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

Comprehensive mechanistic studies on the enantioselective aldol reaction between isatin (1a) and acetone, catalyzed by L-leucinol (3a), 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 (G=26.1kcalmol(-1) for the analogous L-alaninol, 3b) and the kinetic isotope effect (k(H)/k(D)=2.7 observed for the reaction using [D-6]acetone). The subsequent reaction of the syn-enamine 6 with isatin produces (S)-2a (calculated G=11.6kcalmol(-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 2.3kcalmol(-1); and 2)the high preference of the syn-enamine 6 to produce (S)-2a on reaction with isatin (1a) rather than its enantiomer (G=2.6kcalmol(-1)).