Molecular mechanics (MM3(pi)) conformational analysis of molecules containing conjugated pi-electron fragments:...

The conformations of the 16-membered macrolide antibiotic leucomycin-V (1) were studied with molecular mechanics. Leucomycin-V contains a conjugated pi-electron fragment and necessitates special treatment with the MM3(pi) modeling protocol. Comparison was made with results from the standard MM3 scheme. The CONFLEX conformational search procedure was used for finding low-energy conformations. The computed data are indicative for the existence of mainly one conformation of the macro-ring of 1 and minor participation of several others. Intramolecular hydrogen bonds play important roles for the preferred geometry of the macro-ring and the conformations of the side chains. The most probable macro-ring conformation of 1 is very similar to the preferred conformation of another 16-ring macrolide antibiotic, tylosin. The same order of conformational preference for 1 was estimated with the MM3 and the MM3(pi) methods. Surprisingly, when changing the chirality of the C(9) macro-ring atom of 1, the two methods produced different order of conformational preferences for the 9-epi form (2), as well as enhanced population of several clusters of conformations.