Presentation description

Enantiomers are molecules that are non-superimposable mirror images of each other. Atropisomers are a subtype of enantiomers that exhibit chirality along a sigma bond and are constrained from free rotation due to steric hindrance. This unique property makes atropisomers especially compelling in drug development, as their locked confirmations have the potential to enhance binding affinity. They are categorized into three classes based on the free-energy barrier for racemization - the process where one enantiomer converts into the other. In collaboration with Genentech, this project aims to develop methods for synthesizing a class three atropisomeric scaffold with chirality along carbon-nitrogen bonds which would feature a rotational barrier greater than 30 kcal/mol.

Building upon existing literature, we propose a selective cyclization catalyzed by a Palladium complex with a chiral ligand to achieve enantioselectivity. The starting materials required for the cyclization step could be synthesized via amide coupling reactions. We explored various combinations of Palladium precursors, ligands, solvents, bases and temperatures in cyclizations of five and six-membered rings with diverse ortho substituents. Our findings indicate that synthesizing the starting materials for five-membered ring carbamates were significantly more challenging than for their six member ring counterparts, most likely due to stabilization from the additional CH2 group. In cyclization reactions, control experiments using non-chiral ligands yielded decent results with 49/51 enantiomeric excess. However, cyclizations using chiral ligands resulted in notably lower yields, with most products being barely detectable. Further optimization is needed to improve yields and enhance chiral induction.