Enantioselective synthesis of tetra-substituted 3- hydroxyphthalide esters by isothiourea-catalysed acylative dynamic kinetic resolution

Shubham Kumar Agrawal, Pankaj Majhi, Alister Stewart Goodfellow, Raj Tak, David Bradford Cordes, Aidan McKay, Kevin Kasten, Michael Buehl, Andrew David Smith

Research output: Contribution to journalArticlepeer-review

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 computation, with a key substrate heteroatom donor O•••acyl-isothiouronium interaction identified through DFT analysis as necessary for enantiodiscrimination.
Original languageEnglish
JournalAngewandte Chemie International Edition
DOIs
Publication statusAccepted/In press - 6 May 2024

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