Enantioselective Suzuki–Miyaura Chemistry: Route Evolution for the Synthesis of PKMYT1 Inhibitor XL495
Abstract
An asymmetric synthetic route to XL495, an atropisomeric PKMYT1 inhibitor, is reported. While a kilogram-scale and practical process was established by classic salt resolution, concerns related to the commercial process led to the study of an enantioselective alternative. The new route leverages an enantioselective Suzuki-Miyaura reaction as a key step in the atroposelective synthesis of biaryl compounds. A crystallization method for selectively purifying the target atropisomer was developed through high-throughput experimentation (HTE), enabling an enantiomeric excess (ee) of >95%. This new chemistry has been demonstrated and shows promise for utility at large scale, typical of a late-stage clinical and commercial route, due to significant improvements in overall yield, process mass intensity (PMI), and production efficiency.
Fields of Study & Subjects
Axial and Atropisomeric Chirality Synthesis
Catalytic Cross-Coupling Reactions
Asymmetric Synthesis and Catalysis
Publication details
- Journal / source
- The Journal of Organic Chemistry
- Publisher
- American Chemical Society (ACS)
- Volume
- 91
- Issue
- 15
- Pages
- 5379–5387
- Publication date
- 6 April 2026
- Language
- EN