Late‐Stage C−H Activation of Drug (Derivative) Molecules with Pd(ll) Catalysis DOI Creative Commons
Su Yong Shim

Chemistry - A European Journal, Journal Year: 2023, Volume and Issue: 29(71)

Published: Oct. 17, 2023

Abstract This review comprehensively analyses representative examples of Pd(II)‐catalyzed late‐stage C−H activation reactions and demonstrates their efficacy in converting bonds at multiple positions within drug (derivative) molecules into diverse functional groups. These transformative hold immense potential medicinal chemistry, enabling the efficient selective functionalization specific sites molecules, thereby enhancing pharmacological activity expanding scope candidates. Although notable articles have focused on drug‐like using transition‐metal catalysts, reviews specifically focusing Pd(II) catalysts are required owing to prominence as most widely utilized metal for ability introduce a myriad groups bonds. The utilization Pd‐catalyzed methodologies impressive success introducing various groups, such cyano (CN), fluorine (F), chlorine (Cl), aromatic rings, olefin, alkyl, alkyne, hydroxyl with high regioselectivity functional‐group tolerance. breakthroughs serve invaluable tools discovery development, offering strategic options optimize candidates drive exploration innovative therapeutic solutions.

Language: Английский

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

Citations

29
Late-stage meta-C–H alkylation of pharmaceuticals to modulate biological properties and expedite molecular optimisation in a single step DOI Creative Commons
Lucas Guillemard, Lutz Ackermann, Magnus J. Johansson

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 18, 2024

Catalysed C-H activation has emerged as a transformative platform for molecular synthesis and provides new opportunities in drug discovery by late-stage functionalisation (LSF) of complex molecules. Notably, small aliphatic motifs have gained significant interest medicinal chemistry their beneficial properties applications sp

Language: Английский

Citations

13
Organocatalytic Activation of Alkynes Enabled Remote Control of Atroposelectivity via Vinylidene para-Quinone Methides DOI
Yuan Cui, Yong‐Bin Wang, Huanhuan Liu

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Axially chiral o-VQMs have been extensively investigated as key intermediates to approach miscellaneous structures. By sharp contrast, their structural isomers p-VQMs not previously documented. The major reason, which results in the significant delay, may ascribe inherent challenges enantioselective activation of alkynes a remote manner. Herein, we demonstrate that mechanism para-hydroxyl-substituted arylacetylenes enables stereochemical induction, resulting axially aryl-alkenes with excellent enantiopurities. A series control experiments are performed elucidate insights this asymmetric transformation and verify involvement multimolecular CPAs reaction process. These findings expected unlock new feature for VQM chemistry inspire investigation into organocatalytic stereoselectivity.

Language: Английский

Citations

1
Functionalized Cycloolefin Ligand as a Solution to Ortho-Constraint in the Catellani-Type Reaction DOI
Fengyuan Wang, Yuxiu Li, Lei Jiao

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(8), P. 4871 - 4881

Published: Feb. 16, 2023

The Catellani reaction, i.e., the Pd/norbornene (NBE) catalysis, has been evolved into a versatile approach to multisubstituted arenes via ortho-functionalization/ipso-termination process of haloarene. Despite significant advances over past 25 years, this reaction still suffered from an intrinsic limitation in substitution pattern haloarene, referred as "ortho-constraint". When ortho substituent is absent, substrate often fails undergo effective mono ortho-functionalization process, and either ortho-difunctionalization products or NBE-embedded byproducts predominate. To tackle challenge, structurally modified NBEs (smNBEs) have developed, which were proved for ortho-aminative, -acylative, -arylative reactions ortho-unsubstituted haloarenes. However, strategy incompetent solving ortho-constraint with ortho-alkylation, date there lacks general solution challenging but synthetically useful transformation. Recently, our group developed Pd/olefin unstrained cycloolefin ligand served covalent catalytic module enable ortho-alkylative without NBE. In work, we show that chemistry could afford new reaction. A functionalized bearing amide internal base was designed, allowed iodoarenes suffering before. Mechanistic study revealed capable both accelerating C-H activation inhibiting side reactions, accounts its superior performance. present work showcased uniqueness catalysis well power rational design metal catalysis.

Language: Английский

Citations

19
Regiodivergent and Enantioselective Hydroxylation of C−H bonds by Synergistic Use of Protein Engineering and Exogenous Dual‐Functional Small Molecules DOI
Jie Chen, Sheng Dong, Wenhan Fang

et al.

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 62(4)

Published: Nov. 24, 2022

It is a great challenge to optionally access diverse hydroxylation products from given substrate bearing multiple reaction sites of sp3 and sp2 C-H bonds. Herein, we report the highly selective divergent alkylbenzenes by an engineered P450 peroxygenase driven dual-functional small molecule (DFSM). Using combinations various P450BM3 variants with DFSMs enabled more than half all possible hydroxylated each excellent regioselectivity (up >99 %), enantioselectivity % ee), high total turnover numbers 80963). Crystal structure analysis, molecular dynamic simulations, theoretical calculations revealed that synergistic effects between exogenous protein environment controlled regio- enantioselectivity. This work has implications for exogenous-molecule-modulated enzymatic regiodivergent enantioselective potential applications in synthetic chemistry.

Language: Английский

Citations

27
Divergent Synthesis of Scabrolide A and Havellockate via an exo-exo-endo Radical Cascade DOI
Peng Chen, Quanping Guo,

Guo-Xiong Xu

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(21), P. 14422 - 14426

Published: May 6, 2024

Here we report a concise and divergent synthesis of scabrolide A havellockate, representative members polycyclic marine natural product furano(nor)cembranoids. The features highly efficient exo-exo-endo radical cascade. Through the generation two rings, three C–C bonds, contiguous stereocenters in one step, this remarkable transformation not only assembles bowl-shaped, common 6–5–5 fused ring system from simple building blocks but also precisely installs functionalities at desired positions sets stage for further preparation both target molecules. Further studies reveal that robust unusual 6-endo addition cascade is likely facilitated by rigidity substrate.

Language: Английский

Citations

6
Molecular Editing of Pyrroles to Benzenes/Naphthalenes by N2O Deletion DOI
Wenjie Xiao, Chang‐Jiu Li,

Jing-yi Lv

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: unknown

Published: July 15, 2024

A molecular editing reaction for converting pyrrole rings into benzene through a sequential pathway of Diels-Alder and cheletropic reactions was developed. The nitrogen atom in N-bridged intermediate is eliminated the form N

Language: Английский

Citations

6
Diversified ring expansion of saturated cyclic amines enabled by azlactone insertion DOI
Licheng Wu,

Hanyu Xia,

Jin Bai

et al.

Nature Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 21, 2024

Language: Английский

Citations

6
Skeletal Editing of Benzene Motif: Photopromoted Transannulation for Synthesis of DNA-Encoded Seven-Membered Rings DOI
Yue Zhang,

Jia‐ying Xue,

Xiao‐can Su

et al.

Organic Letters, Journal Year: 2024, Volume and Issue: 26(11), P. 2212 - 2217

Published: March 7, 2024

In this report, we present a photopromoted, metal-free transannulation of phenyl azides for the synthesis DNA-encoded seven-membered rings. The transformation is efficiently achieved through skeletal editing strategy targeting benzene motif coupled with Reversible Adsorption to Solid Support (RASS) strategy. A variety valuable ring compounds, including 3H-azepines, azepinones, and unnatural amino acids, are now accessible. Crucially, DNA-compatible protocol can also be applied introduction complex molecules, as exemplified by Lorcaserin Betahistine. selective conversion readily available rings into high-value offers promising avenue construction diversified drug-like library.

Language: Английский

Citations

5
Skeletal Editing of Isatins for Heterocycle Molecular Diversity DOI
Tiantian Zhang, Huangdi Feng

The Chemical Record, Journal Year: 2024, Volume and Issue: 24(6)

Published: June 1, 2024

Isatins have been widely used in the preparation of a variety heterocyclic compounds, where skeletal editing isatins has shown significant advantages for construction diverse heterocycles. This review highlights progress made last decade (2013-2023) isatin scaffold. A series ring expansion reactions quinoline skeleton, quinolone polycyclic quinazoline medium-sized as well opening generation 2-(azoly)aniline skeleton by cleavage C-C bond and C-N are highlighted. It is hoped that this will provide some understanding chemical transformations contribute to further realization its molecular diversity.

Language: Английский

Citations

5