A facile one-pot, three-component protocol for, chiral synthesis of Cyanolactone as key intermediate of the Nafithromycin

Abstract

A facile one-pot, three-component protocol, for the large scale process of cyanide insertion was developed for synthesis of Cyanolactone (3) [Chemical name (11S, 21R)-11,12-dideoxy-6-O-methyl-2’,4’’-O-bis-(triethylsilyl)-12,11-[oxycarbonyl-(cyano)-methylene]-erythromycin A] as a key drug intermediate of Nafithromycin (6). The cesium carbonate used as a base for cyclisation and carried out insitu 1,4 Michael addition. Furthermore methanol as reaction promotor, which reacts with Trimethylsilyl cyanide (TMSCN) to produce methoxytrimethylsilane and liberate cyanide as nucleophile, which undergoes insitu nucleophilic substitution on 7 by SN2 pathway resulting in the asymmetric compound 3. This procedure has major advantages like insitu cyanide generation under close condition, cost-effective, short reaction time, good atom economy, ease of operation at manufacturing scale. The most significant aspect of the process was that it did not involve any direct handling of poisonous cyanide compounds like potassium or sodium cyanide. In addition, a key feature of optimization and isolation on kilogram scale is described herein.