Synthetic Innovations in Efforts Toward the Development of Spongistatin 1 as an Anti-Cancer Therapeutic

A major focus of the Leighton group is on the development of chemistry to aid in the efficient and scalable synthesis of polyketides. Over the past several years, our group has been interested in utilizing strained silanes to rapidly access the structural motifs commonly found in polyketides. Notably, our EZ-CrotylMix methodology allows for the crotylation of deactivated and sterically hindered aldehydes that popular methods, such as the Brown crotylation, fail to achieve. In order to improve the practicality of our crotylation methodology, we have developed a new, more powerfully activating diamine ligand scaffold that provides access to highly active allyl- and crotyl-silanes. These silanes can be generated in situ, precluding the need for a laborious isolation of the moisture sensitive crotylsilane reagents that is necessary for our previously reported methodology. The group’s crotylation methodology has proved useful in our current efforts toward the total synthesis of spongistatin 1 and its analogs. Work on the synthesis of an analog of spongistatin 1, specifically on the completion of the northern ABCD hemisphere, will also be discussed.