title: Synthesis, absolute configuration, and enantioselectivity of antiretroviral effect of (R)-(-)- and (S)-(+)-cytallene. Lipase-catalyzed enantioselective acylations of (+/-)-N4-acylcytallenes.
abstract: 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 microM. (+/-)-Cytallene (1b) exhibited IC50 0.8 and IC90 3.4 microM. Both compounds completely suppressed replication of HIV-1 at 10 microM with no detectable cytotoxicity. The S-enantiomer (3c) was inactive.
authors.affiliation: Department of Chemistry, Michigan Cancer Foundation, Wayne State University School of Medicine, Detroit 48201, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Jones
authors.forename: J V
authors.initials: JV
authors.lastname: Silverton
authors.forename: C
authors.initials: C
authors.lastname: Simons
authors.forename: S
authors.initials: S
authors.lastname: Megati
authors.forename: H
authors.initials: H
authors.lastname: Nishimura
authors.forename: Y
authors.initials: Y
authors.lastname: Maeda
authors.forename: H
authors.initials: H
authors.lastname: Mitsuya
authors.forename: J
authors.initials: J
authors.lastname: Zemlicka
mesh_terms: D000215:Acylation; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D003596:Cytosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008049:Lipase / Q000378:metabolism*; D009000:Monocytes / Q000821:virology; D013237:Stereoisomerism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C056908:cytallene; D003596:Cytosine; D008049:Lipase