A DFT and AIM study of the proline-catalyzed asymmetric cross-aldol addition of acetone to isatins: A rationalization for the reversal of chirality

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, 2008.