Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Biomimetic Enantioselective Total Synthesis of (−)-Petromindole Dattatraya H. Dethe* and Susanta Kumar Sau Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur-208016, India S Supporting Information *
ABSTRACT: The first enantioselective total synthesis of (−)-petromindole, an architecturally distinct congener of indole diterpene family, has been achieved. Key features of this synthetic route include the scalable and concise synthesis of tricyclic allylic alcohol from enantiopure Wieland−Mischer ketone derivative, and TMSOTf-mediated, highly efficient biomimetic C-4 cyclization of indole derivative for the rapid construction of a hexacyclic skeleton of petromindole. C-3 and C-4 carbons of indole. Petromindole (4) was first isolated from a soil fungus Petromyces muricatus by Ooike et al. in 1997.4 Despite its unique and alluring structural features, containing a trans−anti−trans−anti−trans-fused hexacyclic skeleton, no reports directed at the total synthesis of 4 have appeared to date, except an elegant enzymatic synthesis by Matsuda and co-workers using lupeol synthase enzyme.6 The biosynthesis of petromindole (4) is believed to proceed by the condensation of geranylgeranyl pyrophosphate with a tryptophan precursor to give 3-geranylgeranylindole, followed by epoxidation at the farthest olefin and polyene cyclization via C-4 of indole. After achieving the biomimetic total synthesis of (−)-mycoleptodiscin A (6),7 synthesis of petromindole (4) was of great interest to us, not merely due to the stereochemical challenge of its seven asymmetric centers, but also complex architectural problem that presented us with the opportunity of developing the scope of biomimetic indole C-4 cyclization.8 With reminiscence of the proposed biosynthetic route, the cornerstone of our synthetic strategy was envisioned to be the C4 cyclization of 8 to generate 7, as outlined in Scheme 1, because the cyclized product 7 was expected to provide a convenient intermediate for completion of total synthesis after some usual deprotections of the protecting groups. We reasoned that the efficiency of the proposed route would depend partly on successful synthesis of tricyclic alcohol 99 since the key precursor for the C-4 cyclization 8 could be realized by the Lewis acidcatalyzed Friedel−Crafts reaction between 7-methoxyindole and the alcohol 9. A brief literature survey and an extensive experimentation revealed that the tricyclic alcohol 9 having five asymmetric centers could be easily obtained from enantiopure Wieland−Mischer ketone derivative 10.10 The synthesis of petromindole (4) was set out with a gramscale synthesis of the tricyclic alcohol 9, prepared from enatiopure Wieland−Mischer ketone derivative 10. However, our initial attempts to synthesize the tricyclic alcohol 9 were not very delightful.9 After extensive studies and experimentations, an
I
ndole diterpenes represent a group of structurally diverse fungal secondary metabolites, which usually appear to be restricted to a limited number of fungi, e.g., Penicillium, Aspergillus, Claviceps, and Epichloe species, among others.1 These metabolites exhibit a uniquely rich and diverse portfolio of biological activities, having the ability to cause notable neurotoxic effects in mammals.2 In general, the core structure of these metabolites, e.g., paxilline (1)-type indole diterpenes, is constituted of a diterpene part usually derived from geranylgeranyl diphosphate attached to the C-3 and C-2 positions of indole (Figure 1).3 However, a notable structural exception is found in petromindole (4)4 and 17-hydroxyeujindole (5),5 two nonpaxilline indole diterpenes, where the diterpene part is attached to the
Figure 1. Representative indole diterpenes and related indoloterpenoids. © XXXX American Chemical Society
Received: December 4, 2017
A
DOI: 10.1021/acs.orglett.7b03768 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
58% overall yield via a two-step sequence involving Nozaki− Yamamoto homologation13 of 16 followed by Luche reduction of the resulting α,β-unsaturated aldehyde 17. Since this route provided tricyclic alcohol 9 in gram-scale to advance the synthesis of petromindole (4), we next turned toward the required installation of the indole ring onto the tricyclic terpene part. However, before proceeding to this second stage of our synthesis, a much straightforward strategy was envisioned, where the 7-methoxyindole was replaced by a simple indole because a selective C-4 cyclization on the C-3 alkylated derivative 18 could in turn give rise to the best access for petromindole (4) and removal of the methoxy group would not be required (Scheme 3). So, for continuation of this improved
Scheme 1. Retrosynthetic Analysis
Scheme 3. Different Strategy for Petromindole (4)
improved method was developed in which we could achieve the tricyclic alcohol 9 in decagram-scale (Scheme 2). We realized that enone 11 was a viable synthetic intermediate to achieve the tricyclic alcohol 9, and hence, we focused majorly on devising an elegant route to the enone 11. We observed that thermodynamically controlled alkylation on the monoketal derivative of 10 by using 1-chloro-3-pentanone/KOtBu11 followed by an intramolecular aldol condensation on the diketone thus formed readily accessed the tricyclic enone 11 in 83% yield. Reductive methylation12 on enone 11 furnished the ketone 12 in 80% yield. Ketone 12 in turn was subjected to LAH reduction and an acid mediated deketalization to generate alcohol 13 in 80% yield as a single diastereomer. Controlled hydrogenation of the olefinic part was next achieved on the alcohol 13 by using H2−Pd/C conditions to generate the requisite alcohol 14 in 81% yield, which upon treatment with TBSCl and imidazole led to TBS ether 15 in 81% yield. α-Methylation of the carbonyl 15 was then carried out using LDA/MeI, and the resulting diastereomeric mixture was converted to a single diastereomer 16 by epimerization at the newly generated stereocenter by treatment with NaOMe in methanol in 90% yield. To this end, the ketone 16 was effectively converted to the requisite tricyclic alcohol 9 in
strategy, BF3·OEt2 mediated Friedel−Crafts alkylation on indole was carried out with the allylic alcohol 9, and not surprisingly, the C-3 of indole was substituted by the tricyclic terpene providing 27 in 82% yield. Earlier studies, however, had demonstrated that a similar C-3 substituted indole derivative was a highly suitable substrate for intramolecular C-2 cyclization7c upon treatment with Lewis acid-catalyzed Friedel−Crafts alkylation conditions. Guided by the aforementioned observation, we protected the indole nitrogen of 19 as the corresponding sulfonamide 20 in nearly quantitative yield, and hence, a logical substrate was formed to move forward for the C-4 cyclization. So, we started our experimentation on the proposed C-4 cyclization on 20. Unfortunately, the substrate 20 was found to be completely inert to the C-4 cyclization. Standard conditions7 (various Lewis acids like TMSOTf, SnCl4, AlCl3, etc., and Brønsted acids) led only to the deprotection of the TBS group providing 18 in 80% yield,
Scheme 2. Synthesis of Tricyclic Allylic Alcohol 9
B
DOI: 10.1021/acs.orglett.7b03768 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. Initial Attempt of Petromindole (4) Synthesis
Scheme 5. Total Synthesis of Petromindole (4)
indole nitrogen of 23 was required in order to attenuate the reactivity of C-2, and so was achieved upon treatment with benzenesulfonyl chloride to provide the corresponding sulfonamide 24 in 81% yield. Now, the additional modification for stabilizing substrate 24 was imposed with the conversion of TBS ether into the corresponding acetate 25 in two steps and 80% overall yield via a TMSOTf-promoted TBS deprotection and reprotection of the resulting alcohol employing acetic anhydride in dichloromethane to make it more susceptible toward C-4 cyclization. Pleasingly, treatment with TMSOTf in dichloromethane at room temperature triggered facile Friedel−Crafts cyclization at C-4 on 25 to furnish the requisite hexacyclic skeleton 26, which was readily demethylated by BBr3 in CH2Cl2 to form the corresponding 7-hydroxyindole derivative 27 as a single diastereomer in 35% overall yield. Having achieved the critical C-4 cyclization, we turned to complete the total synthesis of petromindole (4), namely, by reductive removal of the hydroxy group along with the exclusion of the remaining protecting groups from 27. Thus, the hydroxy of
while prolonged exposure to these strongly acidic conditions resulted in decomposition of the starting substrate. A replacement for alcohol protection was therefore required in order to stabilize the substrate, and it was achieved by acetyl protection with acetic anhydride to furnish the corresponding acetate 21 in 96% yield. To our disappointment, all the gingerly attempts for C-4 cyclization were ended with the recovery of starting material, most probably due to the absence of any triggering force that can make the C-4 of 21 amenable to cyclization (Scheme 4). Before proceeding further in our synthetic venture, we were able to realize that a straightforward route involving an indole derivative without having any electron donating substituent at C7 (Scheme 4) would be extremely difficult, and hence, the previously mentioned strategy involving 7-methoxyindole (Scheme 1) was highly encouraged. So, as the commencement of our new synthetic route, the tricyclic alcohol 9 and 7methoxyindole were made united with the aid of BF3·OEt2 to furnish C-3 substituted indole 23 in 72% yield. A protection on C
DOI: 10.1021/acs.orglett.7b03768 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
1665. (l) Smith, A. B., III; Kürti, L.; Davulcu, A. H.; Cho, Y. S.; Ishiyama, H.; Ohmoto, K. J. Org. Chem. 2007, 72, 4596. (m) Enomoto, M.; Morita, A.; Kuwahara, S. Angew. Chem., Int. Ed. 2012, 51, 12833. (n) Asanuma, A.; Enomoto, M.; Nagasawa, T.; Kuwahara, S. Tetrahedron Lett. 2013, 54, 4561. (o) Teranishi, T.; Murokawa, T.; Enomoto, M.; Kuwahara, S. Biosci., Biotechnol., Biochem. 2015, 79, 11. (p) Sharpe, R. J.; Johnson, J. S. J. Am. Chem. Soc. 2015, 137, 4968. (q) Zou, Y.; Melvin, J. E.; Gonzales, S. S.; Spafford, M. J.; Smith, A. B., III J. Am. Chem. Soc. 2015, 137, 7095. (4) (a) For extraction reference of petromindole: Ooike, M.; Nozawa, K. S.; Udagawa, I.; Kawai, K. I. Chem. Pharm. Bull. 1997, 45, 1694−1696. Selected synthesis of structurally related indolo-terpenoids: (b) Allan, K. M.; Kobayashi, K.; Rawal, V. H. J. Am. Chem. Soc. 2012, 134, 1392− 1395. (c) Bhat, V.; Allan, K. M.; Rawal, V. H. J. Am. Chem. Soc. 2011, 133, 5798−5801. (d) Vaillancourt, V.; Albizati, K. F. J. Am. Chem. Soc. 1993, 115, 3499. (e) Fukuyama, T.; Chen, X. J. Am. Chem. Soc. 1994, 116, 3125. (f) Sakagami, M.; Muratake, H.; Natsume, M. Chem. Pharm. Bull. 1994, 42, 1393. (g) Kinsman, A. C.; Kerr, M. A. Org. Lett. 2001, 3, 3189. (h) Kinsman, A. C.; Kerr, M. A. J. Am. Chem. Soc. 2003, 125, 14120. (i) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450. (j) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127, 15394. (k) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404. (l) Chandra, A.; Johnston, J. N. Angew. Chem., Int. Ed. 2011, 50, 7641; Angew. Chem. 2011, 123, 7783. (m) Rafferty, R. J.; Williams, R. M. J. Org. Chem. 2012, 77, 519. (5) (a) Nakadate, S.; Nozawa, K.; Horie, H.; Fujii, Y.; Yaguchi, T. Heterocycles 2011, 83, 351−356. (b) Bian, M.; Wang, Z.; Xiong, X.; Sun, Y.; Matera, C.; Nicolaou, K. C.; Li, A. J. Am. Chem. Soc. 2012, 134, 8078− 8081. (6) Xiong, Q.; Zhu, X.; Wilson, W. K.; Ganesan, A.; Matsuda, S. P. T. J. Am. Chem. Soc. 2003, 125, 9002−9003. (7) For total syntheses of mycoleptodiscin A: (a) Zhou, S.; Chen, H.; Luo, Y.; Zhang, W.; Li, A. Angew. Chem., Int. Ed. 2015, 54, 6878−6882. (b) Nagaraju, K.; Chegondi, R.; Chandrasekhar, S. Org. Lett. 2016, 18, 2684−2687. (c) Dethe, D. H.; Sau, S. K.; Mahapatra, S. Org. Lett. 2016, 18, 6392−6395. (8) (a) Kornfeld, E. C.; Fornefeld, E. J.; Kline, G. B.; Mann, M. J.; Morrison, D. E.; Jones, R. G.; Woodward, R. B. J. Am. Chem. Soc. 1956, 78, 3087−3114. (b) Bonjoch, J.; Boncompte, F.; Casamitjana, N.; Bosch, J. Tetrahedron 1986, 42, 6693−6702. (9) Mori, K.; Koga, Y. Bioorg. Med. Chem. Lett. 1992, 2, 391−394. (10) Ling, T.; Xu, J.; Smith, R.; Ali, A.; Cantrell, C. L.; Theodorakis, E. Tetrahedron 2011, 67, 3023−3029. (11) Kokosi, J.; Schmidt, C. Synth. Commun. 1985, 15, 341−354. (12) Hagiwara, H.; Uda, H. J. Org. Chem. 1988, 53, 2308−2311. (13) Taguchi, H.; Tanaka, S.; Yamamoto, H.; Nozaki, H. Tetrahedron Lett. 1973, 14, 2465−2468. (14) Dethe, D. H.; Murhade, G. M.; Dherange, B. D.; Sau, S. K. Eur. J. Org. Chem. 2017, 2017, 1143−1150.
27 was converted into triflate 28 by protection with triflic anhydride in 69% yield. To this end, a Pd(PPh3)4-catalyzed removal of triflate from 2814 and subsequent Na/Hg-mediated simultaneous deprotection of the sulfonyl and acetyl groups revealed both the secondary hydroxyl and indole nitrogen provide (−)-petromindole (4) in 51% overall yield (Scheme 5), whose spectral data and physical properties were in complete agreement with the previously reported natural product.4 In conclusion, the enantioselective first total synthesis of (−)-petromindole (4) was accomplished in an 18-step longest linear sequence with 1.16% overall yield from enantiopure Wieland−Mischer ketone derivative 10. The eight-step synthesis of tricyclic allylic alcohol 9 and a biomimetic C-4 cyclization of 25 are the key features in rapid construction of the petromindole (4) skeleton, which we anticipate will allow the efficient preparation of a library of simplified petromindole analogues for detailed biological activity studies. Finally, it is envisioned that this strategy could provide a useful guide for the synthesis of various structurally related indolo-terpenoids.
■
ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03768. Experimental procedures and spectral data for all the compounds (PDF)
■
AUTHOR INFORMATION
Corresponding Author
* E-mail:
[email protected]. ORCID
Dattatraya H. Dethe: 0000-0003-2734-210X Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We thank Ms. Samarpita Mahapatra and Mr. Vijay Kumar B from IIT Kanpur for their kind help in improving the manuscript and some reactions. S.K.S. thanks CSIR, New Delhi for the award of a research fellowship. Financial support from IIT Kanpur is gratefully acknowledged.
■
REFERENCES
(1) Parker, E. J.; Scott, B. Handbook of Industrial Mycology; Marcel Dekker: New York, 2004. (2) Knaus, H. G. O.; McManus, B.; Lee, S. H.; Schmalhofer, W. A.; Garcia-Calvo, M.; Helms, L. M.; Sanchez, M.; Giangiacomo, K.; Reuben, J. P.; Smith, A. B., 3rd Biochemistry 1994, 33, 5819−5828. (3) For earlier syntheses of paxiline-type indole diterpenes: (a) Smith, A. B., III; Mewshaw, R. J. Am. Chem. Soc. 1985, 107, 1769. (b) Smith, A. B., III; Leenay, T. L. Tetrahedron Lett. 1988, 29, 2791. (c) Mewshaw, R.; Taylor, M. D.; Smith, A. B., III J. Org. Chem. 1989, 54, 3449. (d) Smith, A. B., III; Leenay, T. L. J. Am. Chem. Soc. 1989, 111, 5761. (e) Smith, A. B., III; Sunazuka, T.; Leenay, T. L.; Kingery-Wood, J. J. Am. Chem. Soc. 1990, 112, 8197. (f) Smith, A. B., III; Kingery-Wood, J. T.; Leenay, L.; Nolen, E. G.; Sunazuka, T. J. Am. Chem. Soc. 1992, 114, 1438. (g) Smith, A. B., III; Kanoh, N.; Ishiyama, H.; Hartz, R. A. J. Am. Chem. Soc. 2000, 122, 11254. (h) Smith, A. B., III; Cui, H. Org. Lett. 2003, 5, 587. (i) Smith, A. B., III; Kanoh, N.; Ishiyama, H.; Minakawa, N.; Rainier, J. D.; Hartz, R. A.; Cho, Y. S.; Cui, H.; Moser, W. M. J. Am. Chem. Soc. 2003, 125, 8228. (j) Smith, A. B., III; Cui, H. Helv. Chim. Acta 2003, 86, 3908. (k) Smith, A. B., III; Davulcu, A. H.; Kürti, L. Org. Lett. 2006, 8, D
DOI: 10.1021/acs.orglett.7b03768 Org. Lett. XXXX, XXX, XXX−XXX
