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.

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 concise total synthesis of S-14-methoxy-epothilone 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.Polyketide natural products are typically produced by microorganisms to create an environmental advantage for the producing organism through antibiotic and antifungal activity. Their structures evolve during the ancestral history of the producing organism through modification in their PKS gene clusters and the development or sequestration of genes encoding post-PKS processing enzymes. 1 The polyketide backbone is generated through the sequential incorporation of two-carbon extender units derived most commonly from malonyl-CoA or methylmalonyl-CoA. Advances in the genetic engineering of the gene clusters responsible for the production of biological active polyketides represents a valuable new source of chemical Unfortunately, the biological implications of even minor structural modifications are typically difficult to predict. Our unique approach to this classic structure-activity relationship (SAR) problem was based on the initial appreciation that the main role for the functionality that adorns a polyketide is to control the overall conformation. Through extensive computer-based conformational analysis coupled with solution NMR studies on the naturally-ocurring epothilones as well as designed analogues, we were able to develop a conformationalactivity relationship profile which was used to propose a binding conformation for the class. 3,4,5,6 With this information in hand it is possible to design biologically active analogues of the epothilones, such as epothilones C and D, Figure 1, which may be accessible through genetic engineering.Herein we report the total synthesis and biological evaluation of S-14-methoxy-epothilone D 2, a novel epothilone analogue. The stereochemistry of the C14-substitution was chosen to provide further support for the proposed binding conformation in the C11-C15 region. 7 Moreover, the incorporation of a methoxy group at this position represents a target potentially available through modification to the acyltransferase domain of module 3 in the epothilone PKS gene cluster 8 and the incorporation of an extender unit derived from methoxymalonyl CoA. 9The significant efforts required to develop a fermentation based route could be justified if the biological activity of the target were significant. Thus, a synthetic strategy for the production of S-14-methoxy-epothilone D was developed based upon modificatons to our previously reported route to epothilones B and D. 10 This route relied on a sequential Nozaki-HiyamaKishi (NHK) 11 couplingthionyl chloride induced allylic rearrangement 12 to stereoselectively...

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.

Abstract: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.