Asymmetric Total Synthesis and Biological Evaluation of (+)-Cycloclavine

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 receptors

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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

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