Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α‑Phenyl Benzyl Cation

Development of a practical asymmetric synthesis of a
glucagon receptor
antagonist drug candidate for the treatment of type 2 diabetes is
described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane
core substituted with a propyl and three aryl groups including a fluoro-indole.
The key steps to construct the ethane core and the two stereogenic
centers involved a ketone arylation, an asymmetric hydrogenation via
dynamic kinetic resolution, and an anti-selective
Friedel–Crafts alkylation of a fluoro-indole with a chiral
α-phenyl benzyl cation. We also developed two new efficient
syntheses of the fluoro-indole, including an unusual Larock-type indole
synthesis and a Sugasawa-heteroannulation route. The described convergent
synthesis was used to prepare drug substance in 52% overall yield
and 99% ee on multikilogram scales.

本文报道了一款用于治疗2型糖尿病的胰高血糖素受体拮抗剂候选药物的实用不对称合成工艺。该拮抗剂以1,1,2,2-四取代乙烷为母核，其上连有一个丙基与三个芳基，其中一个为氟代吲哚（fluoro-indole）。构建该乙烷母核与两个手性中心的关键步骤包括：酮芳基化反应、基于动态动力学拆分的不对称氢化反应，以及氟代吲哚与手性α-苯基苄基正离子参与的反选择性傅-克烷基化（Friedel–Crafts alkylation）反应。此外，本研究还开发了两种新型高效的氟代吲哚合成方法，分别为罕见的Larock型吲哚合成法（Larock-type indole synthesis）与Sugasawa杂环化路线（Sugasawa-heteroannulation route）。本文所报道的汇聚式合成工艺可在千克级规模下以52%的总收率与99%对映体过量（enantiomeric excess, ee）制备原料药。