Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

Drouin, Myriam; Paquin, Jean‐François

doi:10.3762/bjoc.13.262

Cited by 65 publications

(20 citation statements)

References 55 publications

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“…Fluoro- and trifluoromethyl-alkenes and chloroalkenes have been proposed as potential amide bioisosteres based on the topological, steric, and electronic relationships illustrated in Figure , and some of these structural elements have found application in the design of both small molecule drugs and peptidomimetics. ,− However, while the geometries are similar, the dipoles associated with the fluorinated and chlorinated olefins are of a lower strength when compared to an amide, more comparable to an aldehyde or ketone, and although the dipole vectors are similarly aligned, DFT calculations indicate that a chloroalkene more closely approximates an amide than a fluoroalkene. , …”

Section: Fluorine and Carbonyl Bioisosterismmentioning

confidence: 99%

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

2018

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The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.

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Section: Fluorine and Carbonyl Bioisosterismmentioning

confidence: 99%

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

2018

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“…16 Due to their rigidity and hydrolytic stability, fluoro-and chloro-alkenes have found use in medicinal chemistry as peptide-bond bioisosteres. 22,23 The similar sizes of fluorine and oxygen atoms (van der Waals radii = 1.47 Å and 1.52 Å, respectively), 24 and the similar bond lengths of C=O (1.2 Å) and C-F (1.4 Å), allow for analogous pseudo-1,3-allylic strain. 25 However, since fluorine is smaller and more electronegative than oxygen (EN = 3.98 and 3.44, respectively), 26 nàπ* donation by the fluoro-alkene may be less prevalent.…”

Section: Introductionmentioning

confidence: 99%

Conformational Analysis of Fluoro-, Chloro-, and Proteo-Alkene Gly–Pro and Pro–Pro Isosteres to Mimic Collagen

et al. 2021

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Collagen is the most abundant human protein, with the canonical sequence (Gly-Pro-Hyp)n in its triple helix region. Cis-trans isomerization of the Xaa-Pro amide has made two of these amide bonds the target of alkene replacement: the Gly-Pro and the Pro-Hyp positions. The conformations of Gly-Pro and Pro-Pro (as a Pro-Hyp model) fluoro-, chloro-and proteo-alkene mimic models were investigated computationally to determine whether these alkenes can stabilize the polyproline type II (PPII) conformation of collagen. MP2 calculations with various basis sets were used to perform the conformational analyses and locate stationary points. The calculation results predict that fluoro-and chloro-alkene mimics of Gly-Pro and Pro-Pro can participate in nàπ* donation to stabilize PPII conformations, yet they are poor nàπ* acceptors, shifting the global minima away from PPII conformations. For the proteo-alkene mimics, the lack of significant nàπ* interactions and unstable PPII-like geometries explains their known destabilization of the triple helix in collagen-like peptides.

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“… 43 Vinyl fluoride functional groups, such as those in 2a - 2d , are highly desirable due to their role as bioisosteres for amide and enol functional groups. 11 , 44 − 52 …”

Section: Results and Discussionmentioning

confidence: 99%

Au(I) Catalyzed HF Transfer: Tandem Alkyne Hydrofluorination and Perfluoroarene Functionalization

et al. 2022

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HF transfer reactions between organic substrates are potentially useful transformations. Such reactions require the development of catalytic systems that can promote both defluorination and fluorination steps in a single reaction sequence. Herein, we report a catalytic protocol in which an equivalent of HF is generated from a perfluoroarene | nucleophile pair and transferred directly to an alkyne. The reaction is catalyzed by [Au(IPr)N i Pr 2 ] (IPr = N , N ′-1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene). HF transfer generates two useful products in the form of functionalized fluoroarenes and fluoroalkenes. Mechanistic studies (rate laws, KIEs, density functional theory (DFT) calculations, competition experiments) are consistent with the Au(I) catalyst facilitating a catalytic network involving both concerted S N Ar and hydrofluorination steps. The nature of the nucleophile impacts the turnover-limiting step. The cS N Ar step is turnover-limiting for phenol-based nucleophiles, while protodeuaration likely becomes turnover-limiting for aniline-based nucleophiles. The approach removes the need for direct handling of HF reagents in hydrofluorination and offers possibilities to manipulate the fluorine content of organic molecules through catalysis.

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Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

Cited by 65 publications

References 55 publications

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

Conformational Analysis of Fluoro-, Chloro-, and Proteo-Alkene Gly–Pro and Pro–Pro Isosteres to Mimic Collagen

Au(I) Catalyzed HF Transfer: Tandem Alkyne Hydrofluorination and Perfluoroarene Functionalization

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