Department of Medicinal Chemistry, Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
Org Lett. 2012 Dec 21;14(24):6306-9. doi: 10.1021/ol303070k. Epub 2012 Dec 4.
Two distinct and scalable enantioselective approaches to the tricyclic indole (R)-2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate, an important synthon for a preclinical S1P(1) receptor agonist, are reported. Route 1 employs a modified version of Smith's modular 2-substituted indole synthesis as the key transformation. Route 2 involves a highly enantioselective CuH-catalyzed 1,4-hydrosilylation as the stereodefining step. Both routes can be performed without chromatography to provide multigram quantities of the tricycle in ≥98% ee.
现报道两种独特且可规模化的手性方法，用于合成三环吲哚（R）-2-（7-羟基-2,3-二氢-1H-吡咯并[1,2-a]吲哚-1-基）乙酸酯，这是一种临床前 S1P（1）受体激动剂的重要前体。路线 1 采用了 Smith 的模块化 2-取代吲哚合成的改良版本作为关键转化。路线 2 涉及高度对映选择性的 CuH 催化 1,4-硅氢化反应作为立体定义步骤。这两种路线都可以在无需进行色谱分离的情况下进行，以提供多克数量的具有 ≥98%ee 的三环产物。
