DyCat3

Kinetic resolution is a useful process in industry and academia for the preparation of enantiomerically pure compounds. Despite its widespread use, a recognised drawback is that the theoretical maximum yield of a single enantiomer is 50%. This limitation can potentially be overcome by using dynamic kinetic resolution (DKR), in which the individual enantiomers of the racemic starting material interconvert dynamically. This process needs to be coupled with a selective KR event that allows the faster reacting enantiomer of the racemate to be selectively derivatised. The current state-of-the-art in this area has been reported by Bäckvall, who has reported and explored extensively the dual catalytic acylative DKR of secondary alcohols using chemoenzymatic methods. In contrast, the DKR of tertiary alcohols is a widely recognized challenge in the area of enantioselective catalysis as both enantiomerization and KR steps are difficult individually, but need to work synergistically and without inhibition for an effective DKR. The current state-of-the-art with respect to tertiary alcohol DKR has been demonstrated in a single isolated example by Gröger, using a metal-supported racemization catalyst coupled with enzymatic KR. Although moderate selectivity due to catalyst deactivation was observed, a sequential iterative batch process was successful and shows proof of principle that this challenging transformation is feasible. This proposal aims to develop a range of effective tertiary alcohol dynamic kinetic resolution strategies. Racemization approaches will rely upon either reversible nucleophilic addition to a carbonyl group, or boronic acid catalysis to reversibly prepare racemic tertiary alcohols, that coupled with a Lewis-base catalysed kinetic resolution will lead to efficient tertiary alcohol DKR.