Studies toward the total synthesis of epothilone A
Date of Award
Doctor of Philosophy (PhD)
Epothilone A, Natural products, Wittig rearrangement-[2, 3]
Chemistry | Medicinal-Pharmaceutical Chemistry | Organic Chemistry | Physical Sciences and Mathematics
The goal of this work was the total synthesis of the promising antitumor candidate epothilone A. Recent work in our laboratories has focused on the use of stereocontrolled sigmatropic reactions for the construction of complex, polyketide-derived natural products. Particularly useful for the elaboration of polypropionate systems is the [2,3] Wittig rearrangement of tertiary allylic ethers, which generates stereodefined trisubstituted olefins.
Our approach to the epothilones, focused on the development of the C1-C12 subunit of the parent macrolide using the stabilized [2,3] Wittig rearrangement, was unique in that the C-3 hydroxyl stereochemistry was to be installed not through a stereoselective reduction of a carbonyl group, but via the [2,3] Wittig rearrangement. The [2,3] Wittig rearrangement of our epothilone A tertiary allylic ether intermediate produced trans olefin selectivity with low stereoselectivity observed at C-3.
The introduction of stereochemistry at C-6 was to be accomplished by stereoselective hydroboration of the trisubstituted trans olefin generated by [2,3] Wittig rearrangement; chemistry developed in this regard will find direct application to the synthesis of other biologically significant polyketide systems. However, attempts to investigate the stereoselective hydroboration of the stabilized [2,3] Wittig rearrangement product were unsuccessful.
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St. Denis, Francine Joy, "Studies toward the total synthesis of epothilone A" (2005). Chemistry - Dissertations. Paper 49.