Transition-Metal-Catalyzed C–H Bond Activation for the Formation of C–C Bonds in Complex Molecules

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(12), P. 7692 - 7760

Published: May 10, 2023

Site-predictable and chemoselective C–H bond functionalization reactions offer synthetically powerful strategies for the step-economic diversification of both feedstock fine chemicals. Many transition-metal-catalyzed methods have emerged selective activation bonds. However, challenges regio- chemoselectivity with application to highly complex molecules bearing significant functional group density diversity. As molecular complexity increases within structures risks catalyst intolerance limited applicability grow number groups potentially Lewis basic heteroatoms. Given abundance bonds already diversified such as pharmaceuticals, natural products, materials, design selection reaction conditions tolerant catalysts has proved critical successful direct functionalization. such, innovations formation carbon–carbon been discovered developed overcome these limitations. This review highlights progress made metal-catalyzed C–C forming including alkylation, methylation, arylation, olefination targets.

Language: Английский

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Electrochemical Late-Stage Functionalization

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(19), P. 11269 - 11335

Published: Sept. 26, 2023

Late-stage functionalization (LSF) constitutes a powerful strategy for the assembly or diversification of novel molecular entities with improved physicochemical biological activities. LSF can thus greatly accelerate development medicinally relevant compounds, crop protecting agents, and functional materials. Electrochemical synthesis has emerged as an environmentally friendly platform transformation organic compounds. Over past decade, electrochemical late-stage (eLSF) gained major momentum, which is summarized herein up to February 2023.

Language: Английский

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Late-Stage C–H Functionalization of Azines

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(12), P. 7655 - 7691

Published: May 3, 2023

Azines, such as pyridines, quinolines, pyrimidines, and pyridazines, are widespread components of pharmaceuticals. Their occurrence derives from a suite physiochemical properties that match key criteria in drug design is tunable by varying their substituents. Developments synthetic chemistry, therefore, directly impact these efforts, methods can install various groups azine C–H bonds particularly valuable. Furthermore, there growing interest late-stage functionalization (LSF) reactions focus on advanced candidate compounds often complex structures with multiple heterocycles, functional groups, reactive sites. Because factors electron-deficient nature the effects Lewis basic N atom, distinct arene counterparts, application LSF contexts difficult. However, have been many significant advances reactions, this review will describe progress, much which has occurred over past decade. It possible to categorize radical addition processes, metal-catalyzed activation transformations occurring via dearomatized intermediates. Substantial variation reaction within each category indicates both rich reactivity heterocycles creativity approaches involved.

Language: Английский

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Late-stage Functionalization for Improving Drug-like Molecular Properties

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(13), P. 8127 - 8153

Published: June 7, 2023

The development of late-stage functionalization (LSF) methodologies, particularly C–H functionalization, has revolutionized the field organic synthesis. Over past decade, medicinal chemists have begun to implement LSF strategies into their drug discovery programs, allowing for process become more efficient. Most reported applications drugs and drug-like molecules been rapidly diversify screening libraries explore structure–activity relationships. However, there a growing trend toward use methodologies as an efficient tool improving molecular properties promising candidates. In this review, we comprehensively reviewed recent progress in emerging area. Particular emphasis is placed on case studies where multiple techniques were implemented generate library novel analogues with improved properties. We critically analyzed current scope improve commented how believe can transform future. Overall, aim provide comprehensive survey tools efficiently properties, anticipating its continued uptake programs.

Language: Английский

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Native Amides as Enabling Vehicles for Forging sp³–sp³ Architectures via Interrupted Deaminative Ni-Catalyzed Chain-Walking

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(7), P. 3869 - 3874

Published: Feb. 8, 2023

Herein, we disclose an interrupted deaminative Ni-catalyzed chain-walking strategy that forges sp3-sp3 architectures at remote, yet previously unfunctionalized, methylene sp3 C-H sites enabled by the presence of native amides. This protocol is characterized its mild conditions and wide scope, including challenging substrate combinations. Site-selectivity can be dictated a judicious choice ligand, thus offering opportunity to enable bond formations are otherwise inaccessible in conventional events.

Language: Английский

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Enabling late-stage drug diversification by high-throughput experimentation with geometric deep learning

Nature Chemistry, Journal Year: 2023, Volume and Issue: 16(2), P. 239 - 248

Published: Nov. 23, 2023

Abstract Late-stage functionalization is an economical approach to optimize the properties of drug candidates. However, chemical complexity molecules often makes late-stage diversification challenging. To address this problem, a platform based on geometric deep learning and high-throughput reaction screening was developed. Considering borylation as critical step in functionalization, computational model predicted yields for diverse conditions with mean absolute error margin 4–5%, while reactivity novel reactions known unknown substrates classified balanced accuracy 92% 67%, respectively. The regioselectivity major products accurately captured classifier F -score 67%. When applied 23 commercial molecules, successfully identified numerous opportunities structural diversification. influence steric electronic information performance quantified, comprehensive simple user-friendly format introduced that proved be key enabler seamlessly integrating experimentation functionalization.

Language: Английский

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Recent Advances in Transition-Metal-Catalyzed C–H Alkylation with Three-Membered Rings

ACS Catalysis, Journal Year: 2022, Volume and Issue: 12(4), P. 2330 - 2347

Published: Feb. 1, 2022

Transition-metal-catalyzed alkylation of (hetero)arenes with three-membered carbo-/heterocycles involving C–H activation and ring scission has been greatly developed over the past few years. The chelation-assisted strategies for controlling reactivity site selectivity in these protocols include use nitrogen-containing directing groups, pre-existing functional a Catellani-type intermediate, thereby providing rapid access to numerous oxygen- or heterocyclic systems. This review gives an update area various catalytic methodologies applications total synthesis natural products rings as alkylating reagents, which are classified into following three categories on basis employed strategies: (i) directed by (ii) (iii) aryl-NBE intermediates (Catellani-type cascade reaction).

Language: Английский

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Preparative Scale Applications of C−H Activation in Medicinal Chemistry

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(45)

Published: June 7, 2023

C-H activation is an attractive methodology to increase molecular complexity without requiring substrate prefunctionalization. In contrast well-established cross-coupling methods, less explored on large scales and its use in the production of pharmaceuticals faces substantial hurdles. However, inherent advantages, such as shorter synthetic routes simpler starting materials, motivate medicinal chemists process overcome these challenges, exploit steps for synthesis pharmaceutically relevant compounds. this review, we will cover examples drugs/drug candidates where has been implemented a preparative scale (range between 355 mg 130 kg). The optimization processes be described, each example examined terms advantages disadvantages, providing reader with in-depth understanding challenges potential methodologies pharmaceuticals.

Language: Английский

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Late‐Stage Functionalisation of Pyridine‐Containing Bioactive Molecules: Recent Strategies and Perspectives

European Journal of Organic Chemistry, Journal Year: 2023, Volume and Issue: 26(16)

Published: Feb. 21, 2023

Abstract Late‐Stage Functionalisation (LSF) is an innovative technique that has been successfully applied to the C−H diversification of pharmaceuticals. However, LSF pyridine ring in drug‐like molecules often unselective. As a result, mixture structurally related products obtained, thus making purification tedious and time‐consuming. This review shines light on recent strategies addressing selectivity issue complex natural or drugs containing moiety. Specifically, we have reviewed efforts reported both academia industries with hope providing guide for elaborated pyridines.

Language: Английский

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Late-stage modification of bioactive compounds: Improving druggability through efficient molecular editing

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 14(3), P. 1030 - 1076

Published: Nov. 18, 2023

Synthetic chemistry plays an indispensable role in drug discovery, contributing to hit compounds identification, lead optimization, candidate drugs preparation, and so on. As Nobel Prize laureate James Black emphasized, "the most fruitful basis for the discovery of a new is start with old drug"

Language: Английский

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