title: Stereoselective synthesis of D- and L-carbocyclic nucleosides by enzymatically catalyzed kinetic resolution.
abstract: An efficient synthesis of (S)- or (R)-3-(benzyloxy-methyl)-cyclopent-3-enol was developed by appling an enzyme-catalyzed kinetic-resolution approach. This procedure allowed the syntheses of the enantiomeric building blocks (S)- and (R)-cyclopentenol with high optical purity (>98 % ee). In contrast to previous approaches, the key advantage of this procedure is that the resolution is done on the level of enantiomers that only contain one stereogenic center. Owing to this feature, it was possible to chemically convert the enantiomers into each other. By using this route, the starting materials for the syntheses of carbocyclic D- and L-nucleoside analogues were readily accessible. 3',4'-Unsaturated D- or L-carbocyclic nucleosides were obtained from the condensation of various nucleobases with (S)- or (R)-cyclopentenol. Functionalization of the double bond in 3'-deoxy-3',4'-didehydro-carba-D-thymidine led to a variety of new nucleoside analogues. By using the cycloSal approach, their corresponding phosphorylated metabolites were readily accessable. Moreover, a new synthetic route to carbocyclic 2'-deoxy-nucleosides was developed, thereby leading to D- and L-carba-dT. D-Carba-dT was tested for antiviral activity against multidrug-resistance HIV-1 strain E2-2 and compared to the known antiviral agent d4T, as well as L-carba-dT. Whilst L-carba-dT was found to be inactive, its D-analogue showed remarkably high activity against the resistant virus and significantly better than that of d4T. However, against the wild-type virus strain NL4/3, d4T was found to be more-active than D-carba-dT.
authors: Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Hamburg, Germany.
authors: Miriam
authors: M
authors: Mahler
authors: Bastian
authors: B
authors: Reichardt
authors: Philip
authors: P
authors: Hartjen
authors: Jan
authors: J
authors: van Lunzen
authors: Chris
authors: C
authors: Meier
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002384:Catalysis; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003500:Cyclization; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology; D024921:Drug Resistance, Multiple, Viral; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D010194:Pancreatin / Q000737:chemistry / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D018119:Stavudine / Q000494:pharmacology; D013237:Stereoisomerism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D003517:Cyclopentanes; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D010194:Pancreatin; D018119:Stavudine; D054303:HIV Reverse Transcriptase