Ranjan Jana; Hasina Mamataj Begam; Enakshi Dinda Chem. Commun., 2021, 57, 10842-10866 https://doi.org/10.1039/D1CC04083A
Abstract
Owing to the market competitiveness and urgent societal need, an optimum speed of drug discovery is an important criteria for successful implementation. Despite the rapid ascent of artificial intelligence, computational and bioanalytical techniques to accelerate drug discovery in big pharma; organic synthesis of privileged scaffolds predicted in silico for in vitro and in vivo studies is still considered as the rate-limiting step. C−H activation is the latest technology added into an organic chemist’s toolbox for the rapid construction and late-stage modification of functional molecules to achieve required chemical and physical properties. Particularly, elimination of prefunctionalization steps, exceptional functional group tolerability, complexity-to-diversity oriented synthesis, late-stage functionalization of privileged medicinal scaffolds expand the dimension of chemical space. It has immense potential for the rapid synthesis of a library of molecules, structural modification to achieve required pharmacological properties such as absorption, distribution, metabolism, excretion, toxicology (ADMET) and attachment of chemical reporters for proteome profiling, metabolite synthesis, etc. for preclinical studies. Although, heterocycle synthesis, late-stage drug modification, 18F labelling, methylation, etc. via C−H functionalization have been reviewed from synthetic standpoint; a general overview of these protocols from medicinal and drug discovery aspects has not been reviewd. In this feature article, we will discuss recent trends of C−H activation methodologies such as synthesis of medicinal scaffolds through C–H activation/annulation cascade; C–H arylation for sp2–sp2 and sp2–sp3 cross-coupling; C–H borylation/silylation to introduce functional linchpin for further manipulations; C–H amination for N-heterocycle and hydrogen bond acceptor; C–H fluorination/fluoroalkylation to tune polarity and lipophilicity; C–H methylation: methyl magic in drug discovery; peptide modification and macrocyclization for therapeutics and biologics; fluorescent and radiolabelling for bioimaging; bioconjugation for chemical biology studies; drug-metabolite synthesis for biodistribution and exctretion studies; late-stage diversification of drug-molecules to incraese efficacy and safety; cutting-edge DNA encoded library synthesisand improved synthesis of drug molecules via C–H activation in medicinal chemistry and drug discovery.