Theoretical study on the conformational diversity and dynamic effect in Pd-catalyzed atroposelective Suzuki–Miyaura cross coupling

Atroposelective Suzuki-Miyaura cross coupling serves as a powerful synthetic approach for the direct assembly of biaryl products with axial chirality. However, theoretical understanding and prediction for atroposelectivity remain elusive because the conformational diversity is complicated. Moreover, dynamic paths deviating from the minimum energy path also contribute to the product distribution. Herein, we performed a conformation sampling workflow based on molecular dynamics simulation with a constrained harmonic potential for coordinate bonds to completely sample the conformations of transition states for the crucial reductive elimination step in the catalytic cycle. Through statistical analysis of transition states conformations, an atroposelectivity ratio of 94:6 was determined, which matches well with the experimental results (97:3 er). On the other hand, ab initio molecular dynamics simulations were utilized to explore the dynamic path on the free energy surface. We are addressing persistent challenges in modeling highly irreversible processes using current enhanced sampling methodologies. This work is expected to stimulate future investigations on the conformational diversity and dynamic effect in Pd-catalyzed atroposelective Suzuki-Miyaura cross coupling reactions.