Synthesis of Chiral Amines by C–C Bond Formation with Photoredox Catalysis

Synthesis ◽  
2021 ◽  
Author(s):  
Gregory K. Friestad ◽  
Stephen T. J. Cullen
Keyword(s):  
Radical Addition ◽  
Biologically Active ◽  
Chiral Amines ◽  
Photoredox Catalysis ◽  
Conjugate Additions ◽  
Drug Candidates ◽  
Radical Intermediates ◽  
Radical Coupling ◽  
Amine Oxidation ◽  
Imine Reduction

AbstractChiral amines are key substructures of biologically active natural products and drug candidates. The advent of photoredox catalysis has changed the way synthetic chemists think about building these substructures, opening new pathways that were previously unavailable. New developments in this area are reviewed, with an emphasis on C–C bond constructions involving radical intermediates generated through photoredox processes.1 Introduction2 Radical–Radical Coupling of α-Amino Radicals2.1 Radical–Radical Coupling Involving Amine Oxidation2.2 Radical–Radical Coupling Involving Imine Reduction2.3 Couplings Involving both Amine Oxidation and Imine Reduction3 Addition Reactions of α-Amino Radicals3.1 Conjugate Additions of α-Amino Radicals3.2 Addition of α-Amino Radicals to Heteroaromatic Systems3.3 Cross Coupling via Additions to Transition Metal Complexes4 Radical Addition to C=N Bonds Using Photoredox Catalysis4.1 Intramolecular Radical Addition to C=N Bonds4.2 Intermolecular Radical Addition to C=N Bonds5 Conclusion

scholarly journals Visible-Light Radical–Radical Coupling vs. Radical Addition: Disentangling a Mechanistic Knot

Catalysts ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 922
Author(s):  
Fernando Aguilar-Galindo ◽  
Ricardo I. Rodríguez ◽  
Leonardo Mollari ◽  
José Alemán ◽  
Sergio Díaz-Tendero
Keyword(s):  
Radical Addition ◽  
Mechanistic Study ◽  
Cascade Process ◽  
Radical Coupling ◽  
Quantum Chemistry Calculations ◽  
Heterocyclic Derivatives ◽  
Selective Generation ◽  
Imine Reduction ◽  
Process Strategy ◽  
Insight Into

A highly enantioselective protocol has been recently described as allowing the synthesis of five-membered cyclic imines harnessing the selective generation of a β-Csp3-centered radical of acyl heterocyclic derivatives and its subsequent interaction with diverse NH-ketimines. The overall transformation represents a novel cascade process strategy crafted by individual well-known steps; however, the construction of the new C-C bond highlights a crucial knot from a mechanistically perspective. We believe that the full understanding of this enigmatic step may enrich the current literature and expand latent future ideas. Therefore, a detailed mechanistic study of the protocol has been conducted. Here, we provide theoretical insight into the mechanism using quantum chemistry calculations. Two possible pathways have been investigated: (a) imine reduction followed by radical–radical coupling and (b) radical addition followed by product reduction. In addition, investigations to unveil the origin behind the enantioselectivity of the 1-pyrroline derivatives have been conducted as well.

Privileged Structures in the Design of Potential Drug Candidates for Neglected Diseases

2019 ◽  
Vol 26 (23) ◽  
pp. 4323-4354 ◽  
Author(s):  
Ana Cristina Lima Leite ◽  
José Wanderlan Pontes Espíndola ◽  
Marcos Veríssimo de Oliveira Cardoso ◽  
Gevanio Bezerra de Oliveira Filho
Keyword(s):  
Biologically Active ◽  
Neglected Diseases ◽  
Financial Return ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Wide Range ◽  
Methods Of Synthesis ◽  
Current Therapies ◽  
Resistant Strains ◽  
Privileged Structures

Background: Privileged motifs are recurring in a wide range of biologically active compounds that reach different pharmaceutical targets and pathways and could represent a suitable start point to access potential candidates in the neglected diseases field. The current therapies to treat these diseases are based in drugs that lack of the desired effectiveness, affordable methods of synthesis and allow a way to emergence of resistant strains. Due the lack of financial return, only few pharmaceutical companies have been investing in research for new therapeutics for neglected diseases (ND). Methods: Based on the literature search from 2002 to 2016, we discuss how six privileged motifs, focusing phthalimide, isatin, indole, thiosemicarbazone, thiazole, and thiazolidinone are particularly recurrent in compounds active against some of neglected diseases. Results: It was observed that attention was paid particularly for Chagas disease, malaria, tuberculosis, schistosomiasis, leishmaniasis, dengue, African sleeping sickness (Human African Trypanosomiasis - HAT) and toxoplasmosis. It was possible to verify that, among the ND, antitrypanosomal and antiplasmodial activities were between the most searched. Besides, thiosemicarbazone moiety seems to be the most versatile and frequently explored scaffold. As well, phthalimide, isatin, thiazole, and thiazolidone nucleus have been also explored in the ND field. Conclusion: Some described compounds, appear to be promising drug candidates, while others could represent a valuable inspiration in the research for new lead compounds.

Enantioselective Radical Functionalization of Imines and Iminium Intermediates via Visible Light Photoredox Catalysis

Synthesis ◽  
2020 ◽  
Author(s):  
Jia-Jia Zhao ◽  
Hong-Hao Zhang ◽  
Shouyun Yu
Keyword(s):  
Visible Light ◽  
Asymmetric Synthesis ◽  
Carbonyl Compounds ◽  
Asymmetric Reduction ◽  
Chemical Transformations ◽  
Photoredox Catalysis ◽  
Radical Coupling ◽  
Mild Conditions ◽  
Iminium Ions ◽  
Radical Functionalization

Visible light photoredox catalysis has recently emerged as a powerful tool for the development of new and valuable chemical transformations under mild conditions. Visible-light promoted enantioselective radical transformations of imines and iminium intermediates provide new opportunities for the asymmetric synthesis of amines and asymmetric β-functionalization of unsaturated carbonyl compounds. In this review, the advance in the catalytic asymmetric radical functionalization of imines, as well as iminium intermediates, are summarized. 1 Introduction 2 The enantioselective radical functionalization of imines 2.1 Asymmetric reduction 2.2 Asymmetric cyclization 2.3 Asymmetric addition 2.4 Asymmetric radical coupling 3 The enantioselective radical functionalization of iminium ions 3.1 Asymmetric radical alkylation 3.2 Asymmetric radical acylation 4 Conclusion

scholarly journals Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds

2021 ◽  
Vol 379 (5) ◽  
Author(s):  
Giovanna Li Petri ◽  
Maria Valeria Raimondi ◽  
Virginia Spanò ◽  
Ralph Holl ◽  
Paola Barraja ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Binding Mode ◽  
Biologically Active ◽  
Bioactive Molecules ◽  
Biological Profile ◽  
Pyrrolidine Ring ◽  
Reaction Conditions ◽  
Drug Candidates ◽  
Steric Factors ◽  
Proline Derivatives

AbstractThe five-membered pyrrolidine ring is one of the nitrogen heterocycles used widely by medicinal chemists to obtain compounds for the treatment of human diseases. The great interest in this saturated scaffold is enhanced by (1) the possibility to efficiently explore the pharmacophore space due to sp3-hybridization, (2) the contribution to the stereochemistry of the molecule, (3) and the increased three-dimensional (3D) coverage due to the non-planarity of the ring—a phenomenon called “pseudorotation”. In this review, we report bioactive molecules with target selectivity characterized by the pyrrolidine ring and its derivatives, including pyrrolizines, pyrrolidine-2-one, pyrrolidine-2,5-diones and prolinol described in the literature from 2015 to date. After a comparison of the physicochemical parameters of pyrrolidine with the parent aromatic pyrrole and cyclopentane, we investigate the influence of steric factors on biological activity, also describing the structure–activity relationship (SAR) of the studied compounds. To aid the reader’s approach to reading the manuscript, we have planned the review on the basis of the synthetic strategies used: (1) ring construction from different cyclic or acyclic precursors, reporting the synthesis and the reaction conditions, or (2) functionalization of preformed pyrrolidine rings, e.g., proline derivatives. Since one of the most significant features of the pyrrolidine ring is the stereogenicity of carbons, we highlight how the different stereoisomers and the spatial orientation of substituents can lead to a different biological profile of drug candidates, due to the different binding mode to enantioselective proteins. We believe that this work can guide medicinal chemists to the best approach in the design of new pyrrolidine compounds with different biological profiles.

Natural products targeting cancer stem cells: a revisit

2021 ◽  
Vol 28 ◽  
Author(s):  
Jiahua Cui ◽  
Jiajun Qian ◽  
Larry Ming-Cheung Chow ◽  
Jinping Jia
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Natural Products ◽  
Cancer Stem Cells ◽  
Therapeutic Potential ◽  
Tumor Development ◽  
Biologically Active ◽  
Cellular Targets ◽  
Drug Candidates ◽  
Enhanced Expression

Background: The proposed central role of cancer stem cells (CSCs) in tumor development has been extended to explain the diverse oncologic phenomena such as multidrug resistance, metastasis and tumor recurrence in clinics. Due to the enhanced expression of ATP-binding cassette transporters and anti-apoptotic factors, stagnation on G0 phase and the strong ability of self-renewal, the CSCs were highly resistant to clinical anticancer drugs. Therefore, the discovery of new drug candidates that could effectively eradicate cancer stem cells afforded promising outcomes in cancer therapy. Introduction: Natural products and their synthetic analogues are a rich source of biologically active compounds and several of them have already been recognized as potent CSCs killers. We aim to provide a collection of recently identified natural products that suppressed the survival of the small invasive CSC populations and combated the drug resistance of these cells in chemotherapy. Results and Conclusion: These anti-CSCs natural products included flavonoids, stilbenes, quinones, terpenoids, polyketide antibiotics, steroids and alkaloids. In the present review, we highlighted the therapeutic potential of natural products and their derivatives against the proliferation and drug resistance of CSCs, their working mechanisms and related structure-activity relationships. Meanwhile, in this survey, several natural products with diverse cellular targets such as the naphthoquinone shikonin and the stilbene resveratrol were characterized as promising lead compounds for future development.

Synthesis of Pyrazolofuropyrazine via One-Pot SNAr Reaction and Intramolecular Direct C–H Arylation

Synthesis ◽  
2018 ◽  
Vol 50 (07) ◽  
pp. 1493-1498 ◽  
Author(s):  
Shinichiro Fuse ◽  
Hiroyuki Nakamura ◽  
Megumi Inaba ◽  
Shinichi Sato ◽  
Manjusha Joshi
Keyword(s):  
Drug Discovery ◽  
Rapid Development ◽  
Ring System ◽  
Biologically Active ◽  
Drug Candidate ◽  
One Pot ◽  
Ring Systems ◽  
Drug Candidates ◽  
Fused Ring ◽  
Snar Reaction

Fused-ring systems containing heterocycles are attractive templates for drug discovery. Biologically active 6-5-5+6 fused-ring systems that possess heterocycles are available, but these require a relatively large number of synthetic steps for preparation. Therefore, pyrazolofuropyrazine was designed as a 6-5-5+6 ring system template that incorporates ready accessibility for drug discovery. Pyrazolofuropyrazines were successfully constructed in only a few steps via one-pot SNAr reaction/intramolecular C–H direct arylation. As a drug candidate, pyrazolofuropyrazine has earned a favorable LogP, although significant biological activity has yet to be established; the ready accessibility of pyrazolofuropyrazine template, however, offers an opportunity for the rapid development of promising new drug candidates.

scholarly journals Combined Photoredox and Carbene Catalysis for the Synthesis of Ketones from Carboxylic Acids

2020 ◽  
Author(s):  
Anna Davies ◽  
keegan fitzpatrick ◽  
Rick Betori ◽  
Karl Scheidt
Keyword(s):  
Carboxylic Acids ◽  
Late Stage ◽  
Pharmaceutical Compounds ◽  
Single Electron ◽  
Photoredox Catalysis ◽  
Radical Coupling ◽  
Electron Reduction

Disclosed herein is the development of a novel single-electron reduction of acyl azoliums for the formation of ketones from carboxylic acids. Facile construction of the acyl azolium <i>in situ</i> followed by a radical-radical coupling was made possible using merged NHC-photoredox catalysis. The utility of this protocol in synthesis was demonstrated in the late-stage functionalization of a variety of pharmaceutical compounds.

scholarly journals A New Hybrid δ-Lactone Induces Apoptosis and Potentiates Anticancer Activity of Taxol in HL-60 Human Leukemia Cells

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1479 ◽  
Author(s):  
Katarzyna Gach-Janczak ◽  
Joanna Drogosz-Stachowicz ◽  
Angelika Długosz-Pokorska ◽  
Rafał Jakubowski ◽  
Tomasz Janecki ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Anticancer Agents ◽  
Biologically Active ◽  
Human Leukemia ◽  
Apoptosis Induction ◽  
Hybrid Compound ◽  
Drug Candidates ◽  
Natural Substances ◽  
High Cytotoxic Activity ◽  
Induced Apoptosis

In the search for new drug candidates, researchers turn to natural substances isolated from plants which may be either used directly or may serve as a source for chemical modifications. An interesting strategy in the design of novel anticancer agents is based on the conjugation of two or more biologically active structural motifs into one hybrid compound. In this study, we investigated the anticancer potential of 4-benzyl-5,7-dimethoxy-4-methyl-3-methylidene-3,4-dihydro-2H-chroman-2-one (DL-247), a new hybrid molecule combining a chroman-2-one skeleton with an exo-methylidene bond conjugated with a carbonyl group, in human myeloid leukemia HL-60 cell line. The cytotoxicity of the new compound was tested using MTT assay. The effect of DL-247 on cell proliferation and apoptosis induction were studied by flow cytometry, fluorometric assay and ELISA analysis. DL-247 displayed high cytotoxic activity (IC50 = 1.15 µM, after 24 h incubation), significantly inhibited cell proliferation and induced apoptosis by both, the intrinsic and extrinsic pathways. A combination of DL-247 with taxol exhibited a strong synergistic effect on DNA damage generation, apoptosis induction and inhibition of cell growth.

Transition metal-free, visible-light-mediated construction of α,β-diamino esters via decarboxylative radical addition at room temperature

2019 ◽  
Vol 6 (13) ◽  
pp. 2245-2249 ◽  
Author(s):  
Guibing Wu ◽  
Jingwen Wang ◽  
Chengyu Liu ◽  
Maolin Sun ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Transition Metal ◽  
Visible Light ◽  
Carboxylic Acids ◽  
Room Temperature ◽  
Radical Addition ◽  
Metal Free ◽  
Radical Coupling

A metal-free photoredox catalyzed decarboxylative radical coupling of free-carboxylic acids and glyoxylic oximes was developed to synthesize α,β-diamino acids.

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