Gram-scale synthesis of (+)-spongistatin 1: Development of an improved, scalable synthesis of the F-ring subunit, fragment union, and final elaboration

In a quest to develop an effective, scalable synthesis of (+)-spongistatin 1 (1), we devised a concise, third-generation scalable synthesis of (+)-7, the requisite F-ring tetrahydropyran aldehyde, employing a proline-catalyzed cross-aldol reaction. Subsequent elaboration to (+)-EF Wittig salt (+)-3, followed by union with advanced ABCD aldehyde (-)-4, macrolactonization and global deprotection permitted access to >1.0 g of totally synthetic (+)-spongistatin 1 (1).