LIPASE-CATALYZED ACETYLATION OF 3-SUBSTITUTED 2,3-DIHYDRO-1H-1,4-BENZODIAZEPIN-2-ONES - EFFECT OF TEMPERATURE AND CONFORMATION ON ENANTIOSELECTIVITY AND CONFIGURATION

Enantioselectivity of acetylation by vinyl acetate/AcOEt catalyzed by immobilized Candida antarctica lipase (Novozym 433) is studied for rac -3-(hydroxymethyl)-1,4-benzodiazepin-2-ones 7, 9, 14 (n = 1; number of CH2 groups in the chain at C(3)), 20 (n = 2), and for prochiral 3,3-b is(hydroxymethyl) derivative 16. Enantiomeric excess (ee [%]) is corre lated with conformational properties of substrates (relative conformat ion, energy difference betweeen two boat-like ground-state conformatio ns, ring-inversion barrier) as determined by DNMR and MM2 calculations . (3S)-Enantiomers of acetates (+)-8, (+)-10, (+)-15, and(+)-21 were p referentially formed. In the case of the acetate (-)-17 (ee 90.2%), fo rmation of the (3R)-enantiomer was favored. C(3)-OH Group with hemiami nal-like character in rac-3 (n = 0) cannot be acetylated by any of 23 tested lipases and four esterases. For racemic alcohols 7, 9, 14, and 20, preferred acetylation of the (3S)-enantiomers, present in solution in absolute (M)-conformation, was established; only in prochiral diol 16 (n = 1) the CH2OH group in the (pro-R)-position is prevalently ace tylated, presumably due to the binding to the enzyme, in absolute (P)- conformation. Temperature dependence of enantioselectivity revealed in verse correlation of the E value of rac-9, and ee values for prochiral 16, with T [K], indicating prevalent contribution of the enthalpy ter m to enantioselection. Absolute conformation (MIP) and absolute config uration at C(3) of all products was determined by combining CD and H-1 -NMR data.