Asymmetric Synthesis of Polyethers

本项目的具体目标是开发一种实用的、灵活的六元至九元环醚的对映选择性合成策略，并将新策略应用于结构新颖和生物学上重要的天然产物的全合成。在此研究过程中，将探索通过烯烃复分解和串联闭环烯烃复分解反应不对称构建中环醚的新合成技术。方便地获得α，α ′-二取代的醚键，并控制醚键α位的绝对立体化学，这对该计划的整体成功至关重要。两个重要的新方法已经从这个程序中发展出来：1）一个顺或反选择性羟醛缩合反应的氯钛烯醇化的羟乙酰恶唑烷硫酮和2）一个高度通用的不对称乙醇酸烷基化反应的建设α，α '-二取代醚。预计在下一个赠款期间将完成短杆菌毒素A、短杆菌毒素和粘杆菌毒素的合成。中环醚的一般方法的进一步发展将集中于对eunicellin和cladiellin类二萜的分子内Diels-Alder方法的发展，包括细胞毒性剂astrogorgin和4-Deoxyasbestinin A。一个新的策略，快速建设顺式-2，6-二取代的四氢吡喃，建立C2和C6立体异构中心在一个单一的步骤也将进行研究，并应用于细胞毒素lasonglycin A的全合成。

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.