Azide‐free Enantioselective Synthesis of Clinical Antibiotic (1R,2R)‐Chloramphenicol (Chloromycetin)

Abstract

The enantioselective synthesis of the broad‐spectrum antibiotic (1R,2R)‐chloramphenicol and its congener is described here. Our approach is based on the Evans asymmetric aldol reaction, which involves the use of a chiral ‘glycine enolate equivalent’ derived from N‐(N‐Boc‐glycinyl) oxazolidinone and p‐nitrobenzaldehyde. The reaction is catalyzed by TiCl4 and Hunig's base DIPEA, resulting in the production of both Evans syn‐ and non‐Evans anti‐adducts in a 3 : 1 diastereomeric ratio with 85 % combined yield. We achieved diastereoselectivity control in the reaction using Lewis acid TiCl4 along with DIPEA. Subsequently, the syn‐ and anti‐aldol products were transformed into (1R,2R)‐ and (1R,2S)‐chloramphenicol, respectively, using a three‐step method. The stereochemistry of the clinically used chloramphenicol was confirmed by measuring the optical rotation of the final compounds.