Improved Synthesis of Pseudoproline and DMB Dipeptide Carboxylic Acids

Abstract

We report a mild method for the preparation of Fmoc-protected dipeptides containing a 2,4-dimethoxybenzyl (DMB) or 2-hydroxy-4-methoxybenzyl (HMB) group or modified as pseudoprolines. To minimize the loss of the Fmoc protection, we optimized the saponification conditions and included a calcium additive that protected the other base-sensitive functionalities and improved the yield of the free acid (36–82%). The reaction requires a combination of CaCl₂ and NaOH in a mixture of iPrOH and water at room temperature.

Key words

amino acids - dipeptides - saponification - deprotection - calcium

Publication History

Received: 05 March 2024

Accepted after revision: 15 April 2024

Accepted Manuscript online:
15 April 2024

Article published online:
21 May 2024

• References and Notes

• 1 Peptide Synthesis . Hussein WM, Skwarczynski M, Toth I. Humana Press; New York: 2019
• 2a Kashif Khan R, Meanwell NA, Hager HH. Bioorg. Med. Chem. Lett. 2022; 75: 128983
• 2b Zhang B, Gong J, Yang Y, Dong S. J. Pept. Sci. 2011; 17: 601
• 3 Coleman DR, Kaluarachchi K, Ren Z, Chen X, McMurray JS. Int. J. Pept. Res. Ther. 2008; 14: 1
• 4 Wöhr T, Wahl F, Nefzi A, Rohwedder B, Sato T, Sun X, Mutter M. J. Am. Chem. Soc. 1996; 118: 9218
• 5a Fairweather KA, Sayyadi N, Luck IJ, Clegg JK, Jolliffe KA. Org. Lett. 2010; 12: 3136
• 5b Skropeta D, Jolliffe KA, Turner P. J. Org. Chem. 2004; 69: 8804
• 5c Jolliffe KA. Aust. J. Chem. 2018; 71: 723
• 5d Powell WC, Evenson GE, Walczak MA. ACS Catal. 2022; 12: 7789
• 6 Guryanov I, Orlandin A, De Paola I, Viola A, Biondi B, Badocco D, Formaggio F, Ricci A, Cabri W. Org. Process Res. Dev. 2021; 25: 1598
• 7 Carbajo D, El-Faham A, Royo M, Albericio F. ACS Omega 2019; 4: 8674
• 8 Marek P, Woys AM, Sutton K, Zanni MT, Raleigh DP. Org. Lett. 2010; 12: 4848
• 9 Roberts AG, Johnston EV, Shieh J.-H, Sondey JP, Hendrickson RC, Moore MA. S, Danishefsky SJ. J. Am. Chem. Soc. 2015; 137: 13167
• 10a El Oualid F, Merkx R, Ekkebus R, Hameed DS, Smit JJ, de Jong A, Hilkmann H, Sixma TK, Ovaa H. Angew. Chem. Int. Ed. 2010; 49: 10149
• 10b Zhu F, Miller E, Powell WC, Johnson K, Beggs A, Evenson GE, Walczak MA. Angew. Chem. Int. Ed. 2022; 61: e202207153
• 11 Powell WC, Jing R, Walczak MA. J. Am. Chem. Soc. 2023; 145: 21514
• 12a Chaume G, Simon J, Caupène C, Lensen N, Miclet E, Brigaud T. J. Org. Chem. 2013; 78: 10144
• 12b Chaume G, Barbeau O, Lesot P, Brigaud T. J. Org. Chem. 2010; 75: 4135
• 13 Kang YK, Park HS. J. Phys. Chem. B 2007; 111: 12551
• 14 Xu X.-Y, Yang X.-H, Li S.-Z, Song Q.-S. Helv. Chim. Acta 2011; 94: 1470
• 15 Asai Y, Nonaka N, Suzuki S, Nishio M, Takahashi K, Shima H, Ohmori K, Ohnuki T, Komatsubara S. J. Antibiot. 1999; 52: 607
• 16 Townsend CA. Curr. Opin. Chem. Biol. 2002; 6: 583
• 17a Zahariev S, Guarnaccia C, Zanuttin F, Pintar A, Esposito G, Maravić G, Krust B, Hovanessian AG, Pongor S. J. Pept. Sci. 2005; 11: 17
• 17b Levinson AM, McGee JH, Roberts AG, Creech GS, Wang T, Peterson MT, Hendrickson RC, Verdine GL, Danishefsky SJ. J. Am. Chem. Soc. 2017; 139: 7632
• 17c Zahariev S, Guarnaccia C, Pongor CI, Quaroni L, Čemažar M, Pongor S. Tetrahedron Lett. 2006; 47: 4121
• 17d Paradís-Bas M, Tulla-Puche J, Albericio F. Chem. Eur. J. 2014; 20: 15031
• 17e Jacobsen MT, Petersen ME, Ye X, Galibert M, Lorimer GH, Aucagne V, Kay MS. J. Am. Chem. Soc. 2016; 138: 11775
• 17f Wöhr T, Mutter M. Tetrahedron Lett. 1995; 36: 3847
• 18a Joseph R, Morales Padilla M, Garner P. Tetrahedron Lett. 2015; 56: 4302
• 18b Keller M, Boissard C, Patiny L, Chung NN, Lemieux C, Mutter M, Schiller PW. J. Med. Chem. 2001; 44: 3896
• 18c Wahlström K, Planstedt O, Undén A. Tetrahedron Lett. 2008; 49: 3921
• 18d Wang P, Li X, Zhu J, Chen J, Yuan Y, Wu X, Danishefsky SJ. J. Am. Chem. Soc. 2011; 133: 1597
• 19a Pascal R, Sola R. Tetrahedron Lett. 1998; 39: 5031
• 19b Binette R, Desgagné M, Theaud C, Boudreault P.-L. Molecules 2022; 27: 2788
• 20 Calcium-Mediated Hydrolysis: A round-bottom flask was charged with Fmoc-dipeptide ester (1.00 mmol, 0.8 M CaCl₂ in i-PrOH/H₂O (7:3, 25 mL, 0.04 M)) and 1 M NaOH (2.00 mmol, 2 equiv). The mixture was stirred at room temperature for 16 h, then the reaction was quenched with 1 M KHSO₄ (50 mL), and the mixture was extracted with EtOAc (3 × 50 mL), washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified over SiO₂ or a C18 cartridge to afford pure carboxylic acid dipeptide.