Macrocyclic Enyne Methathesis and Its Applications

描述（由申请人提供）： 具体目标1：大环烯炔RCM反应的开发 a.通过开发新的通用底物平台，从以前未开发的大环形成烯炔复分解的系统研究中积累新知识。 B.烯炔复分解反应中取代基效应与环尺寸的关系研究。 C.探索控制环闭合中的外/内模式的参数和所得环状1，3-二烯的E/Z选择性。 D.探讨烯炔复分解反应中引发反应之争议。 具体目标2：开发用于构建大环碳环和大环内酯的硅系串联烯炔复分解反应 a.串联烯炔RCM的硅系链策略的开发以及硅醚和硅缩酮的有效合成。 B.应用硅链串联烯炔RCM反应全合成（+）-耳蜗霉素。 具体目标3：使用大环烯炔RCM反应合成C-1027的烯二炔核的生物遗传前体 a.基于烯炔RCM反应合成烯二炔类天然产物的新策略开发。 B.共轭炔基烷叉化合物的反应活性与选择性之研究。 C. 有效合成多种有效抗肿瘤剂C-1027的推定生物遗传前体。 D.（长期目标）与UW-Madison药学院Ben Shen教授合作研究，整合化学合成和生物合成工具，阐明烯二炔天然产物C-1027的生物合成途径。

DESCRIPTION (provided by applicant): Specific Aim 1: Development of the Macrocyclic Enyne RCM Reaction a. Accumulation of new knowledge from a systematic study of previously unexplored macrocycle-forming enyne metathesis by developing new general substrate platforms. b. The study of ring size-dependency and substituent effect in the enyne metathesis reaction. c. Exploration of the parameters that control exo/endo-mode in ring-closure and the E/Z selectivity of the resultant cyclic 1,3-dienes. d. Mechanistic study to address one of the controversial issues in enyne metathesis regarding the initiation. Specific Aim 2: Development of a Silicon-tethered Tandem Enyne Metathesis for the Construction of Macrocyclic Carbocycles and Macrolides a. Development of silicon tether strategy for tandem enyne RCM and the efficient synthesis of silyl ethers and silaketals. b. Application of silicon-tethered tandem enyne RCM reaction to a total synthesis of (+)-cochleamycin. Specific Aim 3: Synthesis of Biogenetic Precursors of the Enediyne Core of C-1027 using Macrocyclic Enyne RCM Reaction a. Development of novel strategy based on enyne RCM reaction for the synthesis of enediyne natural products. b. The study of the reactivity and selectivity of the conjugated alkynyl alkylidenes. c. Efficient synthesis of a variety of putative biogenetic precursors of a potent antitumor agent C-1027. d. (Long-term goal) Collaborative research with Professor Ben Shen of School of Pharmacy at UW-Madison by integrating the tools for chemical synthesis and biosynthesis for the elucidation of biosynthetic pathway of enediyne natural product C-1027.