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. 2022 Oct 19;87(22):15559–15563. doi: 10.1021/acs.joc.2c02099

Total Synthesis of (±)-Aspidospermidine, (±)-Aspidofractinine, (±)-Limaspermidine, and (±)-Vincadifformine via a Cascade and Common Intermediate Strategy

David L Cain †, Niall A Anderson ‡, David B Cordes †, Alexandra M Z Slawin †, Allan J B Watson †,*
PMCID: PMC9680024  PMID: 36259765

Abstract

graphic file with name jo2c02099_0005.jpg

A concise strategy for the total synthesis of several Aspidosperma alkaloids is reported. A Suzuki–Miyaura cross-coupling provides access to a 2-vinyl indole that undergoes a Diels–Alder cascade reaction with butyn-2-one to deliver a pyrroloindoline intermediate. This undergoes cascade amidation, reduction, skeletal rearrangement, and intramolecular Michael addition to provide a common intermediate containing the full framework of the Aspidosperma alkaloids. The utility of this intermediate is shown in the synthesis of four different natural products.

Introduction

The Aspidosperma alkaloids are a class of monoterpenoid indole alkaloids, which have seen significant interest as synthetic targets (Scheme 1a).1−4 Their intriguing, densely fused polycyclic structures have inspired numerous strategies and methodologies to enable access to the eponymous aspidospermidine (1),5−8 as well as many other members of this family. Of the strategies employed in total synthesis, divergent approaches based on a common intermediate are arguably the most powerful.8a,9 These approaches allow the synthesis of multiple natural products by late-stage modification of a single common intermediate.

Scheme 1. (a) Aspidospermidine and Several Related Alkaloids and (b) This Work: Divergent Synthesis via a Cascade and Common Intermediate Strategy.

Scheme 1

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Here, we report a common intermediate strategy for the synthesis of Aspidosperma natural products, where the common intermediate is accessed through cascade reactions, and demonstrate the utility of this cascade strategy in the synthesis of (±)-aspidospermidine,5−9 (±)-aspidofractinine,10 (±)-limaspermidine,11 and (±)-vincadifformine (Scheme 1b).8d,12

Results and Discussion

Our retrosynthetic approach is shown in Scheme 2.

Scheme 2. Retrosynthetic Strategy.

Scheme 2

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We envisioned that (±)-aspidospermidine (1) could be accessed by straightforward reduction and deprotection of 2, which contained the full carbon skeleton of 1. Indeed, 2 also aligned with our desired divergent synthesis approach as it could be elaborated in several straightforward ways to allow the synthesis of several other members of this class of natural products. As such, 2 was our targeted common intermediate for this overall synthetic campaign. Inspired by previous work,8a we believed that 2 could be swiftly accessed in cascade amidation, reduction, skeletal rearrangement, and intramolecular Michael addition by treatment of pyrroloindoline 4 with acryloyl chloride, a suitable hydride reagent, and a base. The key intermediate 4 would be accessed from vinyl indole 5 via a cascade using the Diels–Alder reaction and intramolecular trapping of the generated iminium by the pendant tryptamine. Vinyl indole 5 would be prepared via Suzuki–Miyaura coupling of bromoindole 6. Based on this proposed sequence, it seemed likely that a cascade synthesis of 4 could be realized beginning from 6.13,14

The forward synthesis (Scheme 3) began with the synthesis of the targeted common intermediate (Scheme 3a). Commercial N-Boc tryptamine (7) was benzyl-protected (8) and brominated to provide 9. Suzuki–Miyaura cross-coupling of 9 with vinyl BPin delivered vinyl indole 10. At this stage, two alternative sequences delivered access to the key common intermediate 16. In route A, Diels–Alder reaction of 10 with butyn-2-one using excess BF3·OEt2 provided pyrroloindoline 11, with concomitant Boc deprotection. This reaction proceeded in good yield, considering the overall number of the overall process involved. Treatment of 11 with acryloyl chloride and reduction of the generated iminium with NaHB(OAc)3 afforded acrylamide 12 in good yield over two steps.

Scheme 3. (a) Synthesis of Common Intermediate 16; (b) Aspidosperma Alkaloid Natural Product Syntheses via 16; Thermal Ellipsoids for Compounds 13 and 16 Shown at 50% Probability, with Hydrogens and Solvent Molecules Removed for Clarity.

Scheme 3

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Treatment of 12 with NaH induced an intramolecular aza-Michael reaction to form the E ring and generate enolate 15, which underwent an intramolecular Michael addition to the acrylamide, forming the D ring, providing common intermediate 16, and completing the carbon scaffold of (±)-aspidospermidine in almost quantitative yield.

The alternative route B involved a minor adjustment to the sequence of events for route A. Vinyl indole 10 underwent the same Diels–Alder reaction with butyn-2-one; however, lowering the stoichiometry of BF3·OEt2 provided pyrroloindoline 13, which retained the Boc protecting group, and was a more efficient approach to a similar intermediate. Treatment of 13 with TFA and NaHB(OAc)3 induced skeletal rearrangement to forge the E ring by elimination of the tryptamine nitrogen, reduction of the generated iminium, and aza-Michael addition of the tryptamine to the C ring enone, affording compound 14 in good yield. Use of 14 in a three-step sequence comprising Boc deprotection using TFA, amidation with acryloyl chloride, and intramolecular Michael addition to forge the D ring delivered 16 in moderate yield. Overall, routes A and B were comparable in overall efficiency in accessing 16.

Finally, it proved possible to access 11 in a telescoped process from 9 by combining the Suzuki–Miyaura and Diels–Alder events (route C). This delivered intermediate 11 in 71% and decreased the number of isolations required for the overall route. Compound 11 was then advanced to 16 using the same sequence of events as route A.

The Lewis acid-mediated Diels–Alder reaction suggested the possibility of an asymmetric process; however, attempts to induce enantioselectivity using chiral Lewis acids in this cascade were unsuccessful.

With access to 16, completion of the synthesis of aspidospermidine was straightforward (Scheme 3b). Reduction of the ketone and lactone was achieved by telescoped Wolff–Kishner and LiAlH4 reductions, affording 17 in good yield. Hydrogenative debenzylation delivered (±)-aspidospermidine 1 (11 chemical transformations and 7 isolations). This also enabled access to (±)-vincadifformine (18) via a three-step process including Swern oxidation, deprotonation, and trapping of the generated enaminate with Mander’s reagent (14 chemical steps and 8 isolations).

In alignment with the design plan, the utility of the common intermediate 16 was then shown by elaboration to several other members of this class of natural products. Treatment of 16 with LiAlH4 afforded alcohol 19, which was dehydrated with Martin sulfurane to afford alkene 20. This allowed Brown hydroboration/oxidation to afford alcohol 21, which was debenzylated to afford (±)-limaspermidine 22 (13 chemical steps and 9 isolations). Last, debenzylation of 16 afforded amine 23, which underwent one-pot Swern oxidation and an intramolecular acid-promoted Mannich reaction to afford 24. Reduction of the ketone and lactam using the Wolff–Kishner/LiAlH4 sequence then provided (±)-aspidofractinine 25 (13 steps and 8 isolations).

Conclusions

In summary, a concise, divergent route to the Aspidosperma alkaloids has been developed based on a cascade and a common intermediate strategy. The main design element is a cascade cross-coupling/Diels–Alder process, which allows construction of the majority of the necessary ring system. A cascade aza-Michael/Michael reaction then completes the carbon skeleton and provides the key common intermediate, which can be readily elaborated to various members of this natural product family.

Acknowledgments

D.L.C. thanks EPSRC and GSK for a Ph.D. studentship. We thank Dr. Eva M. Israel for assistance with NMR processing, Dr. Matthew Andrews for assistance with X-ray data processing, and Mr. John M. Halford-McGuff for assistance with manuscript preparation.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.2c02099.

Author Present Address

§ Sygnature Discovery, Biocity, Pennyfoot Street, Nottingham, NG1 1GR, U.K

Author Present Address

∥ AstraZeneca, Darwin Building, Unit 310, Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.

Author Contributions

All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Originally published ASAP October 19, 2022; Scheme 3 and Supporting Information updated October 26, 2022.

Supplementary Material

jo2c02099_si_001.pdf (7.4MB, pdf)

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Supplementary Materials

jo2c02099_si_001.pdf (7.4MB, pdf)

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