Synthesis of Trifluoromethyl‐Substituted Proline Analogues as <sup>19</sup>F NMR Labels for Peptides in the Polyproline II Conformation

Mykhailiuk, Pavel K.; Afonin, Sergii; Palamarchuk, G. V.; Шишкин, Олег В.; Ulrich, Anne S.; Komarov, Igor V.

doi:10.1002/anie.200801022

Cited by 117 publications

(55 citation statements)

References 34 publications

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“…Among these modifications were derivatives that incorporate spin-1/2 nuclei that could be used as NMR probes, specifically probes that might be exploited site-specifically without background from natural sources. 73 19 F NMR spectra were collected for fluorinated proline peptides (Figure 12), including those containing flp ( 26 ), Flp ( 27 ), 4,4-difluoroproline ( 101 , 134 ), pentafluorophenyl ethers ( 33 , 34 ), and perfluoro- tert -butyl ethers ( 55 , 56 ). 19 F NMR spectra are characterized in general by excellent chemical shift dispersion, a feature which was observed in fluorinated peptides, with an overall chemical shift range of over 100 ppm in the fluorinated peptides: δ from −70 ppm (perfluoro- tert -butyl ethers) to −178 ppm (fluoroprolines), with difluoroprolines (∼ −100 ppm) and aryl fluorines (∼ −160 ppm) intermediate (Table 6).…”

Section: Resultsmentioning

confidence: 99%

Proline Editing: A General and Practical Approach to the Synthesis of Functionally and Structurally Diverse Peptides. Analysis of Steric versus Stereoelectronic Effects of 4-Substituted Prolines on Conformation within Peptides

et al. 2013

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Functionalized proline residues have diverse applications. Herein we describe a practical approach, proline editing, for the synthesis of peptides with stereospecifically modified proline residues. Peptides are synthesized by standard solid-phase-peptide-synthesis to incorporate Fmoc-Hydroxyproline (4R-Hyp). In an automated manner, the Hyp hydroxyl is protected and the remainder of the peptide synthesized. After peptide synthesis, the Hyp protecting group is orthogonally removed and Hyp selectively modified to generate substituted proline amino acids, with the peptide main chain functioning to “protect” the proline amino and carboxyl groups. In a model tetrapeptide (Ac-TYPN-NH2), 4R-Hyp was stereospecifically converted to 122 different 4-substituted prolyl amino acids, with 4R or 4S stereochemistry, via Mitsunobu, oxidation, reduction, acylation, and substitution reactions. 4-Substituted prolines synthesized via proline editing include incorporated structured amino acid mimetics (Cys, Asp/Glu, Phe, Lys, Arg, pSer/pThr), recognition motifs (biotin, RGD), electron-withdrawing groups to induce stereoelectronic effects (fluoro, nitrobenzoate), handles for heteronuclear NMR (19F:fluoro; pentafluorophenyl or perfluoro-tert-butyl ether; 4,4-difluoro; 77SePh) and other spectroscopies (fluorescence, IR: cyanophenyl ether), leaving groups (sulfonate, halide, NHS, bromoacetate), and other reactive handles (amine, thiol, thioester, ketone, hydroxylamine, maleimide, acrylate, azide, alkene, alkyne, aryl halide, tetrazine, 1,2-aminothiol). Proline editing provides access to these proline derivatives with no solution phase synthesis. All peptides were analyzed by NMR to identify stereoelectronic and steric effects on conformation. Proline derivatives were synthesized to permit bioorthogonal conjugation reactions, including azide-alkyne, tetrazinetrans-cyclooctene, oxime, reductive amination, native chemical ligation, Suzuki, Sonogashira, cross-metathesis, and Diels-Alder reactions. These proline derivatives allowed three parallel bioorthogonal reactions to be conducted in one solution.

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Section: Resultsmentioning

confidence: 99%

Proline Editing: A General and Practical Approach to the Synthesis of Functionally and Structurally Diverse Peptides. Analysis of Steric versus Stereoelectronic Effects of 4-Substituted Prolines on Conformation within Peptides

et al. 2013

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“…Simple and safe protocols for the generation of (trifluoromethyl)diazomethaneh ave recentlya ppeared in the literature. [10,11] As ac onsequence, ac onsiderable number of reports concerning its use, mainly in cyclopropanations [12] and dipolar cycloadditions, [11d, h, i, 13] have been published over the last decade. With their high ring strain,d ifluorocyclopropenes should be compatible partners in a1 ,3-dipolar cycloaddition with (trifluoromethyl)diazomethane.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Functionalized 4‐Fluoropyridazines

et al. 2017

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Ar oute to 4-fluoropyridazines by a[ 2 + +1]/[3+ +2] cycloaddition sequence betweena na cetylenic derivative, ad ifluorocarbenes ource,a nd ad iazo compound is reported. This approach is highly modulara nd compatiblew ith ab road range of functional groups. The protocol does not require the isolation of any reactive intermediates and,t hus, allows for access to aw ide range of 4-fluoropyridazines in as ingle synthetics tep from simple alkynes. Furthermore, these fluorinated compounds can be easily diversified by nucleophilic aromatic substitution (S N Ar) to displace the fluoro group to give aw ider range of 3,4,6-trisubstituted pyridazines. As ar esult of increasing interest in functionalized pyridazines as wella sf luorinated derivatives, this efficient and concise approacht o4 -fluoropyridazines should be of value to medicinal chemists. Scheme1.(1) Synthesis of 5-fluoropyridazinesb ya[ 2 + +1]/[3+ +2] cycloaddition sequencew ith alkyl diazoacetates;(2) Synthesis of 4-fluoropyridazines by a[ 2 + +1]/[3+ +2] cycloaddition sequence with other diazo compounds (TMS = trimethylsilyl, TFDA = trimethylsilyl fluorosulfonyldifluoroacetate, Nu = nucleophile).Scheme2.Mechanism of the [2+ +1]/[3+ +2] cycloaddition sequence with (trimethylsilyl)diazomethane (E).

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“…et al (Scheme 38) [98]. Thus, treatment of optically pure 3,4-dehydroproline derivative 147 with an excess amount of CF 3 CHN 2 in the presence of CuOTf affords two diastereomeric products 148a and 148b in modest yield as a separable mixture.…”

Section: Transition Metal-catalyzed Cyclopropanationmentioning

confidence: 97%

Stereoselective Construction of an Asymmetric Carbon Center Possessing a Trifluoromethyl Group

Konno¹

2010

COS

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Synthesis of Trifluoromethyl‐Substituted Proline Analogues as ¹⁹F NMR Labels for Peptides in the Polyproline II Conformation

Cited by 117 publications

References 34 publications

Proline Editing: A General and Practical Approach to the Synthesis of Functionally and Structurally Diverse Peptides. Analysis of Steric versus Stereoelectronic Effects of 4-Substituted Prolines on Conformation within Peptides

Proline Editing: A General and Practical Approach to the Synthesis of Functionally and Structurally Diverse Peptides. Analysis of Steric versus Stereoelectronic Effects of 4-Substituted Prolines on Conformation within Peptides

Synthesis of Functionalized 4‐Fluoropyridazines

Stereoselective Construction of an Asymmetric Carbon Center Possessing a Trifluoromethyl Group

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Synthesis of Trifluoromethyl‐Substituted Proline Analogues as 19F NMR Labels for Peptides in the Polyproline II Conformation

Cited by 117 publications

References 34 publications

Proline Editing: A General and Practical Approach to the Synthesis of Functionally and Structurally Diverse Peptides. Analysis of Steric versus Stereoelectronic Effects of 4-Substituted Prolines on Conformation within Peptides

Proline Editing: A General and Practical Approach to the Synthesis of Functionally and Structurally Diverse Peptides. Analysis of Steric versus Stereoelectronic Effects of 4-Substituted Prolines on Conformation within Peptides

Synthesis of Functionalized 4‐Fluoropyridazines

Stereoselective Construction of an Asymmetric Carbon Center Possessing a Trifluoromethyl Group

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Product

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Synthesis of Trifluoromethyl‐Substituted Proline Analogues as ¹⁹F NMR Labels for Peptides in the Polyproline II Conformation