C–H Bonds as Functional Groups: Simultaneous Generation of Multiple Stereocenters by Enantioselective Hydroxylation at Unactivated Tertiary C–H Bonds

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(29), P. 15742 - 15753

Published: July 11, 2023

Enantioselective C–H oxidation is a standing chemical challenge foreseen as powerful tool to transform readily available organic molecules into precious oxygenated building blocks. Here, we describe catalytic enantioselective hydroxylation of tertiary bonds in cyclohexane scaffolds with H2O2, an evolved manganese catalyst that provides structural complementary the substrate similarly lock-and-key recognition operating enzymatic active sites. Theoretical calculations unveil enantioselectivity governed by precise fitting scaffold site, through network weak non-covalent interactions. Stereoretentive C(sp3)–H results single-step generation multiple stereogenic centers (up 4) can be orthogonally manipulated conventional methods providing rapid access, from single precursor variety chiral scaffolds.

Language: Английский

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An Active Site Tyr Residue Guides the Regioselectivity of Lysine Hydroxylation by Nonheme Iron Lysine-4-hydroxylase Enzymes through Proton-Coupled Electron Transfer

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(17), P. 11726 - 11739

Published: April 18, 2024

Lysine dioxygenase (KDO) is an important enzyme in human physiology involved bioprocesses that trigger collagen cross-linking and blood pressure control. There are several KDOs nature; however, little known about the factors govern regio- stereoselectivity of these enzymes. To understand how can selectively hydroxylate their substrate, we did a comprehensive computational study into mechanisms features 4-lysine dioxygenase. In particular, selected snapshot from MD simulation on KDO5 created large QM cluster models (A, B, C) containing 297, 312, 407 atoms, respectively. The largest model predicts regioselectivity matches experimental observation with rate-determining hydrogen atom abstraction C4–H position, followed by fast OH rebound to form 4-hydroxylysine products. calculations show C, dipole moment positioned along bond substrate and, therefore, electrostatic electric field perturbations protein assist creating hydroxylation selectivity. Furthermore, active site Tyr233 residue identified reacts through proton-coupled electron transfer akin axial Trp cytochrome c peroxidase. Thus, upon formation iron(IV)-oxo species catalytic cycle, phenol loses proton nearby Asp179 residue, while at same time, transferred iron create iron(III)-oxo species. This charged tyrosyl directs guides selectivity C4-hydroxylation substrate.

Language: Английский

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Mechanisms of C(sp3)–H and C=C selective oxidative heterofunctionalizations by non-heme Fe and Mn mimics of oxygenase enzymes

Coordination Chemistry Reviews, Journal Year: 2024, Volume and Issue: 508, P. 215793 - 215793

Published: March 18, 2024

Language: Английский

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Heme and nonheme high-valent manganese(V)-oxo complexes: Synthesis, characterization, and reactivity

Coordination Chemistry Reviews, Journal Year: 2025, Volume and Issue: 528, P. 216429 - 216429

Published: Jan. 11, 2025

Language: Английский

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Rhodium-Catalyzed Homogeneous Asymmetric Hydrogenation of Naphthol Derivatives

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 29, 2025

Due to their strong aromaticity and difficulties in chemo-, regio-, enantioselectivity control, asymmetric hydrogenation of naphthol derivatives 1,2,3,4-tetrahydronaphthols has remained a long-standing challenge. Herein, we report the first example homogeneous catalyzed by tethered rhodium-diamine catalysts, affording wide array optically pure high yields with excellent enantioselectivities (up 98% yield >99% ee). Mechanistic studies experimental computational approaches reveal that fluorinated solvent 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) plays vital roles control reactivity selectivity, 1-naphthol is reduced via cascade reaction pathway, including dearomative tautomerization, 1,4-hydride addition, 1,2-hydride addition sequence. A novel synergistic activation mode was proposed which HFIP assists both hydrogen molecule presence base, situ-generated fleeting keto tautomer immediately trapped Rh(III)-H species before it escapes from cage. This protocol provides straightforward practical pathway for synthesis key intermediates several chiral drugs. Particularly, Nadolol, drug treatment hypertension, angina pectoris, congestive heart failure, certain arrhythmias, enantioselectively synthesized time.

Language: Английский

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Hydrogen‐Bond‐Mediated Formation of C−N or C=N Bond during Photocatalytic Reductive Coupling Reaction over CdS Nanosheets

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(26)

Published: April 19, 2024

Abstract Reductive amination of carbonyl compounds and nitro represents a straightforward way to attain imines or secondary amines, but it is difficult control the product selectivity. Herein, we report selective formation C−N C=N bond readily manipulated through solvent‐induced hydrogen bridge, facilitating swift photocatalytic reductive coupling process. The reductive‐coupling with using formic acid sodium formate as donors over CdS nanosheets selectively generates bonds in acetonitrile solvent; while taking methanol solvent, are hydrogenated via hydrogen‐bonding activation. Experimental theoretical study reveals that building hydrogen‐bond bridge between hydroxyl groups N atoms motifs facilitates transfer from surface upon illumination, resulting rapid hydrogenation give rise amines bonds. Our method provides simple selectivity by altering solvents organic transformations.

Language: Английский

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Catalyst and Medium Control over Rebound Pathways in Manganese-Catalyzed Methylenic C–H Bond Oxidation

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(13), P. 8904 - 8914

Published: March 20, 2024

The C(sp3)–H bond oxygenation of a variety cyclopropane containing hydrocarbons with hydrogen peroxide catalyzed by manganese complexes aminopyridine tetradentate ligands was carried out. Oxidations were performed in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and 2,2,2-trifluoroethanol (TFE) using different catalysts carboxylic acid co-ligands, where steric electronic properties systematically modified. Functionalization selectively occurs at the most activated C–H bonds that are α- to cyclopropane, providing access carboxylate or 2,2,2-trifluoroethanolate transfer products, no competition, favorable cases, from generally dominant hydroxylation reaction. formation mixtures unrearranged rearranged esters (oxidation HFIP presence acid) ethers TFE) full control over diastereoselectivity observed, confirming involvement delocalized cationic intermediates these transformations. Despite such complex mechanistic scenario, fine-tuning catalyst sterics electronics leveraging on relative contribution pathways reaction mechanism, product chemoselectivity could be achieved. Taken together, results reported herein provide powerful catalytic tools rationally manipulate ligand oxidations hydrocarbons, delivering novel products good yields and, some outstanding selectivities, expanding available toolbox for development synthetically useful functionalization procedures.

Language: Английский

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A preparative small-molecule mimic of liver CYP450 enzymes in the aliphatic C–H oxidation of carbocyclic N -heterocycles

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(29)

Published: July 10, 2023

An emerging trend in small-molecule pharmaceuticals, generally composed of nitrogen heterocycles (

Language: Английский

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Mechanisms of Mn(V)‐Oxo to Mn(IV)‐Oxyl Conversion: From Closed‐Cubane Photosystem II to Mn(V) Catalysts and the Role of the Entering Ligands

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(35)

Published: April 25, 2024

Abstract The low activation barrier for O−O coupling in the closed‐cubane Oxygen‐Evolving Centre (OEC) of Photosystem II (PSII) requires water coordination with Mn4 ′dangler′ ion Mn(V)‐oxo fragment. This transforms complex into a more reactive Mn4(IV)‐oxyl species, enhancing coupling. study explains mechanism behind and indicates that most stable form OEC, fragment adopts trigonal bipyramidal geometry but needs to transition square pyramidal be activated stabilizes d xy orbital, enabling electron transfer from oxo ligand converting an oxyl species. role is coordinate structure, reducing energy gap between forms, thereby lowering applies not only OEC system also other Mn(V)‐based catalysts. For catalysts, ligands such as OH − stabilize Mn(IV)‐oxyl species better than water, improving catalyst reactions like C−H bond activation. first explain conversion, providing new foundation Mn‐based design.

Language: Английский

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Highly Selective C(sp³)–H Bond Oxygenation at Remote Methylenic Sites Enabled by Polarity Enhancement

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(40), P. 22086 - 22096

Published: Sept. 26, 2023

A detailed study on the C(sp3)–H bond oxygenation reactions with H2O2 catalyzed by [Mn(OTf)2(TIPSmcp)] complex at methylenic sites of cycloalkyl and 1-alkyl substrates bearing 19 different electron-withdrawing functional groups (EW FGs) was carried out. Oxidations in MeCN were compared to corresponding ones strong hydrogen donating (HBD) solvents 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) nonafluoro tert-butyl alcohol (NFTBA). Formation products deriving from most remote observed, yields, product ratios (PR) for over next sites, associated site-selectivities that significantly increased going HFIP NFTBA. Unprecedented obtained oxidation cyclohexyl, cycloheptyl, cyclooctyl, 1-pentyl, 1-hexyl, 1-heptyl substrates, approaching >99%, 90%, 93%, 88% (PR >99, 9.4, 14, 7.5) cyclohexyl-2-pyridinecarboxylate, cycloheptyl-2-pyridinecarboxylate, cyclooctyl-4-nitrobenzenesulfonamide, 1-pentyl-3,5-dinitrobenzoate, 1-hexyl-3,5-dinitrobenzoate, 1-heptyl-3,5-dinitrobenzoate, respectively. The results are rationalized basis a polarity enhancement effect via synergistic electronic deactivation proximal imparted EWG coupled solvent HB. Compared previous procedures, provides opportunity tune site-selectivity among multiple methylenes substrate classes, extending determined native EWGs two carbon atoms. This uncovers simple procedure predictable, high-yielding, highly site-selective occurs under mild conditions, large scope, providing an extremely powerful tool be implemented synthetically useful procedures.

Language: Английский

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