Transition Metal Catalysis: Construction of Chiral Lactones, Ketones, Sulfoxides and 6-deoxyerythronolide B

The products of organic synthesis affect countless aspects of our everyday lives, from our medicines to our fuels, plastics and more. The discovery of new methods for organic synthesis is of paramount importance if we are to find greener and more efficient ways to synthesize commodity and fine chemicals, and lower the impact of the chemical industry on our environment. The aim of my doctoral thesis is to discover fundamentally new enantioselective transformations using transition metal catalysis, which can be applied to the synthesis of pharmaceutical agents, natural products or other fine chemicals. Hydroacylation is the atom economical addition of an aldehyde C–H bond across an unsaturated functional group such as an olefin or ketone. Theoretical studies on an intramolecular ketone hydroacylation catalyzed by rhodium were performed. The insights gained from this mechanistic study were then applied to the development of an asymmetric olefin hydroacylation using ethers, sulfides and sulfoxides as directing groups. Motivated by a desire to discover new catalysts with high activity and selectivity in rhodium catalyzed transformations, a chiral tridentate sulfoxide ligand was designed and synthesized. This ligand was found to be highly enantioselective in rhodium catalyzed 1,4-addition reactions. The use of allylic sulfoxides in a dynamic kinetic resolution was then investigated. The sulfoxide was found to direct a rhodium catalyzed olefin hydrogenation with simultaneous substrate racemization through a rhodium π-allyl pathway. Progress was made towards the total synthesis of a complex polyketide natural product, 6-deoxyerythronolide B. The key macrocyclization step was achieved in a model system by ring closing metathesis, and future work will be directed at completing the synthesis of the natural product.Ph