Synthesis of the Anti-tumor Marcrolide Amphidinolide C

描述（由申请人提供）：本提案详细描述了针对两性霉素C全合成的研究。两性环内酯是一组结构多样的30多种大环内酯类化合物，具有强效和选择性的抗肿瘤作用。在这类中的无与伦比的结构异质性是指示要么主机的机械独特的侵入治疗癌症或一个单一的身份不明的细胞内效应，表现出巨大的混杂在配体结合。两性环内酯的作用机制尚未研究，主要是由于缺乏可用的天然产物、类似物和生化试剂（例如，基于两性环内酯的亲和探针和/或柱等）。建议的合成涉及一个串联的不对称Heck/烯醇醚氧化策略的发展，用于制备手性烯丙基1，2-反二醇，并描述了它的应用对制备高度氧化的C3-C9区域的amphidinobenzene C。该路线是高度收敛的，将扩大对映选择性和双非对映选择性[3+2]成环策略的范围，以有效地构建四氢呋喃，并将代表第一个全合成的amphidinobenzene 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.