ABSTRACT
An electrochemical method to synthesize the core macrolactam of diazonamides is described. Large ring-forming dehydrogenation is initiated by anodic oxidation at a graphite surface. The reaction requires no tailoring of the substrate and occurs at ambient temperature in aqueous DMF in an undivided cell open to air. This unique chemistry has enabled a concise, scalable preparation of DZ-2384; a refined analog of diazonamide A slated for clinical development as a cancer therapeutic.
Subject(s)
Amides/chemistry , Lactams, Macrocyclic/chemistry , Oxazoles/chemistry , Pharmaceutical Preparations/chemistry , Amides/chemical synthesis , Azo Compounds/chemistry , Crystallography, X-Ray , Cyclization , Graphite/chemistry , Lactams, Macrocyclic/chemical synthesis , Molecular Conformation , Oxazoles/chemical synthesis , Oxidation-Reduction , Surface PropertiesABSTRACT
A novel series of 3-morpholino rifamycins in which the C25 acetate group was replaced by a carbamate group were prepared and found to exhibit significantly improved antimicrobial activity than rifampin against Mycobacterium smegmatis. Further characterization of such compounds suggests that relatively large groups attached to the rifamycin core via a C25 carbamate linkage prevent inactivation via ribosylation of the C23 alcohol as catalyzed by the endogenous rifampin ADP-ribosyl transferase of M. smegmatis. SAR studies of the C25 carbamate rifamycin series against M. smegmatis and other bacteria are reported.
