Stereochemical problems in macrolide antibiotics.

Since 1950, well over fifty macrolides have been derived from various Actinomycetes in screening laboratories located at many corners of the world. Among the most intensely studied macrolides are those produced on a commercial scale (erythromycin, oleandomycin, tylosin, leucomycin and spiramycin) as well as examples of particular historical/scientific importance (Magnamycin, pikromycin, narbomycin, methymycin). As a result of chemical studies by numerous investigators, many macrolides are now structurally defined. Their overall constitutional structures reveal an unusual wealth of stereochemical features involving numerous asymmetric centres and conformational possibilities among 12-, 14or 16-membered lactone rings containing an array of substituents including one, two or three glycoside units. Fruitful approaches to the special macrolide sugar problems have followed classical carbohydrate stereochemistry while numerous aglycone asymmetric centres have been successfully defined through localization in a variety of diagnostic fragments. X-ray studies are now complete on three macrolide derivatives. Total absolute configurations are ascribed to oleandomycin, erythromycin, Magnamycins, leucomycins, spiramycins, methymycin and pikromycin. Moreover, considerable configurational data are available on the aglycones of narbomycin, neomethymycin, lankamycin and chalcomycin. Recent structural revisions have greatly simplified the overall stereochemical problem by bringing 'into line' certain biogenetically 'out-of-step' proposals that have involved unusual 17-, 18and 22-membered rings as well as misplaced sugars. Growing stereochemical knowledge has largely confirmed an earlier biogenetically-based hypothesis that all antibacterial macrolides can be viewed as following the same configurational model regardless of ring size or degree of carbon branching in the aglycone chain. Application of the model to specific macrolides in need of further configurational definition affords likely insight to the chirality at many experimentally unprobed asymmetric centres. Recent conformational analyses of the 14-membered ring system in erythromycin aglycones using 100 MHz nuclear magnetic resonance and circular dichroism techniques indicate that the shape of the molecule in solution is relatively stable and similar to that in the crystal. The conformation most evident for erythronolide B is a modification of the diamond-lattice section model, taken from the geometry of cyclotetradecane. Available evidence suggests that 'isosteric' macrolides (erythromycin, lankamycin and oleandomycin) have similar conformations. Although the configurational and conformational models for macrolide antibiotics are still undergoing further refinements, they have proven useful during the entire course of their development in testing certain biogenetic and physico-chemical theories. At present, they are finding increasing applica-