Total Syntheses of Amphidinolide T1, T3, T4, and T5

A concise, flexible, and high yielding entry into the family of amphidinolide T macrolides, a series
of cytotoxic natural products of marine origin, has been developed. All individual members, except
amphidinolide T3 (3), derive from compound 39 as a common synthetic intermediate which is formed from
three building blocks of similar size and complexity. The fragment coupling steps involve a highly
diastereoselective SnCl4 mediated reaction of the furanosyl sulfone derivative 11 with the silyl enol ether
18 and a palladium-catalyzed Negishi type coupling reaction between the polyfunctional organozinc reagent
derived from iodide 32a and the enantiopure acid chloride 24b. The 19-membered macrocyclic ring is then
formed by a high yielding ring closing metathesis (RCM) reaction of diene 33 catalyzed by the “second
generation” ruthenium carbene complex 34. The efficiency of the RCM transformation stems, to a large
extent, from the conformational bias introduced by the syn−syn-configured stereotriad at C12−C14 of the
substrate which constitutes a key design element of the synthesis plan. The use of Nysted's reagent 38 in
combination with TiCl4 was required for the olefination of the sterically hindered ketone group in 36, whereas
more conventional alkene formations were unsuccessful for this elaboration. Finally, it is shown that the
inversion of a single and seemingly remote stereocenter (C12) in one of the building blocks not only affects
the efficiency and stereochemical outcome of the RCM step but also exerts a significant influence on the
course of the acyl-Negishi reaction, allowing a radical manifold to compete with productive cross coupling.

本研究开发了一种简洁、灵活且高产率的合成路径，可用于制备双鞭霉素T大环内酯类（amphidinolide T macrolides）化合物家族。该类化合物均为具有细胞毒性的海洋来源天然产物。除双鞭霉素T3（3）外，所有成员均以化合物39作为通用合成中间体，该中间体由三个规模与复杂度相近的结构单元构建得到。片段偶联步骤包含两个核心反应：一是四氯化锡（SnCl4）介导的呋喃基砜衍生物11与硅烯醇醚18的高非对映选择性反应；二是由碘化物32a衍生得到的多官能团有机锌试剂与对映纯酰氯24b之间的钯催化根岸型偶联反应。随后，通过二烯33在“第二代”钌卡宾配合物34催化下的高产率闭环复分解（Ring Closing Metathesis, RCM）反应，成功构建19元大环环系。该闭环复分解反应的高效性在很大程度上源自底物C12-C14位syn-syn构型立体三单元组所引入的构象偏向性，这也是本合成方案的关键设计要素。对于中间体36中空间位阻较大的酮基进行烯烃化反应时，需使用奈斯特试剂（Nysted's reagent）38与四氯化钛（TiCl4）联用，而常规烯烃形成方法在此步反应中均未获得成功。最后研究表明，在其中一个结构单元内单个看似远离反应位点的立体中心（C12）发生构型翻转时，不仅会影响闭环复分解步骤的反应效率与立体化学结果，还会显著改变酰基-根岸偶联反应的进程，使自由基反应路径能够与高效的交叉偶联反应相互竞争。