Cross-Aldol Reaction of Isatin with Acetone Catalyzed by Leucinol: A Mechanistic Investigation.

Comprehensive mechanistic studies on the enantioselective aldol reaction between isatin (1 a) and acetone, catalyzed by L-leucinol (3 a), unraveled that isatin, apart from being a substrate, also plays an active catalytic role. Conversion of the intermediate oxazolidine 4 into the reactive syn-enamine 6, catalyzed by isatin, was identified as the rate-determining step by both the calculations (ΔG(≠) =26.1 kcal mol(-1) for the analogous L-alaninol, 3 b) and the kinetic isotope effect (kH /kD =2.7 observed for the reaction using [D6 ]acetone). The subsequent reaction of the syn-enamine 6 with isatin produces (S)-2 a (calculated ΔG(≠) =11.6 kcal mol(-1) ). The calculations suggest that the overall stereochemistry is controlled by two key events: 1) the isatin-catalyzed formation of the syn-enamine 6, which is thermodynamically favored over its anti-rotamer 7 by 2.3 kcal mol(-1) ; and 2) the high preference of the syn-enamine 6 to produce (S)-2 a on reaction with isatin (1 a) rather than its enantiomer (ΔΔG(≠) =2.6 kcal mol(-1) ).