Asymmetric Synthesis of Lactones and Lactams: Rhodium Catalysis in the Hydroacylation of Ketones and the Hydrogenation of Cyclic Dehydropeptides

Organic synthesis allows access complex materials in the context of fine chemicals, pharmaceuticals, and natural products, but many contemporary methods are wasteful – the focus is on the target rather than the process. Stoichiometric reagents, protecting groups, and multi-step processes are often involved to synthesize moieties such as chiral lactones and lactams, which are prevalent in biologically-relevant molecules like antibiotics (for example, the macrolides, typified by erythromycin) and cyclic peptides (such as cyclosporin and gramicidin). We have developed a rhodium-catalyzed lactonization of prochiral keto-aldehydes to access chiral lactones in a mild and atom-economical fashion, and a synthesis of cyclic peptides from achiral dehydropeptides using asymmetric rhodium-catalyzed hydrogenation to set the chirality in the peptide. In this fashion, we avoid using expensive and wasteful activating agents, protecting groups, and a host of other drawbacks endemic in lactonizations and peptide synthesis. This dissertation details: 1) the development of asymmetric rhodium-catalyzed hydroacylation, elucidation of the mechanism of this transformation through experimental and theoretical analyses, and the synthesis of chiral benzoxazecinones using this method, and 2) the synthesis of prochiral linear dehydropeptides, efficient cyclization of these molecules, and asymmetric reduction of multiple enamides in a highly enantio- and diastereoselective manner to access cyclic peptides.Ph