ENZYMATIC KINETIC SEPARATION OF STEREOISOMERIC MACROCYCLIC LACTONE DERIVATIVES, 7-ALPHA,BETA-O-ACYL TRANS-ZEARALENOLS AND 7-ALPHA,BETA-O-ACYL ZEARANOLS

Diastereomeric mixtures of resorcylic acid macrocyclic lactones, 7-alpha, beta-O-acyl zearalenols (1,2 and 3,4, full name: trans-3,4,5,6,9,10-octahydro-14,16-dihydroxy-7-acyloxy-3-methyl 1H-2-benzoxacyclotetradecin-1-ones (3S,7S or 3S,7R)), and 7-alpha, beta-acyl zearanols (5,6 and 7,8, full name: 3,4,5,6,9,10,11,12-decahydro-14,16-dihydroxy-7-acyloxy-3-methyl-1H-2-benzoxacyclotetradecin-1-ones (3S,7S or 3S,7R)) are hydrolyzed by lipases. Kinetic separation affords 7-beta-alcohols with complete site-selectivity and nearly complete diastereoselectivity. Among lipases examined, those from Pseudomonas sp., Pseudomonas fluorescens and Candida cylindracea exhibit the broadest substrate specificity. In all cases 7-beta-alcohols are major products, diastereomeric excess (d.e. in %, determined by HPLC) approaches 100% for 1,2, 80% for 3,4, and varies between 10% and 90% for 5,6 and 7,8, respectively. Faster and less stereoselective hydrolysis is observed for 7-alpha, beta-O-chloroacetyl derivatives 3,4 and 7,8 as compared with acetyl derivatives 1,2 and 5,6. The effect of ionic strength and of organic cosolvent on the rate and selectivity is studied. Explanation of stereoeslectivity of this enzymatic reaction is based on die conformational properties of macrocyclic ring around the chiral acyloxymethine center C(7). Perturbation by the local helical arrangement of die two trimethylenic side-chains attached to this center renders 7-beta-O-acyl diastereomers much more reactive counterparts.