Lipase-catalyzed acetylation of 3-substituted 2,3-dihydro-1H-1,4- benzodiazepin-2-ones: Effect of temperature and conformation on enantioselectivity and configuration

Article abstract of DOI:10.1002/hlca.19980810558

Enantioselectivity of acetylation by vinyl acetate/AcOEt catalyzed by immobilized Candida antarctica lipase (Novozym 435) 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- bis(hydroxymethyl) derivative 16. Enantiomeric excess (ee [%]) is correlated with conformational properties of substrates (relative conformation, energy difference between two boat-like ground-state conformations, ring-inversion barrier) as determined by DNMR and MM2 calculations. (3S)-Enantiomers of acetates (+)-8, (+)-10, (+)-15, and (+)-21 were preferentially formed. In the case of the acetate (-)-17 (ee 90.2%), formation of the (3R)-enantiomer was favored. C(3)-OH Group with hemiaminal-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 acetylated, presumably due to the binding to the enzyme, in absolute (P)-conformation. Temperature dependence of enantioselectivity revealed inverse correlation of the E value of rac-9, and ee values for prochiral 16, with T[K], indicating prevalent contribution of the enthalpy term to enantioselection. Absolute conformation (M/P) and absolute configuration at C(3) of all products was determined by combining CD and ¹H- NMR data.