Light-activated hypervalent iodine agents enable diverse aliphatic C–H functionalization

Nature Chemistry, Journal Year: 2025, Volume and Issue: 17(3), P. 365 - 372

Published: Feb. 24, 2025

Language: Английский

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α,β-Desaturation and Formal β-C(sp³)–H Fluorination of N-Substituted Amines: A Late-Stage Functionalization Strategy Enabled by Electrochemistry

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(33), P. 22982 - 22992

Published: Aug. 12, 2024

Incorporation of C(sp

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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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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Harnessing the Power of C–H Functionalization Chemistry to Accelerate Drug Discovery

Synlett, Journal Year: 2024, Volume and Issue: 35(08), P. 862 - 876

Published: Jan. 15, 2024

Abstract The field of C–H functionalization chemistry has experienced rapid growth in the past twenty years, with increasingly powerful applications organic synthesis. Recognizing potential this emerging to impact drug discovery, a dedicated effort was established our laboratories more than ten years ago, goal facilitating application chemistries active medicinal-chemistry programs. Our approach centered around strategy late-stage (LSF) wherein is employed systematic and targeted manner generate high-value analogues from advanced leads. To successfully realize approach, we developed broadly useful LSF platforms workflows that increased success rates accelerated access new derivatives. strategy, when properly applied, enabled synthesis molecules designed address specific issues. Several case studies are presented, along descriptions group’s workflows. 1 Introduction 2 Building an Chemistry Toolbox 2.1 Borylation 2.2 Minisci Platforms 2.3 Automated Direct-Metalation Platform 3 Workflow 4 Application Case Studies 4.1 BTK Inhibitor Program 4.2 GPR40 Agonist 5 Conclusions

Language: Английский

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A platinum glutamate acid complex as a peroxidase mimic: high activity, controllable chemical modification, and application in biosensors

Analytical Methods, Journal Year: 2024, Volume and Issue: 16(7), P. 1093 - 1101

Published: Jan. 1, 2024

Recent strides in nanotechnology have given rise to nanozymes, nanomaterials designed emulate enzymatic functions. Despite their promise, challenges such as batch-to-batch variability and limited atomic utilization persist. This study introduces Pt(Glu)2, a platinum glutamic acid complex, versatile small-molecule peroxidase mimic. Synthesized through straightforward method, Pt(Glu)2 exhibits robust catalytic activity stability. Steady-state kinetics reveal lower Km value compared that of natural enzymes, signifying strong substrate affinity. was explored for controllable chemical modification integration into cascade reactions with surpassing other nanomaterials. Its facile synthesis seamless enhance beyond the capabilities nanozymes. In biosensing applications, enabled simultaneous detection cholesterol alkaline phosphatase human serum high selectivity sensitivity. These findings illustrate potential small molecule mimetics catalysis biosensing, paving way broader applications.

Language: Английский

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A Miniaturized Chemical High Throughput Experimentation Plate to Enable Late-Stage Oxidation Screening and Scale-up

ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown

Published: June 2, 2025

Language: Английский

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An Electrochemical Pipette for the Study of Drug Metabolite

Analytical Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 3, 2024

Electrochemistry offers an effective means of mimicking enzymatic metabolic pathways, particularly the oxidative pathways catalyzed by cytochrome P450 superfamily. The electrochemical generation and identification metabolites are time-sensitive, necessitating adjustable cell designs for accurate mechanistic interpretation. We present a thin-layer electrode (TLE) that addresses needs both analytical synthetic drug metabolites. TLE's ability to conduct experiments on minute-to-hour time scale allows detailed observation reaction mechanisms not easily identified traditional methods. utility TLE was benchmarked oxidation acetaminophen, acebutolol, 2-acetyl-4-butyramidophenol, known produce quinone imine metabolites, i.e., NAPQI, upon oxidation. When combined with microelectrode (μE), enables probing concentration profiles these drugs. micromole pipette-type structure facilitate comprehensive structural elucidation intermediates products using chromatographic spectroscopic techniques.

Language: Английский

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Small molecule drug metabolite synthesis and identification: why, when and how?

Drug Discovery Today, Journal Year: 2024, Volume and Issue: 29(5), P. 103943 - 103943

Published: March 5, 2024

The drug discovery and development process encompasses the interrogation of metabolites arising from biotransformation drugs. Here we look at why, when how small-molecule drugs are synthesised perspective a specialist contract research organisation, with particular attention paid to projects for which regulatory oversight is relevant during this journey. To illustrate important aspects, recent case studies, trends learnings our experience making identifying over past ten years, along selected examples literature. Teaser: impact in clinical development, obligations, diverse challenging problems were solved real-life examples.

Language: Английский

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