Date of Award
Doctor of Philosophy (PhD)
Professor R. A. Bell
A unique approach to the synthesis of Erythromycins, involving the stereoselective synthesis of acyclic precursors, was studied. The simple materials; 3-pentanone, ethyl formate, and propionic anhydride were assembled to give the allylic ester 51. Subsequent stereoselective enolate formation of the propionate unit followed by a stereospecific Claisen rearrangement gave erythro-ϒ,δ-heptenoic acid 46. Stereo-selective epoxidation of the ϒ,δ-heptenoic acid followed by lactonization gave the ϒ-lactone system 49. This ϒ-lactone contains the correct array of functional groups and stereochemistry of the C₉-C₁₃ fragment of Erythronolide A, the aglycone of Erythromycin A and C.
The above starting materials; 3-pentanone, ethyl formate, and propionic anhydride together with propylene oxide were also assembled to give the allylic ester 55, which contains all of the carbon atoms and correct stereochemistry of the C₁-C₈ fragment of Erythronolide A (and B). The Claisen rearrangement of this ester is expected to give the carbon framework of the C₁-C₈ fragment. An important step in the synthesis of ester 55 was the mercuric assisted solvolysis of the α-methylthiohydrazone 61, which proceeded in a stereoselective manner. The reduction of enone 57, contrary to expectations, proceeded in a non-stereoselective manner.
Castelhano, Arlindo Lucas, "Synthons for the Construction of Erythromycin" (1980). Open Access Dissertations and Theses. Paper 613.