The total synthesis of Rhizoxin D, a samarium diiodide reduction method for beta-hydroxy and beta-alkoxy ketones, and an approach to Epothilone B.

摘要

Rhizoxin D is a 16-membered macrolide that has been isolated from Rhizopus chinesis. It has been found to possess antimitotic activity in eukaryotic cells by inhibition of tubulin polymerization and has shown activity in vincristine and adriamycin resistant tumor cells in vivo and in vitro.; Described herein is our second generation approach to the C₁₀-C ₂₀ fragment. This fragment utilizes our CAA reaction as a key element, as well as an unprecendented samarium diiodide reduction method of a (3-alkoxy ketone to the anti diol. The synthesis of Rhizoxin D was accomplished. Fragment assembly utilized modified Julia couplings that were developed for this application. Finally, the synthesis was completed through an efficient intramolecular Homer-Emmons reaction followed by one deprotection step.; A samarium diiodide-mediated stereoselective reduction of β-hydroxy ketones was developed that has several advantages over the traditional hydride reduction protocols. This method is operationally simple and tolerant of many functional groups.; The reduction of β-alkoxy ketones to anti diol mono-ethers is unprecedented. A reaction to accomplish this transformation is presented. The directing group ability of several alkoxy groups was examined. Finally we have shown that this reaction was amenable to multigram synthesis.; Epothilone B is a 16-membered macrolide that was isolated from the mvxobacterium Sorangium cellulosum. It also possesses antimitotic activity; however, the epothilones cause microtubule polymerization. It has the same binding site as Taxol and has been shown to be more potent and active in systems that are Taxol resistant.; Described herein is our approach to epothilone B and our synthesis of the C₁-C₉ fragment. This fragment utilizes the addition of a unique allyl stannane reagent, as a dianion equivalent, in a diastereoselective addition to a known aldehyde. Finally, the C₃ stereocenter is then set using the samarium diiodide-mediated method discovered during this synthesis.