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Total Synthesis of (-)-Ambiguine P Jiasu Xu, and Viresh H. Rawal J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 11 Mar 2019 Downloaded from http://pubs.acs.org on March 11, 2019
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Journal of the American Chemical Society
Total Synthesis of (−)-Ambiguine P Jiasu Xu and Viresh H. Rawal* Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States
Supporting Information Placeholder ABSTRACT: Described is a concise total synthesis of (−)ambiguine P, a cycloheptane-containing member of the hapalindole alkaloids. The challenging pentacyclic framework of the natural product was assembled rapidly via a [4+3] cycloaddition reaction-inspired strategy, and the tertiary hydroxy group was introduced by an NBSmediated bromination-nucleophilic substitution sequence.
Since the report of the first few ambiguine indole alkaloids from blue-green algae in 1992 by Smitka, Moore, et al.,1a a total of 18 members of this group of hapalindoles have been identified.1 These secondary metabolites exhibit a broad range of bioactivities including antimycotic, antifungal, and antibiotic properties,1a,1c,1e,1f,2 with two members showing activities comparable to clinical agents streptomycin, puromycin, and amphotericin.1c Ambiguines possess the core structure of hapalindoles, but with an additional reverse prenyl group at the C-2 position of the indole moiety (cf., 1 and 2, Figure 1). Frequently, as found in 13 members of the group, the prenyl group connects the indole C-2 position and the distal cyclohexane ring, to form a 7-memberd ring (3-6).
From the outset, our objective was to design a unified strategy, one that would rapidly assemble the pentacyclic framework of the ambiguines, thereby opening up avenues to all cycloheptane-containing members of the family. The key step in the envisioned strategy was construction of the signature cyclohepta[b]indole motif through a formal [4+3] cycloaddition reaction between indole-stabilized tertiary carbocation 9 and a suitably functionalized diene 10 (Scheme 1).9 A Friedel-Crafts-type electrophilic substitution reaction was expected to forge the final ring, creating pentacyclic intermediate 7. Allylic oxidation would then complete the total synthesis of ambiguine P.
Scheme 2. Exploration of the [4+3] Cycloaddition
Figure 1. Representative members of the ambiguine group. Given their intriguing structural complexity and desirable biological activities, ambiguines have been the focus of the synthetic community for many years.3 In 2007, Baran et al. reported an elegant synthesis of the tetracyclic ambiguine H,4 the end-game of which enabled Maji’s formal synthesis of the same target.5 On the other hand, the more intricate pentacyclic ambiguines, with the added difficulty presented by the indole-fused 7-membered ring, have resisted total synthesis efforts.6 As part of an ongoing campaign aimed at developing concise solutions to the varied structural challenges posed by the hapalindole family of alkaloids,7 we have explored the synthesis of the pentacyclic ambiguines and present here an effective solution for the total synthesis of (−)-ambiguine P (5). During the preparation of this manuscript, Sarpong and coworkers published their breakthrough synthesis of 5.8
Scheme 1. Synthetic Strategy to Access the Ambiguines
Model studies were performed to establish the feasibility of the key [4+3] cycloaddition reaction (Scheme 2). The reaction of tertiary alcohol 11, prepared in quantitative yield from ethyl indole-2carboxylate, with 2-siloxybutadiene 12 and TMSOTf afforded tricycle 13 in good yield, ostensibly through a [4+3] cycloaddition reaction between the indole-stabilized tertiary carbocation intermediate and the diene. We were especially delighted to observe that under the same reaction conditions the more substituted 1-acetylcyclohexene derived diene 14 gave the expected [4+3] cycloaddition product, tetracycle 15, in excellent yield.
Scheme 3. Construction of the Pentacyclic Ambiguine Framework
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Based on the encouraging results of the model studies, we embarked on the construction of the ambiguine pentacycle using a suitably decorated diene (Scheme 3). The required siloxydiene 19 was prepared by a four step sequence starting from the known ketone 16, which was reported by the Baran group and prepared readily on a multi-gram scale from a terpene precursor.4,10 Ketone 16 was converted to its enol triflate 17 by deprotonation with KHMDS followed by treatment with Comins’ reagent. The required acetyl group was installed through a Stille coupling-hydrolysis sequence to provide 18 in good yield,11 which upon silyl enol ether formation protocol gave the desired diene 19. A solution of diene 19 and alcohol 11 was subjected to the formal [4+3] cycloaddition reaction conditions, with the expectation that tetracycle 21 would be formed. However, unlike with the model compounds, the major product of the reaction was enone 23, rather than cycloadduct 21. Formation of 23 can be understood by considering the reaction as proceeding through a stepwise pathway, wherein formation of a bond between the benzylic carbon and the enol ether generates an allyl cation (cf., 22) that is expected to be intercepted by the indole to give the seven-membered ring.9c,9d,12,13 Evidently, the greater steric encumbrance of diene 19, especially the flanking 2-propenyl unit, impedes the second C-C bond formation. Several methods were explored to accomplish the required C-C bond formation to complete the tetracycle. Attempted cyclization using common Lewis and Brønsted acids, or bases, were complicated by isomerization of the isopropenyl double bond into conjugation with the enone moiety, along with unidentifiable side products. Fortunately, gold salts were found to promote the desired Michael reaction.14 Treatment of 23 with NaAuCl4•2H2O in 1-propanol afforded tetracycle 21, the product of the envisioned [4+3] cycloaddition.15 Having assembled all the carbons required for the ambiguines, the remaining task was to forge the final C-C bond. This objective was accomplished by treating 21 with BF3•OEt2 and MeOH, which formed the ambiguine framework in good yield. The structure assigned to 24 was consistent with that assigned to the C-12 gem-dimethyl analog 25, which was synthesized by the same sequence and whose structure was established by X-ray crystallography.16
Scheme 4. Completion of the Synthesis toward (−)Ambiguine P (5)
Having achieved the construction of pentacycle 24, what remained for completing the synthesis of ambiguine P (5) was functional group manipulation to give diene 7 and installation of the tertiary hydroxy group (Scheme 4). The reaction of ketone 24 with DDQ oxidized it to enone 26 in excellent yield. After blocking the indole nitrogen with a Boc group, the carbonyl group was reduced with LiAl(OMe)3H, which gave allylic alcohol 28 as a single diastereomer in nearly quantitative yield.17 The stereochemistry of the hydroxy group was inconsequential, as it was eliminated in the subsequent step. Dehydration of 28 with Martin sulfurane followed by Boc group removal afforded the electronrich diene 7, poised to provide access to several members of the ambiguine family. Our initial plan was to treat diene 7 with a halogenating reagent, with the expectation of achieving electrophilic halogenation at C-23, which after transition metal mediated cyanation would provide the first total synthesis of ambiguine Q (6). Remarkably, the reaction of 7 with NBS gave a product wherein the C-15 hydrogen had been replaced with a hydroxy group. When the same reaction was performed with added water, 7 was cleanly transformed to the C-15 hydroxylated product, isolated in 62% yield as a 2.0:1 mixture of diastereomers, from which pure (−)-ambiguine P (5) was separated in 39% yield.
Scheme 5. Probable Mechanism for the Formation of (−)-Ambiguine P (5) from Diene 7
The unexpected formation of the C-15 hydroxylated product can be explained by plausible reactivity considerations (Scheme 5). Electrophilic bromination of 7 should take place at C-23, the terminal carbon of the diene, to give intermediate 30.18 The loss of a proton from C-15 rather than C-23, which would have given the expected C-23 bromoalkene, would generate doubly allylic bromide 31. Dissociation of the bromide followed by capture of the resulting delocalized carbocation at C-15 by water would give the observed product.
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Journal of the American Chemical Society In summary, we have completed the total synthesis of (−)ambiguine P through a concise sequence starting from known ketone 16. The synthesis, inspired by a [4+3] cycloaddition reaction, features a two-step sequence to construct the cyclohepta[b]indole motif and a Friedel-Crafts reaction to assemble the pentacyclic ambiguine framework. An NBS-mediated bromination in the presence of water achieved an electrophilic bromination/SN1’ displacement to install the crucial C-15 hydroxy group of the natural product. The strategy is sufficiently general so as to lay the groundwork for accessing other pentacyclic members of the ambiguine alkaloid family.
ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures, characterization data, and NMR spectra (PDF); X-ray crystallographic data for 25 (CIF)
AUTHOR INFORMATION Corresponding Author
[email protected] ORCID Jiasu Xu: 0000-0003-3625-8129 Viresh H. Rawal: 0000-0003-4606-0239
Notes The authors declare no competing financial interests.
ACKNOWLEDGMENT JX thanks the Chemistry Department for the Windt Graduate Fellowship. We thank Mr. Lingbowei Hu for preparing gram quantities of 16. We thank Mr. Andrew McNeece and Dr. Alexander S. Filatov for X-ray crystallographic structure determination, and Dr. Antoni Jurkiewicz for assistance with NMR experiments.
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(4) (a) Baran, P. S.; Maimone, T. J.; Richter, J. M. Total Synthesis of Marine Natural Products without Using Protecting Groups. Nature 2007, 446, 404. (b) Maimone, T. J.; Ishihara, Y; Baran, P. S. Scalable Total Syntheses of (−)Hapalindole U and (+)-Ambiguine H. Tetrahedron 2015, 71, 3652. (5) Sahu, S.; Das, B.; Maji, M. S. Stereodivergent Total Synthesis of Hapalindoles, Fischerindoles, Hapalonamide H, and Ambiguine H Alkaloids by Developing a Biomimetic, Redox-Neutral, Cascade Prins-Type Cyclization. Org. Lett. 2018, 20, 6485. (6) Synthetic studies toward ambiguine: (a) Chandra, A.; Viswanathan, R.; Johnston, J. N. Synthesis of the ABC- and D-Ring Systems of the Indole Alkaloid Ambiguine G. Org. Lett. 2007, 9, 5027. (b) Rafferty, R. J.; Williams, R. M. Synthetic Studies on the Ambiguine Family of Alkaloids: Construction of the ABCD Ring System. Tetrahedron Lett. 2011, 52, 2037. (c) Rafferty, R. J.; Williams, R. M. Formal Synthesis of Hapalindole O and Synthetic Efforts towards Hapalindole K and Ambiguine A. Heterocycles 2012, 86, 219. (7) (a) Bhat, V.; Allan, K. M.; Rawal, V. H. Total Synthesis of NMethylwelwitindolinone D Isonitrile. J. Am. Chem. Soc. 2011, 133, 5798. (b) Allan, K. M.; Kobayashi, K.; Rawal, V. H. A Unified Route to the Welwitindolinone Alkaloids: Total Syntheses of (−)-N-Methylwelwitindolinone C Isothiocyanate, (−)-N-Methylwelwitindolinone C Isonitrile, and (−)-3-Hydroxy-Nmethylwelwitindolinone C Isothiocyanate. J. Am. Chem. Soc. 2012, 134, 1392. (c) Reyes, J. R.; Xu, J.; Kobayashi, K.; Bhat, V.; Rawal, V. H. Total Synthesis of (−)-N-Methylwelwitindolinone B Isothiocyanate. Angew. Chem., Int. Ed. 2017, 56, 9962. (8) Johnson, R. E.; Ree, H.; Hartmann, M.; Lang, L.; Sawano, S.; Sarpong, R. Total Synthesis of Pentacyclic (−)-Ambiguine P using Sequential Indole Functionalizations. J. Am. Chem. Soc. 2019, 141, 2233. (9) Selected examples of [4+3] cycloaddition reactions: (a) Winne, J. M.; Catak, S.; Waroquier, M.; Van Speybroeck, V. Scope and Mechanism of the [4+3] Cycoaddition Reaction of Furfuryl Cations. Angew. Chem., Int. Ed. 2011, 50, 11990. (b) Zhang, J.; Li, L.; Wang, Y.; Wang, W.; Xue, J.; Li, Y. A Novel, Facile Approach to Frondosin B and 5-epi-Liphagal via a New [4 + 3]Cycloaddition. Org. Lett. 2012, 14, 4528. (c) Granger, B. A.; Jewett, I. T.; Butler, J. D.; Hua, B.; Knezevic, C. E.; Parkinson, E. I.; Hergenrother, P. J.; Martin, S. F. Synthesis of (±)-Actinophyllic Acid and Analogs: Applications of Cascade Reactions and Diverted Total Synthesis. J. Am. Chem. Soc. 2013, 135, 12984. (d) Granger, B. A.; Jewett, I. T.; Butler, J. D.; Martin, S. F. Concise Total Synthesis of (±)-Actinophyllic Acid. Tetrahedron 2014, 70, 4094. (e) Zhang J.; Shao, J.; Xue, J.; Wang, Y.; Li, Y. One Pot Hydroamination/[4 + 3] Cycloaddition: Synthesis towards the Cyclohepta[b]indole Core of Silicine and Ervatamine. RSC Adv. 2014, 4, 63850. (f) Liu, J.; Wang, L.; Wang, X.; Xu, L.; Hao, Z.; Xiao, J. Fluorinated Alcohol-Mediated [4 + 3] Cycloaddition Reaction of Indolyl Alcohols with Cyclopentadiene. Org. Biomol. Chem. 2016, 14, 11510. (10) Please see supporting information for more information on the preparation of ketone 16. (11) Enquist, J. A., Jr.; Virgil, S. C.; Stoltz, B. M. Total Syntheses of Cyanthiwigins B, F, and G. Chem. – Eur. J. 2011, 17, 9957. (12) Fu, T.-H.; Bonaparte, A.; Martin, S. F. Synthesis of β-Heteroaryl Propionates via Trapping of Carbocations with π-Nucleophiles. Tetrahedron Lett. 2009, 50, 3253. (13) Muratake, H.; Natsume, M. Synthetic Studies of Marine Alkaloids Hapalindoles. Part 1. Total Synthesis of (±)-Hapalindoles J and M. Tetrahedron 1990, 46, 6331. (14) Pirovano, V. Gold-Catalyzed Functionalization Reactions of Indole. Eur. J. Org. Chem. 2018, 1925, and references cited therein. (15) Arcadi, A.; Bianchi, G.; Chiarini, M.; D’Anniballe, G.; Marinelli, F. Gold-Catalyzed Conjugate Addition Type Reaction of Indoles with α,βEnones. Synlett 2004, 944. (16) Compound 25 was prepared by the same route from (5S)-2,2dimethyl-5-isopropenylcyclohexanone. See supporting information for characterization and X-ray data of 25. (17) Stereochemistry of 28 was assigned based on NOESY spectra. (18) The bromination can also take place at C-11, that product would proceed through an analogous path to afford the observed product.
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