New Synthetic Route to a Dipeptidyl Peptidase-4 Inhibitor

Lafrance, Danny; Caron, Stéphane

doi:10.1021/op200309z

Cited by 12 publications

(21 citation statements)

References 16 publications

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“…21l, 31d, 33 In general, the proline mesylates ( 5 , 6 ) and para -nosylates ( 9 , 10 ) were similarly effective for S N 2 reactions on solid phase (see HPLC chromatograms in the Supporting Information), whereas the tosylates ( 7 , 8 ) were less effective, resulting in poorer conversion and/or more side products. 21j, k …”

Section: Resultsmentioning

confidence: 99%

“…19a, 21b, 21e, 21j, k, 31 Hydroxyproline residues were readily converted to include leaving groups including mesylates, tosylates, para -nosylates, and ortho -nosylates. These derivatives were stable to standard TFA cleavage conditions and isolable as the sulfonates (see below for structural analysis of the sulfonates and all derivatives).…”

Section: Resultsmentioning

confidence: 99%

“…These reactions were applied to generate the respective 4-substituted prolines, including the highly versatile 4-azidoprolines (4 R ( 18 ) and 4 S ( 21 )) with good conversion. 17o, p, 21f, 32 In addition, the azidoproline-containing peptides were converted to the ionizable aminoprolines ( 19 , 22 ) and guanidinoprolines ( 20 , 23 ) via reduction of the azide to the amine and guanylation. 21l, 31d, 33 In general, the proline mesylates ( 5 , 6 ) and para -nosylates ( 9 , 10 ) were similarly effective for S N 2 reactions on solid phase (see HPLC chromatograms in the Supporting Information), whereas the tosylates ( 7 , 8 ) were less effective, resulting in poorer conversion and/or more side products.…”

Section: Resultsmentioning

confidence: 99%

“…21b, 21i, 38 Other aryl prolyl ethers synthesized included cyanophenyl, which could be used as a spectroscopic probe (IR or fluorescence, see below), and aryl halides (I, Br) for palladium-mediated cross-coupling reactions. These phenyl ethers could also be employed to tune the recognition properties of proline-containing peptides.…”

Section: Resultsmentioning

confidence: 99%

“…20 There is an extensive history of development of novel proline derivatives, particularly for applications in medicinal chemistry, which has been the stimulus for the synthesis of most proline derivatives. 5d, 19, 21 Proline derivatives have also been significantly applied to the field of collagen mimetics, where multiple copies of proline derivatives are incorporated in the collagen triple helix, allowing modulation of stability of synthetic collagens. 9,11,17a-f,h,p-q …”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Synthesis and Characterization of β‐Trifluoromethyl‐Substituted Pyrrolidines

et al. 2013

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A practical synthetic approach to the construction of a library of three isomeric/homologous β‐trifluoromethyl‐substituted pyrrolidines is disclosed. All products were prepared in multigram quantities from a common precursor. The key synthetic step was a [3+2] cycloaddition reaction. The influence of the trifluoromethyl group on the physicochemical characteristics of the pyrrolidine fragment was studied.

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