Biocatalytic Desymmetrization of an Atropisomer with both an Enantioselective Oxidase and Ketoreductases

Abstract

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 ...

Nonbiaryl and Heterobiaryl Atropisomers: Molecular Templates with Promise for Atropselective Chemical Transformations

“…Clayden, Turner, and co-workers documented a biocatalytic desymmetrization approach to access enantiomerically pure atropisomeric diaryl ethers (Scheme 48). 105 The reaction proceeded through enantioselective oxidation of diol 161 by galactose oxidase (GOase), resulting in monoaldehyde (P)-162 with 88% ee. Surprisingly, longer reaction times led to an increase in enantiomeric purity in 162 (up to 94% ee).…”

Stereoselective Hydride Transfer by Aryl‐Alcohol Oxidase, a Member of the GMC Superfamily

“…Stereoselective (or stereospecific) redox reactions have been described in oxidases, dehydrogenases, and other oxidoreductases, often being associated with active site architectures 11–17. Microbial and, more recently, enzymatic transformations are being actively investigated for a variety of asymmetric redox reactions of increasing commercial interest 18.…”

Enzymatic Desymmetrising Redox Reactions for the Asymmetric Synthesis of Biaryl Atropisomers

“…A schematic representation of the binding of the biaryl substrate 6 a is shown in Figure 3 b. Interestingly, diaryl ether substrates (for example, 7 ) are oxidised to the P -enantiomer by GOase M 3−5 10. We reason that the ether linkage in 7 allows the upper ring to lean over into the space above this plateau, thereby allowing the tert -butyl group in 7 to be placed towards the “cliff”.…”