Letter Cite This: Org. Lett. 2017, 19, 6168-6171
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Directed Fischer Indolization as an Approach to the Total Syntheses of (+)-Aspidospermidine and (−)-Tabersonine Joo-Young Kim,† Chang-Heon Suhl,† Joon-Ho Lee, and Cheon-Gyu Cho* Center for New Directions in Organic Synthesis, Department of Chemistry, Hanyang University, 222 Wangshimni-ro, Seongdong-gu, Seoul 04763, Korea S Supporting Information *
ABSTRACT: A conceptually new synthetic approach that provides general access to the aspidosperma alkaloids (+)-aspidospermidine and (−)-tabersonine was developed. This method is based on the regioselective indolization of an ene−hydrazide, which was obtained via a base-catalyzed intramolecular aza-Michael reaction, in situ trapping of the resulting enolate, and subsequent C−N coupling with phenyl hydrazide. Scheme 1. Regiocontrolled “Directed” Fischer Indolization
T
he aspidosperma alkaloids are a family of monoterpene indole natural products comprising >250 members and are widely distributed in the plants of the Aspidosperma (Apocyanaceae) genus. These compounds boast a long history of use in traditional medicine due to their intriguing pharmacological properties and biological activities, which range from antimalarial, analgesic, anti-inflammatory, and psychotropic to anticancer effects.1 In general, the aspidosperma terpenoid alkaloids contain highly congested polycyclic frameworks with multiple chiral centers (Figure 1). These
reaction of protected aryl hydrazide 5 with vinyl bromide 6 to give ene−hydrazide 7, which subsequently cyclized to give the corresponding indole 8 in a highly regioselective manner (eq 2). Although this method provides a facile route to indoles that are not readily accessible via the conventional Fischer protocol, its application in the synthesis of aspidosperma indole alkaloids (and other polycyclic indole alkaloids) is significantly hampered by the poor regiochemical control of reactions involving the preparation of vinyl halides from unsymmetrical cyclic ketones. In light of these limitations, we previously developed an alternative strategy based on the coupling of aryl hydrazide 9 with the more readily obtainable enol triflates, i.e., 10, to give intermediate 11 and indole 12 in regiochemically pure form (Scheme 1, eq 3).6 Enthused by these early studies, we herein propose a conceptually new approach that could provide general access to the aspidosperma indole alkaloids. Thus, we
Figure 1. Selected examples of aspidosperma alkaloids.
unique and intricate molecular structures, together with the above-described pharmacological properties, have spurred intense investigation over the past few decades, leading to the development of many elegant synthetic methods and strategies for their preparation.2,3 As part of our ongoing investigation into aryl hydrazides, we previously reported that aryl hydrazide 1 and vinyl iodide 2 could be used to directly prepare ene−hydrazide 3 via a Pdcatalyzed coupling reaction. The obtained ene−hydrazide then undergoes an acid-catalyzed [3,3]-sigmatropic rearrangement and cyclization reaction, similar to those taking place during the Fischer indole synthesis, to yield indole 4 (Scheme 1, eq 1).4 Later, Zhan and Liang5 demonstrated the utility of this reaction toward a “directed” Fischer indole synthesis through the © 2017 American Chemical Society
Received: October 2, 2017 Published: November 9, 2017 6168
DOI: 10.1021/acs.orglett.7b03078 Org. Lett. 2017, 19, 6168−6171
Letter
Organic Letters
with chloroacetyl chloride to give 27 in 51% yield over two steps (Scheme 4). Subsequent application of the protocol developed by Heathcock12 completed the asymmetric total synthesis of (+)-aspidospermidine via intermediate 28.13
report the total syntheses of (+)-aspidospermidine and (−)-tabersonine through the directed indolization of ene− hydrazides 14/16 to give indoles 13/15 (Scheme 2). Scheme 2. Retrosynthetic Analysis of Aspidospermidine and Tabersonine
Scheme 4. Endgame Synthesis of (+)-Aspidospermidine
We began with the preparation of enantiopure cyclohexene (+)-17 according to the process reported by Kotsuki and coworkers.7 Reduction of the ester group to give alcohol 18 and subsequent treatment with the benzyl Burgess reagent 19 gave cyclohexene 20 in 52% yield8 (Scheme 3). Allylic oxidation
We then turned our attention to the synthesis of (−)-tabersonine, which contains a pentacyclic framework almost identical to that of (+)-aspidospermidine but with the opposite stereochemistry. To achieve installation of the characteristic D-ring double bond, we opted to use a hydroxyl group as a latent olefin function. Thus, base-mediated αhydroxylation of ester (−)-17 was conducted (Scheme 5).
Scheme 3. Synthesis and Directed Fischer Indolization of 23
Scheme 5. Directed Fischer Indolization To Give 40
with CrO3/t-BuOOH then afforded enone 21 in 66% yield,9 and 21 was subjected to the key intramolecular aza-Michael addition and enol triflate formation. The reaction conditions for this unprecedented base-catalyzed tandem process were optimized through variation of the base, solvent, and triflate donor.10 The successive addition of potassium tert-butoxide and PhNTf2 at 0 °C gave the best results, affording enol triflate 22 in 77% yield. The subsequent C−N coupling reaction with phenyl hydrazide 9 delivered ene−hydrazide 23, which in turn gave the desired indole 24 in 67% yield along with regioisomer 25 in 8% yield when subjected to ZnCl2-mediated Fischer cyclization conditions.6 Conventional Fischer indolization between ketone 26 and phenylhydrazine gave mostly undesired indole product 25 in 60% yield (with the desired indole 24 in 22% yield).11 The Cbz group of the obtained indole product 24 was then removed by hydrogenolysis under typical Pd-catalyzed conditions. The resulting amine product was then reacted
Deprotonation with LDA followed by hydroxylation with (1R)(+)-(10-camphorsulfonyl)oxaziridine (29a) delivered 30a and 30b as an inseparable 5:1 mixture (as determined by 1H NMR spectroscopy) in 73% combined yield.14 The hydroxyl group stereochemistry of the major product 30a as indicated in Scheme 5 was established in hindsight after completion of the synthetic strategy (vide infra). Reduction of the ester groups present in 30a/30b and subsequent Bu2SnO-mediated selective tosylation at the primary hydroxyl group provided an inseparable mixture of 32a and 32b (S:R = 5:1) in 87% yield.15 Protection of the hydroxyl group as the TBS ether and azidation then gave 34 6169
DOI: 10.1021/acs.orglett.7b03078 Org. Lett. 2017, 19, 6168−6171
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Organic Letters ORCID
(S:R > 5/1) in an overall yield of 74%. Subsequent transformations, including a Staudinger reaction and protection (→36), oxidation (→37),16 tandem aza-Michael addition and triflation (→38), and a C−N coupling reaction gave ene− hydrazide 39 (S:R > 5/1) in 30% total yield from 34. Upon subjecting the ene−hydrazide to standard indolization conditions, we obtained indole 40 (S:R > 5/1) in 62% yield along with a small quantity of isomer 41. The isolated indole 40 was then subjected to a sequence of reactions to complete the synthesis of tabersonine (Scheme 6). Hydrogenolysis of the N-
Cheon-Gyu Cho: 0000-0003-4851-5671 Author Contributions †
J.-Y.K. and C.-H.S. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by a grant from the National Research Foundation of Korea (2014R1A5A1011165). We also thank Dr. Hyun-Kyu Cho (SK Innovation) for the initial contribution.
Scheme 6. Endgame Synthesis of (−)-Tabersonine
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(1) (a) Blair, L. M.; Calvert, M. B.; Gaich, T.; Lindel, T.; Phaffenbach, M.; Sperry, J. In The Alkaloids: Chemistry and Biology; Knölker, H.-J., Ed.; Academic Press: New York, 2017; Vol. 77. (b) O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23, 532. (c) Saxton, J. E. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998; Vol. 51, Chapter 1. (2) For recent syntheses of aspidospermidine, see: (a) Pandey, G.; Burugu, S. K.; Singh, P. Org. Lett. 2016, 18, 1558. (b) Tong, S.; Xu, Z.; Mamboury, M.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2015, 54, 11809. (c) Zhao, S.; Andrade, R. B. J. Am. Chem. Soc. 2013, 135, 13334. (d) Li, Z.; Zhang, S.; Wu, S.; Shen, X.; Zou, L.; Wang, F.; Li, X.; Peng, F.; Zhang, H.; Shao, Z. Angew. Chem., Int. Ed. 2013, 52, 4117. (e) Kawano, M.; Kiuchi, T.; Negishi, S.; Tanaka, H.; Hoshikawa, T.; Matsuo, J.-i.; Ishibashi, H. Angew. Chem., Int. Ed. 2013, 52, 906. (f) Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature 2011, 475, 183. (3) For total syntheses of tabersonine, see: (a) Zhao, S.; Andrade, R. B. J. Org. Chem. 2017, 82, 521. (b) Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 4628. (c) Kuehne, M. E.; Podhorez, D. E. J. Org. Chem. 1985, 50, 924. (d) Ziegler, F. E.; Bennett, G. B. J. Am. Chem. Soc. 1973, 95, 7458 and ref 2c. (4) Lim, Y.-K.; Cho, C.-G. Tetrahedron Lett. 2004, 45, 1857. (5) Zhan, F.; Liang, G. Angew. Chem., Int. Ed. 2013, 52, 1266. (6) Lim, B.-Y.; Jung, B.-E.; Cho, C.-G. Org. Lett. 2014, 16, 4492. (7) Horinouchi, R.; Kamei, K.; Watanabe, R.; Hieda, N.; Tatsumi, N.; Nakano, K.; Ichikawa, Y.; Kotsuki, H. Eur. J. Org. Chem. 2015, 2015, 4457. (8) (a) Nicolaou, K. C.; Huang, X.; Snyder, S. A.; Rao, P. B.; Bella, M.; Reddy, M. V. Angew. Chem., Int. Ed. 2002, 41, 834. (b) Wood, M. R.; Kim, J. Y.; Books, K. M. Tetrahedron Lett. 2002, 43, 3887. (9) (a) Toyota, M.; Wada, T.; Ihara, M. J. Org. Chem. 2000, 65, 4565. (b) Muzart, J. Tetrahedron Lett. 1987, 28, 4665. (10) Fukui, Y.; Liu, P.; Liu, Q.; He, Z.-T.; Wu, N.-Y.; Tian, P.; Lin, G.-Q. J. Am. Chem. Soc. 2014, 136, 15607. (11) Rawal and co-workers observed similar results in the attempt to install the indole moiety through Fischer indolization of ketone 49 to give 50 and 51 during their synthesis of tabersonine (ref 3b).
Cbz group and N-alkylation with bromoethanol gave 42 (82% from 40), and successive treatment with MsCl and KOt-Bu then allowed installation of the C-ring to afford 44a (separated from the minor epimer, 41% from 42a).3a Incorporation of the ester group followed by desilylation and PPh3/CCl4-mediated elimination completed the total synthesis of (−)-tabersonine via intermediate 47a (50% from 44a).17 As observed previously in similar systems,3d,14 epimer 46b, bearing the OH group on the α-face, gave no elimination product.18 In summary, we have successfully developed a conceptually new synthetic approach based on the regioselective indolization of ene−hydrazides as the key reaction to provide general access to the aspidosperma alkaloids (+)-aspidospermidine and (−)-tabersonine. In this process, a base-catalyzed intramolecular aza-Michael reaction, in situ trapping of the resulting enolate, and subsequent C−N coupling with phenyl hydrazide afforded the key ene−hydrazides, which were cyclized to give the desired indole alkaloid products. We believe that this approach will be suitable for the synthesis of other indole alkaloids. Such investigations are currently underway, and the results will be presented in due course.
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REFERENCES
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03078. Experimental procedures and spectral data (PDF)
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(12) Toczko, M. A.; Heathcock, C. H. J. Org. Chem. 2000, 65, 2642. (13) Spectral data (1H and 13C NMR, optical rotation) were in agreement with those reported in the literature (ref 2). (14) (a) Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 10596. (b) Kobayashi, S.; Ueda, T.; Fukuyama, T. Synlett 2000, 2000, 883. (c) Kuehne, M. E.; Okuniewicz, F. J.; Kirkemo, C. L.; Bohnert, J. C. J. Org. Chem. 1982, 47, 1335. (15) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.; Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. 6170
DOI: 10.1021/acs.orglett.7b03078 Org. Lett. 2017, 19, 6168−6171
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Organic Letters (16) (a) Elamparuthi, E.; Fellay, C.; Neuburger, M.; Gademann, K. Angew. Chem., Int. Ed. 2012, 51, 4071. (b) Salmond, W. G.; Barta, M. A.; Havens, J. L. J. Org. Chem. 1978, 43, 2057. (17) Spectral data (1H and 13C NMR, optical rotation) were in agreement with those reported in the literature (ref 3). (18) 46b prepared from 30 [(S):(R) = 1:5] produced substitution product 52 when subjected to the same conditions as for 46a, since neither Ha nor Hb of the putative aziridinium intermediate 47b were sufficiently coplanar to the nascent C−N bond to allow the E2 reaction to take place. Hydroxylation of (−)-17 with (1S)-(+)-(10camphorsulfonyl)oxaziridine gave mainly 30b in a 5:1 ratio with 30a.
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DOI: 10.1021/acs.orglett.7b03078 Org. Lett. 2017, 19, 6168−6171
