A Convenient Late‐Stage Fluorination of Pyridylic C−H Bonds with N‐Fluorobenzenesulfonimide

Meanwell, Michael; Nodwell, Matthew B.; Martin, Rainer E.; Britton, Robert

doi:10.1002/ange.201606323

Cited by 25 publications

(7 citation statements)

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“… 13 , 14 To this end, 4-fluoro and 3-fluoro prolines have been incorporated in proteins such as collagen, 16 ubiquitin, 17 and GFP, 18 used to probe prolyl isomerase enzyme activity by NMR 19 and used as PET probes. 20 Beyond proteins, fluorinated prolines have also found applications as building blocks for medicinal chemistry, 21 reflecting the wide interest in fluorination as a strategy to finely tune conformational and physicochemical properties of biologically active small molecules and peptides. 22 − 25 For instance, the incorporation of (4 S )- or (4 R )-4-fluoroprolines into inhibitors of fibroblast activation protein (FAP) 26 and thrombin 27 ( Chart 1 B) stabilizes a single conformational pucker of the pyrrolidine ring (the C 4 -endo in the case of FAP inhibitor and the C 4 -exo for thrombin inhibitor), which results in improved potency compared to the unsubstituted proline analogues.…”

Section: Introductionmentioning

confidence: 99%

“…Introduction of fluorine substituents can modulate the electronic and conformational properties of small molecules, thus impacting protein–ligand and protein–protein binding affinities, as well as metabolism and cell permeability. 21 We therefore became interested in exploring the synthesis and stereoelectronic properties of fluorinated hydroxyprolines, which we call F-Hyps ( Chart 1 C). We hypothesized that the addition of the highly electronegative F atom adjacent to the hydroxyl group on the pyrrolidine ring could significantly alter the puckering preference of the ring and affect the cis:trans amide ratio.…”

Section: Introductionmentioning

confidence: 99%

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3-Fluoro-4-hydroxyprolines: Synthesis, Conformational Analysis, and Stereoselective Recognition by the VHL E3 Ubiquitin Ligase for Targeted Protein Degradation

et al. 2018

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Hydroxylation and fluorination of proline alters the pyrrolidine ring pucker and the trans:cis amide bond ratio in a stereochemistry-dependent fashion, affecting molecular recognition of proline-containing molecules by biological systems. While hydroxyprolines and fluoroprolines are common motifs in medicinal and biological chemistry, the synthesis and molecular properties of prolines containing both modifications, i.e., fluoro-hydroxyprolines, have not been described. Here we present a practical and facile synthesis of all four diastereoisomers of 3-fluoro-4-hydroxyprolines (F-Hyps), starting from readily available 4-oxo-l-proline derivatives. Small-molecule X-ray crystallography, NMR spectroscopy, and quantum mechanical calculations are consistent with fluorination at C having negligible effects on the hydrogen bond donor capacity of the C hydroxyl, but inverting the natural preference of Hyp from C-exo to C-endo pucker. In spite of this, F-Hyps still bind to the von Hippel-Lindau (VHL) E3 ligase, which naturally recognizes C-exo Hyp in a stereoselective fashion. Co-crystal structures and electrostatic potential calculations support and rationalize the observed preferential recognition for (3 R,4 S)-F-Hyp over the corresponding (3 S,4 S) epimer by VHL. We show that (3 R,4 S)-F-Hyp provides bioisosteric Hyp substitution in both hypoxia-inducible factor 1 alpha (HIF-1α) substrate peptides and peptidomimetic ligands that form part of PROTAC (proteolysis targeting chimera) conjugates for targeted protein degradation. Despite a weakened affinity, Hyp substitution with (3 S,4 S)-F-Hyp within the PROTAC MZ1 led to Brd4-selective cellular degradation at concentrations >100-fold lower than the binary K for VHL. We anticipate that the disclosed chemistry of 3-fluoro-4-hydroxyprolines and their application as VHL ligands for targeted protein degradation will be of wide interest to medicinal organic chemists, chemical biologists, and drug discoverers alike.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

3-Fluoro-4-hydroxyprolines: Synthesis, Conformational Analysis, and Stereoselective Recognition by the VHL E3 Ubiquitin Ligase for Targeted Protein Degradation

et al. 2018

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“…The unique ability of fluorine to extensively alter the biological activity and metabolic stability of a drug candidate has resulted in the synthetic community placing a high value on the development of new fluorination reactions. [41][42][43] The prevailing mechanistic design for current robust Csp 3 -H fluorination strategies rely on the use of electrophilic fluorine (fluorenium) reagents [44][45][46][47][48][49][50][51][52][53][54][55][56][57] , to avoid the use of fluoride as a nucleophile in the key bond-forming step, despite the many advantages they have to offer such as facile translation to radiolabeling (fluorine-18) endeavors, tunable solubility, broader functional group tolerance, comparatively lower costs, more atom economical, and possess improved safety features. [58][59][60][61][62][63][64][65][66] Seminal work from Groves and coworkers showcased the first demonstration of a general Csp 3 -H fluorination utilizing nucleophilic fluoride reagents on aliphatic substrates, albeit via an in-situ conversion of the fluoride to an electrophilic Mn-F species to employ a radical rebound mechanism for C-F bond formation.…”

Section: Current Methods Primarily Functionalize At α-Heteroatom C-h Sites Through the Use Of Strong Lewis Acidsmentioning

confidence: 99%

A Photoredox-Catalyzed Approach for Formal Hydride Abstraction to Enable Csp3–H Functionalization with Nucleophilic Partners

Zhang

Na²,

Das³

et al. 2021

Preprint

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While a great number of C–H functionalization methods have been developed in recent years, new mechanistic paradigms to deconstruct such bonds have been comparatively rare. Amongst possible strategies for breaking a Csp3–H bond are deprotonation, oxidative addition with a metal catalyst, direct insertion via a nitrene intermediate, hydrogen atom transfer (HAT) with both organic and metal-based abstractors, and lastly, hydride abstraction. The latter is a relatively unexplored approach due to the unfavorable thermodynamics of such an event, and thus has not been developed as a general way to target both activated and unactivated Csp3–H bonds on hydrocarbon substrates. Herein, we report our successful efforts in establishing a catalytic C–H functionalization manifold for accessing an intermediate carbocation by formally abstracting hydride from unactivated Csp3–H bonds. The novel catalytic design relies on a stepwise strategy driven by visible light photoredox catalysis and is demonstrated in the context of a C–H fluorination employing nucleophilic fluorine sources. Difluorination of methylene groups is also demonstrated, and represents the first C–H difluorination with nucleophilic fluoride. Additionally, the formal hydride abstraction is shown to be amenable to several other classes of nucleophiles, allowing for the construction of C–C or C–heteroatom bonds.

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“…25 Heteroaromatic benzylic C-H bonds can be selectively fluorinated using a radical mechanism even in the absence of an external radical initiator when Selectfluor ® is employed as a fluorine source 64 , and a complementary ionic approach to achieve the same transformation using NFSI has been proposed. 65 Recently, a novel method has been reported for generating carbon-centred radicals for C-H fluorination using formal Cu III fluorides. 66 A further advance in the field is a bioinspired manganese-porphyrin 67 and later benzylic C-H bonds.…”

Section: [H2] Fluorinationmentioning

confidence: 99%

Contemporary synthetic strategies in organofluorine chemistry

2021

Nat Rev Methods Primers

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At this stage, I've edited the manuscript for brevity and clarity. Queries are meant to draw your attention to edits, inconsistencies or issues that are unclear. If we just ask you to confirm edits are correct, a simple yes/ok between the brackets will do [Au:OK? Is this what you meant? Edits OK? yes]. If questions are asked, please rephrase/update the manuscript text when addressing queries, so that the message is conveyed to the reader (please do not just type your answer to our query unless it is unclear).As the reviewers noted, the manuscript is in very good shape and most comments and edits are fairly minor. However, there is an outstanding issue that must be addressed before we go forward. Figures 7 and 8 are currently referred to in the text in an alternating fashion (e.g. Figure 7A, 8A, 7B, 8B). This is against our style and might make that part of the manuscript difficult to follow for the reader owing to the need to refer to multiple figures at a time while reading the text. To clarify this issue, I recommend restructuring these figures. To do this, can you provide new chemdraw/PDFs with amended figures, including the following amendments: a. Merge Figures 7A and 8A to create a new 'Figure 7' that shows the methods of introducing CF2H at sp3-carbons. b. Merge figures 7B and 8B to make a new figure 8 that shows the main protocols of introducing CF2H at heteroaromatic carbons. 7C could be shown in it's own small figure (Figure 9) or could be added as panel B in the new figure 8. c. Amend the figure legends accordingly Apologies for another figure change but this is essential to keep the figure callouts in style and I think it will make the figures much easier for the reader to follow. I've asked the art editor to delay redrawing these particular figures until we receive these updated chemdraws/PDFs. If there are any issues with this change, please do let me know as soon as possible and we can discuss further.

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A Convenient Late‐Stage Fluorination of Pyridylic C−H Bonds with N‐Fluorobenzenesulfonimide

Cited by 25 publications

References 54 publications

3-Fluoro-4-hydroxyprolines: Synthesis, Conformational Analysis, and Stereoselective Recognition by the VHL E3 Ubiquitin Ligase for Targeted Protein Degradation

3-Fluoro-4-hydroxyprolines: Synthesis, Conformational Analysis, and Stereoselective Recognition by the VHL E3 Ubiquitin Ligase for Targeted Protein Degradation

A Photoredox-Catalyzed Approach for Formal Hydride Abstraction to Enable Csp3–H Functionalization with Nucleophilic Partners

Contemporary synthetic strategies in organofluorine chemistry

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