New Triazole-Containing Branched Bis(dipeptidomimetic) – Switching from Self-Dimerization to Anion-Binding Properties

Tin-Ki Chui; Hak-Fun Chow

doi:10.1055/s-0036-1590884

Synlett, Table of Contents

Synlett 2017; 28(20): 2807-2811
DOI: 10.1055/s-0036-1590884

letter

New Triazole-Containing Branched Bis(dipeptidomimetic) – Switching from Self-Dimerization to Anion-Binding Properties

Authors

Tin-Ki Chui

Department of Chemistry and Institute of Molecular Functional Materials, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR Email: hfchow@cuhk.edu.hk
Hak-Fun Chow *

Department of Chemistry and Institute of Molecular Functional Materials, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR Email: hfchow@cuhk.edu.hk

Abstract

All articles of this category

Dedicated to Professor Victor Snieckus on the occasion of his 80^th birthday

Abstract

A triazole-containing branched bis(dipeptidomimetic) 2 using l-lysine as a flexible branching unit was synthesized and characterized. The compound was found to form weak dimers (K _dim = 19 M^–1) in chloroform as shown by vapor pressure osmometry (VPO) and concentration-dependent ¹H NMR studies. On the other hand, the compound was capable of binding chloride and monobasic diethyl phosphate (DEP) in chloroform. Job plot analysis, MALDI-TOF mass spectrometry, and NMR titration studies revealed a 1:1 binding stoichiometry with good binding affinities (K _a ≈ 640–780 M^–1). Structural studies using ROESY NMR spectroscopy and molecular modelling on the 2–DEP complex indicated the adoption of a helix-like conformation by the host with the guest situated near the branching juncture.

Key words

peptidomimetic - click chemistry - self-assembly - host–guest systems - supramolecular chemistry

Full Text

References

References and Notes
1 Wynn JE. Santos WL. Org. Biomol. Chem. 2015; 13: 5848

2a Scully CC. G. Jensen P. Rutledge PJ. J. Organomet. Chem. 2008; 693: 2869
2b Szyrwiel Ł. Szczukowski Ł. Pap JS. Setner B. Szewczuk Z. Malinka W. Inorg. Chem. 2014; 53: 7951
2c Lakatos A. Gyurcsik B. Nagy NV. Csendes Z. Wéber E. Fülöp L. Kiss T. Dalton Trans. 2012; 41: 1713

3 Pap J. Szyrwiel Ł. Srankó D. Kerner Z. Setner B. Szewczuk Z. Malinka W. Chem. Commun. 2015; 51: 6322

4a Boyce R. Li G. Nestler P. Suenaga T. Still WC. J. Am. Chem. Soc. 1994; 116: 7955
4b Davies M. Bonnat M. Guillier F. Kilburn JD. Bradley M. J. Org. Chem. 1998; 63: 8696
4c Conza M. Wennemers H. J. Org. Chem. 2002; 67: 2696

5a Schneider SE. O’Neil SN. Anslyn EV. J. Am. Chem. Soc. 2000; 122: 542
5b Kuchelmeister HY. Karczewski S. Gutschmidt A. Knauer S. Schmuck C. Angew. Chem. Int. Ed. 2013; 52: 14016

6 Wennemers H. Chimia 2003; 57: 237
7 Ryadnov MG. Woolfson DN. Angew. Chem. Int. Ed. 2003; 42: 3021
8 Gudlur S. Sukthankar P. Gao J. Avila LA. Hiromasa Y. Chen J. Iwamoto T. Tomich JM. PLoS One 2012; 7: e45374
9 Hanessian S. Vinci V. Fettis K. Maris T. Phan Viet MT. J. Org. Chem. 2008; 73: 1181
10 For a review of peptide bond isosteres, see: Choudhary A. Raines RT. ChemBioChem 2011; 12: 1801
11 Lauria A. Delisi R. Mingoia F. Terenzi A. Martorana A. Barone G. Almerico AM. Eur. J. Org. Chem. 2014; 3289
12 Ramírez MA. Martín VS. Gallardo AG. Comput. Theor. Chem. 2013; 1026: 31

13a Horne WS. Stout CD. Ghadiri MR. J. Am. Chem. Soc. 2003; 125: 9372
13b Horne WS. Yadav MK. Stout CD. Ghadiri MR. J. Am. Chem. Soc. 2004; 126: 15366
13c Qin S.-Y. Xu X.-D. Chen C.-S. Chen J.-X. Li Z.-Y. Zhuo R.-X. Zhang X.-Z. Macromol. Rapid Commun. 2011; 32: 758

14 Zhan J. Tian D. Li H. New J. Chem. 2009; 33: 725

15a Li Y. Flood AH. Angew. Chem. Int. Ed. 2008; 47: 2649
15b Hua Y. Flood AH. Chem. Soc. Rev. 2010; 39: 1262
15c Yim S.-L. Chow H.-F. Chan M.-C. Chem. Commun. 2014; 50: 3064
15d Flood AH. Beilstein J. Org. Chem. 2016; 12: 611

16 You L.-Y. Chen S.-G. Zhao X. Liu Y. Lan W.-X. Zhang Y. Lu H.-J. Cao C.-Y. Li Z.-T. Angew. Chem. Int. Ed. 2012; 51: 1657

17a Chow H.-F. Lau K.-N. Ke Z. Liang Y. Lo C.-M. Chem. Commun. 2010; 3437
17b Chow H.-F. Lo C.-M. Chen Y. Top. Heterocycl. Chem. 2012; 28: 137
17c Chow H.-F. Chui T.-K. Qi Q. Synlett 2014; 25: 2246

18 Ke Z. Chow H.-F. Chan M.-C. Liu Z. Sze K.-H. Org, Lett. 2012; 14: 394
19 Chow H.-F. Ng K.-F. Wang Z.-Y. Wong C.-H. Luk T. Lo C.-M. Yang Y.-Y. Org. Lett. 2006; 8: 471
20 See Supporting Information for details.
21 Typical Experimental Procedure – Compound 2 Boc-V-Prg (56 mg, 0.22 mmol) and diazide 7 (57 mg, 0.1 mmol) were dissolved in degassed THF. CuSO₄·5H₂O (5.5 mg, 22 μmol) and sodium ascorbate (22 mg, 0.11 mmol) were then added, followed by the addition of small amount of water. The reaction mixture was stirred at 25 °C for 12 h. Saturated KHSO₄ aqueous solution was added to quench the reaction. THF was removed under reduced pressure, and the remaining slurry aqueous layer was extracted with EtOAc. The organic extracts were then combined, washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane/EtOAc = 1:1) to afford the product 2 (76 mg, 0.07 mmol, 71%) as a white solid; 159–162 °C; R_f = 0.38 (EtOAc). ¹H NMR (400 MHz, CDCl₃): δ = 8.01 (s, T′, 1 H), 7.96 (s, T, 1 H), 7.71 (br d, J = 7.5, L^αNH, 1 H), 7.46 (br s, NH² and NH^2′, 2 H), 7.39 (br s, L^εNH, 1 H), 5.49 (br d, J = 8.7, BocNH or BocNH′, 1 H), 5.44 (br d, J = 8.8, BocNH′ or BocNH, 1 H), 5.16 (d, J = 10.2, V1^αCH, 1 H), 4.95 (d, J = 10.2, V1′^αCH, 1 H), 4.65–4.47 (m, CH₂Triaz and L^αCH, 5 H), 4.20–4.10 (m, V2^αCH and V2′^αCH, 2 H), 4.07–3.97 (m, OCH₂, 2 H), 3.30–3.19 (m, L^εCHH, 1 H), 3.15–3.05 (m, L^εCHH, 1 H), 2.60–2.45 (m, 2 H), 2.17–2.04 (m, 2 H), 1.80–1.70 (m, 1 H), 1.64–1.50 (m, 3 H), 1.50–1.44 (m, 3 H), 1.40 (s, C(CH₃)₃, 18 H), 1.35–1.26 (m, 6 H), 1.20–1.10 (m, 4 H), 1.11 (d, J = 6.4, CH₃, 3 H), 1.05 (d, J = 6.4, CH₃, 6 H), 0.94–0.85 (m, CH₃, 21 H), 0.77 (d, J = 6.4, CH₃, 3 H), 0.76 (d, J = 6.4, CH₃, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.3, 172.2, 171.8, 168.3, 168.2, 156.2, 144.6, 122.2, 122.0, 79.5, 70.1, 69.6, 68.1, 59.6, 52.3, 38.9, 37.6, 35.8, 35.7, 34.9, 32.2, 32.0, 31.5, 31.0, 28.7, 28.6, 28.3, 28.2, 22.6, 19.24, 19.16, 18.7, 18.0, 17.9; [α] –7.4 (c 0.06, CHCl₃); ESI-MS: m/z (%) = 1096 (100) [M + Na⁺]. ESI-HRMS: m/z calcd for C₅₄H₉₆N₁₂O₁₀ + Na⁺: 1095.7265; found: 1095.7297.
22 Baxter NJ. Williamson MP. Lilley TH. Haslam E. J. Chem. Soc., Faraday Trans. 1996; 92: 231
23 Wang Y. Xiang J. Jiang H. Chem. Eur. J. 2011; 17: 613
24 MacroModel, Version 10.9 . Schrödinger, LLC; New York, NY: 2015
25 Jaguar, Version 9.3 . Schrödinger, LLC; New York, NY: 2016

Supplementary Material

Supporting Information (PDF)