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

• Published in: Bioorganic & medicinal chemistry Vol. 8; no. 12; pp. 2681 - 2687
• Main Authors: Hanson, Ronald L, Shi, Zhongping, Brzozowski, David B, Banerjee, Amit, Kissick, Thomas P, Singh, Janak, Pullockaran, Annie J, North, Jeffrey T, Fan, Junying, Howell, Jeffrey, Durand, Susan C, Montana, Michael A, Kronenthal, David R, Mueller, Richard H, Patel, Ramesh N
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.12.2000; Elsevier Science
• Subjects: Acylation; Antiviral drugs; Biological and medical sciences; Biotechnology; Burkholderia cepacia - enzymology; Fundamental and applied biological sciences. Psychology; Guanine - analogs & derivatives; Guanine - chemical synthesis; Guanine - chemistry; Guanine - metabolism; Health. Pharmaceutical industry; Hydrolysis; In Vitro Techniques; Industrial applications and implications. Economical aspects; Lipase - metabolism; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - metabolism; Production of active biomolecules; Aminoacylation; Purine nucleoside; Regioselectivity; Enzyme; Triacylglycerol lipase; Esterases; Prodrug; Transesterification; Carboxylic ester hydrolases; α-Aminoacid; Lobucavir; Burkholderia cepacia; Cyclobutane derivatives; Bacteria; Hydrolases; Antiviral; Enzymatic reaction
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(00)00209-1

Synthesis of lobucavir prodrug, L-valine, [(1 S,2 R,3 R)-3-(2-amino-1,6-dihydro-6-oxo-9 H-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, [(1 R,2 R,4 S)-2-(2-amino-6-oxo-1 H-purin-9-yl)-4-(hydroxymethyl)cyclobutyl]methyl ester ( 3, 82.5% yield), was obtained by selective hydrolysis of N, N′-bis[(phenylmethoxy)carbonyl]bis[L-valine], O, O′-[(1 S,2 R,3 R)-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,2 R,4 S)-2-(2-amino-1,6-dihydro-6-oxo-9 H-purin-9-yl)-4-(hydroxymethyl)cyclobutyl]methyl ester monohydrochloride ( 4, 87% yield) was obtained by hydrolysis of bis[L-valine], O, O′-[(1 S,2 R,3 R)-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, [(1 S,2 R,4 R)-3-(2-amino-6-oxo-1 H-purin-9-yl)-2-(hydroxymethyl)cyclobutyl]methyl ester ( 5), could be obtained by transesterification of lobucavir using ChiroCLEC™ BL (61% yield), or more selectively by using immobilized lipase from Pseudomonas cepacia (84% yield).