Isothiourea catalyzed acylative dynamic kinetic resolution of heterocyclic tetra-substituted hemi-aminols | Poster Board #644

Kinetic resolution is a well-established process widely used in both industrial and academic settings for the efficient preparation of enantiomerically pure compounds. However, its inherent limitation is that the maximum theoretical yield of a single enantiomer from a racemic mixture is 50%. This issue can be addressed by employing a dynamic kinetic resolution (DKR) approach, which requires the individual enantiomers of the racemic starting material to interconvert (enantiomerization) at a timescale compatible with a subsequent enantioselective derivatization event. Current state-of-the-art DKRs are typically applied to secondary alcohols, with enantiomerization often facilitated through reversible dehydrogenation/hydrogenation or intramolecular ring closure/ring-opening mechanisms.
A key remaining challenge in this field is extending the DKR approach to fully substituted/tertiary alcohols. This is difficult due to several factors: (i) steric hindrance; (ii) enantioselective discrimination of fully substituted carbinols by catalyst; and (iii) coupling enantioselective acylation with efficient enantiomerization.
To address this challenge, we devised a reversible intermolecular nucleophilic addition as the enantiomerization strategy, combined with isothiourea-promoted enantioselective acylation. Our approach involves a reversible addition of a pyrazole to an isatin leads to the formation of racemic mixtures of tetra-substituted hemi-aminols, followed by isothiourea-promoted enantioselective acylation (incorporating the key substrate C=O…isothiouronium interaction for selectivity) to generate medicinally relevant N-heterocycles in enantiomerically pure form. The scope and limitations of this methodology have been developed, with high enantioselectivity and good to excellent yields (up to 95%, 99:1 er) observed across a broad range of substrate derivatives. Similarly, this process also works for pyrazolidindiones and different N-nucleophiles with excellent yield and enantioselectivity (>50 examples in total). To the best of our knowledge, this represents the first example of an organocatalytic acylative DKR of tetra-substituted hemi-aminols.