The Development and Application of a New Approach to the Rapid Synthesis of Polypropionate Stereotriads

The construction of polypropionate stereotriads in the synthesis of many non-aromatic polyketide natural products has typically been achieved through the "Roche ester" approach. This process starts with one of the stereocenters purchased as the Roche ester, followed by multiple redox and protecting group manipulations and only one carbon-carbon bond-forming aldol or crotylation reaction to attain the other two stereocenters of the stereotriad. Motivated by a desire for a more direct and rapid synthesis of these stereotriad constructs, we have built upon previous group methodology to develop a new approach utilizing a three step sequence of alkyne silylformylation-crotylation-Tamao oxidation. This strategy was first utilized in the synthesis of the C1-C9 fragment of the epothilones, and then this route applied to the synthesis of a C6 methyl-modified analog of epothilone B. We have also pursued the synthesis of versatile polypropionate building blocks as a way of generalizing our new approach.