Janus All‐Cis2,3,4,5,6‐Pentafluorocyclohexyl Building Blocks Applied to Medicinal Chemistry and Bioactives Discovery Chemistry DOI

Joshua L. Clark,

Rifahath M. Neyyappadath,

Cihang Yu

et al.

Chemistry - A European Journal, Journal Year: 2021, Volume and Issue: 27(64), P. 16000 - 16005

Published: Sept. 6, 2021

Monoalkylated derivatives of the unusually polar all-cis 2,3,4,5,6- pentafluorocyclohexyl (Janus face) motif are prepared starting from an aryl hydrogenation pentafluorophenylacetate methyl ester 15. The method used Zeng's Rh(CAAC) carbene catalyst 4 in following protocol developed by Glorius. resultant Janus pentafluorocyclohexylacetate 16 was converted to corresponding alcohol 18, aldehyde 13, bromide 29 and azide 14 through functional group manipulations, some these building blocks were Ugi-multicomponent Cu-catalysed click reactions. NBoc protected pentafluoroarylphenylalanine 35 also subject hydrogenation, then deprotection generate face β-pentafluorocyclohexyl-alanine amino acid 15, which incorporated into representative members emerging class candidate antiviral compounds. Log P measurements demonstrate that 2,3,4,5,6-pentafluorocyclohexyl ring system is more than a phenyl ring. In overview paper introduces new containing this demonstrates their progression molecules typically bioactives discovery programmes.

Language: Английский

Design of robust fluorinated interpenetrating poly(thieno[3,2-b]thiophene) network for highly stable flexible electrochromic-supercapacitor devices DOI

Chunhui Du,

Hui Li, Ge Zhang

et al.

Chemical Engineering Journal, Journal Year: 2024, Volume and Issue: 495, P. 153692 - 153692

Published: July 2, 2024

Language: Английский

Citations

18
Effect of gem‐Difluorination on the Key Physicochemical Properties Relevant to Medicinal Chemistry: The Case of Functionalized Cycloalkanes DOI

Sergey Holovach,

Kostiantyn P. Melnykov,

Artem Skreminskiy

et al.

Chemistry - A European Journal, Journal Year: 2022, Volume and Issue: 28(19)

Published: Feb. 11, 2022

Physico-chemical properties important to drug discovery (pKa , LogP, and aqueous solubility), as well metabolic stability, were studied for a series of functionalized gem-difluorinated cycloalkanes compared those non-fluorinated acyclic counterparts evaluate the impact fluorination. It was found that influence CF2 moiety on acidity/basicity corresponding carboxylic acids amines defined by inductive effect fluorine atoms nearly same cyclic aliphatic compounds. Lipophilicity solubility followed more complex trends affected position atoms, ring size, even nature functional group present; also, significant differences series. Also, gem-difluorination either did not affect or slightly improved stability model derivatives. The presented results can be used guide rational design employing establish first chapter in catalog key vitro fluorinated cycloalkanes.

Language: Английский

Citations

57
Fluorinated Cycloalkyl Building Blocks for Drug Discovery DOI
Oleksandr O. Grygorenko, Kostiantyn P. Melnykov, Serhii Holovach

et al.

ChemMedChem, Journal Year: 2022, Volume and Issue: 17(21)

Published: Aug. 29, 2022

The review covers various aspects of fluorinated cycloalkyl (C3 -C7 ) building blocks for drug discovery, including their synthesis, key physicochemical properties, and biological medicinal applications derivatives. discussed synthetic methods include classical nucleophilic fluorinations substrates, the addition fluorine another heteroatom to double bonds, cycloadditions other transformations fluorine-containing as well some newer reactions like fluorination non-activated remotely activated C-H decarboxylative deborylative fluorinations, etc. known data on effect introducing groups compound's in vitro parameters (such acidity/basicity, lipophilicity, conformational behavior, short contact capabilities) are surveyed. Finally, block derivatives design biologically active compounds (including marketed drugs Maraviroc, Ivosidenib, Sitafloxacin) covered, with a focus impact.

Language: Английский

Citations

57
Regio‐ and Enantioselective Intermolecular Aminofluorination of Alkenes via Iodine(I)/Iodine(III) Catalysis** DOI

Michael Schäfer,

Timo Stünkel,

Constantin G. Daniliuc

et al.

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(32)

Published: May 18, 2022

The regio- and enantio-selective, intermolecular vicinal fluoroamination of α-trifluoromethyl styrenes has been achieved by enantioselective I

Language: Английский

Citations

41
Regioselective, catalytic 1,1-difluorination of enynes DOI Creative Commons
Zixuan Wang, Keith Livingstone,

Carla Hümpel

et al.

Nature Chemistry, Journal Year: 2023, Volume and Issue: 15(11), P. 1515 - 1522

Published: Oct. 16, 2023

Fluorinated small molecules are prevalent across the functional small-molecule spectrum, but scarcity of naturally occurring sources creates an opportunity for creative endeavour in developing routes to access these important materials. Iodine(I)/iodine(III) catalysis has proven be particularly well-suited this task, enabling abundant alkene substrates readily intercepted by situ-generated λ3-iodanes and processed high-value (di)fluorinated products. These organocatalysis paradigms often emulate metal-based processes engaging π bond and, case styrenes, facilitating fluorinative phenonium-ion rearrangements generate difluoromethylene units. Here we demonstrate that enynes competent proxies thereby mitigating recurrent need aryl substituents, highly versatile homopropargylic difluorides generated operationally simple manner. The scope method is disclosed, together with application target synthesis (>30 examples, up >90% yield).

Language: Английский

Citations

26
A General Organophotoredox Strategy to Difluoroalkyl Bicycloalkane (CF2‐BCA) Hybrid Bioisosteres** DOI Creative Commons
Sara Cuadros, Giulio Goti, Giorgia Barison

et al.

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(31)

Published: June 1, 2023

Here, we report a general approach to the synthesis of difluoroalkyl bicycloalkanes (CF2 -BCAs), as structural surrogates aryl ketones and ethers. The chemistry is driven by dihydrobenzoacridine photocatalyst, that engages in catalytic electron-donor acceptor (EDA) complex, or directly reduces fluorinated substrate. These two convergent manifolds lead generation R-CF2 radical, reacts with [1.1.1]- [3.1.1.]-propellane. method extremely general, extendable complex bioactive molecules (30 examples, up 87 % yield). features CF2 -BCP hybrid bioisostere were investigated single crystal X-ray. Finally, synthesised analogue Leukotriene A4 hydrolase inhibitor, replacing original ether motif. In silico docking studies indicated this new maintains same arrangement within enzyme pocket, profiling use -BCA medicinal settings.

Language: Английский

Citations

23
Stereodivergent Synthesis of the Vicinal Difluorinated Tetralin of Casdatifan Enabled by Ru-Catalyzed Transfer Hydrogenation DOI Creative Commons
Guillaume Mata,

Artur K. Mailyan,

Jeremy Fournier

et al.

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

Published: Jan. 13, 2025

We disclose a stereodivergent strategy to prepare vicinal difluorinated tetralins from γ-substituted tetralones via combination of catalyst-controlled transfer hydrogenation and substrate-controlled fluorinations. This process is easily scalable amenable highly functionalized substrates, as demonstrated here in the late-stage synthesis casdatifan, clinical-stage inhibitor hypoxia-inducible factor-2α. Analysis physicochemical properties which features cis-vicinal difluoride, revealed higher level facial polarization compared its trans-vicinal difluoride isomers.

Language: Английский

Citations

1
Fluorinated Sulfinates as Source of Alkyl Radicals in the Photo‐Enantiocontrolled β‐Functionalization of Enals DOI Creative Commons
Ricardo I. Rodríguez, Marina Sicignano, José Alemán

et al.

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(9)

Published: Jan. 4, 2022

The generation of sulfonyl radicals has long been known as a flexible strategy in wide range different sulfonylative transformations. Meanwhile their use alkylation processes somehow limited due to inherent difficulty evolving less-stable after sulfur dioxide extrusion. Herein we report convenient that involves gem-difluorinated sulfinates an "upgrading-mask", allowing these precursors decompose into corresponding alkyl radicals. electron-donor character the formation electron donor-acceptor (EDA) complex with transient iminium ions is displayed, achieving first example stereocontrolled light-driven insertion gem-difluoro derivatives unsaturated aldehydes. This methodology compatible flow conditions, maintaining identical levels enantiocontrol.

Language: Английский

Citations

33
Carbodefluorination of fluoroalkyl ketones via a carbene-initiated rearrangement strategy DOI Creative Commons
Linxuan Li, Xinyu Zhang, Yongquan Ning

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: July 25, 2022

The C-F bond cleavage and C-C formation (i.e., carbodefluorination) of readily accessible (per)fluoroalkyl groups constitutes an atom-economical efficient route to partially fluorinated compounds. However, the selective mono-carbodefluorination trifluoromethyl (CF

Language: Английский

Citations

32
Stereocontrolled Synthesis of Fluorinated Isochromans via Iodine(I)/Iodine(III) Catalysis DOI Creative Commons
Joel Häfliger, Olga O. Sokolova,

Madina Lenz

et al.

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(30)

Published: May 10, 2022

The success of saturated, fluorinated heterocycles in contemporary drug discovery provides a stimulus for creative endeavor main group catalysis. Motivated by the ubiquity isochromans across bioactive small molecule spectrum, prominence anomeric effect regulating conformation, and metabolic lability benzylic position, iodine(I)/iodine(III) catalysis has been leveraged stereocontrolled generation selectively analogs. To augment current arsenal fluorocyclization reactions involving carboxylic acid derivatives, reaction readily accessible 2-vinyl benzaldehydes is disclosed (up to >95 : 05 d.r. 97 03 e.r.). Key stereoelectronic interactions manifest themselves X-ray crystal structures products, thereby validating [CH

Language: Английский

Citations

31