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 (Δ G ≠ =26.1 kcal mol −1 for the analogous L ‐alaninol, 3 b ) 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 )‐ 2 a (calculated Δ G ≠ =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 (ΔΔ G ≠ =2.6 kcal mol −1 ).