Article ; Online: Biocatalytic Enantioselective Synthesis of Atropisomers.
2022 Volume 55, Issue 23, Page(s) 3362–3375
Abstract: ConspectusAtropisomeric compounds are found extensively as natural products, as ligands for asymmetric transition-metal catalysis, and increasingly as bioactive and pharmaceutically relevant targets. Their enantioselective synthesis is therefore an ... ...
| Abstract | ConspectusAtropisomeric compounds are found extensively as natural products, as ligands for asymmetric transition-metal catalysis, and increasingly as bioactive and pharmaceutically relevant targets. Their enantioselective synthesis is therefore an important ongoing research target. While a vast majority of known atropisomeric structures are (hetero)biaryls, which display hindered rotation around a C-C single bond, our group's long-standing interest in the control of molecular conformation has led to the identification and stereoselective preparation of a variety of other classes of "nonbiaryl" atropisomeric compounds displaying restricted rotation around C-C, C-N, C-O, and C-S single bonds.Biocatalytic transformations are finding increasing application in both academic and industrial contexts as a result of a significant broadening of the range of biocatalytic reactions and sources of enzymes available to the synthetic chemist. In this Account, we summarize the main biocatalytic strategies currently available for the asymmetric synthesis of biaryl, heterobiaryl, and nonbiaryl atropisomers. As is the case with more traditional synthetic approaches to these compounds, most biocatalytic methodologies for the construction of enantioenriched atropisomers follow one of two distinct strategies. The first of these is the direct asymmetric construction of atropisomeric bonds. Synthetically applicable biocatalytic methodologies for this type of transformation are limited, despite the extensive research into the biosynthesis of (hetero)biaryls by oxidative homocoupling or cross-coupling of electron-rich arenes. The second of these is the asymmetric transformation of a molecule in which the bond that will form the axis already exists, and this approach represents the majority of biocatalytic strategies available to the synthetic organic chemist. This strategy encompasses a variety of stereoselective techniques including kinetic resolution (KR), desymmetrization, dynamic kinetic resolution (DKR), and dynamic kinetic asymmetric transformation (DYKAT).Nondynamic kinetic resolution (KR) of conformationally stable biaryl derivatives has provided the earliest and most numerous examples of synthetically useful methodologies for the enantioselective preparation of atropisomeric compounds. Lipases (i.e., enzymes that mediate the formation or hydrolysis of esters) are particularly effective and have attracted broad attention. This success has led researchers to broaden the scope of lipase-mediated transformations to desymmetrization reactions, in addition to a limited number of DKR and DYKAT examples. By contrast, our group has used redox enzymes, including an engineered galactose oxidase (GOase) and commercially available ketoreductases (KREDs), to desymmetrize prochiral atropisomeric diaryl ether and biaryl derivatives. Building on this experience and our long-standing interest in dynamic conformational processes, we later harnessed intramolecular noncovalent interactions to facilitate bond rotation at ambient temperatures, which allowed the development of the efficient DKR of heterobiaryl aldehydes using KREDs. With this Account we provide an overview of the current and prospective biocatalytic strategies available to the synthetic organic chemist for the enantioselective preparation of atropisomeric molecules. |
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| MeSH term(s) | Stereoisomerism ; Prospective Studies ; Biocatalysis ; Molecular Conformation ; Catalysis |
| Language | English |
| Publishing date | 2022-11-07 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 1483291-4 |
| ISSN | 1520-4898 ; 0001-4842 |
| ISSN (online) | 1520-4898 |
| ISSN | 0001-4842 |
| DOI | 10.1021/acs.accounts.2c00572 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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