Bring on the substitute: Even outside of macrocyclic structures, such as vancomycin, appropriate substitution can give rise to atropisomerism in diaryl ethers. Stereochemical stability about the ArOAr axis at room temperature or above is possible when neither of the rings is symmetrically substituted and when at least one ring carries an ortho tert‐butyl group or equivalent.

Atropisomeric ligands have found numerous powerful applications in catalysis, [1] and the atropisomeric biaryl bisphosphine binap played an important role in the award of a Nobel Prize to Noyori in 2001.[2] Enantiomerically pure atropisomers commonly employed as chiral ligands are generally made by resolution: there are still relatively few effective methods for direct asymmetric coupling to form single enantiomers. [3] Kinetic resolution [4] and dynamic resolution [5] under kinetic [5a] or thermodynamic [5b] control are particularly appealing given the possibility offered by atropisomerism for thermal racemization of the less reactive enantiomer. The use of desymmetrization for the synthesis of single atropisomers is rare. [6] Following the early example of enantioselective lithiation reported by Raston and co-workers, [6b] the research groups of Hayashi [6c] and Harada [6d] also reported chemical methods for desymmetrizing biphenyl compounds. A single example of the enzymatic desymmetrization of a biaryl compound with a lipase was reported by Matsumoto et al.[6e]Herein, we report two novel and complementary biocatalytic approaches to the enantioselective synthesis of atropisomers by the desymmetrization of appropriate achiral substrates containing a pair of enantiotopic functional groups. The atropisomer in question is the diaryl ether 2, which may be formed either by enantioselective oxidation of the symmetrical diol 1 or by the corresponding reduction of the symmetrical dialdehyde 3 (Scheme 1). The enzymes we employed for these transformations were 1) a variant of galactose oxidase (GOase) which had been previously evolved to accept chiral benzylic alcohols as substrates with high enantioselectivity (1!2) [7] and 2) a family of ketoreductases that are known to possess good activity and enantioselectivity for the asymmetric reduction of benzylic ketones (3!2). [8] Atropisomeric diaryl ethers [9] form part of the structure of vancomycin [10] and are promising scaffolds for the construction for new chiral ligands.[11] Dialdehyde 3 and diol 1 were made by our published route. [9] In an initial screen, we attempted enantioselective acetylation by incubating diol 1 with Candida antarctica lipase B and vinyl acetate. Slow acylation of 1 was observed with approximately 50 % conversion after 24 h to the monoacetate 4 and modest enantioselectivity (60 % ee). In contrast, when diol 1 was incubated with the previously reported M 3-5 variant of GOase, [7] rapid oxidation to the monoaldehyde (P)-2 resulted in 80 % conversion after 24 h to material with 94 % ee.During the oxidation of 1 to 2, rapid formation of the product (P)-2 with approximately 88 % ee (see below for assignment of the absolute configuration) was observed after 1 h, followed by a slower increase in enantiomeric purity to a maximum ee value of 94 % (Figure 1). This increase in the ee value, along with the formation of the dialdehyde 3 (14 % after 24 h), suggested that the minor enantiomer (M)-2 produced in the enantioselective oxidation of 1 was ...

Twisted ethers: Introduction of a bulky alkylsulfinyl substituent ortho to the C–O axis of a diaryl ether imposes a powerful conformational preference (see scheme). The preference persists upon oxidation of the sulfoxide to a sulfone, leading to dynamic thermodynamic resolution of the atropisomeric ether. This is the first enantioselective synthesis of an atropisomeric diaryl ether not forming part of a macrocyclic ring.

The orientation of Ar-C, Ar-N and Ar-O bonds in biaryls, N,N'-diarylureas and diaryl ethers (whose conformers are distinguishable by NMR) may be controlled with a selectivity up to >95 : 5 by an adjacent stereogenic centre; the selectivity may be greater when a second stereogenic axis is inserted between the controlling centre and the slowly rotating bond.

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