Total Synthesis of Mycinolide IV and Path‐Scouting for Aldgamycin N

Abstract

Proof‐of‐concept is provided that a large estate of 16‐membered macrolide antibiotics can be reached by a “unified” approach. The key building block was formed on scale by an asymmetric vinylogous Mukaiyama aldol reaction; its alkene terminus was then converted either into the corresponding methyl ketone by Wacker oxidation or into a chain‐extended aldehyde by catalyst‐controlled branch‐selective asymmetric hydroformylation. These transformations ultimately opened access to two structurally distinct series of macrolide targets. Notable late‐stage maneuvers comprise a rare example of a ruthenium‐catalyzed redox isomerization of an 1,3‐enyne‐5‐ol into a 1,3‐diene‐5‐one derivative, as well as the elaboration of a tertiary propargylic alcohol into an acyloin by trans‐hydrostannation/Chan‐Lam‐type coupling. Moreover, this case study illustrates the underutilized possibility of forging complex macrolactone rings by transesterification under essentially neutral conditions.

Mukaiyama aldol reaction: an effective asymmetric approach to access chiral natural products and their derivatives/analogues

“…39,40 Aldgamycins are D-mycinose containing mycinolide macrolides having glycosylation at hydroxyl group on carbon 20. 41,42 Herle et al 43 reported the total synthesis of mycinolide IV 18, which led to the synthetic pathway towards aldgamycin N. The rst step of their synthetic route involves the reduction of compound 10 followed by its reaction with vinyl acetate and amino lipase in tetrahydrofuran, which resulted in compound 11 in 40% yield with 94% ee. Acetate 11 was then reacted with methyl lithium in the presence of diethyl ether followed by Swern oxidation to yield aldehyde 12.…”