Isothiourea-catalyzed atropselective acylation of biaryl phenols via sequential desymmetrization/kinetic resolution

Elizabeth Sarah Munday, Markas Grove, Taisiia Feoktistova, Alexander C. Brueckner, Daniel Walden, Claire Mary Young, Alexandra Martha Zoya Slawin, Andrew Campbell, Paul Ha-Yeon Cheong, Andrew D. Smith

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Axially chiral phenols are attractive targets in organic synthesis. This motif is central to many natural products and widely used as precursors to, or directly, as chiral ligands and catalysts. Despite their utility few simple catalytic methods are available for their synthesis in high enantiopurity. Herein the atropselective acylation of a range of symmetric biaryl diols is investigated using isothiourea catalysis. Studies on a model biaryl diol substrate shows that the high product er observed in the process is a result of two successive enantioselective reactions consisting of an initial enantioselective desymmetrization coupled with a second chiroablative kinetic resolution. Extension of this process to a range of substrates, including a challenging tetraorthosubstituted biaryl diol, led to highly enantioenriched products (14 examples, up to 98:2 er), with either HyperBTM or BTM identified as the optimal catalyst depending upon the substitution pattern within the substrate. Computation has been used to understand the factors that lead to high enantiocontrol in this process, with maintenance of planarity to maximize a 1,5‐S•••O interaction within the key acyl ammonium intermediate identified as the major feature that determines atropselective acylation and thus product enantioselectivity.
Original languageEnglish
JournalAngewandte Chemie International Edition
VolumeEarly View
Early online date11 Mar 2020
DOIs
Publication statusE-pub ahead of print - 11 Mar 2020

Keywords

  • Desymmetrization
  • Organocatalysis
  • Isothiourea
  • Kinetic resolution
  • Atropisomers

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