Catalytic asymmetric hydrocarboxylation and hydrohydroxymethylation. A two-step approach to the enantioselective functionalization of vinylarenes

A method for the catalytic asymmetric hydrocarboxylation and hydrohydroxyme thylation of vinylarenes is reported. By separating the step in which asymm etry is installed from the one where carbon-carbon bond formation takes pla ce, a highly enantioselective and regioselective synthesis of Ibuprofen and its analogs is achieved. Stereochemistry is installed via an enantioselect ive hydroboration reaction, catalyzed by cationic rhodium BINAP complexes, and the homologation is carried out with halomethyllithium reagents. If CH2 Cl2/n-BuLi is used as the homologating reagent, carboxylic acids are produc ed after oxidation. On the other hand, if CH2ClBr is used in combination wi th n-BuLi, the corresponding primary alcohol is produced. This latter trans formation represents a previously unknown asymmetric hydrohydroxymethylatio n reaction. In both cases, complete retention of stereochemistry is observe d, yielding products in up to 97% ee. Superior results are obtained if the initially formed catecholate is converted into a pinacolate prior to homolo gation.