Cycloclavine Explained

Cycloclavine is an ergot alkaloid. It was first isolated in 1969 from seeds of Ipomoea hildebrandtii vatke.^[1] The first total synthesis of (±)-cycloclavine was published in 2008 by Szántay.^[2] Further reports came from Wipf and Petronijevic,^[3] Cao^[4] and Brewer.^[5] In 2016, Wipf and McCabe completed an 8-step asymmetric synthesis of (–)-cycloclavine,^[6] and in 2018, they expanded this approach toward (+)-cycloclavine and a biological characterization of the binding profile of both enantiomers on 16 brain receptors.^[7] Natural (+)- and unnatural (–)-cycloclavine demonstrated significant stereospecificity and unique binding profiles in comparison to LSD (lysergic acid diethylamide), psilocin, and DMT. Differential 5-HT receptor affinities, as well as novel sigma-1 receptor properties, suggest potential future therapeutic opportunities of clavine alkaloid scaffolds.

Notes and References

1. 10.1016/S0040-4020(01)83095-7. 5373534. Cycloclavin, ein neues alkaloid aus Ipomoea hildebrandtii vatke—71. Tetrahedron. 25. 24. 5879–87. 1969. Stauffacher. D. Niklaus. P. Tscherter. H. Weber. H.P. Hofmann. A.
2. Incze . M. . Dörnyei . G. . Moldvai . I. . Temesvári-Major . E. . Egyed . O. . Szántay . C. . 2008 . New routes to clavine-type ergot alkaloids. Part 2: Synthesis of the last, so far not yet synthesized member of the clavine alkaloid family, (±)-cycloclavine. Tetrahedron . 64 . 13. 2924–2929 . 10.1016/j.tet.2008.01.101.
3. Petronijevic . F. R. . Wipf . P . 2011 . Total Synthesis of (±)-Cycloclavine and (±)-5-epi-Cycloclavine. J. Am. Chem. Soc. . 133 . 20. 7704–7707 . 10.1021/ja2026882. 3111057 . 21517102.
4. Wang . W. . Lu . J.-T. . Zhang . H.-L. . Shi . Z.-F. . Wen . J. . Cao . X.-P . 2013 . Formal Synthesis of (±)-Cycloclavine. J. Org. Chem. . 79 . 1 . 122–127 . 10.1021/jo4023588 . 24279324.
5. Jabre . N. D. . Watanabe . T. . Brewer . M. . 2014 . Formal and total synthesis of (±)-cycloclavine. Tetrahedron Lett. . 55 . 1 . 197–199 . 10.1016/j.tetlet.2013.10.152. 3915717 . 24511164.
6. 10.1002/ange.201608820 . 129 . Eight-Step Enantioselective Total Synthesis of (−)-Cycloclavine . Angewandte Chemie . 330–333 . McCabe . Stephanie R.. 2017 . 1 . 5195887 . 27860203.
7. Wipf. Peter. McCabe. Stephanie. 2018-11-20. Asymmetric Total Synthesis and Biological Evaluation of (+)-Cycloclavine. Synthesis. en. 10.1055/s-0037-1610395. 0039-7881. 51. 213–224. free.