Cyclopropane rings are an important structural motif frequently found in many natural products and pharmaceuticals. Commonly, biocatalytic methodologies for the asymmetric synthesis of cyclopropanes rely on repurposed or artificial heme enzymes. Here, we engineered an unusual cofactor-independent cyclopropanation enzyme based on a promiscuous tautomerase for the enantioselective synthesis of various cyclopropanes via the nucleophilic addition of diethyl 2-chloromalonate to α,β-unsaturated aldehydes. The engineered enzyme promotes formation of the two new carbon-carbon bonds with excellent stereocontrol over both stereocenters, affording the desired cyclopropanes with high diastereo- and enantiopurity (d.r. up to 25:1; e.r. up to 99:1). Our results highlight the usefulness of promiscuous enzymes for expanding the biocatalytic repertoire for non-natural reactions.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596749 | PMC |
| http://dx.doi.org/10.1002/anie.202110719 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Flow chemistry-enabled asymmetric synthesis of cyproterone acetate in a chemo-biocatalytic approach.
Nat Commun
January 2025
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China.
Flow chemistry has many advantages over batch synthesis of organic small-molecules in terms of environmental compatibility, safety and synthetic efficiency when scale-up is considered. Herein, we report the 10-step chemo-biocatalytic continuous flow asymmetric synthesis of cyproterone acetate (4) in which 10 transformations are combined into a telescoped flow linear sequence from commercially available 4-androstene-3, 17-dione (11). This integrated one-flow synthesis features an engineered 3-ketosteroid-Δ-dehydrogenase (ReM2)-catalyzed Δ-dehydrogenation to form the C1, C2-double bond of A ring, a substrate-controlled Co-catalyzed Mukaiyama hydration of 9 to forge the crucial chiral C17α-OH group of D ring with excellent stereoselectivity, and a rapid flow Corey-Chaykovsky cyclopropanation of 7 to build the cyclopropyl core of A ring.
View Article and Find Full Text PDFSelective phosphodiesterase 4 inhibitor roflumilast reduces inflammation and lung injury in models of betacoronavirus infection in mice.
Inflamm Res
January 2025
Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil.
Objective: We aimed to understand the potential therapeutic and anti-inflammatory effects of the phosphodiesterase-4 (PDE4) inhibitor roflumilast in models of pulmonary infection caused by betacoronaviruses.
Methods: Mice were infected intranasally with murine hepatitis virus (MHV-3) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Roflumilast was given to MHV-3-infected mice therapeutically at doses of 1 mg/kg or 10 mg/kg, or prophylactically at 10 mg/kg.
Electrochemical Cyclopropanation of Unactivated Alkenes with Methylene Compounds.
Angew Chem Int Ed Engl
January 2025
Nankai University, College of Chemistry, 94 Weijin Road, 300071, Tianjin, CHINA.
Cyclopropanes are prevalent in natural products, pharmaceuticals, and bioactive compounds, functioning as a significant structural motif. Although a series of methods have been developed for the construction of the cyclopropane skeleton, the development of a direct and efficient strategy for the rapid synthesis of cyclopropanes from bench-stable starting materials with a broad substrate scope and functional group tolerance remains challenging and highly desirable. Herein, we present an electrochemical method for the direct cyclopropanation of unactivated alkenes using active methylene compounds.
View Article and Find Full Text PDFSynthesis and characterization of heterotrimetallic Mg-Ni-Mg complexes with amidinato ligands.
Dalton Trans
January 2025
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. China.
Treatment of amidinato-based magnesium ethyl compounds LMgEt [L = PrPNC(Bu)NAr; Ar = 2,6-PrCH (La) or 2,6-(PhCH)-4-Pr-(CH) (Lb)] with Ni(COD) (COD: 1,5-cyclooctadiene) afforded heterotrimetallic Mg-Ni-Mg complexes [(LMg)Ni(CH)] through β-H elimination. These complexes exhibit approximately linear Mg-Ni-Mg linkage with the central nickel arranged in a planar configuration; the Ni(CH) unit can be considered as nickela-bis-cyclopropane. Reaction of [(LMg)Ni(CH)] with tetrahydrofuran (THF) gave a coordination product [(LMg·THF)Ni(CH)], in which the central structure remained intact and THF coordinated to two magnesium atoms respectively.
View Article and Find Full Text PDFAutomated Flow Synthesis of Artificial Heme Enzymes for Enantiodivergent Biocatalysis.
J Am Chem Soc
January 2025
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
The remarkable efficiency with which enzymes catalyze small-molecule reactions has driven their widespread application in organic chemistry. Here, we employ automated fast-flow solid-phase synthesis to access catalytically active full-length enzymes without restrictions on the number and structure of noncanonical amino acids incorporated. We demonstrate the total syntheses of iron-dependent myoglobin (BsMb) and sperm whale myoglobin (SwMb).
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!