Theoretical investigation on the chemo- and stereoselectivities of isoleucine-catalyzed cross-aldol reactions between two enolizable aldehydes involving isobutyraldehyde and contrasts with proline catalysis

Abstract

The chemo- and stereoselectivities in the isoleucine-catalyzed asymmetric cross-aldol reactions between two potentially enolizable aldehydes with different electronic natures have been investigated by performing density functional theory (DFT) calculations and compared with those of proline catalysis. A detailed mechanism for enamine formation between the catalyst and the representative aldehydes with the electron-rich or electron-deficient characters has been studied and the calculated results confirm that a primary amino acid, such as isoleucine, can effectively discriminate between an electron-rich aldehyde as the enamine component and an electron-deficient aldehyde as the carbonyl component, while similar reactions promoted by proline exhibit different chemoselectivities due to the inferior ability of proline to differentiate between nonequivalent enolizable aldehydes. Furthermore, the unusual enantioselectivity at the newly created stereogenic center for the isoleucine-catalyzed aldol reactions involving a challenging donor, such as an α-branched aldehyde has been explained by the more favorable transition state via the anti-enamine attacking the si face of the acceptor aldehyde in the crucial CC bond-formation step, which is in contrast to the conventionally preferred TSs with re-facial selectivity of the acceptor aldehyde.