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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 ( 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 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). [ABSTRACT FROM AUTHOR]

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A catalyst's catalyst Investigation of the leucinol ‐ catalyzed aldol reaction of isatin with acetone revealed an intriguing and unusual mechanistic concept: apart from being a substrate, isatin also acts as a dichotomous co ‐ catalyst that accelerates the turnover ‐ limiting step: the formation of the reactive syn ‐ enamine. This concept resembles that of a wind turbine: only when the wind is blowing, that is, when the starting material is present, rotation commences and gives rise to the desired product. For more details, see the Full Paper by M. A. Kabeshov, A. V. Malkov, P. Kočovský, and co ‐ workers on page 12026 ff. [ABSTRACT FROM AUTHOR]