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-dihydr o-6-oxo-9H-purin-9-yl)-2-(hydroxymethyl) cyclobutyl]methyl ester monohydroc hloride (BMS 233866), requires regioselective coupling of one of the two hy droxyl groups of lobucavir (BMS 180194) with valine. Either hydroxyl group of lobucavir could be selectively aminoacylated with valine by using enzyma tic 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), wa s 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-diy l]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, dihydroc hloride (2), with lipase from Candida cylindracea. The final intermediate f or 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 mor e selectively by using immobilized lipase from Pseudomonas cepacia (84% yie ld). (C) 2000 Elsevier Science Ltd. All rights reserved.