alstonia scholaris: in 2012 in a 24 step sequence by Smith III and

MacMillan’s work begins with the synthesis of diene 582 from indole 581. Methylation of indole 581 proceeded smoothly, and a directed metalation/Negishi coupling sequence gave diene 582. The optimized conditions for the cascade reaction involved use of (S)-5-benzyl-2,2,3-trimethylimidazolidin-4-one (552) as an organocatalyst and HBF4 as a Brønsted acid catalyst. The showcase reaction occurs in the following manner: iminium formation occurs first via condensation of aldehyde 583 with organocatalyst 552. An endo and enantioselective Diels−Alder reaction occurs next between the chiral iminium complex and 582 via transition state 584 (with the dienophile beneath the plane of the page). The resulting enamine is protonated by HBF4 and the N-Boc secondary amine then cyclizes to form pyrroloindoline 585. Running the reaction at higher temperatures resulted in lower enantioselectivity and poorer yields. With compound 585 in hand, efforts to close the final azepanyl ring by way of a 7-exo-dig radical cyclization commenced. Pinnick oxidation gave carboxylic acid 586 that was converted into the acyl telluride 587. N-Boc removal with TFA liberated the secondary amine to couple with aldehyde 588 via a reductive amination sequence, giving 589. Homolytic thermolysis of the acyl telluride generated the telluride radical, carbon monoxide, and a secondary carbon radical, the latter of which engaged in a 7exo-dig cyclization with elimination of a sulfide radical and generation of allene 590. Notably, the acyl telluride portion of 589 tolerated both acidic (TFA) and reductive (NaBH3CN) conditions prior to thermolysis. Finally, hydrogenation of the BE


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Scheme 65. Smith’s Synthesis of (+)-Scholarisine A (2012/2013)

co-workers287 and in 2013 by Snyder and team288 in an 15 step sequence. 3.8.2.1. Smith’s Synthesis of (+)-Scholarisine A (2012/2013) (Scheme 65). Amos B. Smith III and his team were the first to complete a synthesis of scholarisine A (565). Smith’s synthesis, detailed in a 2012 communication287 and then fully in a 2013 full paper,289 was completed in a 24 step sequence from commercially available materials with a 5.6% yield from 591. As key steps, the synthesis featured reduction of a nitrile with concomitant addition of the resultant amine to an epoxide, late stage oxidative lactonization of a diol in the presence of an indole, a Fischer indole synthesis, and a late stage enamine cyclization en route to the caged scaffold. Smith began his synthesis with chiral (−)-594, which can be made in five steps from meso compound 591 via reduction, acylating enzymatic resolution with porcine pancreatic lipase, alcohol tosylation/cyanide displacement, and lactonization. The lactone (−)-594 was functionalized at its α position with cyanide through use of N-cyano-benzotriazole (BtCN) and then was alkylated with ethyl iodide to furnish the quaternary carbon center of 595. Both functionalizations occur on the less sterically hindered convex face so that the cyano group, installed first, ends

up endo to the concave face of the molecule. An mCPBA epoxidation on the convex face of the alkene gave (−)-595. Next, nitrile reduction with hydrogen on rhodium/alumina gave a primary amine, which cyclized to open up the epoxide and give amino alcohol (−)-596. Secondary amine protection with benzyl chloride, oxidation of the alcohol to the ketone with DMP, and condensation of that ketone with 1-benzyl-1phenylhydrazine gave hydrazone 597. Heating the reaction induced the pericyclic reaction/condensation sequence of the Fischer indole synthesis to yield the indole (−)-598. One more homologation was required to install the final carbon of scholarisine A. Accordingly, LiAlH4 reduction of (−)-598 furnished a diol, and TBDPS protection of the more accessible alcohol gave (+)-599. Oxidation of the remaining primary alcohol to an aldehyde preceded addition of benzyloxymethyllithium, generated from the corresponding tin reagent in the presence of butyllithium, which gave (+)-600 after TBDPS deprotection with potassium hydroxide. To complete the molecule, one C−C bond and several oxidation state changes were needed. Smith and co-workers effected these transformations in nine steps. First, a Ley−Griffith oxidation formed lactone (−)-601 in one step, albeit in a 36% BF


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Scheme 66. Snyder’s Synthesis of (+)-Scholarisine A (2013)

dienophile 604 was a significant factor in the success of this reaction. The O-TBS congener of 604 gave lower yield and diastereoselectivity, for example. After removal of the acetonide protecting group of 606 with TFA and replacement of the free alcohol with a bromine atom via an Appel-type reaction to form intermediate 607, the stage was set for a radical ring closing/Keck allylation cascade. Use of triethylborane as a radical initiator while heating in air accomplished the ring-closing, allylation sequence in 59% yield as a single diastereomer (608). It was now necessary to epimerize the R-NHBoc stereocenter so that the amine would be endo to the concave face of the ring and thereby in a position to undergo lactamization. Initial efforts revealed that DBU in the presence of air could effect the transformation to 609 through a radical intermediate. The team optimized the reaction on the basis of these observations and found that use of TEMPO in air with tetramethylguanidine (TMG) as a base at 50 °C installed the unsaturation of enamine 609 in 68% yield. Application of reductive amination conditions resulted in exo-face reduction of the enamine along with removal of the N-Boc protecting group. Heating the reaction in ethyl acetate accomplished the lactamization. Unfortunately, NaBH3CN also reduced the ketone of 609, so oxidation with IBX was required to finally obtain 610 at the ketone oxidation state. When the authors conducted the enamine reduction without reducing the ketone, pyrazine dimer formation resulted, so the team decided that the redox manipulation was the best way to proceed. Condensation of ketone 610 with 2-iodoaniline gave imine 611 and set the stage for the unique arylation reaction to append the indolenine domain to the caged skeleton. Optimized conditions revealed that treatment with 1,1′-azobis(cyclohexanecarbonitrile) (ACHN) and Bu3SnH with heating successfully forged the requisite bond in 612 in a ∼2.6:1 mixture

yield. An alternative two-step sequence in which IBX oxidation formed the aldehyde/hemiacetal prior to a TPAP oxidation to form lactone (−)-601 gave a better overall yield (57%). Removal of only the indole and alcohol benzyl protecting groups was accomplished with AlCl3 in toluene. Attempts to form the final C−C bond at this point failed though due to intramolecular cyclization of the Lewis basic benzyl protected tertiary amine. Consequently, the benzyl protecting group of the secondary aliphatic amine was exchanged with an acyl trifluoromethane protecting group to give (−)-602. Upon this exchange, C−C bond formation occurred smoothly. After activation of the primary alcohol with mesyl chloride, tert-butylimino-tri(pyrrolidino)phosphorane (BTPP) deprotonated the indole and induced ring closure at the C(3) position of the indole to forge the final carbon−carbon bond and form the indolenine core. Smith’s synthesis was completed via a base mediated hydrolysis of the acyl protecting group and oxidation of the amine to the imine with PhIO to give (+)-scholarisine A (565). 3.8.2.2. Snyder’s Synthesis of (+)-Scholarisine A (2013) (Scheme 66). In 2013, Snyder published a second synthesis of (+)-scholarisine A (565) featuring a unique C−H arylation as the key step along with a pyrone Diels−Alder reaction and a radical cyclization/Keck allylation sequence as other notable steps.288 Snyder’s strategy effected synthesis of the molecule in 15 steps from commercial materials in an overall yield of 1.7%. Snyder reached intermediate 606 through use of dienophile 604, available in three steps of N-Boc-D-serine, and methyl coumalate 605 as a diene in a pyrone Diels−Alder reaction. This reaction gave the desired cycloaddition product 606 as the major product in a 3:1 ratio with an undesired, but separable, diastereomer and 0.1 equivalent of an unknown product. Snyder remarks that it is noteworthy that the cycloaddition proceeds with the ease it does considering that both diene and dienophile are electron-deficient. The nature of the protecting groups on BG


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longer sway granting agency study sections. The potentiators have been largely technological: it is now routine to attempt a chemoselective chemical reaction on a microgram scale and immediately obtain good data from spectroscopic analysis, which accelerates discovery of short, high-risk routes. The consequences are broad reaching: fewer FGIs mean shorter syntheses, higher throughput of material, and therefore broader distribution to researchers hoping to interface with synthetic chemistry. The logic itself, however, has remained the same. This is not surprising. Like the Stoic view of logos, practitioners of synthetic chemistry recognize that there is a logic to synthesis that stands apart from, or behind, the application of known chemical reactions.93 This register of thought identifies strategic bonds within a molecule whose cleavage reduces chemical complexity, independent of a known transform. Sometimes even the structure of the retrosynthetic precursor is not specified: this is the idea of a “synthon” that corresponds in approximate reactivity, if not in structure or isolability, to a real intermediate.93 Progress in the chemical synthesis of alkaloids is not just due to the ability to perceive simplifying transforms, but to invent the corresponding chemical reactions. This synergy between molecular complexity and chemical ingenuity has propelled the synthesis of alkaloids over the last century. In the modern era, the value of new reactions is increasingly measured by their ability to circumvent multiple FGI maneuvers. Laborious exercises in juggling complexity are now becoming simple protocols for molecular construction. Although the shape of the future is nebulous, there is reason to believe this trend will continue, if not accelerate. In so doing, complex molecules, as typified by secondary metabolites, will not become merely accessible through synthesis, but will become available on a large scale at low cost. The chemical space populated by drugs will therefore expand to truly reflect the imagination of the medicinal chemist, not the limitations of his or her tools. Thus, the reality that lies behind the application of chemical reactions will be brought to the fore, and the synthesis of alkaloids will move closer to perfection.

(desired:undesired) of geometrical isomers. Other methods, such as a Fischer indole synthesis, failed to do the same. Snyder describes the mechanism of this transformation as most likely involving iodine atom abstraction to form an aryl radical, a 1,5hydrogen atom abstraction to form a tertiary aliphatic radical, and addition of that radical into the aromatic ring at the ortho position followed by a terminating oxidation to rearomatize the ring. With all the skeletal atoms in place, only functional group interconversion of the amide and allyl groups of 612 to the imine and ethyl groups of (+)-scholarisine A (565) were required to complete the synthesis, but these proved to be nontrivial. The amide of 612 was particularly recalcitrant toward reduction and proved resistant to over 20 methods. The team finally overcame this problem by using a brilliant tactic that tied amide reduction to ethyl installation. Ozonolysis of the allyl group followed by sodium borohydride reduction gave a primary alcohol. With the alcohol installed, a thiation/cyclodehydration sequence yielded thioimidate 613 upon treatment with Lawesson’s reagent at 110 °C. Both carbon−sulfur bonds were cleaved easily upon treatment with Raney nickel in THF. Treatment of the substrate with sodium borohydride in the ozonolysis step had also reduced the indolenine imine, so final treatment with PhIO restored its oxidation state to yield the desired (+)-scholarisine A (565). 3.8.2.3. Scholarisine A Conclusion. Scholarisine A epitomizes caged alkaloids whose stereogenic centers are completely entangled in the caged architecture. In other words, because each stereocenter frames the molecule cage, each must either cause formation of the ring system, be controlled by the concavity of the ring system, or overcome the concavity of the ring system. Determination of which stereocenter influences the cage and vice versa is the main difficulty and affects both higher strategy and tactical maneuvers. In addition to these topological concerns, the use of chemoselective reactions and careful strategizing is necessary for scholarisine A, especially due to its bis-imine functionality. Like MacMillan’s synthesis of vincorine, Snyder’s synthesis relies on highly chemo- and regioselective radical reactions to forge the caged skeleton of the target (the syntheses were published only 4 months apart, part of a “radical renaissance” of this decade). What emerges is a concise synthesis whose FGIs are mainly setup maneuvers to enable highly simplifying cascade sequences to form skeletal bonds. Further innovations in radical method development will likely result in further compression of this already efficient strategy by excision of FGI steps.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

4. CONCLUSION In the foregoing review, we discuss recent syntheses of alkaloids and couch them in the history of alkaloid synthesis. Undoubtedly, the structures of many of these alkaloids were well beyond the reach of synthetic chemistry at the dawn of the 20th century. Advances in chemical theory and especially in spectroscopy have made the prediction and observation of chemical reaction outcomes immediately accessible to the synthetic chemist. And obviously, the explosion of new chemical reactions (methods) accrued in the latter half of the 20th century have added branches to any given target’s retrosynthetic “tree.” The rise of chemoselective (FG-specific) reactions then allowed circumvention of functional group interconversions (FGIs), shortening the length of each tree branch. In the 21st century, syntheses of remarkably complex molecules are becoming practical, easily scaled,290 and economical.291 The stimuli have been largely financial: proof-of-principle exercises in synthesis no

Steven Crossley received his B.Sc. in chemistry with honors (first class) from the University of British Columbia in Vancouver in 2012. As an undergraduate student, he explored dinitrogen activation, diiminepyridine, and β-diimininate chemistry of group 9 metals, and indium allyl BH


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chemistry in the laboratories of Michael Fryzuk, Peter Budzelaar, and Parisa Mehrkodavandi, respectively. He also investigated C−H functionalization chemistry in the laboratory of Marco Ciufolini. In 2013, he began graduate studies with Ryan Shenvi at The Scripps Research Institute in La Jolla, California. At Scripps, he gets to pursue his fascination with both organometallic chemistry and organic synthesis through his research on the development of organotransition metal radical chemistry for use in organic synthesis.

Ryan Shenvi is an associate professor with tenure in the Department of Chemistry at The Scripps Research Institute. He earned his B.S. degree with honors and distinction in chemistry from Penn State University, where he was a research student in the laboratories of John Desjarlais and Ray Funk. He obtained his Ph.D. in 2008 as an NDSEG predoctoral fellow with Phil Baran at The Scripps Research Institute, and then joined the laboratory of E. J. Corey at Harvard University as an NIH-funded postdoctoral fellow. In 2010, Ryan returned to Scripps to start his own lab, which explores the chemical synthesis of secondary metabolites that are relevant to human health. These efforts frequently require the invention of new chemical reactions and also lead to discoveries in biology.

ACKNOWLEDGMENTS This work was supported by the NIH (GM105766) and NSERC (PGSD3, S.W.M.C.). We thank Amgen, Boehringer Ingelheim, the Baxter Foundation, Bristol-Myers Squibb, Eli Lilly, Novartis, and the Sloan Foundation for additional financial support. REFERENCES (1) This historical section was compiled from an extraordinary book on alkaloids: Hesse, M. Alkaloids: Nature’s Curse or Blessing; Verlag Helvetica Chimica Acta: Zürich, and Wiley-VCH: Weinheim, 2002. (2) Marcet, A. An Essay on the Chemical History and Medical Treatment of Calculous Disorders; London, 1817. (3) Pelletier, P. J.; Magendie, F. Recherches chimiques et physiologiques sur l’ipecacuanha. Ann. Chim. Phys. 1817, 4, 172−185. (4) Pelletier, P. J.; Caventou, J. B. Note sur un nouvel alkalai. Ann. Chim. Phys. 1818, 8, 323−324. (5) Oersted, H. C. Ü ber das Piperin, ein neues Pflanzenalkaloid. J. Chem. Phys. 1820, 29, 80−82. (6) Pelletier, P. J.; Caventou, J. B. Recherches chimiques sur les quinquinas. Ann. Chim. Phys. 1820, 15, 289−318. (7) Pelletier, P. J.; Caventou, J. B. Recherches chimiques sur les quinquinas. Ann. Chim. Phys. 1820, 15, 337−365. (8) Runge, F. F. Neueste phytochemische Entdeckungen zur Begründung einer wissenschaftlichen Phytochemie; G. Reimer: Berlin, 1820; pp 144− 159. (9) Garson, M. J.; Simpson, J. S. Marine isocyanides and related natural productsstructure, biosynthesis and ecology. Nat. Prod. Rep. 2004, 21, 164−179. BI


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