First-Generation Asymmetric Synthesis of the Selective Estrogen Receptor Degrader GDC-9545 (Giredestrant) Featuring a Highly Efficient Pictet-Spengler Reaction and a C-N Coupling Reaction

An asymmetric synthesis of the selective estrogen receptor degrader GDC-9545 (1) is described. The synthesis features a Friedel-Crafts indole functionalization and a strain-release aminoazetidine formation to construct the two key starting materials 2 and 4, respectively, a diastereoselective Pictet-Spengler reaction (98% yield, 95:5 dr) to assemble the tetrahydrocarboline core, and a highly efficient Pd-catalyzed C-N coupling (90% yield) using [t-BuBrettPhos Pd(allyl)]OTf as the catalyst and DBU as the base to furnish the final C-N bond. This expedient route produces GDC-9545.tartrate active pharmaceutical ingredient in a longest linear sequence of six steps in 37% overall yield with 99.0 area % HPLC purity without chromatographic purification.

Automated summary

This article describes an asymmetric synthesis of the selective estrogen receptor degrader GDC-9545, which involves key steps such as indole functionalization and aminoazetidine formation to construct the starting materials. The target compound is successfully synthesized through a diastereoselective reaction and a highly efficient coupling reaction.