Isothiourea‐Catalyzed Atropselective Acylation of Biaryl Phenols via Sequential Desymmetrization/Kinetic Resolution

• Published in: Angewandte Chemie International Edition Vol. 59; no. 20; pp. 7897 - 7905
• Main Authors: Munday, Elizabeth S., Grove, Markas A., Feoktistova, Taisiia, Brueckner, Alexander C., Walden, Daniel M., Young, Claire M., Slawin, Alexandra M. Z., Campbell, Andrew D., Cheong, Paul Ha‐Yeon, Smith, Andrew D.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 11-05-2020
• Edition: International ed. in English
• Subjects: Acylation; Ammonium; atropisomers; Catalysis; Catalysts; desymmetrization; Diols; Enantiomers; isothiourea; kinetic resolution; Natural products; organocatalysis; Phenols; Substrates; organocatalysis; kinetic resolution; atropisomers; desymmetrization; isothiourea
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201916480

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.
Atropselective acylation of symmetric biaryl diols using isothiourea catalysis leads to chiral biaryls with high enantioselectivity. This process consists of two successive enantioselective reactions with an initial desymmetrization coupled with a chiroablative kinetic resolution.