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. 2022 Aug 24;144(33):15026-15032.
doi: 10.1021/jacs.2c06529. Epub 2022 Aug 15.

An Enantioselective Suzuki-Miyaura Coupling To Form Axially Chiral Biphenols

Robert Pearce-Higgins  1 , Larissa N Hogenhout  1 , Philip J Docherty  1 , David M Whalley  1 , Padon Chuentragool  1 , Najung Lee  1 , Nelson Y S Lam  1 , Thomas M McGuire  2 , Damien Valette  3 , Robert J Phipps  1
Affiliations

An Enantioselective Suzuki-Miyaura Coupling To Form Axially Chiral Biphenols

Robert Pearce-Higgins et al. J Am Chem Soc. .

Abstract

Axial chirality features prominently in molecules of biological interest as well as chiral catalyst designs, and atropisomeric 2,2'-biphenols are particularly prevalent. Atroposelective metal-catalyzed cross-coupling is an attractive and modular approach to access enantioenriched biphenols, and yet existing protocols cannot achieve this directly. We address this challenge through the use of enantiopure, sulfonated SPhos (sSPhos), an existing ligand that has until now been used only in racemic form and that derives its chirality from an atropisomeric axis that is introduced through sulfonation. We believe that attractive noncovalent interactions involving the ligand sulfonate group are responsible for the high levels of asymmetric induction that we obtain in the 2,2'-biphenol products of Suzuki-Miyaura coupling, and we have developed a highly practical resolution of sSPhos via diastereomeric salt recrystallization.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Background, 2,2′-biphenols and sSPhos.
Scheme 1
Scheme 1. Scope of the Enantioselective Suzuki–Miyaura Coupling for Both Biphenols and Triphenols
Yields are isolated. ee values determined by SFC. 2.6 equiv of 2 used. 5.0 equiv of 2 used with 10 mol % Pd(OAc)2 and 12 mol % (R)-sSPhos for 64 h. 2.0 equiv of 2 used with 2.5 mol % Pd2(dba)3 and 6 mol % (R)-sSPhos for 16 h.
Scheme 2
Scheme 2. Control Experiments, Desymmetrizing Cross-Coupling, and Ligand Recrystallization
See this image and copyright information in PMC

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