Asymmetric Synthesis of Polyethers

描述(由8申请人提供)：该计划的具体目标是开发一种实用、灵活的策略，用于六到九元环醚的对映选择性合成，并将新策略应用于结构新颖和具有生物重要性的天然产物的全合成。在本研究过程中，将探索通过烯烃歧化反应和串联闭环烯烃歧化反应合成不对称中环醚的新技术。方便地获得α，α‘-二取代醚键，并控制α到醚键上的绝对立体化学，是该计划总体成功的关键。两个重要的新方法已经从这个项目中发展出来：1)乙醇基恶唑硫酮的氯钛烯醇酸盐的合成或反选择性Aldol反应和2)用于构建α，α‘-二取代醚的高度通用的不对称乙醇酸酸烷基化反应。短杆菌毒素A、长春新菌素和粘菌素的合成预计将在下一批赠款期间完成。进一步开发中环醚的一般方法将集中于开发分子内Diels-Alder方法来研究包括细胞毒剂阿司匹林和4-脱氧石棉素A在内的月见草素和枝状二萜类二萜化合物。一种快速构建顺式-2，6-二取代四氢吡喃的新策略也将被研究并应用于细胞毒素lasonolide A的全合成，该策略一步即可建立C2和C6立体生成中心。

DESCRIPTION (provided by 8applicant): The specific aims of this program are to develop a practical, flexible strategy for the enantioselective synthesis of six to nine membered ring ethers and apply the new strategies to the total synthesis of structurally novel and biologically important natural products. During the course of this investigation, new synthetic technologies will be explored for the asymmetric construction of medium ring ethers via olefin metathesis and tandem ring closing olefin metathesis reactions. Convenient access to alpha, alpha'-disubstituted ether linkages with control of the absolute stereochemistry at the positions alpha to the ether linkage is critical to the overall success of this program. Two important new approaches have already evolved from this program: 1) a syn or anti selective aldol reaction of chlorotitanium enolates of glycolyl oxazolidinethiones and 2) a highly versatile asymmetric glycolate alkylation reaction for the construction of alpha, alpha'-disubstituted ethers. Completion of the syntheses of brevetoxin A, gigantecin and mucocin are anticipated during the next grant period. Further development of the general approach to medium ring ethers will focus on the development of an intramolecular Diels-Alder approach to the eunicellin and cladiellin class of diterpenes including the cytotoxic agents astrogorgin and 4-Deoxyasbestinin A. A new strategy for the rapid construction of cis-2,6-distubstituted tetrahydropyrans that establishes both the C2 and the C6 stereogenic centers in a single step will also be investigated and applied to the total synthesis of the cytotoxin lasonolide A.