Synthesis, Absolute Configuration, and Enantioselectivity of Antiretroviral Effect of (R)-(-)- and (S)-(+)-Cytallene. Lipase-Catalyzed Enantioselective Acylations of (+/-)-N4-Acylcytallenes

Article abstract of DOI:10.1021/jm00008a018

Enantioselectivity of acylations of (+/-)-cytallene (1b), (+/-)-N⁴-acetylcytallene (11a), (+/-)-N⁴-benzoylcytallene (11b), and (+/-)-N⁴-(9-fluorenylmethoxycarbonyl)cytallene (11c) using vinyl butyrate or acetate catalyzed by lipases in organic solvents was investigated.Reactions with 1b, 11a, and adenallene (1a) did not display a high enantioselectivity but all resulted in a predominant acylation of the (-)-enantiomers.Application of the Lowe-Brewster rule led to a tentative assignment of the R-configuration to all acylated products.Studies of the time course of acylation of (+/-)-N⁴-benzoylcytallene (11b) in chloroform, tetrahydrofuran (THF), tetrahydropyran (THP), tetrahydrothiophene (THT), and dioxane with lipase PS30 and/or AK showed that the reaction in THF catalyzed by lipase AK was the most promising for resolution of 11b.Indeed, a large-scale acylation afforded, after separation and deprotection of intermediates 3e and 10d, (+)- and (-)-cytallene (3c and 2b) in high yield and enantioselectivity.Acylation of 11c in THF led also to formation of 3c and 2b in high enantioselectivity.Single crystal X-ray diffraction established the S-configuration of (+)-cytallene (3c), thus confirming the assignment made on the basis of Lowe-Brewster rule.An improved large-scale synthesis of (+/-)-cytallene (1b) is also described.The R-enantiomer 2b inhibited the replication of a primary human immunodeficiency virus (HIV-1) isolate in phytohemagglutinin-activated peripheral blood mononuclear cells (PHA-PBM) with IC50 0.4 and IC90 1.7 μM. (+/-)-Cytallene (1b) exhibited IC50 0.8 and IC90 3.4 μM.Both compounds completely suppressed replication of HIV-1 at 10 μM with no detecable cytotoxicity.The S-enantiomer (3c) was inactive.