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CC BY-ND-NC 4.0 · Synthesis 2019; 51(01): 213-224
DOI: 10.1055/s-0037-1610395
DOI: 10.1055/s-0037-1610395
feature
Asymmetric Total Synthesis and Biological Evaluation of (+)-Cycloclavine
The authors are grateful to Boehringer-Ingelheim Pharmaceuticals Inc., Ridgefield CT, for partial financial support of this work. SRM also acknowledges support from the Mary E. Warga and the University of Pittsburgh Arts and Sciences Mellon Fellowships.Further Information
Publication History
Received: 29 October 2018
Accepted: 31 October 2018
Publication Date:
20 November 2018 (online)
Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue
Abstract
The first total synthesis of natural (+)-cycloclavine uses a catalytic asymmetric cyclopropanation of allene, a regiospecific Pd-catalyzed enone formation, and two intramolecular Diels–Alder reactions for indole/indoline annulations. The binding properties of natural (+)- and unnatural (–)-cycloclavine on 16 CNS receptors revealed significant stereospecificity and unique binding profiles in comparison to LSD, psilocin, and DMT. Differential 5-HT affinities, as well as novel sigma-1 receptor properties bode well for potential therapeutic developments of clavine alkaloid scaffolds.
Key words
clavine ergot alkaloids - enantioselective allene cyclopropanation - psychedelics - stereospecific GPCR binding - LSD - psilocin - DMT - 5-HTA - sigma-1 receptorsSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1610395. Spectral data (1H and 13C NMR for selected new compounds and (+)-cycloclavine).
- Supporting Information
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References
- 1a Hager A, Vrielink N, Hager D, Lefranc J, Trauner D. Nat. Prod. Rep. 2016; 33: 491
- 1b Susick RB, Morrill LA, Picazo E, Garg NK. Synlett 2017; 28: 1
- 1c Wang Y, Xie F, Lin B, Cheng M, Liu Y. Chem. Eur. J. 2018; 24: 14302
- 1d Xie X, Zu L. Synlett 2018; 29: 1008
- 1e Liu H, Jia Y. Nat. Prod. Rep. 2017; 34: 411
- 2a Chadha N, Silakari O. Eur. J. Med. Chem. 2017; 134: 159
- 2b Bharate SS, Mignani S, Vishwakarma RA. J. Med. Chem. 2018; 61: in press; doi.org/10.1021/acs.jmedchem.7b01922
- 2c Homer JA, Sperry J. J. Nat. Prod. 2017; 80: 2178
- 3 McCabe SR, Wipf P. Org. Biomol. Chem. 2016; 14: 5894
- 4 Stauffacher D, Niklaus P, Tscherter H, Weber HP, Hofmann A. Tetrahedron 1969; 25: 5879
- 5 Incze M, Doernyei G, Moldvai I, Temesvari-Major E, Egyed O, Szantay C. Tetrahedron 2008; 64: 2924
- 6a Pierce JG, Kasi D, Fushimi M, Cuzzupe A, Wipf P. J. Org. Chem. 2008; 73: 7807
- 6b Petronijevic F, Timmons C, Cuzzupe A, Wipf P. Chem. Commun. 2009; 104
- 6c Wang C, Widom J, Petronijevic F, Burnett JC, Nuss JE, Bavari S, Gussio R, Wipf P. Heterocycles 2009; 79: 487
- 6d LaPorte M, Hong KB, Xu J, Wipf P. J. Org. Chem. 2013; 78: 167
- 6e Alverez C, Arkin MR, Bulfer SL, Colombo R, Kovaliov M, LaPorte MG, Lim C, Liang M, Moore WJ, Neitz RJ, Yan Y, Yue Z, Huryn DM, Wipf P. ACS Med. Chem. Lett. 2015; 6: 1225
- 6f Xu J, Wipf P. Org. Biomol. Chem. 2017; 15: 7093
- 7 Petronijevic FR, Wipf P. J. Am. Chem. Soc. 2011; 133: 7704
- 8 Jabre ND, Watanabe T, Brewer M. Tetrahedron Lett. 2014; 55: 197
- 9a Wang W, Lu J.-T, Zhang H.-L, Shi Z.-F, Wen J, Cao X.-P. J. Org. Chem. 2014; 79: 122
- 9b Chen J.-Q, Song L.-L, Li F.-X, Shi Z.-F, Cao X.-P. Chem. Commun. 2017; 53: 12902
- 9c Chen J.-Q, Mi Y, Shi Z.-F, Cao X.-P. Org. Biomol. Chem. 2018; 16: 3801
- 10 Netz N, Opatz T. J. Org. Chem. 2016; 81: 1723
- 11 McCabe SR, Wipf P. Angew. Chem. Int. Ed. 2017; 56: 324
- 12 Chaudhuri S, Ghosh S, Bhunia S, Bisai A. Chem. Commun. 2018; 54: 940
- 13 Deng L, Chen M, Dong G. J. Am. Chem. Soc. 2018; 140: 9652
- 14 Diao T, Stahl SS. J. Am. Chem. Soc. 2011; 133: 14566
- 15 Lizza JR, Bremerich M, McCabe SR, Wipf P. Org. Lett. 2018; 20: 6760
- 16 Padwa A, Flick AC. Adv. Heterocycl. Chem. 2013; 110: 1
- 17 Panne P, DeAngelis A, Fox JM. Org. Lett. 2008; 10: 2987
- 18 Goto T, Takeda K, Anada M, Ando K, Hashimoto S. Tetrahedron Lett. 2011; 52: 4200
- 19a Davies HM. L, Stafford DG, Doan BD, Houser JH. J. Am. Chem. Soc. 1998; 120: 3326
- 19b Qin C, Boyarskikh V, Hansen JH, Hardcastle KI, Musaev DG, Davies HM. L. J. Am. Chem. Soc. 2011; 133: 19198
- 19c DeAngelis A, Dmitrenko O, Yap GP. A, Fox JM. J. Am. Chem. Soc. 2009; 131: 7230
- 20 Lindsay VN. G, Fiset D, Gritsch PJ, Azzi S, Charette AB. J. Am. Chem. Soc. 2013; 135: 1463
- 21 Uchida T, Katsuki T. Synthesis 2006; 1715
- 22a House HO, Trost BM. J. Org. Chem. 1965; 30: 1341
- 22b Velluz L, Valls J, Nominé G. Angew. Chem., Int. Ed. Engl. 1965; 4: 181
- 23 Nasipuri D. Stereochemistry of Organic Compounds: Principles and Applications. New Age International; New Delhi: 1994
- 24 dos Santos RG, Bouso JC, Alcazar-Corcoles MA, Hallak JE. C. Exp. Rev. Clin. Pharm. 2018; 11: 889
- 25 Bennett JP. Jr, Snyder SH. Brain Res. 1975; 94: 523
- 26 Hofmann A. LSD – My Problem Child . McGraw-Hill Book Company; New York: 1980
- 27 Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P, Rothman RB. Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 11934
- 28 Rickli A, Luethi D, Reinisch J, Buchy D, Hoener MC, Liechti ME. Neuropharmacology 2015; 99: 546
- 29 Nichols DE, Nichols CD. Chem. Rev. 2008; 108: 1614
- 30a Glennon RA, Titeler M, McKenney JD. Life Sci. 1984; 35: 2505
- 30b Nichols CD, Sanders-Bush E. Heffter Rev. Psychedel. Res. 2001; 2: 73
- 30c Ref. 24
- 31 Rickli A, Moning OD, Hoener MC, Liechti ME. Eur. Neuropsychopharmacol. 2016; 26: 1327
- 32 Ray TS. PLoS One 2010; 5: e9019
- 33 Fontanilla D, Johannessen M, Hajipour AR, Cozzi NV, Jackson MB, Ruoho AE. Science 2009; 323: 934
- 34 Timmermann C, Roseman L, Williams L, Erritzoe D, Martial C, Cassol H, Laureys S, Nutt D, Carhart-Harris R. Front. Psych. 2018; 9: 1424
- 35a Nutt D. J. Psychopharm. 2016; 30: 1163
- 35b Prochazkova L, Lippelt DP, Colzato LS, Sjoerds Z, Kuchar M, Hommel B. Psychopharmacology (Berl) 2018; in press; doi.org/10.1007/s00213-018-5049-7
- 36 Chu UB, Ruoho AE. Mol. Pharmacol. 2016; 89: 142
- 37 Szabo A, Frecska E. Neural Regen. Res. 2016; 11: 396
- 38 Goto T, Takeda K, Shimada N, Nambu H, Anada M, Shiro M, Ando K, Hashimoto S. Angew. Chem. Int. Ed. 2011; 50: 6803
- 39 Rainbolt JE, Miller GP. J. Org. Chem. 2007; 72: 3020