Macrocyclic Enyne Methathesis and Its Applications

描述(由申请人提供)： 具体目标1：大环烯炔RCM反应的研究进展 A.通过开发新的通用底物平台，从以前未探索的大环形成烯炔歧化反应的系统研究中积累新知识。 B.烯炔歧化反应中环大小依赖关系和取代基效应的研究。 C.探索了控制环合外模和内模的参数以及环状1，3-二烯的E/Z选择性。 D.机理研究，以解决enyne化合反应中关于起始的争议问题之一。 具体目标2：开发用于构建大环碳环和大环内酯类化合物的硅系联烯炔复位反应 A.开发串联烯炔RCM的硅系留策略以及硅醚和硅酮的高效合成。 B.硅系链烯炔RCM反应在()-耳霉素全合成中的应用。 特定目标3：利用大环烯炔RCM反应合成C-1027的烯二炔核心的生物发生前体 A.开发基于烯二炔RCM反应合成烯二炔天然产物的新策略。 B.共轭炔基烷基烯的反应性和选择性的研究。 有效地合成了一种有效的抗肿瘤药物C-1027的各种可能的生物遗传前体。 D.(长期目标)通过整合化学合成和生物合成工具，与威斯康星大学麦迪逊分校药学院沈本教授合作研究天然产物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.