New convertible isocyanides for the Ugi reaction; application to the stereoselective synthesis of omuralide.

摘要

Omuralide, derived from natural product lactacystin, is a member of a family of proteasome inhibitors, including the salinosporamides and the cinnabaramides, that all contain a novel fused gamma-lactam-beta-lactone core structure. A great deal of attention from the synthetic community has been paid to these natural products due to recent validation of proteasome inhibition as a novel therapeutic target in human cancer. A formal total synthesis of omuralide is introduced along with an efficient synthetic route to the shared common fused gamma-lactam-beta-lactone core structure among the aforementioned proteasome inhibitors. Key features of my synthetic studies include the development of two convertible isocyanides for use in the Ugi 4-center 3-component condensation reaction, their application in pyroglutamic acid derivative synthesis, and the development of a novel stereoselective Ugi reaction.