Many therapeutic agents are macrocyclic trisubstituted alkenes but preparation of these structures is typically inefficient and non-selective. A possible solution would entail catalytic macrocyclic ring-closing metathesis, but these transformations require high catalyst loading, conformationally rigid precursors and are often low yielding and/or non-stereoselective. Here we introduce a ring-closing metathesis strategy for synthesis of trisubstituted macrocyclic olefins in either stereoisomeric form, regardless of the level of entropic assistance. The goal was achieved by addressing several unexpected difficulties, including complications arising from pre-ring-closing metathesis alkene isomerization. The power of the method is highlighted by two examples. The first is the near-complete reversal of substrate-controlled selectivity in the formation of a macrolactam related to an antifungal natural product. The other is a late-stage stereoselective generation of an E-trisubstituted alkene in a 24-membered ring, en route to the cytotoxic natural product dolabelide C.

许多治疗剂是大环三取代烯烃，但这些结构的制备通常效率低下且没有选择性。一种可能的解决方案需要催化大环闭环复分解，但这些转化需要高催化剂负载、构象刚性前体，并且通常产率低和/或非立体选择性。在这里，我们介绍了一种闭环复分解策略，用于合成任一立体异构形式的三取代大环烯烃，无论熵助水平如何。该目标是通过解决几个意想不到的困难实现的，包括预闭环复分解烯烃异构化引起的并发症。两个示例突出了该方法的强大功能。第一个是在与抗真菌天然产物相关的大环内酰胺形成中底物控制选择性的几乎完全逆转。另一种是晚期立体选择性生成的24 元环中的E-三取代烯烃，在通往细胞毒性天然产物多拉贝特 C 的途中。