PubMed · 13073602
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J SUPNIEWSKI. 1953-03-23. [Erythromycin].. https://pubmed.ncbi.nlm.nih.gov/13073602/
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The substrate for selective substitution in the C10-methyl group in erythromycin A derivatives was 10,11-anhydro-6O-methyl-descladinosylerythromycin. The latter, as an N-oxide, was reacted with NBS in acetic acid to form an allylic acetate. Nucleophilic substitutions and carbylation by Pd-catalysed cross-coupling reactions provided products substituted in the C10-methyl group. Methods for the preparation of 10-methylene derivatives of 11N,12O-cyclocarbamate 3-ketolides are described. The methylene group is part of an alpha,beta-unsaturated carbonyl system involving the 9-keto group. The products from conjugated addition are substituted in the C10-methyl group.
Anhydroerythromycin A arises from the acid-catalysed degradation of erythromycin A both in vitro and in vivo. It has negligible antibacterial activity, but inhibits drug oxidation in the liver, and is responsible for unwanted drug-drug interactions. Its structure has 18 chiral centres common with erythromycin A, but C-9 (the spiro carbon) is also chiral in anhydroerythromycin and its stereochemistry has not previously been reported; both 9R- and 9S-anhydroerythromycin A are plausible structures. An understanding of the chirality at C-9 was expected to throw light on the mechanism of acid-catalysed degradation of erythromycin A, a subject that has been debated in the literature over several decades. We now report a determination of the three-dimensional structure of anhydroerythromycin A, including the stereochemistry at C-9, by NMR and molecular modelling. In parallel, the relative stereochemistry of anhydroerythromycin A 2'-acetate was determined by X-ray crystallography. Both compounds were shown to have 9R stereochemistry, and anhydroerythromycin A exhibited considerable conformational flexibility in solution.
Chemobiosynthesis has been used to prepare analogs of erythromycins having unique functional groups at the 15-position. Using diketide thioester feeding to genetically engineered Streptomyces coelicolor, analogs of 6-deoxyerythronolide B were prepared having 15-fluoro, 15-chloro, and 15-azido groups. Bioconversion using a genetically engineered mutant of Saccharopolyspora erythraea was used to produce 15-fluoroerythromycin A and 15-azidoerythromycin A. These new erythromycin analogs provide antibacterial macrolides with unique physicochemical properties and functional groups that allow for selective derivatization.