A DFT and AIM Study of the Proline‐Catalyzed Asymmetric Cross‐Aldol Addition of Acetone to Isatins: A Rationalization for the Reversal of Chirality

Abstract

Abstract The steric and stereoelectronic effects that control the enantioselectivity in the cross‐aldol addition of acetone to isatin catalyzed by L ‐proline have been studied by means of DFT and AIM calculations. This reaction results in a reversal of enantioselectivity compared with the corresponding cross‐aldol addition to 4,6‐dibromoisatin and aldehydes. DFT calculations of the cross‐aldol transition states indicate that product formation follows different pathways for the substrates isatin and 4,6‐dibromoisatin. In the case of isatin, the S enantiomer is favoured as a consequence of a stereoelectronic effect that results in a lower‐energy transition state for the S enantiomer relative to the R enantiomer. In contrast, the cross‐aldol addition of acetone to 4,6‐dibromoisatin furnishes the expected R enantiomer owing to a steric effect of the 4‐bromo substituent which inhibits the formation of the S enantiomer via the stereoelectronically favoured transition state.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)