Axially chiral aldehydes have emerged recently as a unique class of motifs for drug design. However, few biocatalytic strategies have been reported to construct structurally diverse atropisomeric aldehydes. Herein, we describe the characterization of alcohol dehydrogenases to catalyze atroposelective desymmetrization of the biaryl dialdehydes. Investigations into the interactions between the substrate and key residues of the enzymes revealed the distinct origin of atroposelectivity. A panel of 13 atropisomeric monoaldehydes was synthesized with moderate to high enantioselectivity (up to >99% ee) and yields (up to 99%). Further derivatization allows enhancement of the diversity and application potential of the atropisomeric compounds. This study effectively expands the scope of enzymatic synthesis of atropisomeric aldehydes and provides insights into the binding modes and recognition mechanisms of such molecules.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10900225 | PMC |
| http://dx.doi.org/10.1021/jacsau.3c00814 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Atroposelective synthesis of axially chiral imidazo[1,2-]pyridines via asymmetric multicomponent reaction.
Sci Adv
December 2024
School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210 China.
Imidazo[1,2-]pyridines are privileged heterocycles with diverse applications in medicinal chemistry; however, the catalytic asymmetric synthesis of these heterocyclic structures remains underexplored. Herein, we present an efficient and modular approach for the atroposelective synthesis of axially chiral imidazo[1,2-]pyridines via an asymmetric multicomponent reaction. By utilizing a chiral phosphoric acid catalyst, the Groebke-Blackburn-Bienaymé reaction involving various 6-aryl-2-aminopyridines, aldehydes, and isocyanides gave access to a wide range of imidazo[1,2-]pyridine atropoisomers with high to excellent yields and enantioselectivities.
View Article and Find Full Text PDFA stereodivergent multicomponent approach for the synthesis of C-N atropisomeric peptide analogues.
Chem Sci
September 2024
School of Natural and Environmental Sciences, Newcastle University Newcastle Upon Tyne NE1 7RU UK
Article Synopsis
- A four-component Ugi reaction is introduced for creating novel C-N atropisomeric peptide analogues, using common materials like anilines and aldehydes to achieve complex compounds with high yields and strong stereoselectivity.
- Adjusting the reaction temperature allows for stereodivergent outcomes, enabling the selective formation of either diastereoisomer from the same starting materials while maintaining excellent stereocontrol.
- Research includes detailed experimental and computational analysis of the reaction mechanism, revealing that the new atropisomeric compounds exhibit varying levels of inhibitory activity, highlighting the importance of the different atropisomers' structures in their efficacy.
Atroposelective Synthesis of Aldehydes via Alcohol Dehydrogenase-Catalyzed Stereodivergent Desymmetrization.
JACS Au
February 2024
Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China.
Axially chiral aldehydes have emerged recently as a unique class of motifs for drug design. However, few biocatalytic strategies have been reported to construct structurally diverse atropisomeric aldehydes. Herein, we describe the characterization of alcohol dehydrogenases to catalyze atroposelective desymmetrization of the biaryl dialdehydes.
View Article and Find Full Text PDFBiocatalytic Enantioselective Synthesis of Atropisomers.
Acc Chem Res
December 2022
School of Chemistry, University of Bristol, Bristol BS8 1TS, U.K.
Atropisomeric 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.
View Article and Find Full Text PDFAtropisomerism in Drug Discovery: A Medicinal Chemistry Perspective Inspired by Atropisomeric Class I PI3K Inhibitors.
Acc Chem Res
September 2022
Gilead Sciences, Inc., 199 E Blaine Street, Seattle, Washington 98102, United States.
Atropisomerism is a type of axial chirality resulting from hindered rotation about a σ bond that gives rise to nonsuperimposable stereoisomers (termed "atropisomers"). The inversion of chirality of an atropisomeric axis is a time- and temperature-dependent dynamic process occurring by simple bond rotation. For this reason, the rotational energy barrier (Δ) and the interconversion rate between an atropisomeric pair of biologically active molecules are important parameters to consider in drug discovery.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!