title: Regioselective enzymatic aminoacylation of lobucavir to give an intermediate for lobucavir prodrug.
abstract: 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)cyclobutyl]methyl 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-1H-purin-9-yl)cyclobuta-1,2-diyl]methyl ester (1) with lipase M, and L-valine, [(1R,2R,4S)-2-(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)-4-(hydroxymethyl)cyclobutyl]methyl ester monohydrochloride (4, 87% yield) was obtained by hydrolysis of bis[L-valine], O,O'-[(1S,2R,3R)-3-(2-amino-6-oxo-1H-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-(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).
authors.affiliation: Department of Process Research and Development, Bristol-Myers Squibb Pharmaceutical Research Institute, New Brunswick, NJ 08903, USA. ronald.hanson@bms.com
authors.forename: R L
authors.initials: RL
authors.lastname: Hanson
authors.forename: Z
authors.initials: Z
authors.lastname: Shi
authors.forename: D B
authors.initials: DB
authors.lastname: Brzozowski
authors.forename: A
authors.initials: A
authors.lastname: Banerjee
authors.forename: T P
authors.initials: TP
authors.lastname: Kissick
authors.forename: J
authors.initials: J
authors.lastname: Singh
authors.forename: A J
authors.initials: AJ
authors.lastname: Pullockaran
authors.forename: J T
authors.initials: JT
authors.lastname: North
authors.forename: J
authors.initials: J
authors.lastname: Fan
authors.forename: J
authors.initials: J
authors.lastname: Howell
authors.forename: S C
authors.initials: SC
authors.lastname: Durand
authors.forename: M A
authors.initials: MA
authors.lastname: Montana
authors.forename: D R
authors.initials: DR
authors.lastname: Kronenthal
authors.forename: R H
authors.initials: RH
authors.lastname: Mueller
authors.forename: R N
authors.initials: RN
authors.lastname: Patel
mesh_terms: D000215:Acylation; D016956:Burkholderia cepacia / Q000201:enzymology; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D006868:Hydrolysis; D066298:In Vitro Techniques; D008049:Lipase / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011355:Prodrugs; D006147:Guanine; C063638:lobucavir; D008049:Lipase