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 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 acetylationof 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.