Asymmetric Synthesis and Determination of the Absolute Configuration of FK584, an Agent for the Treatment of Overactive Detrusor

cal properties for the treatment of overactive detrusor and its clinical development is in progress. In the course of developing a new clinical agent, pharmacokinetic studies are necessary which require radiolabelled compound. The synthesis of FK584 1) was carried out by optical resolution of the synthetic racemate but this method is not applicable to the synthesis of radiolabelled compound. Consequently, we pursued an asymmetric synthesis of FK584 by two different methods, A and B, using 2-methyl-[2- 14 C]-propylamine as a labelled precursor which is available from the Amersham Company (Fig. 1). Method A consists of the introduction of tert-butylamine to p-allylpalladium 3 generated from cyclopentenyl acetate 1 or 2, while method B involves the introduction of tert-butylamine to 5,5-diphenyl-2,3-epoxycyclopentan-1-ol (5) and subsequent conversion to the required final product. Herein, we report the details of the asymmetric synthesis of FK584 and its absolute configuration. Our initial attempt at the synthesis of FK584 involved a kinetic resolution of 6 1) or 7 2) with lipase PS (Amano) and isopropenyl acetate to afford optically active cyclopentenol (1)7 and cyclopentenyl acetate (2)-2, respectively, and the results are shown in Table 1 (Chart 1). 3) In the case of 6, no reaction occurred, probably due to too large steric hindrance of