Nickel-Catalyzed Decarboxylative Cross-Coupling of Bicyclo[1.1.1]pentyl Radicals Enabled by Electron Donor–Acceptor Complex Photoactivation DOI
Viktor C. Polites, Shorouk O. Badir, Sebastian Keeß

et al.

Organic Letters, Journal Year: 2021, Volume and Issue: 23(12), P. 4828 - 4833

Published: June 8, 2021

The use of bicyclo[1.1.1]pentanes (BCPs) as para-disubstituted aryl bioisosteres has gained considerable momentum in drug development programs. Carbon–carbon bond formation via transition-metal-mediated cross-coupling represents an attractive strategy to generate BCP–aryl compounds for late-stage functionalization, but these typically require reactive organometallics prepare BCP nucleophiles on demand from [1.1.1]propellane. In this study, the synthesis and Ni-catalyzed functionalization redox-active esters with (hetero)aryl bromides action a photoactive electron donor–acceptor complex are reported.

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

408

Transition-Metal-Catalyzed C–H Bond Activation for the Formation of C–C Bonds in Complex Molecules DOI Creative Commons
Jamie H. Docherty,

Thomas M. Lister,

Gillian McArthur

et al.

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

Citations

241

A catalytic alkene insertion approach to bicyclo[2.1.1]hexane bioisosteres DOI

Soumitra Agasti,

Frédéric Beltran,

Emma Pye

et al.

Nature Chemistry, Journal Year: 2023, Volume and Issue: 15(4), P. 535 - 541

Published: Feb. 13, 2023

Language: Английский

Citations

174

Bicyclobutanes: from curiosities to versatile reagents and covalent warheads DOI Creative Commons
Christopher B. Kelly, John A. Milligan, Leon J. Tilley

et al.

Chemical Science, Journal Year: 2022, Volume and Issue: 13(40), P. 11721 - 11737

Published: Jan. 1, 2022

A flurry of reports for preparing, functionalizing, and using bicyclo[1.1.0]butanes (BCBs) have positioned them to be powerful synthons with numerous applications. This review discusses the recent developments regarding this strained carbocycle.

Language: Английский

Citations

157

Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]heptanes DOI
Yongxiang Zheng, Weichen Huang,

Roshan K. Dhungana

et al.

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(51), P. 23685 - 23690

Published: Dec. 16, 2022

The development of synthetic strategies for the preparation bioisosteric compounds is a demanding undertaking in medicinal chemistry. Numerous have been developed synthesis bicyclo[1.1.1]pentanes (BCPs), bridge-substituted BCPs, and bicyclo[2.1.1]hexanes. However, progress on bicyclo[3.1.1]heptanes, which serve as meta-substituted arene bioisosteres, has not previously explored. Herein, we disclose first photoinduced [3σ + 2σ] cycloaddition trisubstituted bicyclo[3.1.1]heptanes using bicyclo[1.1.0]butanes cyclopropylamines. This transformation only uses mild operationally simple conditions but also provides unique bioisosteres. applicability this method showcased by derivatization reactions.

Language: Английский

Citations

141

An intramolecular coupling approach to alkyl bioisosteres for the synthesis of multisubstituted bicycloalkyl boronates DOI
Yangyang Yang, Jet Tsien, Jonathan M. E. Hughes

et al.

Nature Chemistry, Journal Year: 2021, Volume and Issue: 13(10), P. 950 - 955

Published: Sept. 28, 2021

Language: Английский

Citations

132

Pyridine-Boryl Radical-Catalyzed [2π + 2σ] Cycloaddition of Bicyclo[1.1.0]butanes with Alkenes DOI
Yuan Liu,

Shuang Lin,

Yin Li

et al.

ACS Catalysis, Journal Year: 2023, Volume and Issue: 13(7), P. 5096 - 5103

Published: March 30, 2023

Bicyclo[2.1.1]hexanes (BCHs) represent an intriguing class of structurally rigid hydrocarbons that can serve as the bioisosteres benzenoids in medicinal chemistry. Methods for synthesis BCHs are, however, limiting. Reported herein is a facile via strain-release-driven [2π + 2σ] cycloaddition bicyclo[1.1.0]butanes (BCBs) with alkenes facilitated by pyridine-boryl radical catalyst. The mild reaction conditions, broad substrate scope, and decent functional group tolerance this protocol render it appealing relevant fields drug design synthesis. Theoretical mechanistic studies reveal relay mechanism involved. Synthetic applications products are performed.

Language: Английский

Citations

113

Photocatalyzed [2σ + 2σ] and [2σ + 2π] Cycloadditions for the Synthesis of Bicyclo[3.1.1]heptanes and 5- or 6-Membered Carbocycles DOI
Tin V. T. Nguyen, André Bossonnet, Matthew D. Wodrich

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(46), P. 25411 - 25421

Published: Nov. 7, 2023

We report the use of photocatalysis for homolytic ring-opening carbonyl cyclopropanes. In contrast to previous studies, our approach does not require a metal cocatalyst or strong reductant. The cyclopropanes can be employed both [2σ + 2σ] and 2π] annulation with either alkenes/alkynes bicyclo[1.1.0]butanes, yielding cyclopent-anes/-enes bicyclo[3.1.1]heptanes (BCHs), respectively. BCHs are promising bioisosteres 1,2,4,5 tetra-substituted aromatic rings. Mechanistic including density functional theory computation trapping experiment DMPO, support 1,3-biradical generated from cyclopropane as key intermediate these transformations.

Language: Английский

Citations

96

Metal-Free Photochemical Imino-Alkylation of Alkenes with Bifunctional Oxime Esters DOI
Jadab Majhi,

Roshan K. Dhungana,

Ángel Rentería‐Gómez

et al.

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(34), P. 15871 - 15878

Published: Aug. 19, 2022

The concurrent installation of C-C and C-N bonds across alkene frameworks represents a powerful tool to prepare motifs that are ubiquitous in pharmaceuticals bioactive compounds. To construct such prevalent bonds, most difunctionalization methods demand the use precious metals or activated alkenes. We report metal-free, photochemically mediated imino-alkylation electronically diverse alkenes install both alkyl iminyl groups highly efficient manner. exceptionally mild reaction conditions, broad substrate scope, excellent functional group tolerance, facile one-pot protocol highlight utility this method privileged from readily available acid feedstocks. One key striking feature transformation is an electrophilic trifluoromethyl radical equally with electron-deficient electron-rich Additionally, dispersion-corrected density theory (DFT) empirical investigations provide detailed mechanistic insight into reaction.

Language: Английский

Citations

93

Applications of Bioisosteres in the Design of Biologically Active Compounds DOI
Nicholas A. Meanwell

Journal of Agricultural and Food Chemistry, Journal Year: 2023, Volume and Issue: 71(47), P. 18087 - 18122

Published: March 24, 2023

The design of bioisosteres represents a creative and productive approach to improve molecule, including by enhancing potency, addressing pharmacokinetic challenges, reducing off-target liabilities, productively modulating physicochemical properties. Bioisosterism is principle exploited in the bioactive compounds interest both medicinal agricultural chemists, this review, we provide synopsis applications where kind molecular editing has proved be advantageous molecule optimization. examples selected for discussion focus on carboxylic acids, fluorine fluorinated motifs compound design, some sulfoximine functionality, drug-H2O complexes, phenyl ring.

Language: Английский

Citations

84