Postsynthetic Modification of Phenylalanine Containing Peptides by C–H Functionalization

Terrey, Myles J.; Perry, Carole C.; Cross, Warren B.

doi:10.1021/acs.orglett.8b03536

Cited by 29 publications

(25 citation statements)

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“…In our previous study of the C-H olefination of phenylalanine residues, we noted that Phe residues were not modified at the N-terminus of a peptide; to rationalise this finding, we proposed that for Phe modification, bidentate coordination of the peptide to the Pd catalyst was required, through two amide groups of the peptide backbone. 37,41 Likewise here, the peptide Ac-Phe-Trp(Boc)-OMe (4d) was only modified at the Trp residue and not at the N-terminal Phe residue (5d, 52% yield). We then explored if N-terminal Trp residues could be modified, and in contrast to N-terminal Phe, Trp residues at the Nterminus did react: C-H olefination of the peptides Ac-Trp(Boc)-Leu-OMe (4e) and Ac-Trp(Boc)-Met-OMe (4f) gave the modified peptides 5e and 5f with isolated yields of 47 and 45% respectively.…”

Section: Scheme 4 C-h Olefination Of Trp Residues In Di-and Tri-peptmentioning

confidence: 70%

“…45 For broad application, which includes the modification of peptides containing more than one aromatic amino acid, we were aware that control of residue-selectivity is important. Having established methods for the C-H olefination of Trp containing peptides and Phe containing peptides, 37 we next investigated the C-H functionalization of peptides containing both Trp and Phe, where modification of both aromatic residues was possible. This investigation began with the dipeptide Ac-Trp(Boc)-Phe-OMe (8a), which had the potential to react at the Trp residue via Boc directed C-H activation, and at the Phe residue via bidentate coordination of the peptide backbone.…”

Section: Scheme 4 C-h Olefination Of Trp Residues In Di-and Tri-peptmentioning

confidence: 99%

“…Our investigation began by employing Fujiwara-Moritani reaction conditions that we had previously optimised for the olefination of phenylalanine containing peptides. 37 Hence, the model dipeptide Ac-Gly-Trp-OMe (1a) was treated with 4 equivalents of styrene in the presence of Pd(OAc)2 (10 mol %) and AgOAc (2.5 equivalents) at 130 °C in t-amyl alcohol, Scheme 2. However, 1a proved to be unreactive under these conditions.…”

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C–H Olefination of Tryptophan Residues in Peptides: Control of Residue Selectivity and Peptide–Amino Acid Cross-linking

et al. 2019

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There is high-demand for new methods to modify peptides, for application in drug discovery and biomedicine. A C-H functionalization protocol for the olefination of tryptophan residues in peptides is described. The modification is successful for Trp residues at any position in the peptide, has broad scope in the styrene coupling partner, and offers opportunities for conjugating peptides with other biomolecules. For peptides containing both Trp and Phe, directing group manipulation enables full-control of residue selectivity. Peptide modification has a critical role to play in drug discovery, the diagnosis of disease, and the understanding of biological mechanism and function. 1,2 As examples, peptidefluorophore conjugates, 3-5 which enable the imaging of biological systems, have been used to diagnose infection, 6,7 and to aid surgery. 8,9 In drug discovery, where peptide therapeutics often have higher potency and target specificity than small molecule drugs, 10-12 synthetic peptide modification can provide necessary improvements to drug stability, cell penetration and oral bioavailability. 13-16 Of the large number of methods that have been developed for the modification of peptides, 2,17 most rely upon the reactions of heteroatoms, which may themselves be crucial to structure and biological function. 18,19 Alternatively, peptides and proteins have been modified at carbon atoms by metalcatalyzed cross-coupling reactions, but these methods require the incorporation of non-natural amino acids. 20-22 Consequently, new methods of peptide modification that operate at carbon atoms and in native peptides are needed. To achieve this goal, there has been rapid progress in developing methods for the C-H functionalization of peptides. 23-37 For example, C(sp 3)-H functionalization of alanine residues can give rise to phenylalanine derivates. 25 C(sp 2)-H functionalization of aromatic amino acids has focussed almost entirely on tryptophan (Trp) residues, that have been modified using arylation, alkynylation and allylation, Scheme 1A. 26-35 In addition , the modification of phenylalanine (Phe) residues in peptides has recently been achieved through C-H olefination, Scheme 1B. 36-38 Scheme 1. C-H functionalization of aromatic amino acids in peptides.

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Section: Scheme 4 C-h Olefination Of Trp Residues In Di-and Tri-peptmentioning

confidence: 70%

Section: Scheme 4 C-h Olefination Of Trp Residues In Di-and Tri-peptmentioning

confidence: 99%

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C–H Olefination of Tryptophan Residues in Peptides: Control of Residue Selectivity and Peptide–Amino Acid Cross-linking

et al. 2019

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“…Capitalizing the peptide backbone as an efficient DG, Cross and co‐workers developed a practical diolefination reaction with styrenes in the presence of 5.0 equivalents of AgOAc [32] . A wide variety of styrenes smoothly underwent the target difunctionalization process in Phe‐containing di‐, tri‐ and tetrapeptides (Scheme 10).…”

Section: C−c Bond‐forming Reactionsmentioning

confidence: 99%

Metal‐Catalyzed C(sp²)−H Functionalization Processes of Phenylalanine‐ and Tyrosine‐Containing Peptides

Correa

2021

Eur J Inorg Chem

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The site‐selective chemical diversification of biomolecules constitutes an unmet challenge of capital importance within medicinal chemistry and chemical biology. The functionalization of otherwise unreactive C−H bonds holds great promise for reducing the reliance on existing functional groups, thereby streamlining chemical syntheses. Over the last years, a myriad of peptide labelling techniques featuring metal‐catalyzed C−H functionalization reactions have been developed. Despite the wealth of reports in the field, the site‐selective modification of both phenylalanine (Phe) and tyrosine (Tyr) compounds upon metal catalysis remain comparatively overlooked. This review highlights these promising tagging strategies, which generally occur through the formation of challenging 6‐membered metallacycles and enable the late‐stage diversification of peptides in a tailored fashion.

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“…MINI REVIEW DOI: 10.31635/ccschem.020.202000426 Citation: CCS Chem. 2020, 2, 1797-1820 Citation denotes calendar and volume year of first online publication.Issue Assignment: Volume 3 (2021),117 reported a protocol of Pd-catalyzed backbone-directed bis C 2 -H olefination of Phe in short peptides with styrenes. In 2019, Zheng and Song 93 reported a similar Pd-catalyzed backbone-directed C 2 -selective C-H alkynylation of Phe in short protected peptides.…”

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Postassembly Modifications of Peptides via Metal-Catalyzed C–H Functionalization

Tong

et al. 2021

CCS Chem

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The growing importance of peptides and proteins in therapeutic and biomedical applications has provided immense motivation toward the development of new ways to construct and transform peptide molecules. As in other areas of organic synthesis, C-H functionalization (CHF) chemistry could potentially exemplify disruptive technologies for peptide engineering. Over the past decade, the field has witnessed an exciting surge of reports of various metal-catalyzed CHF chemistry for postassembly modification of peptides and proteins. This review chronicles present advances in this research area up to June 2020. The content is organized based on the location of CHF on peptides: amino acid side chains (aromatic and nonaromatic), backbone, and appendant groups on peptide terminus. In addition to the reaction mechanisms of the metal-catalyzed CHF chemistry used in these peptide modification protocols, brief comments on the corresponding nonmetal-mediated strategies are included to provide readers a broad view of the current status of CHF-enabled peptide modification.

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Postsynthetic Modification of Phenylalanine Containing Peptides by C–H Functionalization

Cited by 29 publications

References 43 publications

C–H Olefination of Tryptophan Residues in Peptides: Control of Residue Selectivity and Peptide–Amino Acid Cross-linking

C–H Olefination of Tryptophan Residues in Peptides: Control of Residue Selectivity and Peptide–Amino Acid Cross-linking

Metal‐Catalyzed C(sp²)−H Functionalization Processes of Phenylalanine‐ and Tyrosine‐Containing Peptides

Postassembly Modifications of Peptides via Metal-Catalyzed C–H Functionalization

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Postsynthetic Modification of Phenylalanine Containing Peptides by C–H Functionalization

Cited by 29 publications

References 43 publications

C–H Olefination of Tryptophan Residues in Peptides: Control of Residue Selectivity and Peptide–Amino Acid Cross-linking

C–H Olefination of Tryptophan Residues in Peptides: Control of Residue Selectivity and Peptide–Amino Acid Cross-linking

Metal‐Catalyzed C(sp2)−H Functionalization Processes of Phenylalanine‐ and Tyrosine‐Containing Peptides

Postassembly Modifications of Peptides via Metal-Catalyzed C–H Functionalization

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Metal‐Catalyzed C(sp²)−H Functionalization Processes of Phenylalanine‐ and Tyrosine‐Containing Peptides