Pro-Atropisomeric Ynamides as Starting Materials for the Synthesis of C–N Atropisomers by Dynamic Kinetic Resolution Reactions

Abstract

Tertiary N-sulfonyl anilides in which the aromatic ring bears a bulky ortho-substituent typically display robust atropisomerism as a result of slow C–N bond rotation. There is intense interest in such molecules, but methods for their catalytic enantioselective synthesis remain underdeveloped. In this work, we report that N-sulfonyl ynamides, in which the nitrogen atom bears an alkynyl substituent, undergo rapid racemization on the time scale of seconds making them an ideal class of starting materials for dynamic kinetic resolution reactions to access C–N atropisomeric targets. We have shown that these ynamides can be straightforwardly prepared and undergo a wide range of different transformations, including hydration, rearrangement, oxidation, (hetero)annulation, and addition processes. All of these reactions lead to a remarkable enhancement in configurational stability, with the products racemizing 5–12 orders of magnitude more slowly than the corresponding ynamide precursors. This is an ideal scenario to achieve dynamic kinetic resolution, a concept which has been validated by the development of a catalytic asymmetric sulfa-Michael addition reaction of pro-atropisomeric ynamides, which delivers highly enantioenriched C–N atropisomeric enamides in up to 97% yield and 97:3 e.r. Detailed experimental and computational studies were performed to explore the origins of asymmetry in this process, and the utility of the novel products was established through a series of derivatization reactions.