Studies Towards Functionalization of Cyclohexenones, Synthesis of Azabicycles and HDAC 6 Inhibitors

Carbonyl groups have been exploited in organic synthesis as powerful building blocks to access a wide variety of molecules with a high level of complexity. Indeed, one of the largest and most diverse classes of synthetic reactions involves the conjugate addition of m to the carbonyl groups, also known as enones. The first part of this dissertation describes methods to functionalize cyclohex-2-en-1-ones, or enones. Despite significant advances in approaches to functionalize the alpha and beta positions of enones and carbonyl groups, the introduction of substitution at the gamma position of these systems remains challenging. In this regard, we have developed a synthetic methodology for the gamma-amination of enones using a nitroso Diels–Alder reaction and subsequent copper-catalyzed ring opening and N-O bond cleavage. Although dienol phosphates have much potential as building blocks for organic synthesis, their full value has yet to be realized. We report a strategy to access beta-substituted enones through the nickel-catalyzed Suzuki–Miyaura coupling of dienol phosphates. This method is efficient and displays broad substrate scope. In the second part of this thesis, two projects are discussed. Azabicycles constitute the skeletal core of a wide array of alkaloids and, for that reason, have proven popular targets for total synthesis. We have explored the oxidative cyclization of O-alkyl hydroxamates to access various azabicyclic systems, particularly the role played by the O-alkyl substituent in this process. In the final portion of the dissertation, the discovery and development of a family of highly potent inhibitors of the enzyme HDAC6 is described.