Synthesis and evaluation of a stabilized propellane analog of the proteasome inhibitor salinosporamide A and total synthesis of mearsine and synthetic studies towards grandisine B

Naturally occurring salinosporamide A exhibits potent and selective inhibition of proteasome activity. Despite its efficacy as a reversible inhibitor of the 20S proteasome and possible clinical utility in the treatment of certain types of cancer, salinosporamide A still suffers from a lack of stability. We have developed a propellane analog of salinosporamide A that stabilizes the beta-lactone by virtue of its structure. Construction of the core structure -- the fused gamma-lactam, beta-lactone rings -- was efficiently achieved utilizing the Ugi 4-center 3-component reaction involving a gamma-ketoacid and a novel convertible isocyanide.;The second part of my research pertains to the total synthesis of mearsine and synthetic studies towards the total synthesis of grandisine B. Grandisine B is a human delta-opioid receptor agonist which presents the possibility of pain modulation without the negative side effects of mu-type agonists such as morphine. We have developed a unified synthetic route to mearsine and grandisine B which has allowed for the synthesis of the former. Key to the synthetic strategy is a novel ketimine forming methodology involving alkylithium addition to a pyrrolidinomethyl-protected [2.2.2]-bicyclic lactam.