Isothiourea‐Catalysed Regioselective Acylative Kinetic Resolution of Axially Chiral Biaryl Diols

Abstract

An operationally simple isothiourea‐catalysed acylative kinetic resolution of unprotected 1,1′‐biaryl‐2,2′‐diol derivatives has been developed to allow access to axially chiral compounds in highly enantioenriched form (s values up to 190). Investigation of the reaction scope and limitations provided three key observations: i) the diol motif of the substrate was essential for good conversion and high s values; ii) the use of an α,α‐disubstituted mixed anhydride (2,2‐diphenylacetic pivalic anhydride) was critical to minimize diacylation and give high selectivity; iii) the presence of substituents in the 3,3′‐positions of the diol hindered effective acylation. This final observation was exploited for the highly regioselective acylative kinetic resolution of unsymmetrical biaryl diol substrates bearing a single 3‐substituent. Based on the key observations identified, acylation transition state models have been proposed to explain the atropselectivity of this kinetic resolution.

Continuous Flow Preparation of Enantiomerically Pure BINOL(s) by Acylative Kinetic Resolution

“…We decided to evaluate isothioureas 5 a – d as catalysts for this study. The selection includes monomers 5 b – c as well as the first and second generation PS‐immobilized BTM‐type catalysts 5 a and 5 d , and is guided by previous results in the KR of axially chiral diols with homogeneous isothioureas (Figure ) …”

“…Chiral isothioureas, first reported by Birman in 2006, have become useful catalysts for the acylative KR of alcohols and carboxylic acids and, quite recently, for the desymmetrization of axially chiral diols . Benzotetramisole (BTM), the archetypical example of chiral isothioureas, is among the most readily available and effective nonenzymatic enantioselective acylation catalysts reported to date .…”

Catalytic Kinetic Resolution by Enantioselective Aromatization: Conversion of Racemic Intermediates of the Barton–Zard Reaction into Enantioenriched 3‐Arylpyrroles

“…The latter could in turn be converted into ent ‐ 3 . Kinetic resolution of the racemic biaryls by alcoholysis, N‐acylation/alkylation,– O‐acylation,– and direct arene functionalization– have been developed. However, kinetic resolution of nonbiaryl compounds by enantioselective aromatization, as illustrated in Scheme b, is, to the best of our knowledge, unprecedented.…”

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

“…They are recognized as effective catalysts for the acylative kinetic resolution (KR) of point chiral primary, secondary, and tertiary alcohols, and the acylative desymmetrization of diols . Building upon our work on enantioselective acyl transfer using isothiourea catalysis, we considered the generation of atropisomeric species through the acylative desymmetrization of symmetric biaryl diols (Figure B). We set out to deliver a process that would be applicable to a diverse scope of biaryls, without the requirement of incorporating a directing group, such as that utilized in the previous work of Akiyama (an ether) or Wang and Zhao (N‐protected aniline).…”