Enzyme-catalyzed regioselective acylation of castanospermine

• Published in: Journal of the American Chemical Society Vol. 112; no. 8; pp. 2849 - 2854
• Main Authors: Margolin, Alexey L, Delinck, Deborah L, Whalon, Michael R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.04.1990; Amer Chemical Soc
• Subjects: Bioconversions. Hemisynthesis; Biological and medical sciences; Biotechnology; Chemistry; Chemistry, Multidisciplinary; Fundamental and applied biological sciences. Psychology; Methods. Procedures. Technologies; Physical Sciences; Science & Technology; Enzymatic synthesis; Alkaloid; Regioselectivity; Biotransformation; Enzyme inhibitor; Reaction mechanism; Subtilisin; Acylation
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja00164a001

Several biologically active esters of castanospermine [(S,6S,7R,8R,8aR)-1,6,7,8-tetrahydroxyoctahydroindolizine] have been synthesized on a preparative scale in pyridine by using the the proteolytic enzyme subtilisin as a catalyst. Under these conditions, subtilisin possesses a high regioselectivity and at the same time a broad substrate specificity and enantioselectivity. This fact makes possible the synthesis of a wide variety of 1-O-acyl derivatives via castanospermine esterification. It is possible to regulate the hydrophobicity of the acylating group (acetyl, butyryl, octanoyl) or to incorporate an aromatic moiety (phenylacetyl) or L and D amino acids (phenylalanyl, L- and D-alanyl). Since 1-esters of castanospermine are soluble in several organic solvents, they have been employed as intermediates in the preparation of diesters. Porcine pancreatic lipase, lipase from Chromobacterium viscosum, and subtilisin have been used as catalysts for further enzymatic acylation of 1-O-acyl derivatives of castanospermine in tetrahydrofuran. The regioselectivity of subtilisin is different from that of the lipases tested. Subtilisin shows a strong preference for acylation of the OH group at the C6 position, while lipases prefer the OH group at C7. Among lipases tested, the lipase from C. viscosum is especially active. The reactions catalyzed by this enzyme usually result in isolated yields of .apprx. 80%. In order to prepare mono-O-acyl compounds other than 1-O-acylcastanospermine, 1,7-di-O-butyrylcastanospermine has been enzymatically hydrolyzed. Two enzymes - porcine liver esterase and subtilisin-catalyzed this reaction with opposite regioselectivities: while esterase preferentially cleaves off the butyryl group from the C7 position with regioselectivity (C1:C7) better than 1:25, subtilisin hydrolyzed the ester bond at the C1 position with regioselectivity more than 25:1. For synthetic purposes this property of subtilisin in especially important, because it makes possible a three-step enzyme-catalyzed synthesis of 7-O-butyrylcastanospermine.