Abstract
Bicyclo[2.1.1]hexanes have generated considerable interest in recent years as bioisosteres of benzene. In this article, a C-H functionalization approach is described to derivatize the bicyclo[2.1.1]hexanes. The approach relies on dirhodium-catalyzed C-H insertion by donor/acceptor carbenes, which proceeds in a highly diastereoselective and enantioselective manner. By the appropriate choice of substrates, the reaction can also be highly site-selective. The bicyclo[2.1.1]hexane is a difficult system for C-H functionalization via carbene intermediates because it is a strained molecule, which causes the C-H bonds to be stronger than in an unstrained system. The only catalyst that performed well in this transformation is the newly developed D(4) symmetric catalyst, Rh(2)(S-megaBNP)(4), which contains four (4,4'-dichloro-6,6'-di(3,5-di-tert-butyl)phenyl)binaphthyl phosphate ligands. Computational studies revealed that the donor-acceptor carbene binds in a defined cleft within the bowl-shape of the dirhodium catalyst. Due to the high symmetry of the catalyst, only two orientations of the carbene are possible, and the most stable one has an open face for attack by the substrate. The substrate also needs to approach through a defined cleft causing the reaction to proceed with high levels of diastereoselectivity and enantioselectivity. These studies represent a further example of how the dirhodium catalysts can display many of the characteristics typically associated with enzymes with well-defined secondary interactions between the wall of the catalyst and the approaching substrate controlling the stereochemical outcome.