Chemoenzymatic synthesis of (R)-(+)-alpha-(4-fluorophenyl)-4-(2-pyrimidinyl piperazinebutanol) and (R)-(+)-alpha-(4-fluorophenyl)-4-methyl-1-piperidinebutanol as potential antipsychotic agents

A chemoenzymatic straightforward synthesis of (R)-(+)-alpha-(4-fluorophenyl)-4-methyl-1-piperidinebutanol (2) and (R)-(+)-alpha-(4-fluorophenyl)-4-(2-pyrimidinyl)-1-piperazinebutanol (3), two potential antipsychotic agents, has been developed by two different approaches involving lipase-mediated resolution of the racemic compounds or through asymmetrization of the precursor alcohol 4. A second enzymatic resolution followed by condensation of (R)-4 with 4-methylpiperidine (6) or 1-(2-pyrimidinyl)piperazine (7) leads to (R)-2 and (R)-3 in good chemical and excellent optical yields (>99% ee). (C) 1997 Elsevier Science Ltd.