Synthesis of the Anti-tumor Marcrolide Amphidinolide C

描述(由申请人提供)：本提案详细介绍了针对两面体内酯C全合成的研究。两面体内酯是由30多个大环内酯组成的结构多样化的基团，显示出有效和选择性的抗肿瘤特性。这一类无与伦比的结构异质性表明，要么是治疗癌症的一系列机械上独特的进展，要么是单一的未鉴定的细胞内效应器在配体结合中表现出巨大的混杂。由于缺乏可用的天然产物、类似物和生化试剂(例如，基于两性内酯的亲和探针和/或色谱柱等)，两性内酯的作用机理尚未得到研究。本文介绍了一种用于制备手性烯丙基1，2-反二醇的串联不对称Heck/enol-ether氧化策略的发展，并描述了它在制备苯内酯C的高氧C3-C9区域中的应用。该路线高度收敛，将扩大用于高效构建四氢呋喃的对映体选择性和双非对映选择性[3+2]环化策略的范围，并将是首次全合成苯二内酯C。

DESCRIPTION (provided by applicant): This proposal details studies directed toward the total synthesis of amphidinolide C. The amphidinolides, a structurally diverse group of over 30 macrolides, exhibit potent and selective anti-tumor profiles. The unparalleled structural heterogeneity in this class is indicative either of a host of mechanistically unique inroads to the treatment of cancers or a single unidentified intracellular effector which exhibits tremendous promiscuity in ligand binding. The mechanisms of action of the amphidinolides have gone unstudied, primarily due to a lack of available natural products, analogs, and biochemical reagents (e.g., amphidinolide-based affinity probes and/or columns, etc.). The proposed synthesis involves the development of a tandem asymmetric Heck/enol-ether oxidation strategy for the preparation of chiral allylic 1,2-anti diols and describes its application toward the preparation of the highly oxygenated C3-C9 region of amphidinolide C. The route is highly convergent, will expand the scope of enantioselective and doubly-diastereoselective [3+2] annulation strategies for the efficient construction of tetrahydrofurans, and will represent the first total synthesis of amphidinolide C.