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. 2024 Feb 12;146(7):4340–4345. doi: 10.1021/jacs.3c13590

Enantioselective Total Synthesis of (−)-Hunterine A Enabled by a Desymmetrization/Rearrangement Strategy

Elliot F Hicks 1, Kengo Inoue 1, Brian M Stoltz 1,*
PMCID: PMC10885145  PMID: 38346145

Abstract

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The first enantioselective total synthesis of (−)-hunterine A is disclosed. Our strategy employs a catalytic asymmetric desymmetrization of a symmetrical diketone and subsequent Beckmann rearrangement to construct a 5,6-α-aminoketone. A convergent 1,2-addition joins a vinyl dianion nucleophile and the enantioenriched ketone. The endgame of the synthesis features an aza-Cope/Mannich reaction and azide-olefin dipolar cycloaddition to complete the pentacyclic ring system. The synthesis is completed through a regioselective aziridine ring opening.

Monoterpene indole alkaloids (MIAs) are a structurally diverse class of natural products that have captured the attention of synthetic chemists for decades due to their complexity and varied biological activities.1 Molecules in this family are generally characterized by a conserved indole or indoline moiety bound to various rearranged terpene units (Figure 1). However, a small number of MIAs have been isolated containing rearranged indole units in which the C2–C7 bond has been cleaved (carbon numbering follows that given in the isolation of these molecules). Many elegant total synthetic approaches to members of the MIA family have been disclosed, including those containing C2–C7 indole cleavage.2,3

Figure 1.

Figure 1

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(−)-Hunterine A (1) and representative monoterpene indole alkaloids. Carbon numbering follows that given in the isolation of these molecules.

(−)-Hunterine A (1), isolated in 2019 by Zhang, Ye, and co-workers,4 belongs to a structurally distinct class of monoterpene indole alkaloids in which the N1–C2 indole bond has been cleaved (Figure 1). To date only one structurally related natural product has been isolated,5 and there are no reported syntheses of either alkaloid. From a synthetic perspective, the bridging azabicyclo[4.3.1]decane core, dissonant oxidation pattern of N1 and the C18 alcohol, and C19 stereochemistry all present challenges. Additionally, 1 shows moderate cytotoxic activity against HepG2 liver cancer cell lines (35 μM). Because of its structural complexity from a synthetic perspective, unique scaffold within the historic class of MIA natural products, as well as its intriguing biological activity, we were motivated to pursue a total synthesis of hunterine A. Although our group has completed total syntheses of several MIAs and bisindole dimers,6 the unique structure of hunterine A necessitated the development of a distinct synthetic approach.

When devising our retrosynthetic strategy, we began by focusing on the seven-membered azepane motif. Disconnection of the C19–N1 bond within this ring would eliminate the bridging ring system, leading to tricyclic intermediate 2 (Scheme 1A). Although at the outset of the synthesis it was unclear how this would be accomplished in the forward direction, an azide-olefin cycloaddition ultimately proved successful.7 Given that 1 does not contain an indole, construction of the highlighted C7 all-carbon quaternary center could not be accomplished in the same manner as in the synthesis of related MIAs, which commonly utilize strategies such as Fischer indole synthesis and nucleophilic indole alkylation (Scheme 1B).8,9 Instead, we imagined forming the C7 quaternary center via an aza-Cope/Mannich rearrangement, developed by Overman and co-workers for the synthesis of similar 3-acyl pyrrolidine motifs,10,11 tracing back to bicyclic alcohol 3. Alcohol 3 could be formed via a convergent, diastereoselective 1,2-addition of vinyl species 4 to ketone 5. Finally, bicyclic ketone 5 was envisioned to arise from a desymmetrization and Beckmann rearrangement of symmetrical bicyclic diketone 6.

Scheme 1. (A) Retrosynthetic Strategy and (B) Common Strategies for Quaternary Center Formation in MIA Synthesis.

Scheme 1

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Construction of diketone 6 commenced with an umpolung ylide addition of cyclopentenone to ethyl acrylate activated with TMSOTf, as disclosed by Kim and co-workers,12 which furnished enone 8 in 64% yield (Scheme 2A). Installation of the vinyl group through Cu-catalyzed 1,4-addition required careful optimization (see the Supporting Information for details). All attempts to translate protocols reported for the 1,4-addition of vinyl nucleophiles to β-substituted enones were met with failure when vinyl-MgBr was employed, and only 1,2-addition was observed. Instead, an inverse addition protocol13,14 in which the Grignard is added to all other reagents at −40 °C proved to be the key to successful 1,4-addition, providing ketone 9 in 75% yield, precluding competitive 1,2-addition and addition to the ester. With the vinyl group installed, an intramolecular Claisen condensation of ketone 9 cleanly afforded symmetrical diketone 6 in 86% yield.15

Scheme 2. (A) Synthesis of Keto-Alcohol 10; (B) Advancement of 10 to Ketone 5 Using a Beckmann Rearrangement; (C) Completion of (–)-Hunterine A.

Scheme 2

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We next envisioned performing an asymmetric reduction to desymmetrize diketone 6. Since asymmetric reductions of simple alkyl–alkyl ketones tend to be poorly enantioselective due to difficulties in catalyst differentiation of the ketone re- and si-faces,16 a variety of both chemical and enzymatic ketone reduction strategies were explored; representative entries are shown in Table 1. Enantioselective reduction using Baker’s yeast17 proceeded with high levels of enantioselectivity, albeit in the incorrect enantiomeric series. Additionally, the long reaction time, excessive dilution required, and low conversion were all undesirable (entry 1). Reduction with CBS catalyst and catecholborane18 was unsuccessful (entry 2). Ruthenium-catalyzed transfer hydrogenation in the presence of catalytic KOH and i-PrOH19 proceeded with low conversion and poor enantioselectivity (entries 3 and 4). Ultimately, a scalable, enantioselective reduction was realized through a modified version of Noyori’s transfer hydrogenation conditions employing RuCl(mesitylene)(R,R-TsDPEN) and a (5:2) formic acid/triethylamine mixture20,21 in 1,4-dioxane, which gave a separable mixture of keto-alcohol 10 (57% yield, 91% ee) and diol 11 (entry 7). Over-reduction to the meso-diol (11) was necessary as it resulted in an appreciable degree of chiral resolution, improving the enantiomeric purity of alcohol 10 (entries 8 and 9). Diol 11 was recycled to diketone 6 via oxidation with TEMPO and (diacetoxyiodo)benzene in 68% yield. To our knowledge, this is the first report of a non-enzymatic enantioselective reduction of a symmetrical [3.3.0] diketone,22 making both enantiomers of the alcohol readily accessible (S,S-enantiomer of catalyst is commercially available). Further investigation of this sequence for the desymmetrization of other symmetrical diketone substrates is currently underway.

Table 1. Desymmetrization of Diketone 6.

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a

Reactions were conducted with 1 mol % [Ru] catalyst.

b

Five mol % KOH added.

c

Conversion determined by the 1H NMR ratio of the remaining diketone 6 relative to the CH2Br2 internal standard.

With the enantioselective desymmetrization complete, synthesis of the necessary piperidine ring was accomplished via a Beckmann rearrangement and subsequent reduction. To this end, enantioenriched alcohol 10 was first protected with TBSCl to give silyl ether 12 nearly quantitatively (Scheme 2B). Condensation of hydroxylamine proceeded smoothly, although as a 1:1.3 mixture of oxime isomers (13 and 14). While some reports have shown that mixtures of oxime isomers can be isomerized in situ to give single Beckmann rearrangement products,23 this could not be accomplished in our hands. Instead, the two isomers were chromatographically separated; the undesired isomer was then resubjected to oxime formation conditions, which led to a 1:1 mixture that could again be separated. In two cycles, we isolated desired oxime 14 in 74% yield on the multigram scale. Exposure of this oxime to an excess of thionyl chloride resulted in smooth Beckmann rearrangement and produced lactam 15 in 75% yield. Lactam 15 was then exhaustively reduced with LiAlH4, which simultaneously and unexpectedly removed the silyl protecting group. This proved to be of little consequence as the crude amino alcohol was selectively alkylated with K2CO3 and bromoacetonitrile to give aminonitrile 16 in 80% yield over two steps. Finally, Swern oxidation of the alcohol afforded bicyclic ketone 5 in 84% yield.

With bicyclic ketone 5 in hand, a variety of 1,2-addition protocols were evaluated using different vinyl iodides with varying substituents on the aniline nitrogen as precursors to vinyl lithium or magnesium species (see Supporting Information for details). While metal-halogen exchange occurred readily for the vinyl iodides employed, addition to ketone 5 was never detected. Ultimately, a successful strategy was realized through generation of a dianion by deprotonation and magnesium-halogen exchange and subsequent addition to ketone 5, inspired by Knochel and co-workers.24 Moreover, LaCl3·2LiCl25 proved to be critical in promoting the dianion 1,2-addition. Under the optimized conditions, N–H deprotonation of vinyl iodide 17 with PhMgBr was followed by magnesium-halogen exchange using i-PrMgCl·LiCl to form the dianion, to which LaCl3·2LiCl was added, followed by ketone 5 to efficiently produce the corresponding alcohol (not shown) without reaction of the nitrile. Deprotonation with i-PrMgCl·LiCl occurred at a rate similar to that of magnesium-halogen exchange, thereby necessitating the initial deprotonation with PhMgBr. The N-Boc aniline was immediately deprotected with TMSCl in MeOH to give alcohol 18 in 59% yield over the two-step sequence (Scheme 2C).

With both fragments joined via the 1,2-addition, our initial attempts to complete the synthesis of hunterine A commenced with the aza-Cope/Mannich reaction (Scheme 3). Treatment of aniline 18 with AgNO3,26 while successful in effecting the aza-Cope/Mannich reaction, led to an additional, unavoidable condensation to form indolimine 23.27 Despite being undesired for the synthesis of hunterine A, the crude indolimine could be treated first with NaBH4 and subsequently with H2 in the presence of Pd/C to provide divergent access to (−)-aspidospermidine in 71% yield over 3 steps.

Scheme 3. Divergent Access to (−)-Aspidospermidine via Aniline 18.

Scheme 3

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To remedy the issue of undesired condensation, aniline 18 was first converted to the corresponding aryl azide (19) in 73% yield (Scheme 2C). Gratifyingly, treatment of this intermediate with AgNO3 smoothly formed tricyclic azide 2 in 82% yield. Notably, the successful execution of an aza-Cope/Mannich reaction in the presence of an azide has, to our knowledge, not previously been reported. Additionally, the terminal olefin did not appear to negatively impact the formation of tricycle 2 despite its potential to undergo an alternative and undesired aza-Cope rearrangement. These potential pitfalls were likely circumvented by the mild conditions used to effect this transformation by employing an N-cyanomethyl group as the iminium precursor for the aza-Cope rearrangement.

At this stage, the remaining objectives were closure of the seven-membered azepane ring and installation of the primary alcohol. To our delight, simply dissolving azide 2 in heptane resulted in spontaneous azide-alkene dipolar cycloaddition at ambient temperature to give triazoline 20 in an overall 80% yield as a 2.5:1 mixture of separable diastereomers at C19, completing the pentacyclic ring system of 1. The structures of both diastereomers were unambiguously confirmed by X-ray crystallography. The mixture of triazolines could also be synthesized in a telescoped sequence directly from aryl azide 19 by simply adding heptane following completion of the aza-Cope/Mannich reaction, although this resulted in slightly lower levels of diastereoselectivity (1.85:1 dr). To advance triazoline 20 to the natural product, the desired diastereomer was irradiated with long-wave UV light (350 nm) to form the putative aziridine 21.28 Acetic acid was then added to the reaction mixture, which led to regioselective ring opening29 to form O-acetyl-hunterine A (22). This intermediate was deacetylated without further purification using K2CO3 in MeOH to give (−)-hunterine A in 54% yield over the final two steps, completing the total synthesis.

Attempts to streamline the endgame sequence by excluding the triazoline photolysis resulted in unexpected differences in reactivity. Treatment of triazoline 20 with acetic acid in benzene successfully generated O-acetyl-hunterine A, although with a poor reaction profile which resulted in a lower overall yield of (−)-hunterine A from 20 (Scheme 4). By contrast, treatment of undesired C19-epi-20 with acetic acid in benzene formed imine 26 in 55% yield, likely via intermediate 25.30 No C19-epimer of O-acetyl-hunterine A was detected. We speculate that this difference in reactivity relates to different degrees of pyramidality of the respective nitrogen atoms. Summation of the relevant bond angles in the crystal structure of 20 suggests that the nitrogen atom is 45% pyramidal, while in C19-epi-20, the nitrogen atom is only 9% pyramidal.31 Thus, the formation of imine 26 (presumably via intermediate imine 25) from C19-epi-20 may be a reflection of this diastereomer’s propensity to retain a planar geometry. A further investigation of this phenomenon is currently underway, and the results will be reported in due course.

Scheme 4. Reactivity Differences between Triazoline 20 and C19-epi-20 and Nitrogen Pyramidality.

Scheme 4

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In conclusion, we have developed an enantioselective total synthesis of hunterine A, a novel member of the historic MIA class of natural products. Key features of this synthesis are the development of a catalytic, enantioselective desymmetrization of a symmetrical bicyclo[3.3.0]diketone, a dianion 1,2-addition using LaCl3·2LiCl, an aza-Cope/Mannich reaction with spontaneous azide-olefin cycloaddition, and a regioselective aziridine ring opening. Additionally, we have uncovered a potential connection between the structure and divergent reactivity of late-stage triazoline diastereomers. Finally, we have also demonstrated that intermediate 18 provides a point of divergence to access other members of the MIA family of natural products.

Acknowledgments

This manuscript is dedicated to Professor Larry E. Overman of the University of California, Irvine, on the occasion of his 80th birthday. The NIH-NIGMS (R35GM145239), Heritage Medical Research Investigators Program, and Caltech are thanked for the support of our research program. We thank Dr. David VanderVelde (Caltech) for NMR expertise; Dr. Mona Shagholi (Caltech) for mass spectrometry assistance; Dr. Michael Takase (Caltech) for assistance with X-ray crystallography; and Dr. Scott C. Virgil (Caltech) for instrumentation, HPLC, and SFC assistance. Additional thanks to Kevin Gonzalez, Ben Gross, Samir Rezgui, and Hao Yu for many helpful discussions. E.F.H. would like to thank the NSF GRFP for funding.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c13590.

  • Experimental procedures, spectroscopic data (1H NMR, 13C NMR, IR, and HRMS), and crystallographic data (PDF)

The authors declare no competing financial interest.

Supplementary Material

ja3c13590_si_001.pdf (4.5MB, pdf)

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