Tryptophan N ¹-Alkylation: Quick and Simple Access to Diversely Substituted Tryptophans

Abstract

The diversification of amino acid sidechains is a major challenge in the synthesis and derivatization of peptides for pharmaceutical applications. We herein present a new protocol to alkylate the indole-nitrogen (N1) of N ^α-protected tryptophans. This method provides quick and epimerization-free access to tryptophan derivatives, which can directly be incorporated into peptides. Depending on the functionalities introduced in the side chain, different options for the late-stage modification of peptides are possible.

Key words

tryptophan - N-alkylation - amino acids - late-stage diversification - peptide modification

• References

• 1 Schaller A. Stud. Nat. Prod. Chem. 2001; 25: 367
• 2 Carroll AR, Copp BR, Davis RA, Keyzers RA, Prinsep MR. Nat. Prod. Rep. 2020; 37: 175
• 3 Dang T, Süssmuth RD. Acc. Chem. Res. 2017; 50: 1566
• 4a Ullrich A, Herrmann J, Müller R, Kazmaier U. Eur. J. Org. Chem. 2009; 6367
• 4b Gorges J, Kazmaier U. Org. Lett. 2018; 20: 2033
• 4c Servatius P, Kazmaier U. J. Org. Chem. 2018; 83: 11341
• 5a Karmann L, Schultz K, Herrmann J, Müller R, Kazmaier U. Angew. Chem. Int. Ed. 2015; 54: 4502 ; Angew. Chem. 2015, 127, 4585
• 5b Hoffmann J, Gorges J, Junk L, Kazmaier U. Org. Biomol. Chem. 2015; 13: 6010
• 5c Junk L, Kazmaier U. Angew. Chem. Int. Ed. 2018; 57: 11432 ; Angew. Chem. 2018, 130, 11602
• 6 Jamieson AG, Boutard N, Sabatino D, Lubell WD. Chem. Biol. Drug Des. 2012; 81: 148
• 7 Servatius P, Junk L, Kazmaier U. Synlett 2019; 30: 1289
• 8a Barbie P, Kazmaier U. Org. Lett. 2016; 18: 204
• 8b Kiefer A, Bader CD, Held J, Esser A, Rybniker J, Empting M, Müller R, Kazmaier U. Chem. Eur. J. 2019; 25: 8894
• 9 Yamada S, Shiori T, Itaya T, Hara T. Chem. Pharm. Bull. 1965; 13: 88
• 10 Haitham Abusara O, Freeman S, Aojula HS. Eur. J. Med. Chem. 2017; 137: 221
• 11 Sun T, Li ZL, Tian H, Wang SC, Cai J. Molecules 2009; 14: 5339
• 12a Sanz-Cervera JF, Stocking EM, Usui T, Osada H, Williams RM. Bioorg. Med. Chem. 2000; 8: 2407
• 12b Okada M, Sato I, Cho SJ, Suzuki Y, Ojika M, Dubnau D, Sakagami Y. Biosci. Biotechnol. Biochem. 2004; 68: 2374
• 12c Park K, Gopalsamy A, Aplasca A, Ellingboe JW, Xu W, Zhang Y, Levin JI. Bioorg. Med. Chem. 2009; 17: 3857
• 12d Schultz AW, Lewis CA, Luzung MR, Baran PS, Moore BS. J. Nat. Prod. 2010; 73: 373
• 12e Estevão MS, Carvalho LC, Ribeiro D, Couto D, Freitas M, Gomes A, Ferreira LM, Fernandes E, Marques MM. B. Eur. J. Med. Chem. 2010; 45: 4869
• 12f Henrottin J, Zervosen A, Lemaire C, Sapunaric F, Laurent S, Van Den Eynde B, Goldman S, Plenevaux A, Luxen A. ACS Med. Chem. Lett. 2015; 6: 260
• 12g Tayu M, Hui Y, Takeda S, Higuchi K, Saito N, Kawasaki T. Org. Lett. 2017; 19: 6582
• 12h Mitra P, Eckenrode JM, Mandal A, Jha AK, Salem SM, Leggas M, Rohr J. J. Med. Chem. 2018; 61: 8001
• 13 Yu H, Zong Y, Xu T. Chem. Sci. 2020; 11: 656
• 14 McGrath S, Tortorici M, Drouin L, Solanki S, Vidler L, Westwood I, Gimeson P, Van Montfort R, Hoelder S. Chem. Eur. J. 2017; 23: 9577
• 15 Chang CY, Lin YH, Wu YK. Chem. Commun. 2019; 55: 1116
• 16 Baseline separation could not be reached for rac-2 on chiral HPLC columns.