Regioselective enzymatic aminoacylation of lobucavir to give an intermediate for lobucavir prodrug

Synthesis of lobucavir prodrug, L-valine, [(1S,2R,3R)-3-(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)-2-(hydroxymethyl) cyclobutyl]methyl ester monohydrochloride (BMS 233866), requires regioselective coupling of one of the two hydroxyl groups of lobucavir (BMS 180194) with valine. Either hydroxyl group of lobucavir could be selectively aminoacylated with valine by using enzymatic reactions. N-[(Phenylmethoxy)carbonyl]-L-valine, [(1R,2R,4S)-2-(2-amino-6-oxo-1H-purin-9-yl)-4-(hydroxymethyl)cyclobuty ester (3, 82.5% yield), was obtained by selective hydrolysis of N,N-bis[(phenylmethoxy)carbonyl]bis[L-valine] O,O'-[(1S,2R,3R)-3(2-amino-6-oxo-1 H-purin-9;yl)cyclobuta- 1,2-diyl]methyl ester (1) with lipase M, and L-valine, [(1 R,2R,4S)-2-(2-amino- 1,6-dihydro-6-oxo-9H-purin-9-yl)-4-(hydroxymethyl)cy ester monohydrochloride (4, 87% yield) was obtained by hydrolysis of bis[L-valine], O,O'-[(1S,2R,3R)-3-(2-amino-6-oxo-1 H-purin-9-yl)cyclobuta-1,2-diyl]methyl ester, dihydrochloride (2), with lipase from Candida cylindracea. The final intermediate for lobucavir prodrug, N-[(phenylmethoxy)carbonyl]-L-valine, [(1S,2R,4R)-3-(2-amino-6-oxo-1H-purin-9-yl)-2-(hydroxymet ester (5), could be obtained by transesterification of lobucavir using ChiroCLEC(TM) BL (61% yield), or more selectively by using immobilized lipase from Pseudomonas cepacia (84% yield). (C) 2000 Elsevier Science Ltd. All rights reserved.