C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV, 26506, USA.
Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah, 84112, USA.
Org Biomol Chem. 2021 Dec 15;19(48):10596-10600. doi: 10.1039/d1ob02106k.
Developing an efficient, concise synthesis of the fungal natural product illudalic acid has been a long-standing challenge, made more pressing by the recent discovery that illudalic acid and analogs are selective phosphatase inhibitors. Syntheses of illudalic acid have become progressively more efficient over the decades yet remain strategically grounded in a 17-step synthesis reported in 1977. Here we validate a two-step process-convergent [4 + 2] benzannulation and one-pot coordinated functional group manipulations-for preparing the key trifunctional pharmacophore of illudalic acid. The modular building blocks are readily available in 2-3 steps, for a longest linear sequence (LLS) of 5 steps to illudalic acid from 3,3-dimethylcyclopentanone. A small collection of analogous indanes and tetralins featuring the same pharmacophore were prepared by a similar route. These compounds potently and selectively inhibit the human leukocyte common antigen-related (LAR) subfamily of protein tyrosine phosphatases (PTPs). Evidence supporting a postulated covalent ligation mechanism is provided herein.
开发真菌天然产物艾鲁达酸的高效、简洁合成方法一直是一个长期存在的挑战，最近发现艾鲁达酸及其类似物是选择性磷酸酶抑制剂，这使得这一挑战变得更加紧迫。几十年来，艾鲁达酸的合成方法已经变得越来越高效，但仍在战略上立足于 1977 年报道的 17 步合成方法。在这里，我们验证了一种两步法——收敛的[4+2]苯并环化和一锅协同官能团操作——用于制备艾鲁达酸的关键三功能药效团。模块化构建块可在 2-3 步内获得，从 3,3-二甲基环戊酮到艾鲁达酸的最长线性序列（LLS）为 5 步。通过类似的路线，还制备了一小部分具有相同药效团的类似茚烷和四氢萘。这些化合物能够强烈且选择性地抑制人类白细胞共同抗原相关（LAR）蛋白酪氨酸磷酸酶（PTP）亚家族。本文提供了支持假定的共价键合机制的证据。
