Practical Synthesis of Macrobicyclic Thiolincosamines

J Am Chem Soc. 2024 Oct 23;146(42):29135-29139. doi: 10.1021/jacs.4c11270. Epub 2024 Oct 12.

Abstract

Scalable syntheses of the northern macrobicyclic thiolincosamine fragments of two structurally complex antibiotic candidates, BT-33 and cresomycin, are presented. A key transformation in each route is the highly diastereoselective addition of a putative allenylzinc nucleophile to a common Ellman sulfinimine intermediate using a zinc-promoted Barbier-type propargylation protocol that is detailed herein. These transformations proceed with dynamic kinetic resolution and use just 1.2 equiv of each respective propargyl bromide precursor.