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Abstract Hemoproteins have recently emerged as promising biocatalysts for new-to-nature carbene transfer reactions. However, mechanistic understanding of the interplay between productive and unproductive pathways in these processes is limited. Using spectroscopic, structural, and computational methods, we investigate the mechanism of a myoglobin-catalyzed cyclopropanation reaction with diazoketones. These studies shed light on the nature and kinetics of key catalytic steps in this reaction, including the formation of an early heme-bound diazo complex intermediate, the rate-determining nature of carbene formation, and the cyclopropanation mechanism. Our analyses further reveal the existence of a complex mechanistic manifold for this reaction that includes a competing pathway resulting in the formation of an N-bound carbene adduct of the heme cofactor, which was isolated and characterized by X-ray crystallography, UV-Vis, and Mössbauer spectroscopy. This species can regenerate the active biocatalyst, constituting a non-productive, yet non-destructive detour from the main catalytic cycle. These findings offer a valuable framework for both mechanistic analysis and design of hemoprotein-catalyzed carbene transfer reactions. 

Abstract Engineered heme proteins were developed to possess numerous excellent biocatalytic nitrenoid C−H functionalizations. Computational approaches such as density functional theory (DFT), hybrid quantum mechanics/molecular mechanics (QM/MM), and molecular dynamics (MD) calculations were employed to help understand some important mechanistic aspects of these heme nitrene transfer reactions. This review summarizes advances of computational reaction pathway results of these biocatalytic intramolecular and intermolecular C−H aminations/amidations, focusing on mechanistic origins of reactivity, regioselectivity, enantioselectivity, diastereoselectivity as well as effects of substrate substituent, axial ligand, metal center, and protein environment. Some important common and distinctive mechanistic features of these reactions were also described with brief outlook of future development. 

Abstract Carbon‐centered radicals stabilized by adjacent boron atoms are underexplored reaction intermediates in organic synthesis. This study reports the development of vinyl cyclopropyl diborons (VCPDBs) as a versatile source of previously unknown homoallylic α,α‐diboryl radicals via thiyl radical catalyzed diboron‐directed ring opening. These diboryl stabilized radicals underwent smooth [3+2] cycloaddition with a variety of olefins to provide diboryl cyclopentanes in good to excellent diastereoselectivity. In contrast to thetrans‐diastereoselectivity observed with most of the dicarbonyl activated VCPs, the cycloaddition of VCPDBs showed a remarkable preference for formation ofcis‐cyclopentane diastereomer which was confirmed by quantitative NOE and 2D NOESY studies. Thecis‐stereochemistry of cyclopentane products enabled a concise intramolecular Heck reaction approach to rare tricyclic cyclopentanoid framework containing the diboron group. The mild reaction conditions also allowed a one‐pot VCP ring‐opening, cycloaddition‐oxidation sequence to afford disubstituted cyclopentanones. Control experiments and DFT analysis of reaction mechanism support a radical mediated pathway and provide a rationale for the observed diastereoselectivity. To the authors’ knowledge, these are the first examples of the use of geminal diboryl group as an activator of VCP ring opening and cycloaddition reaction of α‐boryl radicals. 

Abstract Porous noble metal nanoparticles have received particular attention recently for their unique optical, thermal, and catalytic functions in biomedicine. However, limited progress has been made to synthesize such porous metallic nanostructures with large mesopores (≥25 nm). Here, a green yet facile synthesis strategy using biocompatible liposomes as templates to mediate the formation of mesoporous metallic nanostructures in a controllable fashion is reported. Various monodispersed nanostructures with well‐defined mesoporous shape and large mesopores (≈ 40 nm) are successfully synthesized from mono‐ (Au, Pd, and Pt), bi‐ (AuPd, AuPt, AuRh, PtRh, and PdPt), and tri‐noble metals (AuPdRh, AuPtRh, and AuPdPt). Along with a successful demonstration of its effectiveness in synthesis of various mesoporous nanostructures, the possible mechanism of liposome‐guided formation of such nanostructures via time sectioning of the synthesis process (monitoring time‐resolved growth of mesoporous structures) and computational quantum molecular modeling (analyzing chemical interaction energy between metallic cations and liposomes at the enthalpy level) is also revealed. These mesoporous metallic nanostructures exhibit a strong photothermal effect in the near‐infrared region, effective catalytic activities in hydrogen peroxide decomposition reaction, and high drug loading capacity. Thus, the liposome‐templated method provides an inspiring and robust avenue to synthesize mesoporous noble metal‐based nanostructures for versatile biomedical applications. 

Abstract Engineered heme protein biocatalysts provide an efficient and sustainable approach to develop amine‐containing compounds through C−H amination. A quantum chemical study to reveal the complete heme catalyzed intramolecular C−H amination pathway and protein axial ligand effect was reported, using reactions of an experimentally used arylsulfonylazide with hemes containing L=none, SH⁻, MeO⁻, and MeOH to simulate no axial ligand, negatively charged Cys and Ser ligands, and a neutral ligand for comparison. Nitrene formation was found as the overall rate‐determining step (RDS) and the catalyst with Ser ligand has the best reactivity, consistent with experimental reports. Both RDS and non‐RDS (nitrene transfer) transition states follow the barrier trend of MeO⁻⁻ 

This article highlights recent computational research on heme-based carbene transfer reactions. Mechanistic insights reveal how cofactor components, coordination modes, substrates, and protein environments influence reactivity and selectivity. 

Calculations provide the first comprehensive mechanistic study of carbene N–H insertion for His-ligated heme biocatalysts, as validatedvianew experiments.