Regioselective Radical Alkylation of Arenes Using Evolved Photoenzymes DOI
Claire G. Page,

Jingzhe Cao,

Daniel G. Oblinsky

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(21), P. 11866 - 11874

Published: May 18, 2023

Substituted arenes are ubiquitous in molecules with medicinal functions, making their synthesis a critical consideration when designing synthetic routes. Regioselective C–H functionalization reactions attractive for preparing alkylated arenes; however, the selectivity of existing methods is modest and primarily governed by substrate's electronic properties. Here, we demonstrate biocatalyst-controlled method regioselective alkylation electron-rich electron-deficient heteroarenes. Starting from an unselective "ene"-reductase (ERED) (GluER-T36A), evolved variant that selectively alkylates C4 position indole, elusive using prior technologies. Mechanistic studies across evolutionary series indicate changes to protein active site alter character charge transfer (CT) complex responsible radical formation. This resulted significant degree ground-state CT complex. on C2-selective ERED suggest evolution GluER-T36A helps disfavor competing mechanistic pathway. Additional engineering campaigns were carried out C8-selective quinoline alkylation. study highlights opportunity use enzymes reactions, where small molecule catalysts struggle selectivity.

Language: Английский

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design DOI
Murugaiah A. M. Subbaiah, Nicholas A. Meanwell

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 64(19), P. 14046 - 14128

Published: Sept. 30, 2021

The benzene moiety is the most prevalent ring system in marketed drugs, underscoring its historic popularity drug design either as a pharmacophore or scaffold that projects pharmacophoric elements. However, introspective analyses of medicinal chemistry practices at beginning 21st century highlighted indiscriminate deployment phenyl rings an important contributor to poor physicochemical properties advanced molecules, which limited their prospects being developed into effective drugs. This Perspective deliberates on and applications bioisosteric replacements for have provided practical solutions range developability problems frequently encountered lead optimization campaigns. While effect compound contextual nature, substitution can enhanced potency, solubility, metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, inhibition cytochrome P450 enzymes hERG channel.

Language: Английский

Citations

399
Toolbox for Distal C–H Bond Functionalizations in Organic Molecules DOI

Soumya Kumar Sinha,

Srimanta Guin,

Sudip Maiti

et al.

Chemical Reviews, Journal Year: 2021, Volume and Issue: 122(6), P. 5682 - 5841

Published: Oct. 18, 2021

Transition-metal-catalyzed C–H activation has developed a contemporary approach to the omnipresent area of retrosynthetic disconnection. Scientific researchers have been tempted take help this methodology plan their synthetic discourses. This paradigm shift helped in development industrial units as well, making synthesis natural products and pharmaceutical drugs step-economical. In vast zone bond activation, functionalization proximal bonds gained utmost popularity. Unlike bonds, distal is more strenuous requires distinctly specialized techniques. review, we compiled various methods adopted functionalize mechanistic insights within each these procedures, scope methodology. With give complete overview expeditious progress made field organic chemistry while also highlighting its pitfalls, thus leaving open for further modifications.

Language: Английский

Citations

380
A Perspective on Late-Stage Aromatic C–H Bond Functionalization DOI Creative Commons
Li Zhang, Tobias Ritter

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(6), P. 2399 - 2414

Published: Jan. 27, 2022

Late-stage functionalization of C-H bonds (C-H LSF) can provide a straightforward approach to the efficient synthesis functionalized complex molecules. However, LSF is challenging because bond must be in presence various other functional groups. In this Perspective, we evaluate aromatic on basis four criteria─reactivity, chemoselectivity, site-selectivity, and substrate scope─and our own views current challenges as well promising strategies areas growth going forward.

Language: Английский

Citations

229
Site-selective C–H functionalization to access the arene backbone of indoles and quinolines DOI
B. Prabagar, Youqing Yang, Zhuangzhi Shi

et al.

Chemical Society Reviews, Journal Year: 2021, Volume and Issue: 50(20), P. 11249 - 11269

Published: Jan. 1, 2021

The site-selective C-H bond functionalization of heteroarenes can eventually provide chemists with great techniques for editing and building complex molecular scaffolds. During the past decade, benzo-fused N-heterocycles such as indoles quinolines have been among most widely investigated organic templates. Early developments led to on pyrrole pyridine cores quinolines; however, benzenoid ring has remained a challenge in catalysis. In this review, we elaborate recent highly challenging bonds less-reactive core quinolines. These findings are mainly described selective directing group assisted strategies, remote their reaction mechanisms. underlying principle each strategy is elucidated, which aims facilitate design more advanced structure heterocycles based bioactive molecules, synthetic drugs, material aspects. Moreover, challenges perspectives catalytic access arene backbone also proposed conclusion section.

Language: Английский

Citations

166
C–H deuteration of organic compounds and potential drug candidates DOI
Gaurav Prakash,

Nilanjan Paul,

Gwyndaf A. Oliver

et al.

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(8), P. 3123 - 3163

Published: Jan. 1, 2022

This review summarises deuteration methods of various organic motifs containing C(sp 2 )−H and 3 bonds utilizing C−H bond functionalisation as a key step along with variety catalysts, exemplifies their biological relevance.

Language: Английский

Citations

162
Remote steric control for undirected meta -selective C–H activation of arenes DOI Open Access

Ramadoss Boobalan,

Yushu Jin, Sobi Asako

et al.

Science, Journal Year: 2022, Volume and Issue: 375(6581), P. 658 - 663

Published: Feb. 10, 2022

Regioselective functionalization of arenes remains a challenging problem in organic synthesis. Steric interactions are often used to block sites adjacent given substituent, but they do not distinguish the remaining remote sites. We report strategy based on steric control, whereby roof-like ligand protects distant para site addition ortho sites, and thereby enables selective activation meta carbon-hydrogen (C–H) bonds absence or substituents. demonstrate this concept for iridium-catalyzed -selective borylation various monosubstituted arenes, including complex drug molecules. This has potential expand toolbox C–H bond previously nondifferentiable reaction

Language: Английский

Citations

87
Transition-metal-catalyzed C–H bond alkylation using olefins: recent advances and mechanistic aspects DOI
Debasish Mandal,

Sumali Roychowdhury,

Jyoti Prasad Biswas

et al.

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(17), P. 7358 - 7426

Published: Jan. 1, 2022

Transition metal catalysis has contributed immensely to C-C bond formation reactions over the last few decades, and alkylation is no exception. The superiority of such methodologies traditional evident from minimal reaction steps, shorter times, atom economy while also allowing control regio- stereo-selectivity. In particular, hydrocarbonation alkenes grabbed increased attention due its fundamental ability effectively selectively synthesise a wide range industrially pharmaceutically relevant moieties. This review attempts provide scientific viewpoint systematic analysis recent developments in transition-metal-catalyzed various C-H bonds using simple activated olefins. key features mechanistic studies involved these transformations are described briefly.

Language: Английский

Citations

81
Photoinduced Regioselective Olefination of Arenes at Proximal and Distal Sites DOI
Argha Saha, Srimanta Guin, Wajid Ali

et al.

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(4), P. 1929 - 1940

Published: Jan. 20, 2022

The Fujiwara–Moritani reaction has had a profound contribution in the emergence of contemporary C–H activation protocols. Despite applicability traditional approach different fields, associated reactivity and regioselectivity issues rendered it redundant. revival this exemplary requires development mechanistic paradigm that would have simultaneous control on both regioselectivity. Often, high thermal energy required to promote olefination leads multiple site functionalizations. To aim, we established photoredox catalytic system constituting merger palladium/organo-photocatalyst (PC) forges oxidative an explicit regioselective fashion with diverse arenes heteroarenes. Visible light plays significant role executing "regioresolved" reactions without requirement silver salts energy. is also amenable toward proximal distal aided by respective directing groups (DGs), which entails versatility protocol engaging entire spectrum C(sp2)–H olefination. Furthermore, streamlining synthesis natural products, chiral molecules, drugs, diversification through late-stage functionalizations underscore importance sustainable protocol. photoinduced attainment transformation mechanistically kinetic studies.

Language: Английский

Citations

79
Cobalt(III)/Chiral Carboxylic Acid‐Catalyzed Enantioselective Synthesis of Benzothiadiazine‐1‐oxides via C−H Activation DOI
Yuuki Hirata,

Daichi Sekine,

Yoshimi Kato

et al.

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(28)

Published: May 2, 2022

Abstract Among sulfoximine derivatives containing a chiral sulfur center, benzothiadiazine‐1‐oxides are important for applications in medicinal chemistry. Here, we report that the combination of an achiral cobalt(III) catalyst and pseudo‐ C 2 ‐symmetric H 8 ‐binaphthyl carboxylic acid enables asymmetric synthesis from sulfoximines dioxazolones via enantioselective C−H bond cleavage. With optimized protocol, with several functional groups can be accessed high enantioselectivity.

Language: Английский

Citations

73
Synthesis of planar chiral ferrocenes via enantioselective remote C–H activation DOI
Lan Zhou, Hong‐Gang Cheng, Lisha Li

et al.

Nature Chemistry, Journal Year: 2023, Volume and Issue: 15(6), P. 815 - 823

Published: April 17, 2023

Language: Английский

Citations

56