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. 2025 Jul 18;147(30):26769–26775. doi: 10.1021/jacs.5c07636

Convergent Total Synthesis of Erchinines A and B and Their C20 Epimers

Yong Sun Cho 1, Joseph P Tuccinardi 1, John L Wood 1,*
PMCID: PMC12315839  PMID: 40681163

Abstract

The total synthesis of two monoterpenoid indole alkaloids (MIAs), erchinines A and B, is described. Isolated from the plant Ervatamia chinensis, both compounds display antimicrobial activity against Trichophyton rubrum and Bacillus subtilis. Their structures are composed of a unique caged system, bearing a 1,4-diazepine fused oxazolidine moiety and containing three successive N,O-acetals. Key features of the synthesis include the construction of the 2-aza-3-oxobicyclo[2.2.2]­octene core via an intramolecular pyridone Diels–Alder reaction and a Zr-mediated bisamide reduction that induces a tandem N,O-acetal forming cascade reaction.

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Introduction

Erchinines A (1) and B (2) are structurally complex monoterpene indole alkaloids isolated from the roots of Ervatamia chinensis. Plants of this genus have long been used in traditional and folk medicine for treating a variety of ailments and are the source of many well-known iboga alkaloids that possess potent biological activities. − Structurally (Figure ), 1 and 2 both contain an interesting azabicyclo[2.2.2]­octane system and differ only by the presence of a hemiaminal in 1. There are a significant number of natural products possessing similar yet hydrolytically more stable core structures, such as the spirocyclic congeners voacangine pseudoindoxyl (3), iboluteine (4), , fused azepine ibogaine (5), , and 3-oxo-7R-coronaridine hydroxyindolenine (6). Notably, erchinine A was independently isolated and reported by two separate research groups, each giving it a different name: erchinine A (1) and ervaoffine E. For consistency, the name erchinine A will be used throughout this communication.

1.

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Representative Iboga Alkaloid Natural Products.

As one might expect, the intriguing structures and biological activities of compounds in this natural product family have attracted attention from the synthetic community for many years. However, despite their distinctive structural features, which include a novel oxidized iboga-like core possessing three contiguous N,O-acetals and seven stereogenic centers, no synthetic efforts toward erchinines A and B have been reported. From a biological perspective, these hexacyclic alkaloids were found to display promising antimicrobial activity, with particularly significant activity against Trichophyton rubrum and Bacillus subtilis. Given the unprecedented structures and interesting biological properties manifested by erchinines A and B, we viewed these natural products as excellent targets for total synthesis and herein report the results of these studies.

Though erchinines A and B are structurally unique monoterpene indole alkaloids, their central [2.2.2]-azabicyclooctane framework is found in numerous natural products. Thus, at the outset of our studies, we sought to develop a synthetic strategy that would rapidly and efficiently establish this common motif. Taking inspiration from our recent total synthesis of flueggeacosine C (9) (Scheme A), we envisioned employing an intramolecular Diels–Alder [4 + 2] cycloaddition between a pyridone-based diene and an appropriately substituted, tethered dienophile. − Regarding the daunting array of bridging N,O-acetals that comprise the remainder of the erchinine core, we were drawn to the proposed biosynthetic pathway (Scheme B), , which suggested that an iminium ion, akin to that illustrated in 11, could serve as an intermediate leading to the complete heterocyclic core. Guided by these ideas, as illustrated retrosynthetically in Scheme , we began to develop a strategy wherein the three contiguous N,O-acetals would be introduced late by employing a Zr-mediated reductive cycloacetalization of an intermediate diamide (13) followed by oxidation of indole 12 to the hydroxypseudoindoxyl found in 1 and 2. We envisioned that the oxophilicity of a Zr-based reagent would help both induce reduction of the two amides and promote generation of the hemiaminal/iminium pair leading to the two contiguous N,O-acetals. , The requisite diamide (13) was seen as arising via regio selective intramolecular Diels–Alder cycloaddition (IMDA) of an amide-tethered vinylindole dienophile with the pendant ethylpyridone diene. This latter maneuver would, in principle, deliver the entire carbocyclic core of erchinines A and B from an IMDA precursor (14) that would be readily available from the coupling of vinylindole 15 with carboxymethylpyridone 16.

1. (A) Inspiration for Intramolecular Pyridone Diels-Alder Cycloaddition from Our Previous Synthesis of Flueggeacosine C (B) Proposed Biosynthetic Pathway to Access Erchinine A.

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2. Retrosynthetic Analysis of Erchinines A (1) and B (2).

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Results and Discussion

We initiated our synthetic work toward erchinines A and B by first exploring the proposed diene/dienophile combination leading to 13. As illustrated in Scheme , the diene fragment was rapidly assembled in a five-step sequence that furnished 16 in excellent overall yield. Specifically, commercially available 2,5-dibromopyridine (17) was subjected to nucleophilic aromatic substitution of sodium methoxide followed by a lithium-halogen exchange/ethylation reaction to furnish methoxypyridine 18, which, upon potassium iodide-mediated demethylation in aqueous HCl, readily gave the known ethylpyridone 19. Alkylation of 19 with ethylbromoacetate and potassium carbonate cleanly furnished N-alkylated pyridone 20 in good yield over four steps. Saponification of ethyl ester 20 with aqueous NaOH, provided the carboxylic acid (16) required for fragment coupling. The dienophile-containing fragment 15 was prepared following procedures developed by Tsantrizos and Pérez-Castells.

3. Preparation of the Pyridone Fragment.

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With 15 and 16 in hand, we turned next to fragment coupling (Scheme A) and were surprised to find that under a variety of conditions we were unable to effect this transformation. Suspecting the diminished nucleophilicity of the indole nitrogen as the culprit, we focused our efforts on the corresponding indoline. To this end, preparation of the Boc protected precursor (24, Scheme B) began with the 2-step conversion of commercially available methyl 5-methoxyindole-2-carboxylate (22) to ester 23 via a known procedure. , Conversion of 23 to 24 via DIBAL-H reduction and Wittig homologation was followed by Boc deprotection and coupling with 16 to furnish IMDA substrate 25. Although efforts to advance 25 via cycloaddition were successful in delivering 26, the yields under several conditions were consistently below 10% and the desired product was accompanied by equimolar amounts of what appeared to be a regioisomer. To ameliorate this latter issue, we next targeted indoline 28 (Scheme ), wherein the introduction of a sulfone moiety was expected to influence both reactivity and regiochemical outcome in the IMDA, and as before, the enhanced nucleophilicity of the indoline would again facilitate fragment coupling.

4. Initial Studies.

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5. Successful Convergent Coupling and Subsequent Diels–Alder Cycloaddition.

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In preparing IMDA substrate 29, we employed the previously prepared ester 23, which, upon DIBAL-H reduction of the ester to an intermediate indoline carbaldehyde, and Horner–Wadsworth–Emmons homologation with sulfonyl phosphonate 27, furnished 28. Turning our attention to the convergent coupling and ensuing Diels–Alder chemistry, we next deprotected 28 to deliver an intermediate indoline amine, which, upon exposure to 16 in the presence of N,N’-dicyclohexylcarbodiimide (DCC), underwent smooth conversion to the IMDA precursor (29). We were very pleased to find that prolonged heating of a chlorobenzene solution containing 29 and the radical inhibitor butylated hydroxytoluene (BHT) cleanly induces the formation of the desired cycloadduct 30 in good yield.

Having forged the carbocyclic skeleton of erchinines A and B and validated our pyridone IMDA approach, we began to focus on synthesis completion. To this end, we first attempted removal of the phenyl sulfone group to provide azabicycle 26 (Scheme , top). Disappointingly, 1H NMR analysis of the crude reaction mixture indicated that a mixture of isomers had been produced. The structure of the major component of this mixture was established as a rearranged [3.2.1]­azabicycle (31) via single crystal X-ray analysis of the corresponding hydrogenation product 33 (Scheme , bottom). Although not fully delineated at this stage, the spectral data for the minor isomer derived from 30 was consistent with the desired product 26 and, though not isolated in pure form, the corresponding reduction product was by analogy to 33 believed to be 32. As illustrated, 31 likely arises through a Dowd–Beckwith-type rearrangement of the bridging amide wherein the carbon-centered radical (I) undergoes 3-exo-trig cyclization to provide a reactive cyclopropanoxy radical II, which, in turn, rearranges to the more stable allylic radical III. Further reduction of III and quenching then furnishes 31. The unexpected observation of 31 led us to consider changing the order of events by reducing the amide or olefin prior to desulfonylation. Based on the mechanistic hypothesis, we believed hydrogenation of the olefin before desulfonylation would suppress the rearrangement to 31 by destabilizing intermediate III. In exploring this latter notion (Scheme A), we found that diastereoselective hydrogenation of 30 did indeed prevent the deleterious skeletal rearrangement, as spectral data for the derived desulfonylation product were consistent with a [2.2.2] azabicycle. However, it was also clear from this analysis that changing the order of events had resulted in the production of 34, the C20 epimer of the previously observed diastereomer (32). Given that we had yet to rigorously establish the C20 stereochemistry in either 32 or 34, we continued with the planned zirconium-based reduction chemistry and were delighted to observe that subjecting 34 to Schwartz’s reagent induced a doubly reductive cycloacetalization, eventuating in the formation aminooxazolidine 35. As illustrated, 35 proved suitable for single crystal X-ray analysis, thereby confirming success of the reductive cyclization. This analysis also indicated that hydrogenation of 30 had indeed produced the undesired stereochemistry at C20, which, in turn, confirms that hydrogenation of 26 furnishes the diastereomer required for advancement to 1 and 2. Hypothesizing that steric encumbrance by the phenylsulfone was governing the diasterotopic face selectivity, we opted to next explore a sequence wherein 26 would be advanced via initial Zr-mediated reductive cycloacetalization, a maneuver that eliminates the possibility of a deleterious Dowd–Beckwith-type rearrangement upon desulfonylation. To this end (Scheme B), exposure of 30 to Schwartz’s reagent was found to provide oxazolidine 36 in good yield. Moreover, we were pleased to find that exposure of 36 to the previously employed desulfonylation conditions resulted in clean reduction with no observable rearrangement. Though this sequence proved to be quite efficient, we were once again disappointed to find that hydrogenation furnishes the undesired C20 epimer (i.e., 35).

6. Unexpected Dowd–Beckwith Type Rearrangement and Proposed Mechanism.

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7. Attempts to Avoid Undesired Dowd–Beckwith Rearrangement with Desired Stereochemistry at C-20.

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Unable to improve the sequence by changing the order of events, we decided to revisit the conditions for the desulfonylation of 30. In our initial studies, we noted that 30 was sparingly soluble in a variety of solvents including the original methanolic system. Accordingly, we focused our optimization efforts on exploring solvent effects and reagent stoichiometry, an effort that revealed the combination of HFIP/THF (1:1) to be optimal in furnishing 26 (79% yield, Scheme ). Having obtained synthetically useful yields of 26, we turned our attention to diastereoselective hydrogenation. As anticipated by previous studies, we were delighted to find that the exposure of 26 to H2 in the presence of catalytic Pd/C produces an excellent yield of 32. Notably, in this transformation we found diastereoselectivity to be solvent-dependent with the best result (10:1) obtained when using MeOH. In 1:1 DCM/MeOH, the desired isomer remains the major product but the dr drops to 3:1 and a nearly 1:1 mixture of diastereomers is observed when using only DCM as solvent. The obtained diamide (32) was subjected to Zr-mediated reduction using Schwartz’s reagent, which produced the desired oxazolidine (37) bearing the required two contiguous N,O-acetals. The structure of 37 was unambiguously established by single crystal X-ray analysis.

8. Successful Construction of Carbon Skeleton.

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With the entire heterocyclic skeleton of erchinines A and B in hand, we began exploring the final oxidation. As illustrated in Scheme , elevation of 37 to the erchinine oxidation state would first require oxidation of the indoline to the corresponding N-substituted indole, a transformation that is well-precedented in the literature and was readily implemented by exposure of 37 to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The final step was then to further oxidize the derived indole (12) to the corresponding hydroxypseudoindoxyl moiety. Notably, concerns about compatibility of the basic nitrogens and typical peracid-mediated conditions were belayed by literature reports of similarly functionalized indoles being successfully oxidized under a variety of conditions. In this event, treatment of 12 with trifluoroacetic acid (TFA), to deactivate both tertiary amines followed by addition of m-chloroperoxybenzoic acid (m-CPBA), was found to deliver erchinine A (1). Subsequent treatment of 1 with methanolic HCl smoothly produced erchinine B (2) in excellent yield.

9. Total Synthesis of Erchinines A (1) and B (2).

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Although the synthesis of erchinines A and B was now complete, we recognized that the efficiency with which we were accessing intermediates that would lead to C-20-epi congeners had provided an opportunity to access analogs of the natural products that could prove interesting in future biological studies. Thus, we turned our attention to advancing intermediate 35 to the corresponding C20-epi-natural products. As illustrated in Scheme , we quickly discovered that the reaction sequence developed for 1 and 2 was viable for producing corresponding C-20 epimers 39 and 40. Thus, oxidation of aminooxazolidine 35 with DDQ provided indole 38, which, upon exposure to TFA and m-CPBA, furnished C20-epi-erchinine A (39). Subjecting 39 to methanolic HCl resulted in the formation of C20-epi-erchinine B (40).

10. Synthesis of C20-epi-Erchinines A (39) and B (40).

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Conclusions

In summary, we have completed a total synthesis of erchinines A (1) and B (2) in 12- and 13-steps (LLS), respectively, from commercially available indole carboxylate 22. The efficiency of this convergent synthesis derives from a pyridone IMDA reaction, which sets the stage for a novel Zr-mediated reduction/cycloacetalization cascade that transforms a diamide into the unique N,O-acetal moieties present in both natural products. The combined pyridone IMDA and Zr-mediated reduction have potential for providing general and efficient access to numerous biologically active monoterpene indole alkaloids possessing the isoquinuclidine framework. Additionally, we demonstrated that this chemistry can be employed to access C-20-epi analogs and likely other iboga-like monoterpene indole alkaloids. Ongoing efforts are directed toward exploring the biological activity of erchinines A (1) and B (2), their respective C20-epimers (39, 40), and intermediates generated throughout this work.

Supplementary Material

ja5c07636_si_001.pdf (6.4MB, pdf)

Acknowledgments

The authors gratefully acknowledge Dr. X. Xu for assistance with NMR analysis and Professor L. Bayeh-Romero for helpful discussions. The authors gratefully acknowledge financial support from Baylor University, the Welch Foundation (Chair, AA-006), the Cancer Prevention and Research Institute of Texas (CPRIT, R1309), NIGMS-NIH (R01GM136759), and NSF (CHE-1764240).

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.5c07636.

  • Experimental procedures, tabulated spectroscopic data, and copies of NMR spectra (PDF)

The authors declare no competing financial interest.

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