Synthesis of the Anti-tumor Marcrolide Amphidinolide C

描述（由申请人提供）：该提案详细介绍了针对两萜内酯c的全合成的研究。两萜内酯是一组结构多样的30多种大环内酯，具有有效和选择性的抗肿瘤特性。在这一类中，无与伦比的结构异质性表明，在治疗癌症方面，有许多机制上独特的进展，或者是一种未识别的细胞内效应，在配体结合方面表现出巨大的混杂性。两萜内酯的作用机制尚未得到研究，主要是由于缺乏可用的天然产物、类似物和生化试剂（例如，基于两萜内酯的亲和探针和/或色谱柱等）。本文提出了一种串联不对称Heck/烯醇醚氧化策略，用于制备手性烯丙基1,2-抗二醇，并描述了其在制备两萜内酯c的高氧合C3-C9区的应用。该路线高度收敛，将扩大对映选择性和双非对映选择性[3+2]环化策略的范围，用于高效构建四氢呋喃。这将是首次完全合成两萜内酯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.