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. Author manuscript; available in PMC: 2018 Oct 2.
Published in final edited form as: Angew Chem Int Ed Engl. 2017 Sep 5;56(41):12624–12627. doi: 10.1002/anie.201707304

Enantioselective Catalysis Coupled with Stereodivergent Cyclization Strategies Enables Rapid Syntheses of (+)-Limaspermidine and (+)-Kopsihainanine A

Beau P Pritchett 1,†, Etienne J Donckele 1,†, Brian M Stoltz 1,✉
PMCID: PMC5896324  NIHMSID: NIHMS956935  PMID: 28872739

Abstract

Enantioselective Pd-catalyzed allylic alkylations of dihydropyrido[1,2-a]indolone (DHPI) substrates were used to construct the C20-quaternary stereocenters of multiple monoterpene indole alkaloids. Stereodivergent Pictet–Spengler and Bischler–Napieralski cyclization/reduction cascades furnish the cis- and trans-fused azadecalin subunits present in Aspidosperma and Kopsia alkaloids, respectively, en route to highly efficient syntheses of (+)-limaspermidine and (+)-kopsihainanine A.

Keywords: monoterpene indole alkaloids, allylic alkylation, asymmetric catalysis, stereodivergent cyclizations, total synthesis

Put a ring on it

Enantioselective Pd-catalyzed allylic alkylations of dihydropyrido[1,2-a]indolone (DHPI) substrates were combined with stereodivergent Pictet–Spengler and Bischler–Napieralski cyclizations to furnish the cis- and trans-fused azadecalin subunits present in Aspidosperma and Kopsia alkaloids, respectively, en route to highly efficient syntheses of (+)-limaspermidine and (+)-kopsihainanine A.

graphic file with name nihms956935u1.jpg

Monoterpene indole alkaloids from the structurally related Aspidosperma and Kopsia families have been studied for more than half a century due to their intricate polycyclic structures and broad biological activities.1,2 One significant structural difference between these families is the ring fusion geometry of the octa- or decahydroquinoline moiety contained within the polycyclic core. Aspidosperma alkaloids typically possess a cis-fused azadecalin motif (e.g., 1 and 2, Figure 1).3 Conversely, members of the Kopsia family often contain a trans-fused azadecalin substructure (e.g., 3 and 4, Figure 1).4

Figure 1.

Figure 1

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Selected Aspidosperma and Kopsia alkaloids.

We recently reported the enantioselective Pd-catalyzed allylic alkylation of dihydropyrido[1,2-a]indolone (DHPI) substrates (e.g., 5, Scheme 1A).5,6 The utility of the enantioenriched α-quaternary DHPI products (6) was illustrated through regiodivergent indole-iminium cyclization pathways to access multiple Aspidosperma alkaloids (1, 7, and 8). Given the high enantiopurities and rapid accessibility of these chiral building blocks, we sought to further investigate the versatility of the DHPI substrate class through stereodivergent indole-iminium cyclizations toward additional monoterpene indole alkaloid targets (Scheme 1B).

Scheme 1.

Scheme 1

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Enantioenriched α-Quaternary DHPIs as Precursors for Indole-Iminium Cyclizations.

We envisioned that δ-lactam 9, available in two steps from the α-quaternary Pd-catalyzed allylic alkylation product (6, Scheme 1A),5a could undergo hydride reduction and subsequent dehydration to deliver C2-tethered iminium 10 (Scheme 1B, blue path). A Pictet–Spengler-type cyclization could then occur, with the indole moiety approaching from the less hindered α-face, to yield tetracycle 11 bearing a cis-fused octahydroquinoline subunit. We anticipated that such an intermediate could be advanced to members of the Aspidosperma family of alkaloids, such as (+)-limaspermidine (2).7 Alternatively, by reversing the order of these events (i.e., C–C formation then C–H formation), a Bischler–Napieralski cyclization could furnish tetracyclic iminium 12, and the ensuing hydride reduction would proceed from the less hindered α-face to give the trans-fused octahydroquinoline subunit in tetracycle 13 (Scheme 1B, red path).8 We expected that 13 could then be carried on in a total synthesis of (+)-kopsihainanine A (3) and additional Kopsia alkaloids.6b,9

Our synthesis of (+)-limaspermidine (2) began from unsubstituted DHPI 14, which is available in multi-gram quantities in four steps from indole (Scheme 4).5a Straightforward C-acylation using allyl cyanoformate, followed by C-alkylation using (2-benzyloxy)ethyl iodide (15) delivered β-amidoester 16 in 80% yield over two steps. Exposure of 16 to a solution of Pd2(pmdba)3 (5 mol %) and (S)-(CF3)3-t-BuPHOX (L1, 12.5 mol %) in TBME at 60 °C delivered α-quaternary DHPI 17 in 82% yield and with 94% ee. Formal anti-Markovnikov hydroamination was accomplished using a hydrozirconation/amination protocol developed by Hartwig and co-workers.10 Upon complete formation of the intermediate primary amine (18, not isolated), lithium aluminum hydride was added, followed by careful quenching with acetic acid and water to promote the desired indole-iminium cyclization. This one-pot sequence delivered cis-fused tetracycle 19 in 60% yield. Chemoselective piperidine alkylation gave primary alcohol 20 in 83% yield (50% over two steps). Importantly, we found that tetracycle 19 could be advanced without purification to afford ethanolamine 20 in an improved 62% yield over the two steps. Pyrrolidine annulation, followed by subsequent hydride reduction yielded O-benzyl limaspermidine (22), which succumbed to debenzylation using excess BF3•Et2O in ethanethiol to provide (+)-limaspermidine (2) in 60% yield over the final three steps.11

Having successfully synthesized cis-fused azadecalin-containing (+)-limaspermidine (2), we turned our attention to an orthogonal synthesis of trans-fused (+)-kopsihainanine A (3). Beginning from the same tricyclic DHPI core (14), C-acylation followed by Michael addition with methyl acrylate furnished β-amidoester 23 in 92% yield over two steps (Scheme 3). Gratifyingly, subjecting 23 to our enantioselective Pd-catalyzed decarboxylative allylic alkylation conditions delivered α-quaternary DHPI 24 in 90% yield and 92% ee. We observed reduction of the methyl ester in 24 upon treatment with Schwartz’s reagent, much to our disappointment, rendering the aforementioned hydrozirconation/amination protocol intractable in this setting. This setback notwithstanding, we implemented a Rh-catalyzed hydroboration to arrive at primary alcohol 25 in 87% yield.12 Facile conversion of alcohol 25 to azide 26 occurred in 88% yield over two steps. A Staudinger reduction using polymer-bound triphenylphosphine proceeded with concomitant translactamization to afford δ-lactam 27 in 81% yield.13

Scheme 3.

Scheme 3

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Enantioselective Formal Synthesis of (+)-Kopsihainanine A (3).

The Bischler–Napieralski cyclization of 27 proceeded smoothly when employing a combination of triflic anhydride and 2-chloropyridine to provide trans-fused tetracycle 28 in 84% yield.14 We next sought to effect a lactamization between the piperidine nitrogen and the pendant methyl ester. Numerous Lewis acids and Brønsted bases were examined, leading to the discovery that the guanidine base 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) could efficiently promote the desired cyclization to give strained pentacycle 29 in 65% yield.15 The use of TBD for this type of lactamization provides a safer, more scalable alternative to existing procedures, which typically utilize highly pyrophoric trimethylaluminum.

Single crystal X-ray diffraction both confirmed the absolute configuration of 29, and enabled the calculation of distortion geometries for the bridgehead lactam.16,17 The high degree of pyramidalization at the bridgehead nitrogen (χN = 50.5°), along with the amide torsion angle (τ = 23.5°), explains the difficulty observed in forming this C–N bond (i.e., 28 ® 29). Zhu and co-workers previously showed that exposure of (±)-29 to lithium dimethylamide (LDMA) and bis(trimethylsilyl) peroxide in the presence of hexamethylphosphoramide (HMPA) as an additive could furnish (±)-kopsihainanine A (3) in 91% yield.9b As a result, we have completed a highly efficient enantioselective formal synthesis of (+)-kopsihainanine A (3) beginning from N-acyl indole 14.

In conclusion, the combination of enantioselective Pd-catalyzed allylic alkylations of dihydropyrido[1,2-a]indolone (DHPI) substrates with stereodivergent indole-iminium cyclization strategies is a powerful tool for the synthesis of monoterpene indole alkaloids. The Aspidosperma family of alkaloids can be accessed by a stereodefining C–C bond formation, highlighted herein by our synthesis of (+)-limaspermidine (2) in eight linear steps and in 25% overall yield from tricyclic DHPI 14. Critically, a highly productive one-pot hydroamination/reduction/Pictet–Spenger sequence enabled the synthesis of the cis-fused decahydroquinoline moiety present in (+)-2. Furthermore, the Kopsia family of alkaloids can be accessed using a Bischler–Napieralski cyclization, followed by subsequent stereodefining hydride addition to furnish the opposite diastereomeric series. This capability was demonstrated through a nine-step synthesis (28% overall yield) of strained lactam 29, thereby completing a formal synthesis of (+)-kopsihainanine A (3). Efforts to further exploit the synthetic utility conferred by the DHPI substrate class, particularly in the synthesis of more highly caged Kopsia alkaloids, will be reported in due course

Supplementary Material

Supporting Information

Scheme 2.

Scheme 2

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Enantioselective Total Synthesis of (+)-Limaspermidine (2).

Acknowledgments

The authors wish to thank NIH-NIGMS (R01GM080269), Amgen, the Gordon and Betty Moore Foundation, the Caltech Center for Catalysis and Chemical Synthesis, and Caltech for financial support. B.P.P. thanks the NSF for a predoctoral fellowship (Grant DGE-1144469). E.J.D. thanks the Swiss National Science Foundation (SNSF) for a postdoctoral fellowship (Grant P2EZP2_168798). The authors thank Dr. Mona Shahgholi and Naseem Torian (Caltech) for mass spectrometry assistance, Dr. Scott Virgil (Caltech) for instrumentation assistance, and Larry Henling (Caltech) for X-ray crystallographic assistance.

Footnotes

Supporting information for this article is given via a link at the end of the document.

This manuscript is dedicated to the late Professor R. B. Woodward on occasion of his 100th birthday.

References

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Supplementary Materials

Supporting Information
NIHMS956935-supplement-Supporting_Information.pdf (2.3MB, pdf)

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