SYNTHESIS, ABSOLUTE-CONFIGURATION, AND ENANTIOSELECTIVITY OF ANTIRETROVIRAL EFFECT OF (R)-(-)-CYTALLENE AND (S)-(+)-CYTALLENE - LIPASE-CATALYZED ENANTIOSELECTIVE ACYLATIONS OF (+/-)-N-4-ACYLCYTALLENES

Enantioselectivity of acylations of (+/-)-cytallene (1b), (+/-)-N-4-acetylcytallene (11a), (+/-)-N-4-benzoylcytallene (11b), and (+/-)-N-4-(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 (+/-)-N-4-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 mu M. (+/-)-Cytallene (1b) exhibited IC50 0.8 and IC90 3.4 mu M. Both compounds completely suppressed replication of HIV-1 at 10 mu M with no detectable cytotoxicity. The S-enantiomer (3c) was inactive.