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1. Dual-function enzyme catalysis for enantioselective carbon–nitrogen bond formation

   https://doi.org/10.1038/s41557-021-00794-z  

   Liu, Zhen; Calvó-Tusell, Carla; Zhou, Andrew Z.; Chen, Kai; Garcia-Borràs, Marc; Arnold, Frances H. (October 2021, Nature Chemistry)

   null (Ed.)

   Chiral amines can be made by insertion of a carbene into an N–H bond using two-catalyst systems that combine a transition metal-based carbene-transfer catalyst and a chiral proton-transfer catalyst to enforce stereocontrol. Haem proteins can effect carbene N–H insertion, but asymmetric protonation in an active site replete with proton sources is challenging. Here we describe engineered cytochrome P450 enzymes that catalyse carbene N–H insertion to prepare biologically relevant α-amino lactones with high activity and enantioselectivity (up to 32,100 total turnovers, >99% yield and 98% e.e.). These enzymes serve as dual-function catalysts, inducing carbene transfer and promoting the subsequent proton transfer with excellent stereoselectivity in a single active site. Computational studies uncover the detailed mechanism of this new-to-nature enzymatic reaction and explain how active-site residues accelerate this transformation and provide stereocontrol. 

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2. Enzymatic Assembly of Diverse Lactone Structures: An Intramolecular C–H Functionalization Strategy

   https://doi.org/10.1021/jacs.3c11722  

   Wackelin, Daniel J.; Mao, Runze; Sicinski, Kathleen M.; Zhao, Yutao; Das, Anuvab; Chen, Kai; Arnold, Frances H. (January 2024, Journal of the American Chemical Society)

   Lactones are cyclic esters with extensive applications in materials science, medicinal chemistry, and the food and perfume industries. Nature’s strategy for the synthesis of many lactones found in natural products always relies on a single type of retrosynthetic strategy, a C−O bond disconnection. Here, we describe a set of laboratory-engineered enzymes that use a new-tonature C−C bond-forming strategy to assemble diverse lactone structures. These engineered “carbene transferases” catalyze intramolecular carbene insertions into benzylic or allylic C−H bonds, which allow for the synthesis of lactones with different ring sizes and ring scaffolds from simple starting materials. Starting from a serine-ligated cytochrome P450 variant previously engineered for other carbene-transfer activities, directed evolution generated a variant P411-LAS-5247, which exhibits a high activity for constructing a five-membered ε-lactone, lactam, and cyclic ketone products (up to 5600 total turnovers (TTN) and >99% enantiomeric excess (ee)). Further engineering led to variants P411-LAS-5249 and P411-LAS-5264, which deliver six-membered δ-lactones and seven-membered ε-lactones, respectively, overcoming the thermodynamically unfavorable ring strain associated with these products compared to the γ-lactones. This new carbene-transfer activity was further extended to the synthesis of complex lactone scaffolds based on fused, bridged, and spiro rings. The enzymatic platform developed here complements natural biosynthetic strategies for lactone assembly and expands the structural diversity of lactones accessible through C−H functionalization. 

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3. Electro‐ and Photochemical Reduction of CO ₂ by Molecular Manganese Catalysts: Exploring the Positional Effect of Second‐Sphere Hydrogen‐Bond Donors

   https://doi.org/10.1002/cssc.202001940  

   Roy, Sayontani_Sinha; Talukdar, Kallol; Jurss, Jonah_W (November 2020, ChemSusChem)

   Abstract A series of molecular Mn catalysts featuring aniline groups in the second‐coordination sphere has been developed for electrochemical and photochemical CO₂reduction. The arylamine moieties were installed at the 6 position of 2,2’‐bipyridine (bpy) to generate a family of isomers in which the primary amine is located at theortho‐(1‐Mn),meta‐(2‐Mn), orpara‐site (3‐Mn) of the aniline ring. The proximity of the second‐sphere functionality to the active site is a critical factor in determining catalytic performance. Catalyst1‐Mn, possessing the shortest distance between the amine and the active site, significantly outperformed the rest of the series and exhibited a 9‐fold improvement in turnover frequency relative to parent catalyst Mn(bpy)(CO)₃Br (901 vs. 102 s⁻¹, respectively) at 150 mV lower overpotential. The electrocatalysts operated with high faradaic efficiencies (≥70 %) for CO evolution using trifluoroethanol as a proton source. Notably, under photocatalytic conditions, a concentration‐dependent shift in product selectivity from CO (at high [catalyst]) to HCO₂H (at low [catalyst]) was observed with turnover numbers up to 4760 for formic acid and high selectivities for reduced carbon products. 

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4. Mono ‐ and Bis ‐Alkylated Lumazine Sensitizers: Synthetic, Molecular Orbital Theory, Nucleophilic Index and Photochemical Studies

   https://doi.org/10.1111/php.13310  

   Sosa, María José; Urrutia, María Noel; Schilardi, Patricia L.; Quindt, Matías I.; Bonesi, Sergio M.; Denburg, Dobrushe; Vignoni, Mariana; Greer, Alexander; Greer, Edyta M.; Thomas, Andrés H. (August 2020, Photochemistry and Photobiology)

   Abstract Mono‐ andbis‐decylated lumazines have been synthesized and characterized. Namely,mono‐decyl chain [1‐decylpteridine‐2,4(1,3H)‐dione]6aandbis‐decyl chain [1,3‐didecylpteridine‐2,4(1,3H)‐dione]7aconjugates were synthesized by nucleophilic substitution (S_N2) reactions of lumazine with 1‐iododecane inN,N‐dimethylformamide (DMF) solvent. Decyl chain coupling occurred at theN¹site and then theN³site in a sequential manner, without DMF condensation. Molecular orbital (MO) calculations show ap‐orbital atN¹but notN³, which along with a nucleophilicity parameter (N) analysis predict alkylation atN¹in lumazine. Only after the alkylation atN¹in6a, does ap‐orbital onN³emerge thereby reacting with a second equivalent of 1‐iododecane to reach the dialkylated product7a. Data from NMR (¹H,¹³C, HSQC, HMBC), HPLC, TLC, UV‐vis, fluorescence and density functional theory (DFT) provide evidence for the existence ofmono‐decyl chain6aandbis‐decyl chain7a. These results differ to pterinO‐alkylations (kinetic control), whereN‐alkylation of lumazine is preferred and then to dialkylation (thermodynamic control), with an avoidance of DMF solvent condensation. These findings add to the list of alkylation strategies for increasing sensitizer lipophilicity for use in photodynamic therapy. 

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5. Selective Functionalization of Aliphatic Amines via Myoglobin-Catalyzed Carbene N–H Insertion

   https://doi.org/10.1055/s-0039-1690007  

   Steck, Viktoria; Sreenilayam, Gopeekrishnan; Fasan, Rudi (January 2020, Synlett)

   Engineered myoglobins have recently gained attention for their ability to catalyze a variety of abiological carbene transfer reactions including the functionalization of amines via carbene insertion into N–H bonds. However, the scope of myoglobin and other hemoprotein-based biocatalysts in the context of this transformation has been largely limited to aniline derivatives as the amine substrates and ethyl diazoacetate as the carbene donor reagent. In this report, we describe the development of an engineered myoglobin-based catalyst that is useful for promoting carbene N–H insertion reactions across a broad range of substituted benzylamines and α-diazo acetates with high efficiency (82–99% conversion), elevated catalytic turnovers (up to 7,000), and excellent chemoselectivity for the desired single insertion product (up to 99%). The scope of this transformation could be extended to cyclic aliphatic amines. These studies expand the biocatalytic toolbox available for the selective formation of C–N bonds, which are ubiquitous in many natural and synthetic bioactive compounds. 

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