Development of new syntheses and transformations of beta-lactones: Application to a concise total synthesis of (+)-brefeldin A

A highly diastereoselective approach to cis-disubstituted β-lactones has been developed and involves a SnCl₄-mediated reaction between aldehydes and thiopyridyl ketene acetals. Results to date are most consistent with a stepwise [2+2] cycloaddition. Certain substrates and reaction conditions led to two subsequent in situ transformations to deliver β-chloro carboxylic acids and a tetrahydrofuran. 13C KIE studies of Lewis acid-mediated [2+2] cycloadditions of ketenes and aldehydes were conducted, and divergent rate-limiting steps have been proposed for the formation of diastereomeric β-lactones. These results suggest that a broader range of mechanistic possibilities for stereoselectivity in multistep reactions should be considered. A diastereoselective, β-lactone-based route to functionalized cyclopentanes involving intramolecular allylsilane additions was studied and optimized. This transformation was then successfully applied to a concise total synthesis of (+)-brefeldin A and a few brefeldin analogs. The versatility of cross metathesis in the context of natural product synthesis was also demonstrated by highlighting the tolerance of a β-lactone, a β-ketophosphonate and a functionalized aldehyde.