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
- Author(s): Vamos, Mitchell Dennis
- et al.
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 [lambda]-lactam, [beta]-lactone rings - was efficiently achieved utilizing the Ugi 4- center 3-component reaction involving a [lambda]-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