A chemobiocatalytic strategy for the highly stereoselective synthesis of nitrile‐substituted cyclopropanes is reported. The present approach relies on an asymmetric olefin cyclopropanation reaction ...catalyzed by an engineered myoglobin in the presence of ex situ generated diazoacetonitrile within a compartmentalized reaction system. This method enabled the efficient transformation of a broad range of olefin substrates at a preparative scale with up to 99.9 % de and ee and up to 5600 turnovers. The enzymatic product could be further elaborated to afford a variety of functionalized chiral cyclopropanes. This work expands the range of synthetically valuable, abiotic transformations accessible through biocatalysis and paves the way to the practical and safe exploitation of diazoacetonitrile in biocatalytic carbene transfer reactions.
One for many: A chemobiocatalytic strategy involving myoglobin‐catalyzed olefin cyclopropanation in the presence of ex situ generated diazoacetonitrile enables the efficient synthesis of a broad range of nitrile‐substituted cyclopropanes with high diastereo‐ and enantioselectivity. The enzymatic product could be further elaborated to afford a variety of functionalized chiral cyclopropanes.
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We report the development of engineered myoglobin biocatalysts for executing asymmetric intramolecular cyclopropanations resulting in cyclopropane-fused γ-lactones, which are key motifs found in many ...bioactive molecules. Using this strategy, a broad range of allyl diazoacetate substrates were efficiently cyclized in high yields with up to 99% enantiomeric excess. Upon remodeling of the active site via protein engineering, myoglobin variants with stereodivergent selectivity were also obtained. In combination with whole-cell transformations, these biocatalysts enabled the gram-scale assembly of a key intermediate useful for the synthesis of the insecticide permethrin and other natural products. The enzymatically produced cyclopropyl-γ-lactones can be further elaborated to furnish a variety of enantiopure trisubstituted cyclopropanes. This work introduces a first example of biocatalytic intramolecular cyclopropanation and provides an attractive strategy for the stereodivergent preparation of fused cyclopropyl-γ-lactones of high value for medicinal chemistry and the synthesis of natural products.
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Multicomponent reactions (MCRs), which are located between one‐ and two‐component and polymerization reactions, provide a number of valuable conceptual and synthetic advantages over stepwise ...sequential approaches towards complex and valuable molecules. To address current limitations in the number of MCRs and the resulting scaffolds, the concept of union of MCRs was introduced two decades ago by Dömling and Ugi and is rapidly advancing, as is apparent by several recently published works. MCR technology is now widely recognized for its impact on drug discovery projects and is strongly endorsed by industry in addition to academia. Clearly, novel scaffolds accessible in few steps including MCRs will further enhance the field of applications. Additionally, broad expansion of MCR applications in fields such as imaging, materials science, medical devices, agriculture, or futuristic applications in stem cell therapy and theragnostics or solar energy and superconductivity are predicted.
Multicomponent reactions provide a number of valuable conceptual and synthetic advantages over stepwise sequential approaches towards complex and valuable molecules. The combination of two or more multicomponent reactions in the “union of MCRs” concept permits even faster access to greater structural diversity. The application of MCR technology to drug discovery projects and other fields is discussed, along with its future expansion to areas such as imaging, materials science, medical devices, agriculture, stem cell therapy and theragnostics.
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We report the development of an iron-based biocatalytic strategy for the asymmetric synthesis of fused cyclopropane-γ-lactams, which are key structural motifs found in synthetic drugs and bioactive ...natural products. Using a combination of mutational landscape and iterative site-saturation mutagenesis, sperm whale myoglobin was evolved into a biocatalyst capable of promoting the cyclization of a diverse range of allyl diazoacetamide substrates into the corresponding bicyclic lactams in high yields and with high enantioselectivity (up to 99% ee). These biocatalytic transformations can be performed in whole cells and could be leveraged to enable the efficient (chemo)enzymatic construction of chiral cyclopropane-γ-lactams as well as β-cyclopropyl amines and cyclopropane-fused pyrrolidines, as valuable building blocks and synthons for medicinal chemistry and natural product synthesis.
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Convergent Three-Component Tetrazole Synthesis Chandgude, Ajay L.; Dömling, Alexander
European Journal of Organic Chemistry,
20/May , Volume:
2016, Issue:
14
Book Review, Journal Article
Peer reviewed
Open access
A microwave‐accelerated, simple, and efficient method for the construction of the 1,5‐tetrazole scaffold was developed. It comprises a multicomponent reaction of an amine, a carboxylic acid ...derivative, and an azide source. On the basis of the availability of the archetypical starting materials, this method provided very versatile synthetic access to 1,5‐disubstituted tetrazoles. The usefulness of this method was demonstrated in the synthesis of biologically important fused tetrazole scaffolds and the marketed drug cilostazol.
Short, simple, safe, and diverse! The herein described multicomponent reaction arguably provides the most versatile access towards 1,5‐disubstituted and fused tetrazoles. The usefulness of this method is demonstrated in the synthesis of biologically important fused tetrazole scaffolds and the marketed drug cilostazol.
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Abiological enzymes offers new opportunities for sustainable chemistry. Herein, we report the development of biological catalysts derived from sperm whale myoglobin that exploit a carbene transfer ...mechanism for the asymmetric synthesis of cyclopropane‐fused‐δ‐lactones, which are key structural motifs found in many biologically active natural products. While hemin, wild‐type myoglobin, and other hemoproteins are unable to catalyze this reaction, the myoglobin scaffold could be remodeled by protein engineering to permit the intramolecular cyclopropanation of a broad spectrum of homoallylic diazoacetate substrates in high yields and with up to 99 % enantiomeric excess. Via an alternate evolutionary trajectory, a stereodivergent biocatalyst was also obtained for affording mirror‐image forms of the desired bicyclic products. In combination with whole‐cell transformations, the myoglobin‐based biocatalyst was used for the asymmetric construction of a cyclopropyl‐δ‐lactone scaffold at a gram scale, which could be further elaborated to furnish a variety of enantiopure trisubstituted cyclopropanes.
A biocatalytic strategy for the stereodivergent synthesis of cyclopropyl‐δ‐lactones via the intramolecular cyclopropanation of homoallylic diazoacetates is reported. Myoglobin was re‐engineered into two enantiocomplementary biocatalysts capable of producing a range of aryl‐ and alkyl‐substituted cyclopropane‐fused δ‐lactone scaffolds useful for medicinal chemistry and natural product synthesis.
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The catalytic efficiency of mixed Cu(I)–Cu(II) system in situ generated by partial reduction of CuSO4 with glucose in ethanol (nonanhydrous) under open air has been explored. With this catalysis, the ...multicomponent cascade reaction of A3-coupling of heterocyclic amidine with aldehyde and alkyne, 5-exo-dig cycloisomerization, and prototropic shift has afforded an efficient and eco-friendly synthesis of therapeutically important versatile N-fused imidazoles. Diverse heterocyclic amidines, several of which are known to be poorly reactive, and aldehydes are compatible in this catalytic process.
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8.
An Efficient Passerini Tetrazole Reaction (PT-3CR) Chandgude, Ajay L; Dömling, Alexander
Green chemistry : an international journal and green chemistry resource : GC,
01/2016, Volume:
18, Issue:
13
Journal Article
Peer reviewed
Open access
A sonication accelerated, catalyst free, simple, high yielding and efficient method for the Passerini-type three component reaction (PT-3CR) has been developed. It comprises reaction of an ...aldehyde/ketone, a isocyanide and a TMS-azide in methanol:water (1:1) as the solvent system. Use of sonication not only accelerated the rate of the reaction but also provided up to quantitative yields. This reaction is applicable to a broad scope of aldehyde/ketone and isocyanides.
Tetrazole is widely utilized as a bioisostere for carboxylic acid in the field of medicinal chemistry and drug development, enhancing the drug-like characteristics of various molecules. Typically, ...tetrazoles are introduced from their nitrile precursors through late-stage functionalization. In this work, we propose a novel strategy involving the use of diversely protected, unprecedented tetrazole aldehydes as building blocks. This approach facilitates the incorporation of the tetrazole group into multicomponent reactions or other chemistries, aiding in the creation of a variety of complex, drug-like molecules. These innovative tetrazole building blocks are efficiently and directly synthesized using a Passerini three-component reaction (PT-3CR), employing cost-effective and readily available materials. We further showcase the versatility of these new tetrazole building blocks by integrating the tetrazole moiety into various multicomponent reactions (MCRs), which are already significantly employed in drug discovery. This technique represents a unique and complementary method to existing tetrazole synthesis processes. It aims to meet the growing demand for tetrazole-based compound libraries and novel scaffolds, which are challenging to synthesize through other methods.
Recent studies reported the development of biocatalytic heme carbenoid Si−H insertions for the selective formation of carbon‐silicon bonds, but many mechanistic questions remain unaddressed. To this ...end, a DFT mechanistic investigation was performed which reveals an FeII‐based concerted hydride transfer mechanism with early transition state feature. The results from these computational analyses are consistent with experimental data of radical trapping, kinetic isotope effects, and structure‐reactivity data using engineered variants of hemoproteins. Detailed geometric and electronic profiles along the heme catalyzed Si−H insertion pathways were provided to help understand the origin of experimental reactivity trends. Quantitative relationships between reaction barriers and some properties such as charge transfer from substrate to heme carbene and Si−H bond length change from reactant to transition state were found. Results suggest catalyst modifications to facilitate the charge transfer from the silane substrate to the carbene, which was determined to be a major electronic driving force of this reaction, should enable the development of improved biocatalysts for Si−H carbene insertion reactions.
Biocatalysis: An FeII‐based concerted hydride transfer mechanism with nonsynchronous and early transition state was found for biocatalytic heme carbenoid Si−H insertions, with key insights into effects of substrates, carbenes, and protein axial ligands to help understand experimental structure‐reactivity trends and facilitate design of improved (bio)catalysts for challenging Si−H insertion reactions.
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