Synthesis of Tetra‐Substituted 3‐Hydroxyphthalide Esters by Isothiourea‐Catalysed Acylative Dynamic Kinetic Resolution
Shubham Agrawal, Pankaj Kumar Majhi, Alister S. Goodfellow, Raj Kumar Tak, David B. Cordes, Aidan P. McKay, Kevin Kasten, Michael Buehl, Andrew D. Smith
Abstract
A general and highly enantioselective method for the preparation of tetra-substituted 3-hydroxyphthalide esters via isothiourea-catalysed acylative dynamic kinetic resolution (DKR) is reported. Using (2S,3R)-HyperBTM (5 mol %) as the catalyst, the scope and limitations of this methodology have been extensively probed, with high enantioselectivity and good to excellent yields observed (>40 examples, up to 99 %, 99 : 1 er). Substitution of the aromatic core within the 3-hydroxyphthalide skeleton, as well as aliphatic and aromatic substitution at C(3), is readily tolerated. A diverse range of anhydrides, including those from bioactive and pharmaceutically relevant acids, can also be used. The high enantioselectivity observed in this DKR process has been probed computationally, with a key substrate heteroatom donor O⋅⋅⋅acyl-isothiouronium interaction identified through DFT analysis as necessary for enantiodiscrimination.