ja513096x_si_001.pdf (13.93 MB)
Download file

Origins of Stereoselectivity in Intramolecular Aldol Reactions Catalyzed by Cinchona Amines

Download (13.93 MB)
journal contribution
posted on 2015-02-11, 00:00 authored by Yu-hong Lam, K. N. Houk
The intramolecular aldol condensation of 4-substituted heptane-2,6-diones leads to chiral cyclohexenones. The origins of the enantioselectivities of this reaction, disclosed by List et al. using a cinchona alkaloid-derived primary amine (cinchona amine) organocatalyst, have been determined with dispersion-corrected density functional theory (DFT). The stereocontrol hinges on the chair preference of the substrate–enamine intermediate and the conformational preferences of a hydrogen-bonded nine-membered aldol transition state containing eight heavy atoms. The conformations of the hydrogen-bonded ring in the various stereoisomeric transition structures have been analyzed in detail and shown to closely resemble the conformers of cyclooctane. A model of stereoselectivity is proposed for the cinchona amine catalysis of this reaction. The inclusion of Grimme’s dispersion corrections in the DFT calculations (B3LYP-D3­(BJ)) substantially improves the agreement of the computed energetics and experiment, attesting to the importance of dispersion effects in stereoselectivity.