Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, V5A 1S6, Canada.
Nat Commun. 2023 Apr 5;14(1):1904. doi: 10.1038/s41467-023-37346-7.
Eribulin (Halaven) is the most structurally complex non-peptidic drug made by total synthesis and has challenged preconceptions of synthetic feasibility in drug discovery and development. However, despite decades of research, the synthesis and manufacture of eribulin remains a daunting task. Here, we report syntheses of the most complex fragment of eribulin (C14-C35) used in two distinct industrial routes to this important anticancer drug. Our convergent strategy relies on a doubly diastereoselective Corey-Chaykovsky reaction to affect the union of two tetrahydrofuran-containing subunits. Notably, this process relies exclusively on enantiomerically enriched α-chloroaldehydes as building blocks for constructing the three densely functionalized oxygen heterocycles found in the C14-C35 fragment and all associated stereocenters. Overall, eribulin can now be produced in a total of 52 steps, which is a significant reduction from that reported in both academic and industrial syntheses.
依立布林（海乐卫）是通过全合成得到的结构最为复杂的非肽类药物，它挑战了药物发现和开发中合成可行性的先入之见。然而，尽管经过了几十年的研究，依立布林的合成和制造仍然是一项艰巨的任务。在这里，我们报告了两种不同工业路线中用于依立布林（C14-C35）的最复杂片段的合成。我们的聚合策略依赖于双重非对映选择性 Corey-Chaykovsky 反应来实现两个含有四氢呋喃的亚基的结合。值得注意的是，该过程仅依赖于对映体富集的α-氯醛作为构建 C14-C35 片段中三个高度功能化的含氧杂环和所有相关的立体中心的构建块。总体而言，依立布林现在可以通过总共 52 步合成得到，这与学术和工业合成中报道的步骤数相比有了显著的减少。
