Studies directed toward the total synthesis of amphotericin B
Abstract
The polyene macrolide antibiotics are endowed with a unique structure, being composed of a highly functionalized macrocyclic lactone, which incorporates on opposing sides both a lipophilic polyene and hydrophilic polyol carbon chain. They are the last remaining group of known naturally occurring macrolides which have eluded total synthesis and recently, several synthetic studies toward this complex group of natural products have been reported. The ultimate goal of this research project is to develop a general convergent synthetic strategy for the total synthesis of the polyene macrolide amphotericin B (11), since it is the only polyene macrolide whose absolute structure has been verified by X-ray crystallography. The synthetic scheme involves preparation of four chiral fragments via; asymmetric hydrolysis of a $\beta$-hydroxy diester using enzyme catalysis and asymmetric reduction of a $\beta$-keto ester using Bakers' yeast. The carbon skeleton will then be further elaborated using a combination of methods including; biomimetic C-acylation, stereoselective aldol condensations, and various olefin forming reactions. The assembly of these chiral fragments will provide the aglycone of the natural macrolide. Glyocosation with the appropriate amino-glycosyl moiety will then complete the total synthesis. A second objective of this project is to develop selective degradation methods in order to provide fragments of the macrolide which can be used to verify attainment of the correct absolute stereochemistry of the synthetic fragments. It is hoped that the accomplishment of the total synthesis of amphotericin B will ultimately provide synthetic access to many other polyene macrolides and analogs thereof resulting for the first time in new compounds of this type for medicinal study. These analogs may provide a useful probe to define structure-activity relationships of the polyene macrolides which might ultimately lead to new medicinal applications.
Degree
Ph.D.
Advisors
Brooks, Purdue University.
Subject Area
Organic chemistry
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