Metal Catalysis within Tyrosine Bioconjugation

Abstract

The post-modification of biomolecules in a late-stage fashion constitutes an unmet challenge of paramount importance within organic chemistry, drug discovery, and chemical biology. The functionalization of otherwise unreactive C–H bonds holds great promise for reducing the reliance on existing functional groups, thereby streamlining the chemical syntheses. Despite the extensive repertoire of peptide labelling techniques currently available, the site-selective modification of tyrosine (Tyr) compounds remains comparatively underexplored. This review highlights the state-of-the-art regarding the use of metal catalysis within the ortho-C–H functionalization of Tyr-containing compounds.

Keywords

C−H functionalization - Bioconjugation - Metal catalysis - Peptides - Amino acids

Publication History

Received: 03 October 2025

Accepted after revision: 29 November 2025

Accepted Manuscript online:
29 November 2025

Article published online:
22 December 2025

• References

• 1a Zhang P, Hao Y, Xie M, Wang H, Gao J. Drug Discovery Today 2025; 30: 104395
• 1b Ding Y, Ting JP, Liu J, Al-Azzam S, Pandya P, Afshar S. Amino Acids 2020; 52: 1207
• 2a Gare CL, White AM, Malins LR. Trends Biochem Sci 2025; 50: 467
• 2b Swenson CS, Mandava G, Thomas DM, Moellering RE. Chem Rev 2024; 124: 13020
• 2c Craik DJ, Fairlie DP, Liras S, Price D. Chem Biol Drug Des 2013; 81: 136
• 3a Hickey JL, Sindhikara D, Zultanski SL, Schultz DM. ACS Med Chem Lett 2023; 14: 557
• 3b Henninot A, Collins JC, Nuss JM. J Med Chem 2018; 61: 1382
• 4a Ji X, Nielsen AL, Heinis C. Angew Chem Int Ed 2024; 63: e202308251
• 4b Fang P, Pang W-K, Xuan S, Chan W-L, Leung KC-F. Chem Soc Rev 2024; 53: 11725
• 4c Zorzi A, Deyle K, Heinis C. Curr Opin Chem Biol 2017; 38: 24
• 5a de Gruyter JN, Malins LR, Baran PS. Biochemistry 2017; 56: 3863
• 5b Krall N, da Cruz FP, Boutureira O, Bernardes GJL. Nat Chem 2016; 8: 102

For selected reviews, see:
• 6a Kjærsgaard NL, Nielsen TB, Gothelf KV. Chembiochem 2022; e202200245
• 6b Sen S, Das J, Maiti D. Tetrahedron Chem 2022; 1: 100005
• 6c Tong H-R, Li B, Li G, He G, Chen G. CCS Chem 2020; 2: 1797
• 6d Bottecchia C, Noël T. Chem Eur J 2019; 25: 26
• 6e Wang W, Lorion M, Shah J, Kapdi AR, Ackermann L. Angew Chem Int Ed 2018; 57: 14700
• 6f San Segundo M, Correa A. Synthesis 2018; 50: 2853
• 6g Noisier AFM, Brimble MA. Chem Rev 2014; 114: 8775
• 7a Kundu SK, Bandyopadhyay A, Sarkar R. Org Biomol Chem 2025; 23: 1773
• 7b Gruß H, Sewald N. Chem Eur J 2020; 26: 5328
• 8 Correa A. Eur J Inorg Chem 2021; 2928
• 9a Bilgin N, Hintzen JCJ, Mecinovic J. Chem Commun 2025; 61: 3805
• 9b Bhunia S, Purushotham M, Karan G, Paul B, Maji MS. Synthesis 2023; 55: 3701

For selected reviews on the conjugation of Tyr, see:
• 10a Zuo Q, Lu J, Huang Z. et al. Coord Chem Rev 2025; 540: 216765
• 10b Zeng W, Xue J, Geng H. et al. Biotechnol Bioeng 2024; 121: 799
• 10c Zhang S, De Leon Rodriguez LM, Li FF, Brimble MA. Chem Sci 2023; 14: 7782
• 10d Dorta DA, Deniaud D, Mével M, Gouin SG. Chem Eur J 2020; 26: 14257
• 10e Szijj PA, Kostadinova KA, Spears RJ, Chudasama V. Org Biomol Chem 2020; 18: 9018

For selected reviews, see:
• 11a Rej S, Ano Y, Chatani N. Chem Rev 2020; 120: 1788
• 11b Sambiagio C, Schönbauer D, Blieck R. et al. Chem Soc Rev 2018; 47: 6603
• 11c Lyons TW, Sanford MS. Chem Rev 2010; 110: 1147

For selected reviews, see:
• 12a Zhang L, Ritter T. J Am Chem Soc 2022; 144: 2399
• 12b Guillermad L, Kaplaneris N, Ackermann L, Johansson MJ. Nat Rev Chem 2021; 5: 522
• 12c Börgel J, Ritter T. Chem 2020; 6: 1877

For selected O-functionalization techniques, see:
• 13a Declas N, Maynard JRJ, Menin L. et al. Chem Sci 2022; 13: 12808
• 13b Wadzinski TJ, Steinauer A, Hie L, Pelletier G, Schepartz A, Miller SJ. Nat Chem 2018; 10: 644

For selected metal-free bioconjugations, see:
• 14a Huang P, Cao W, Fetzer JL, Dolan NS, Francis MB. J Am Chem Soc 2025; 147: 23834
• 14b Maruyama K, Ishiyama T, Seki Y. et al. J Am Chem Soc 2021; 143: 19844
• 14c McFarland JM, Joshi NS, Francis MB. J Am Chem Soc 2008; 130: 7639
• 14d Ban H, Gavrilyuk J, Barbas III CF. J Am Chem Soc 2010; 132: 1523

For a review, see:
• 14e Chatterjee J, Bandyopadhyay A, Pattabiraman M, Sarkar R. Chem Commun 2024; 60: 8978
• 15a Kharat ND, Mahesha CK, Bajaj K, Sakhuja RS. Org Lett 2022; 24: 6857
• 15b Stangier M, Messinis AM, Oliveira JCA, Yu H, Ackermann L. Nat Commun 2021; 12: 4736
• 16 Murai S, Kakiuchi F, Sekine S. et al. Nature 1993; 366: 529

See, for example:
• 17a Shang W, Sun H, Chen W, Liu J. Green Synth Catal 2023; 4: 104
• 17b Dutta U, Maiti S, Bhattacharya T, Maiti D. Science 2021; 372: 701
• 18 Hu Q-L, Hou K-Q, Li J. et al. Chem Sci 2020; 11: 6070
• 19 San Segundo M, Correa A. Chem Sci 2019; 10: 8872
• 20 San Segundo M, Correa A. Chem Sci 2020; 11: 11531
• 21 Zuo Q, Song X, Yan J. et al. J Am Chem Soc 2025; 147: 9576
• 22 Urruzuno I, Andrade-Sampedro P, Correa A. Org Lett 2021; 23: 7279
• 23 Girón-Elola C, Correa A. Org Chem Front 2024; 11: 7235
• 24 Kharat ND, Naharwal S, Tank D, Panda SS, Bajaj K, Sakhuja R. Org Lett 2023; 25: 7673
• 25 Kharat DN, Naharwal, Panda SS, Bajaj K, Sakhuja R. Chem Commun 2024; 60: 7622
• 26 Zhao Q-Z, Yang S, Guo T-T, Ma J-B, Cheng X-H, Yan S-J. J Org Chem 2025; 90: 6910
• 27 Hou X, Kaplaneris N, Yuan B. et al. Chem Sci 2022; 13: 3461
• 28 Urruzuno I, Andrade-Sampedro P, Correa A. Eur J Org Chem 2023; 26: e20220148
• 29 Grover J, Dutta B, Ghosh D. et al. Chem Sci 2025; 16: 10141
• 30 Andrade-Sampedro P, Matxain JM, Correa A. Adv Synth Catal 2022; 364: 2072

For selected examples, see:
• 31a Bag R, Sharma NK. Org Chem Front 2023; 10: 1252
• 31b Andrade-Sampedro P, Matxain JM, Correa A. Chem Eur J 2021; 27: 5782
• 31c Han B, Li B, Qi L, Yang P, He G, Chen G. Org Lett 2020; 22: 6879
• 31d García-Rubia A, Laga E, Cativiela C, Urriolabeitia EP, Gómez-Arrayás R, Carretero JC. J Org Chem 2015; 80: 3321

See, for example:
• 32a Singh P, Babu SA. Eur J Org Chem 2023; 26: e202300440
• 32b Wang X, Niu S, Xu L. et al. Org Lett 2017; 19: 246
• 33 Bag R, Sharma NK. J Org Chem 2024; 89: 10127
• 34 Karkamar U, Samanta R. J Org Chem 2019; 84: 2850
• 35 Peters DS, Romesberg FE, Baran PS. J Am Chem Soc 2018; 140: 2072
• 36 Ben-Lulu M, Gaster E, Libman A, Pappo D. Angew Chem Int Ed 2020; 59: 4835
• 37 Libman A, Ben-Lulu M, Gaster E. et al. J Am Chem Soc 2023; 145: 21002
• 38 Mintz T, More NY, Gaster E, Pappo D. J Org Chem 2021; 86: 18164
• 39 Guerrero I, Correa A. Asian J Org Chem 2020; 9: 898
• 40 Ichiishi N, Caldwell JP, Lin M. et al. Chem Sci 2018; 9: 4168
• 41 Nguyen T-TH, O’Brien CJ, Tran MLN. et al. Org Lett 2021; 23: 3823
• 42 Kee CW, Tack O, Guibbal F. et al. J Am Chem Soc 2020; 142: 1180
• 43 Dou Y, Kenry, Liu J, Jiang J, Zhu Q. Chem Eur J 2019; 25: 6896
• 44 Song C, Liu K, Wang Z. et al. Chem Sci 2019; 10: 7982
• 45 Li BX, Kim DK, Bloom S. et al. Nat Chem 2021; 13: 902
• 46a Ohlow MJ, Moosmann B. Drug Discov Today 2011; 16: 119
• 46b Yang J, Zhen X, Wang B. et al. Nat Commun 2018; 9: 840
• 47 Girón-Elola C, Sasiain I, Sánchez-Fernández R, Pazos E, Correa A. Org Lett 2023; 25: 4383
• 48 Zhao Y, Huang B, Yang C, Xia W. Org Lett 2016; 18: 3326
• 49a Louillat-Habermeyer M-L, Jin R, Patureau FW. Angew Chem Int Ed 2015; 54: 4102
• 49b Xiao F, Wang X, Ebel B, Oppel IM, Patureau FW. J Org Chem 2025; 90: 1180
• 50 Pérez-Cubero I, Andrade-Sampedro P, Sasiain I, Correa A. ACS Catal 2025; 15: 10320
• 51 Ji X, Nielsen AL, Heinis C. Angew Chem Int Ed 2024; 63: e202308251
• 52 Jia L, Gao S, Xie J, Luo M. Adv Synth Catal 2016; 358: 3840
• 53 Andrade-Sampedro P, Correa A. Org Lett 2024; 26: 8668
• 54 Yamada T. Org Lett 2024; 26: 5358
• 55 Ruffoni A, Juliá F, Svejstrup TD, McMillan AJ, Douglas JJ, Leonori D. Nat Chem 2019; 11: 426
• 56 Sato S, Nakamura H. Angew Chem Int Ed 2013; 52: 8681
• 57 Sato S, Hatano K, Tsushima M, Nakamura H. Chem Commun 2018; 54: 5871