title: Origins of stereoselectivity in intramolecular aldol reactions catalyzed by cinchona amines.
abstract: 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.
authors: Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095-1569, United States.
authors: Yu-Hong
authors: YH
authors: Lam
authors: K N
authors: KN
authors: Houk
mesh_terms: D000588:Amines / Q000737:chemistry*; D002384:Catalysis; D002930:Cinchona Alkaloids / Q000737:chemistry*; D003500:Cyclization; D007659:Ketones / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism
chemical_list: D000588:Amines; D002930:Cinchona Alkaloids; D007659:Ketones