A Post-Synthetic Modification Strategy for the Preparation of Homooligomers of 3-Amino-1-methylazetidine-3-carboxylic Acid

Abstract

Post-synthetic modification is a powerful technique allowing access to noncanonical peptide derivatives in a selective manner, but it has not so far been applied for the installation of multiple arrays of modified side chains. Here, we use this approach in solution phase to prepare short N- and C-capped homooligomers of 3-amino-1-methylazetidine-3-carboxylic acid with all the azetidine side chain functions in free amine form. The key step is the multiple reductive amination reaction of the corresponding post-synthetically deprotected secondary amines.

Key words

azetidines - late-stage modification - peptides - reductive amination - protected amino acid - oligomers

Publication History

Received: 07 February 2023

Accepted after revision: 11 April 2023

Accepted Manuscript online:
11 April 2023

Article published online:
12 May 2023

• References and Notes

• 1a Moon J.-I, Han M.-J, Yu S.-H, Lee E.-H, Kim S.-M, Han K, Park C.-H, Kim C.-H. BMB Rep. 2019; 52: 324
• 1b Wender PA, Mitchell DJ, Pattabiraman K, Pelkey ET, Steinman L, Rothbard JB. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 13003
• 1c Yamashita H, Misawa T, Oba M, Tanaka M, Naito M, Kurihara M, Demizu Y. Bioorg. Med. Chem. 2017; 25: 1846
• 2a Melnyk RA, Partridge AW, Deber CM. Biochemistry 2001; 40: 11106
• 2b Bianchi E, Ingenito R, Simon RJ, Pessi A. J. Am. Chem. Soc. 1999; 121: 7698
• 3a Ponnuswamy N, Bastings MM. C, Nathwani B, Ryu JH, Chou LY. T, Vinther M, Li WA, Anastassacos FM, Mooney DJ, Shih WM. Nat. Commun. 2017; 8: 15654
• 3b Kwok A, McCarthy D, Hart SL, Tagalakis AD. Chem. Biol. Drug Des. 2016; 87: 747
• 4a Nichugovskiy A, Tron GC, Maslov M. Molecules 2021; 26: 6579
• 4b da Silva G, Soengas RG. Curr. Org. Chem. 2017; 21: 546
• 4c Karigiannis G, Papaioannou D. Eur. J. Org. Chem. 2000; 1841
• 5a Raulin M, Drouillat B, Marrot J, Couty F, Wright K. Tetrahedron Lett. 2022; 94: 153710
• 5b Masson G, Gomez Pardo D, Cossy J. Chirality 2021; 33: 5
• 5c Gleede T, Reisman L, Rieger E, Mbarushimana PC, Rupar PA, Wurm FR. Polym. Chem. 2019; 10: 3257
• 5d Altmayer-Henzien A, Declerck V, Guillot R, Aitken DJ. Tetrahedron Lett. 2013; 54: 802
• 5e Couty F. In Science of Synthesis, Vol. 40a, Chap. 40.1.6. Enders D. Thieme; Stuttgart: 2009: 773
• 6 This approach was reported recently for the synthesis of 3-amino-1-benzydrylazetidine-3-carboxylic acid from 1-benzhydryl-azetidin-3-one, see: Ivachtchenko AV, Ivanenkov YA, Mitkin OD, Vorobiev AA, Kuznetsova IV, Shevkun NA, Koryakova AG, Karapetian RN, Trifelenkov AS, Kravchenko DV, Veselov MS, Chufarova NV. Eur. J. Med. Chem. 2015; 99: 51
• 7a Bottecchia C, Noël T. Chem. Eur. J. 2019; 25: 26
• 7b Wang W, Lorion MM, Shah J, Kapdi AR, Ackermann L. Angew. Chem. Int. Ed. 2018; 57: 14700
• 7c deGruyter JN, Malins LR, Baran PS. Biochemistry 2017; 56: 3863
• 7d Lau YH, de Andrade P, Wu Y, Spring DR. Chem. Soc. Rev. 2015; 44: 91
• 7e Boutureira O, Bernardes GJ. L. Chem. Rev. 2015; 115: 2174
• 7f Spicer CD, Davis BG. Nat. Commun. 2014; 5: 4740
• 8 De Zotti M, Clayden J. Org. Lett. 2019; 21: 2209
• 9 Short oligomers of 3-aminopyrrolidine-3-carboxylic acid (the natural product cucurbitin) were prepared by multiple deprotection of the corresponding Boc-protected oligomers, without further functionalization of the liberated side-chain amines; see: Yamaberi Y, Eto R, Umeno T, Kato T, Doi M, Yokoo H, Oba M, Tanaka M. Org. Lett. 2021; 23:  4358
• 10 An example of the late-stage removal of a Boc group from a single Aatc(Boc) residue in a peptidomimetic and its subsequent acylation has been described; see: Boiteau J.-G, Ouvry G, Arlabosse J.-M, Astri S, Beillard A, Bhurruth-Alcor Y, Bonnary L, Bouix-Peter C, Bouquet K, Bourotte M, Cardinaud I, Comino C, Deprez B, Duvert D, Féret A, Hacini-Rachinel F, Harris CS, Luzy A.-P, Mathieu A, Millois C, Orsini N, Pascau J, Pinto A, Piwnica D, Polge G, Reitz A, Reversé K, Rodeville N, Rossio P, Spiesse D, Tabet S, Taquet N, Tomas L, Vial E, Hennequin LF. Bioorg. Med. Chem. 2018; 26: 945
• 11 A preliminary account of the preparation of 6 and its transformation into 1 has been described; see the supporting information in: Mundlapati VR, Imani Z, D’mello VC, Brenner V, Gloaguen E, Baltaze J.-P, Robin S, Mons M, Aitken DJ. Chem. Sci. 2021; 12: 14826
• 12 CCDC 2238732 contains the supplementary crystallographic data for compound 1. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/structures/
• 13a Sharma K, Strizhak AV, Fowler E, Wang X, Xu W, Jensen CH, Wu Y, Sore HF, Lau YH, Hyvönen M, Itzhaki LS, Spring DR. Org. Biomol. Chem. 2019; 17: 8014
• 13b Chandrasekharam M, Chiranjeevi B, Gupta KS. V, Sridhar B. J. Org. Chem. 2011; 76: 10229
• 14 Homooligomer 4; Typical Procedure A 4 M solution of HCl solution in 1,4-dioxane (5.4 mL) was added dropwise to an ice-cooled solution of trimer 9 (96 mg, 0.10 mmol, 1 equiv) in anhyd CH₂Cl₂ (10 mL) under argon, and the resulting solution was stirred at 0 °C for 30 min and then at rt for 15 h. The solution was concentrated under reduced pressure and the remaining volatiles were co-evaporated with CHCl₃ (4 × 10 mL) under reduced pressure to leave the deprotected tetraazetidine as its tetrahydrochloride salt. To an ice-cooled solution of this salt in MeOH (3 mL), were added successively HOAc (32 μL, 0.6 mmol, 6 equiv), paraformaldehyde (15 mg, 0.5 mmol, 5 equiv), and NaBH₃CN (17 mg, 0.3 mmol, 3 equiv), and the mixture was stirred at rt for 10 h. The mixture was cooled to 0 °C, then HOAc (32 μL, 0.6 mmol, 6 equiv), paraformaldehyde (15 mg, 0.5 mmol, 5 equiv), and NaBH₃CN (17 mg, 0.3 mmol, 3 equiv) were added, and the mixture was again stirred at rt for 10 h. This procedure was repeated two more times, so that four aliquots of reagents had been added to the solution. After the final 10 h stirring period at rt, the solvent was removed under reduced pressure and the residue was partitioned between CH₂Cl₂ (10 mL) and sat. aq NaHCO₃ (20 mL). The organic layer was collected and the aqueous layer was extracted with CH₂Cl₂ (10 × 10 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC on a Lux Cellulose-1 column to give a white solid; yield: 28 mg (46%); mp 131–134 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.79, 8.26, 7.98, 7.29* (4 × bs, NH; *signal masked by aromatic protons), 7.42–7.30 (m, 5 H, CH^Ar), 6.77 (bs, 1 H, NH^carbamate), 5.08 (s, 2 H, CH₂ ^Cbz), 3.79–3.46 (m, 16 H, CH₂ ^azetidines), 2.82 (d, J = 4.8 Hz, 3 H, NCH₃ ^amide), 2.44–2.33 (m, 12 H, NCH₃ ^azetidines). ¹³C NMR (100 MHz, CDCl₃): δ = 174.4, 172.3, 170.8, 170.7 (CO^amides), 156.6 (CO^Cbz), 136.0 (C^Ar), 128.8, 128.6, 128.5 (CH^Ar), 67.4 (CH₂ ^Cbz), 63.9, 63.3, 62.9, 62.5 (CH₂ ^azetidines), 55.7, 55.4, 55.3, 54.9 (C^α), 45.3, 45.2, 44.5, 43.4 (NCH₃ ^azetidines), 26.9 (NCH₃ ^amide). HRMS [ESI(+)]: m/z [M + Na]⁺ calcd for C₂₉H₄₃N₉NaO₆: 636.3229; found: 636.3200.
• 15a Žukauskaitė A, Mangelinckx S, Buinauskaitė V, Šačkus A, De Kimpe N. Amino Acids 2011; 41: 541
• 15b Mnich SJ, Hiebsch RR, Huff RM, Muthian S. J. Pharmacol. Exp. Ther. 2010; 333: 445