Organophotoredox-Driven Three-Component Synthesis of β-Trifluoromethyl β-Amino Ketones

The Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

In this work, we present a photoredox three-component reaction that enables the synthesis of medicinally relevant β-trifluoromethyl β-amino ketones from N-trifluoroethylhydroxylamine derivative, styrenes and DMSO. Remarkably, fluoromethyl, difluoromethyl pentafluoroethyl analogues are also accessed using same conditions. The mechanistic investigations, including radical trapping experiments, cyclic voltammetry, Stern-Volmer quenching studies isotope labelling experiments support photoinduced radical/polar crossover Kornblum-type oxidation mechanisms. Finally, applicability organic skeletons is showcased by notable derivatization reactions.

Language: Английский

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Switchable Nucleophilic Site Enables Expedient Synthesis of CF₃-Containing Thiazoles and Allenes from 1,3-Enynes

ACS Catalysis, Journal Year: 2023, Volume and Issue: 13(19), P. 12755 - 12765

Published: Sept. 15, 2023

Typically, trimethylsilyl isothiocyanate (TMSNCS) is used as a nucleophilic thiocyanate building block (−S–C≡N) that reacts with various electrophiles. However, it has been less explored source of isothiocyanates (−N═C═S), which can usually be converted by thermal isomerization allyl or propargyl thiocyanates. Achieving method precise site control even more challenging. Here, we demonstrate an approach uses metal catalysts to switchable sites and provide strategy construct CF3-containing thiazoles allenes via the multicomponent reaction 1,3-enynes, TMSNCS, electrophilic trifluoromethyl reagent. In presence inexpensive Fe(III) Cu(II) catalysts, current practical convenient, compatible substrates bearing sensitive functional groups readily transferred complex scaffolds. The biological evaluation showed two developed exhibited dramatic inhibitory activities for three human cancer cell lines beyond those 5-fluorouracil. Both compounds increased level reactive oxygen species in MCF-7 cells, believed early step tumor apoptosis.

Language: Английский

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Unnatural Amino Acids: Strategies, Designs, and Applications in Medicinal Chemistry and Drug Discovery

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(22), P. 19932 - 19965

Published: Nov. 11, 2024

Peptides can operate as therapeutic agents that sit within a privileged space between small molecules and larger biologics. Despite examples of their potential to regulate receptors modulate disease pathways, the development peptides with drug-like properties remains challenge. In quest optimize physicochemical parameters improve target selectivity, unnatural amino acids (UAAs) have emerged critical tools in peptide- peptidomimetic-based drugs. The utility UAAs is illustrated by clinically approved drugs such methyldopa, baclofen, gabapentin addition drug molecules, for example, bortezomib sitagliptin. this Perspective, we outline strategy deployment FDA-approved targets. We further describe modulation using UAAs. Finally, elucidate how these improved pharmacological role played impact progress analogs preclinical stages an emphasis on

Language: Английский

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Trifluoromethylthiolation of Tryptophan and Tyrosine Derivatives: A Tool for Enhancing the Local Hydrophobicity of Peptides

The Journal of Organic Chemistry, Journal Year: 2023, Volume and Issue: 88(18), P. 13169 - 13177

Published: Sept. 6, 2023

The incorporation of fluorinated groups into peptides significantly affects their biophysical properties. We report herein the synthesis Fmoc-protected trifluoromethylthiolated tyrosine (CF3S-Tyr) and tryptophan (CF3S-Trp) analogues on a gram scale (77–93% yield) demonstrate use as highly hydrophobic building blocks for peptide chemistry. developed methodology was successfully applied to late-stage regioselective trifluoromethylthiolation Trp residues in short (66–80% various CF3S-analogues biologically active monoamines. To prove concept, Fmoc-(CF3S)Tyr -Trp were incorporated endomorphin-1 chain (EM-1) model tripeptides by solid-phase synthesis. A remarkable enhancement local hydrophobicity quantified chromatographic index determination method, demonstrating high potential CF3S-containing amino acids rational design bioactive peptides.

Language: Английский

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Expanding the Scope of Azole-Based γ-Amino Acids

Synthesis, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Abstract The development of non-canonical amino acids is pivotal to peptide engineering, enabling the design molecules with novel structural features, improved activities, and optimized metabolic profiles. Among these, heteroaromatic γ-amino have attracted significant attention for their ability mimic native folds while accessing conformational spaces. In this study, chemical diversity was expanded by introducing two new monomers, ATC* AOC*, designed around a thiazole an oxazole scaffold, respectively. These analogues, characterized tunable substitution patterns precise stereochemical control significantly expand well-established ATC family.

Language: Английский

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Nitrogen-Based Organofluorine Functional Molecules: Synthesis and Applications

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: April 22, 2025

Fluorine and nitrogen form a successful partnership in organic synthesis, medicinal chemistry, material sciences. Although fluorine-nitrogen chemistry has long rich history, this field received increasing interest made remarkable progress over the past two decades, driven by recent advancements transition metal organocatalysis photochemistry. This review, emphasizing contributions from 2015 to 2023, aims update state of art synthesis applications nitrogen-based organofluorine functional molecules chemistry. In dedicated sections, we first focus on fluorine-containing reagents organized according type groups attached nitrogen, including N-F, N-RF, N-SRF, N-ORF. review also covers nitrogen-linked building blocks, catalysts, pharmaceuticals, agrochemicals, underlining these components' broad applicability growing importance modern

Language: Английский

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Biocatalytic Synthesis of Aryl and Heteroaryl γ-Hydroxy-α-amino Acids via an Aldolase–Transaminase One-Pot Reaction

ACS Sustainable Chemistry & Engineering, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Language: Английский

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Construction of Benzoxazole and Isoquinoline Compounds via Base-Mediated Cyclization of Amino Acid Derivatives

Organic Letters, Journal Year: 2025, Volume and Issue: unknown

Published: March 19, 2025

Biological organisms contain bioactive macromolecules such as amino acids, which serve basic materials for constructing cells and repairing tissues. Due to the unique properties of fluorine atom, can alter structure proteins increase their lipophilicity, incorporating a atom into acids has become research hotspot. In this study, ethyl 3-bromo-2-((diphenylmethylene)amino)-3,3-difluoropropanoate was synthesized from glycine derivatives. Under alkaline conditions, compound reacted with 2-aminophenol generate benzoxazole-containing acid derivative. This method is simple operate, without metal participation, performed under relatively eco-friendly reaction providing novel approach synthesis benzoxazole heterocycles.

Language: Английский

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Asymmetric synthesis of difluorinated α-quaternary amino acids (DFAAs) via Cu-catalyzed difluorobenzylation of aldimine esters

Chinese Chemical Letters, Journal Year: 2024, Volume and Issue: 35(12), P. 109665 - 109665

Published: Feb. 23, 2024

Language: Английский

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Enzymatic synthesis of mono- and trifluorinated alanine enantiomers expands the scope of fluorine biocatalysis

Communications Chemistry, Journal Year: 2024, Volume and Issue: 7(1)

Published: May 9, 2024

Abstract Fluorinated amino acids serve as an entry point for establishing new-to-Nature chemistries in biological systems, and novel methods are needed the selective synthesis of these building blocks. In this study, we focused on enzymatic fluorinated alanine enantiomers to expand fluorine biocatalysis. The dehydrogenase from Vibrio proteolyticus diaminopimelate Symbiobacterium thermophilum were selected vitro production ( R )-3-fluoroalanine S )-3-fluoroalanine, respectively, using 3-fluoropyruvate substrate. Additionally, discovered that racemase Streptomyces lavendulae , originally setting alternative cascade leading non-canonical acids, had unprecedented catalytic efficiency β-elimination monosubstituted fluoroalanine. based dehydrogenases V . included a cofactor recycling system, whereby formate Pseudomonas sp. 101 (either native or engineered) coupled oxidation NAD(P)H formation. Under conditions, reaction yields reached >85% substrate proceeded with complete enantiomeric excess. also catalyzed conversion trifluoropyruvate into trifluorinated first-case example biocatalysis carrying trifluoromethyl group.

Language: Английский

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