Triisobutylaluminium-Mediated Regioselective Protection of Sterically Hindered Amide NH of Cyclo-(AA-Gly): Key Building Block for Next-Generation Peptide Synthesis

Abstract

In this study, we address the challenge of regioselective Boc protection in the more sterically hindered amide NH of unsymmetrical 2,5-diketopiperazines (DKPs) formed from glycine and various amino acids. Our research introduces a novel technique utilizing cost-effective triisobutylaluminium and trimethoxysilane. Notably, trimethoxysilane selectively reacts with the less hindered amide NH, facilitating the regioselective Boc protection of the more congested amide NH in DKPs. The primary objective of our work is to develop a straightforward and scalable approach for the synthesis of Boc-protected DKPs, with a focus on addressing the steric challenges presented by these compounds. We successfully demonstrate the scalability of this method, enabling the synthesis of a variety of mono-Fmoc-, Cbz-, Alloc-, and EtOCO-protected DKPs. Furthermore, we extend the applicability of this strategy by employing it in the construction of pentapeptides through a twofold peptide-elongation process. Our findings reveal the versatility and efficiency of this regioselective Boc-protection method. Overall, this research introduces a valuable solution to the regioselective Boc-protection challenge in DKPs and demonstrates its applicability in peptide synthesis, showcasing its potential for further advancements in the field.

Key words

triisobutylaluminium - mono-Boc-DKPs - trimethoxysilane - peptide elongation - regioselective protection

Publication History

Received: 13 September 2023

Accepted after revision: 13 November 2023

Accepted Manuscript online:
13 November 2023

Article published online:
12 December 2023

• References

• 1a Craik DJ, Fairlie DP, Liras S, Price D. Chem. Biol. Drug Des. 2013; 81: 136
• 1b Morrison C. Nat. Rev. Drug Discovery 2018; 17: 531
• 1c Henninot A, Collins JC, Nuss JM. J. Med. Chem. 2018; 61: 1382
• 1d Lamers C. Future Drug Discovery 2022; 4: FDD75
• 2a Fosgerau K, Hoffmann T. Drug Discovery Today 2015; 20: 122
• 2b Chen EH.-L, Weng C.-W, Li Y-M, Wu M.-C, Yang C.-C, Lee K.-T, Chen RP.-Y, Cheng C.-P. Front. Plant Sci. 2021; 12: 753217
• 2c Ruan Y, Sohail M, Zhao J, Hu F, Li Y, Wang P, Zhang L. ACS Biomater. Sci. Eng. 2022; 8: 4738
• 2d Kida Y, Sawada T, Iwasaki T. Polym. J. 2023; 55: 289
• 2e Lima TN, Moraes CA. P. Cosmetics 2018; 5: 21
• 3a Hamdan F, Tahoori F, Balalaie S. RSC Adv. 2018; 8: 33893
• 3b Wang L, Wang N, Zhang W, Cheng X, Yan Z, Shao G, Wang X, Wang R, Fu C. Signal Transduction Targeted Ther. 2022; 7
• 4a Han S.-Y, Kim Y.-A. Tetrahedron 2004; 60: 2447
• 4b Valeur E, Bradley M. Chem. Soc. Rev. 2009; 38: 606
• 4c El-Faham A, Albericio F. Chem. Rev. 2011; 111: 6557
• 4d Dunetz JR, Magano J, Weisenburger G. Org. Process Res. Dev. 2016; 20: 140
• 4e Jaradat DM. M. Amino Acids 2018; 50: 39
• 5a Hollanders K, Maes BU. W, Steven Ballet S. Synthesis 2019; 5: 2261
• 5b Hattori T, Yamamoto H. J. Am. Chem. Soc. 2022; 144: 1758
• 5c Wu A, Ikeda H, Yamamoto H. Precis. Chem. 2023; 1: 100
• 5d Yang J, Huang H, Zhao J. Org. Chem. Front. 2023; 10: 1817
• 5e D’Amaral MC, Andrews KG, Denton R, Adler MJ. Synthesis 2023; 55: 3209
• 6a Pattabiraman VR, Bode JW. Nature 2011; 480: 471
• 6b Ting CP, Funk MA, Halaby SL, Zhang Z, Gonen T, Van der Donk WA. Science 2019; 365: 280
• 6c Martin V, Egelund PH. G, Jhonson H, Quement ST. L, Pedersen DS. RSC Adv. 2020; 10: 42457
• 6d Muramatsu W, Hattori T, Yamamoto H. Bull. Chem. Soc. Jpn. 2020; 93: 759
• 6e Muramatsu W, Hattori T, Yamamoto H. Chem. Commun. 2021; 57: 6346
• 6f Hattori T, Yamamoto H. Chem. Sci. 2023; 14: 5795
• 7a Pérez-Picaso L, Escalante J, Olivo HF, Rios MY. Molecules 2009; 14: 2836
• 7b Borthwick AD. Chem. Rev. 2012; 112: 3641
• 7c Scarel M, Marchesan S. Molecules 2021; 26: 3376
• 8a Bojarska J, Mieczkowski A, Ziora ZM, Skwarczynski M, Toth I, Shalash AO, Parang K, El-Mowafi SA, Mohammed EH. M, Elnagdy S, AlKhazindar M, Wolf WM. Biomolecules 2021; 11: 1515
• 8b Bojarska J, Wolf WM. Proceedings 2021; 79: 10
• 8c Harken L, Li S.-M. Appl Microbiol. Biotechnol. 2021; 105: 2277
• 9a Le TX. H, Bussolari JC, Murray WV. Tetrahedron Lett. 1997; 38: 3849
• 9b Becker C, Hoben C, Schollmeyer D, Scherr G, Kunz H. Eur. J. Org. Chem. 2005; 1497
• 9c Kienle M, Argyrakis W, Baro A, Laschat S. Tetrahedron Lett. 2008; 49: 1971
• 9d Morris EN, Nenninger EK, Pike RD, Scheerer JR. Org. Lett. 2011; 13: 4430
• 9e Metrano AJ, Chinn AJ, Shugrue CR, Stone EA, Kim B, Miller SJ. Chem. Rev. 2020; 120: 11479
• 9f Petsi M, Zografos AL. ACS Catal. 2020; 10: 7093
• 10a Farran D, Echalier D, Martinez J, Dewynter GJ. Pept. Sci. 2009; 15: 474
• 10b Mendoza-Sanchez R, Corless VB, Nguyen QN. N, Bergeron-Brlek M, Frost J, Adachi S, Tantillo DJ, Yudin AK. Chem. Eur. J. 2017; 23: 13319
• 10c Muramatsu W, Yamamoto H. Chem. Sci. 2022; 13: 6309
• 10d Gallina C, Liberator A. Tetrahedron 1974; 30: 667
• 11a Alcaraz C, Fernandez MD, de Frutos MP, Marco JL, Bernabe M, Foces-Foces C, Cano FH. Tetrahedron 1994; 50: 443
• 11b Oba M, Nakajima S, Nishiyama K. Chem. Commun. 1996; 1875
• 11c Oba M, Terauchi T, Owari Y, Imai Y, Motoyama I, Nishiyama K. J. Chem. Soc., Perkin Trans. 1 1998; 1275
• 11d Kelley EW, Norman SG, Scheerer JR. Org. Biomol. Chem. 2017; 15: 8634
• 12a Tezgel Ö, Puchelle V, Du H, Illy N, Guégan P. J. Polym. Sci., Part A: Polym. Chem. 2019; 57: 1008
• 12b Liao S, Qin X, Li D, Tu Z, Li J, Zhou X, Wang J, Yang B, Lin X, Liu J, Yang X, Liu Y. Eur. J. Med. Chem. 2014; 83: 236