| A stepwise strategy for the catalytic asymmetric hydrocarboxylation, hydroformylation, and hydrohydroxymethylation of vinyl arenes has been developed. By separating the initial hydrometalation step, where both excellent regio- and enantiocontrol can be realized using rhodium-catalyzed hydroboration, from the subsequent homologation step, where the requisite carbon-carbon bond formation actually takes place, it became possible to directly access the one-carbon homologue of the same chiral boronate ester intermediate in all three oxidation states. Using this protocol, Ibuprofen(TM) was prepared in 79% yield and 93% enantiopurity from its corresponding vinyl arene precursor.;In order to apply this methodology to the first asymmetric total synthesis of heptamethyllithiospermate, a potent inhibitor of several sex hormones, a search for a more active catalyst capable of functionalizing a trisubstituted, semi-aromatic double bond became necessary. This research initiative eventually led to the development of several novel rhodium-NHC (N-heterocyclic carbene) complexes whose respective abilities to hydroborate and hydroformylate a variety of olefins were studied.;A direct experimental demonstration of the primary stereoelectronic effect in the Baeyer-Villiger oxidation was carried out on a variety of alpha-fluorocyclohexanones. Through the threat of a debilitating dipole, it was possible to bias the migration to take place primarily from a conformer where only the CHF substituent is properly stereo-electronically aligned. The resulting regioisomeric product distributions revealed that for these fluoroketones, the primary stereoelectronic effect is more important than intrinsic migratory aptitudes. Although the same strategy was applied to their chlorinated analogues, the product derived from the migration of the non-chlorinated substituent was always the preponderate regioisomer. These results, accompanied by some preliminary kinetic studies, implied that contrary to the currently accepted axiom, fluorine may be better at stabilizing an adjacent carbenium centre than chlorine. |
