Total synthesis of inostamycin A

Abstract

The first total synthesis of inostamycin A is described. With efficient and stereoselective synthetic routes to aldehyde 128 and ketone 123 developed through asymmetric aldol reactions, addition reactions and reduction, and with chiral building blocks, the two large fragments were coupled with a remarkable anti-stereoselectivity and efficiency by aldol condensation. The coupling reaction provided the whole carbon skeleton with all the requisite functional groups and stereogenic centers for inostamycin A. The two quaternary carbons at C20 and C16 of ketone 123 were elaborated in a highly stereocontrolled manner by addition reactions of the transmetallated 131 to ethyl ketones 132 and the transmetallated 135 to methyl ketones 136, respectively, in which the use of $LaCl_3$ on transmetalation was critical for high coupling efficiency. C11-C24 fragment 122 which was intermediate of ketone 123 was prepared alternatively. The core scaffold of 122 was constructed via a series of addition reactions and an aldol condensation and the two quaternary carbon centers were installed via a diastereoselective desymmetrization.