The Total Synthesis of Macrolide Antibiotics

Citation

Daub, John Powell (1983) The Total Synthesis of Macrolide Antibiotics. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/87f1-5d52. https://resolver.caltech.edu/CaltechTHESIS:09032019-095416829

Abstract

An approach to the total synthesis of macrolide antibiotics via the key spiroketal intermediates i and ii, which possess all of the stereochemistry for the macrolides 10-deoxymethynolide (iii) and methynolide (iv), is described. Initially, the exocyclic enol ether v, which through hetero-Diels-Alder condensation with an α,β-unsaturated carbonyl compound would lead to these spiroketals i and ii, was prepared stereoselectively in optically pure form from 4,6-O-benzylidene-D-allal and was converted into the Prelog-Djerassi lactone (vi) by way of stereochemical confirmation. The low reactivity of this sensitive enol ether v toward hetero-Diels-Alder condensation led to the development of a new, high yield spiroketal synthesis through hetero-Diels-Alder condensation of the keto-enol ether vii with hetero-dienes; and, in this manner, the spiroketals i and ii were prepared stereoselectively. Cleavage of these spiroketals i and ii by thioketal exchange with 1,2-ethanedithiol led to seco-acid derivatives for the synthesis of the macrolides iii and iv. Additionally, a formal total synthesis of the antibiotic methymycin is achieved.

[See abstract in scanned thesis for chemical diagrams referenced above.]

Thesis Files