Synthesis and Biological Evaluation of 7-Deoxy-Epothilone Analogues.

The synthesis of two deoxygenated analogues of potent epothilones is reported in an effort to analyze the relative importance of molecular conformation and ligand-target interactions to biological activity. 7-deoxy-epothilone D and 7-deoxy-(S)-14-methoxy-epothilone D were prepared through total synthesis and shown to maintain the conformational preferences of their biologically active parent congeners through computer modeling and nuclear magnetic resonance (NMR) studies. The significant decrease in observed potency for each compound suggests that a hydrogen bond between the C7-hydroxyl group and the tubulin binding site plays a critical role in the energetics of binding in the epothilone class of polyketides.

Electrophile-induced ether transfer: stereoselective synthesis of 2,6-disubstituted-3,4-dihydropyrans.

Stereoselective synthesis of trans-2,6-disubstituted-3,4-dihydropyrans has been achieved from a simple homoallylic alkoxyether via a three-step sequence: electrophile-induced ether transfer, cyclization, and functionalization, which is highlighted by a rare example of Ferrier rearrangement of allylic ether. This methodology was successfully implemented for the asymmetric synthesis of a C7-C17 fragment of swinholide A.

A diastereoselective intermolecular heck reaction of 1,3-dioxepins.

A highly diastereoselective intermolecular Heck reaction of 1,3-dioxepins is reported. Substitution at both the 2- and 4-positions of the dioxepin directs the Pd coordination and subsequent olefin insertion to provide the trans-disubstituted adduct in good yield and high diastereoselectivity. Chemoselective Heck reaction occurs at the dioxepin alkene in the presence of other olefinic functional groups. A labeling study has been conducted which suggests that the reaction is under kinetic control.

Surveying approaches to the formation of carbon-carbon bonds between a pyran and an adjacent ring.

We have examined several methods for the stereoselective formation of carbon-carbon bonds between contiguous rings where a stereogenic center is already present. The approaches investigated were a [1,3] oxygen to carbon rearrangement of cyclic vinyl acetals, an intermolecular enolsilane addition into an in situ generated oxocarbenium ion, an intramolecular conjugate addition of tethered alkoxy enones, and epimerization of several α-pyranyl cycloalkanones. These routes have been found to be complementary in several cases and have enabled formation of both the trans:anti and cis:anti stereoisomers in good to excellent yields and varying diastereoselectivities. We have proven C2-C2' relative stereochemistry of 1-2 via a chemical correlation.

New sources of chemical diversity inspired by biosynthesis: rational design of a potent epothilone analogue.

A concise total synthesis of (S)-14-methoxyepothilone D has been accomplished. (S)-14-Methoxyepothilone D represents a conceptually novel example of polyketide analogue design based on an alternative biogenetic pattern of extender units. The significant biological activity observed for this compound provides a foundation to support studies designed to prepare derivatives of this type through fermentation of genetically engineered organisms expressing the epothilone PKS gene cluster.