A new efficient approach to chiral delta-hydroxy beta-ketoesters and its application in the synthesis of epothilone B an efficient synthesis of the C(17)--C(27) segment of the bryostatins

A novel allyl stannane reagent with an ester functional group was efficiently prepared. The binaphthol/Ti(O-iPr)₄ catalyzed asymmetric addition of this stannane reagent to a variety of aldehydes has been studied. Our results indicate that under the method B catalyst, the reaction provides high yields of the allylation products with excellent enantioselectivities. The utility of this new process towards the asymmetric generation of chiral δ-hydroxy β-ketoesters and other types of valuable intermediates in organic synthesis has been demonstrated.; The epothilones were first isolated from the myxobacterium Sorangium cellulosum. These 16-membered macrolides possess strong antitumor activity. Interestingly, despite the dramatic structural difference, the epothilones and Taxol share a similar mode of action by binding to the same region of the cellular microtubules, thereby preventing them from depolymerization.; Described herein is our approach to epothilone B and our synthesis of the C₁₀–C₂₁ segment. The synthesis employed our newly developed methodology for making chiral δ-hydroxy β-ketoesters to access a key intermediate, from which the geometrically defined C ₉–C₁₀ olefin was generated via a highly stereoselective formation of a vinyl triflate and its subsequent palladium catalyzed reduction.; The bryostatins are highly oxygenated 20-membered macrolides isolated from marine bryozoans. These compounds represent some of the most promising anticancer drug candidates, which can be highlighted by the remarkable efficacy shown by Bryostatin 1 in a variety of clinical trials for treating human cancers.; Described herein is our initial synthetic effort for making the bryostatins, which results in the successful synthesis of the C₁₇–C ₂₇ segment. Our synthesis began with the preparation of a chloromethallylstannane reagent, which served as an acetone dianion equivalent. The subsequent tandem allylation process using this stannane reagent constructed the carbon skeleton of the segment. The stereocenters in the molecule were established via substrate controlled 1,2- and 1,3-asymmetric induction. Upon successful formation of the C ring and the C₂₁ olefin, we completed the synthesis of a fully functionalized C ring segment of the bryostatins.