Green chemistry meets medicinal chemistry: a perspective on modern metal-free late-stage functionalization reactions

Chemical Society Reviews, Journal Year: 2021, Volume and Issue: 50(19), P. 10955 - 10982

Published: Jan. 1, 2021

This review summarizes the most recent advances of metal-free late-stage functionalization (LSF) pharmaceutically relevant molecules. Particular emphasis is placed on C – H activation as well use endogenous functional groups.

Language: Английский

---

The emergence of the C–H functionalization strategy in medicinal chemistry and drug discovery

Chemical Communications, Journal Year: 2021, Volume and Issue: 57(83), P. 10842 - 10866

Published: Jan. 1, 2021

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

Language: Английский

---

High Site Selectivity in Electrophilic Aromatic Substitutions: Mechanism of C–H Thianthrenation

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(39), P. 16041 - 16054

Published: Sept. 21, 2021

The introduction of thianthrene as a linchpin has proven to be versatile strategy for the C–H functionalization aromatic compounds, featuring broad scope and fast diversification. synthesis aryl thianthrenium salts displayed an unusually high para regioselectivity, notably superior those observed in halogenation or borylation reactions various substrates. We report experimental computational study on mechanism thianthrenation reactions, with emphasis elucidation reactive species nature exquisite site selectivity. Mechanisms involving direct attack arene isolated O-trifluoracetylthianthrene S-oxide (TT+-TFA) dication (TT2+) via electron transfer under acidic conditions are identified. A reversible interconversion different Wheland-type intermediates before subsequent, irreversible deprotonation is proposed responsible exceptional selectivity reaction.

Language: Английский

---

Development of Chiral Ligands for the Transition‐Metal‐Catalyzed Enantioselective Silylation and Borylation of C−H Bonds

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 61(9)

Published: Nov. 3, 2021

Enantioselective reactions that install functional groups at the positions of unactivated C-H bonds can be envisioned to produce intermediates for synthesis active ingredients in pharmaceuticals and agrochemicals directly from simple feedstocks. Among these bond functionalization reactions, those form carbon-silicon (C-Si) carbon-boron (C-B) have been pursued because products converted containing a wide range compounds silicon boron possess unique properties valuable medicinal materials chemistry. Although silylation borylation undergone extensive development during past two decades, enantioselective versions were not known until few years ago. In this Minireview, we present rapid bonds, with an emphasis on design types chiral ligands needed achieve intention inspire expansion transformations.

Language: Английский

---

Late-Stage Diversification: A Motivating Force in Organic Synthesis

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(41), P. 16890 - 16901

Published: Oct. 6, 2021

Interest in therapeutic discovery typically drives the preparation of natural product analogs, but these undertakings contribute significant advances for synthetic chemistry as well. The need a highly efficient and scalable route to complex molecular scaffold diversification frequently inspires new methodological development or unique application existing methods on structurally intricate systems. Additionally, planning with an aim toward late-stage can provide access otherwise unavailable compounds facilitate molecules diverse patterns substitution around shared carbon framework. For reasons among others, programs dedicated frameworks other scaffolds have been increasing popularity, trend likely continue given their fruitfulness breadth impact. In this Perspective, we discuss our experience using guiding principle synthesis analogs reflect impact such efforts future molecule synthesis.

Language: Английский

---

C–H bond functionalization by high-valent cobalt catalysis: current progress, challenges and future perspectives

Chemical Communications, Journal Year: 2021, Volume and Issue: 57(83), P. 10827 - 10841

Published: Jan. 1, 2021

Over the last decade, high-valent cobalt catalysis has earned a place in spotlight as valuable tool for C-H activation and functionalization. Since discovery of its unique reactivity, more attention been directed towards utilization an alternative to noble metal catalysts. In particular, Cp*Co(III) complexes, well simple Co(II) Co(III) salts combination with bidentate chelation assistance, have extensively used development novel transformations. this review, we demonstrated existing trends functionalization methodology using highlighted main challenges overcome, perspective directions, which need be further developed future.

Language: Английский

---

Ni-Catalyzed Aryl Sulfide Synthesis through an Aryl Exchange Reaction

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(27), P. 10333 - 10340

Published: June 28, 2021

A Ni-catalyzed aryl sulfide synthesis through an exchange reaction between sulfides and a variety of electrophiles was developed. By using 2-pyridyl as donor, this achieved the without odorous toxic thiols. The use Ni/dcypt catalyst capable cleaving forming aryl–S bonds important for electrophiles, which include aromatic esters, arenol derivatives, halides. Mechanistic studies revealed that can simultaneously undergo oxidative additions followed by ligand generated aryl–Ni–SR aryl–Ni–OAr species to furnish exchanged compounds.

Language: Английский

---

Algorithm-aided engineering of aliphatic halogenase WelO5* for the asymmetric late-stage functionalization of soraphens

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Jan. 18, 2022

Abstract Late-stage functionalization of natural products offers an elegant route to create novel entities in a relevant biological target space. In this context, enzymes capable halogenating sp 3 carbons with high stereo- and regiocontrol under benign conditions have attracted particular attention. Enabled by combination smart library design machine learning, we engineer the iron/α-ketoglutarate dependent halogenase WelO5* for late-stage complex chemically difficult derivatize macrolides soraphen A C, potent anti-fungal agents. While wild type enzyme does not accept macrolide substrates, our engineering strategy leads active variants improves upon their apparent k cat total turnover number more than 90-fold 300-fold, respectively. Notably, machine-learning guided approach is predicting allows us switch regio-selectivity halogenases facilitating targeted analysis derivatized macrolides’ structure-function activity assays.

Language: Английский

---

A Divergent Strategy for Site‐Selective Radical Disulfuration of Carboxylic Acids with Trisulfide‐1,1‐Dioxides

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 60(28), P. 15598 - 15605

Published: April 30, 2021

The direct conversion of carboxylic acids into disulfides is described. approach employs oxidative photocatalysis for base-promoted decarboxylation the substrate, which yields an alkyl radical that reacts with a trisulfide dioxide through homolytic substitution. dioxides are easily prepared by newly described approach. 1°, 2°, and 3° varied substitution good substrates, including amino substrates highly activated C-H bonds. Trisulfide also used to achieve γ-C(sp3 )-H disulfuration amides relay sequence. In both reactions, sulfonyl results from propagates reaction. Factors governing selectivity at S2 versus S3 have been explored.

Language: Английский

---

Copper‐Catalyzed Intermolecular Enantioselective Radical Oxidative C(sp³)−H/C(sp)−H Cross‐Coupling with Rationally Designed Oxazoline‐Derived N,N,P(O)‐Ligands

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 60(51), P. 26710 - 26717

Published: Oct. 5, 2021

The intermolecular asymmetric radical oxidative C(sp3 )-C(sp) cross-coupling of )-H bonds with readily available terminal alkynes is a promising method to forge chiral because the high atom and step economy, but remains underexplored. Here, we report copper-catalyzed (hetero)benzylic (cyclic)allylic C-H that occurs excellent enantioselectivity. Critical success rational design oxazoline-derived N,N,P(O)-ligands not only tolerate strong conditions which are requisite for hydrogen abstraction (HAA) processes also induce challenging enantiocontrol. Direct access range synthetically useful benzylic 1,4-enynes, site-selectivity among similar bonds, facile synthesis enantioenriched medicinally relevant compounds make this approach very attractive.

Language: Английский

---