Conformational Analysis of Long Chain Seco-Acids Used in Woodward’s Total Synthesis of Erythromycin A — Conformational Space Search as the Basis of Molecular Modeling

Abstract

The crucial step in Woodward’s total synthesis of erythromycin A, published in 1981, was the macrocyclization of appropriately substituted α-hydroxy-ω-carboxylic acid, called seco acid. After a number of unsuccessful attempts, they discovered that only one seco acid cyclized into lactone with an acceptable yield. Since then, it has been assumed that the seco acid that cyclized takes a folded conformation favorable for cyclization but this assumption has never been proved. This lecture reports the progress in our computational work aimed at identifying the structural elements that generated the folded conformation in this particular seco acid but not in the other, similarly substituted seco acids that Woodward and his coworkers studied. While the conformational space search of all of the Woodward’s seco acids have not been completed, we have so far found a cluster of folded conformers having close distance between the reacting hydroxy and carboxylic groups and have been able to determine a transition state of the cyclization reaction that arises from one of the folded conformers by using semi-empirical molecular orbital calculations.