Improved Synthesis of Capuramycin and Its Analogues

Capuramycin and its congeners are considered to be important lead molecules for the development of a new drug for multidrug-resistant (MDR) Mycobacterium tuberculosis infections. Extensive structure-activity relationship studies of capuramycin to improve the efficacy have been limited because of difficulties in selectively chemically modifying the desired position(s) of the natural product with biologically interesting functional groups. We have developed efficient syntheses of capuramycin and its analogues by using new protecting groups, derived from the chiral (chloro-4-methoxyphenyl)(chlorophenyl)methanols, for the uridine ureido nitrogen and primary alcohol. The chiral nonracemic (2,6-dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methanol derivative is a useful reagent to resolve rac-3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, the (S)-configuration isomer of which plays a significant role in improving the mycobactericidal activity of capuramycin.