RETRACTED
This article has been retracted as it was submitted for publication without the prior knowledge or approval of Dr. Aloysius Siriwardena, who has contributed to the article. Additionally, it has been submitted without prior approval of the Centre National de la Recherche Scientifique (CNRS) and the laboratory in which the intellectual ideas behind the syntheses were established.

International Journal of Carbohydrate Chemistry

Volume 2012 (2012), Article ID 394574, 10 pages

doi:10.1155/2012/394574

Research Article

New 1,2,3-Triazole Iminosugars Derivatives Using Click Chemistry

Chahrazed Benhaoua

Laboratoire Synthèse et Catalyse, LSCT, Université Ibn Khaldoun, Tiaret 14000, Algeria

Received 17 March 2012; Accepted 28 April 2012

Academic Editor: R. J. Linhardt

Copyright © 2012 Chahrazed Benhaoua. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

The click concept refers ease, efficient, and the selective chemicals transformations. In this study, a novel regiospecific copper (I)-catalyzed 1, 3-dipolar of terminal alkynes to azide provided a practicable synthetic pathway of triazole iminosugars derivatives. A series of new triazole-pyrrolidinols are reported in good yield.

1. Introduction

There are considerable interests in the design of molecules that are able to mimic carbohydrates which play critical roles in various biological events. This is shown by the following example, the 1-deoxynojirimycin (DNJ) family, for which DNJ itself is a competitive inhibitor of α-D-glucosidase (25 μM) [1], while its derivatives Miglustat (N-nBu DNJ, Zavesa) and Miglitol (N-hydroxyethyl DNJ, Glyset, or Diastabol) have already found therapeutic applications in Gaucher’s disease [2] and type 2 (noninsulin-dependant mellitus) diabetes, respectively [3, 4] (Figure 1). Recently, researches have increasingly accorded to new iminosugars from click chemistry [5].

Figure 1: Structure of inhibitors of glycosidases.

The term click chemistry was introduced by Sharpless and coworkers and promotes the use of efficient, selective, and versatile chemical reactions in synthetic chemistry [6].

The basic reaction, which is nowadays summed up under the name “Sharpless-type click reaction,” is a variant of the Huisgen 1,3-dipolar cycloaddition reaction between C–C triple bonds and alkyl azides [7, 8] (Scheme 1).

Scheme 1: 1,3-dipolar cycloaddition reaction.

Meldal and coworkers published a paper in 2002 that describes the acceleration of this process by CuI salts that leads to a reaction at 25°C in quantitative yields. It was mentioned that the organic azides and the terminal alkynes are united to afford 1,4-regioisomers of 1,2,3-trialoes as sole products [9].

The source of Cu(I) salts commonly used involves the reduction of copper(II) sulfate by sodium ascorbate [9], although other conditions have been described, such as Cu(I) [10] salts, Cu(I) complexes [11] and stabilized derivatives of Cu(I) [9]. The bases used are mostly triethylamine, 2,6-lutidine and N,N-diisopropylethylamine (DIPEA).

1.1. Click Chemistry and Synthesis of Iminosugars Derivatives

The application of CuAAC-catalysed reactions for the synthesis of new α-glucosidase inhibitors containing a 1-deoxynojirimycin (DNJ) was described by Murphy and coworkers.

These compounds indicate that it is possible to modulate the potency and the selectivity towards different glycosidases [5] (Figure 2).

Figure 2: Structures of triazole iminosugars as potential glycosidase inhibitors.

More recently, Diot et al. reported the synthesis of several iminosugars from a click chemistry reaction between oligoethylene scaffolds and N-substituted DNJ derivative.

Thus, compounds of 4 () and 5 () derivatives of the DNJ-based are good inhibitors of different glycosidases [12] (Figure 3).

Figure 3: New triazole -DNJ derivatives.

Kumar et al. reported the synthesis of various pyrrolidine-triazoles, these compounds are achieved by using this intramolecular cycloaddition reaction in water with complete 1,5 regioselectivity [13] (Figure 4).

Figure 4: Various pyrrolidine-triazole.

Researches for new five-membered iminosugars as potential inhibitors of glycosidases reported the synthesis of 1,2,3-triazole iminosugars from a click chemistry reaction between polyhydroxylated pyrrolidine and different azide.

2. Results and Discussion

2.1. Synthesis of 1,2,3-Triazoles Iminosugars

As illustrated in Scheme 2, a protected triazole-pyrrolidine (9) was obtained by condensation of an appropriate azide and the protected pyrrolidine (8).

Scheme 2: Synthesis of 1,2,3-triazole iminosugars.

From the data presented in Table 1, it was noticed that the compounds (9) are prepared in yields ranging from 60% to 84%.

Table 1: Result for the preparation of protected 1,2,3-triazole iminosugars .

Entry
Product triazole
Yields 9(a–e)

1

84%

2

70%

3

80%

4

60%

5

60%

2.2. Identification of Products

The structure elucidation of compounds 9 (a–e) achieved on the basis of their ¹H NMR, ¹³C NMR and masse spectra.

The ¹H and ¹³C NMR spectra showed the formation of the 1,2,3-triazole ring.

For the products 7 (a–e), the signal for the H₅ proton of the pyrrolidine cycle is around 4.11 ppm to 4.71 ppm.

In the ¹³C NMR of the compounds 9 (a–e), characteristic (C=O) appeared at around 169.78 to 173.82. The ¹³C NMR spectrum of all the compounds showed the characteristic of signal for the (C(Me)₂) of isopropylidene at around 112.47 to 115.44 ppm.

The characteristic (C–N=N–N) appeared at around 135.23 to 148.96 ppm and the characteristic (C–N–N=N) is recorded at around 122.98–124.75 ppm.

The yield of compounds (9d) and (9e) is 60%. These results are confirmed to the values of Haridas and coworkers in the synthesis of series of triazoalphanes [14].

3. Conclusion

A series of novel 1,2,3-triazoles iminosugars are synthesized from protected polyhydroxylated pyrrolidine (8). In this work, we have shown that the copper-catalyzed Huisgen cycloaddition of terminal alkyne is a general process affording the 1,4-disubstituted triazole isomer in good yields. This reaction proceeds under mild conditions to afford only one regioisomer.

Work is underway to apply parallel synthesis of triazole-pyrrolidine by condensation of the protected azido-pyrrolidine and an appropriate alkyne. After the deprotection, we study the biological activities of all triazoles-iminosugars.

4. Experimental

4.1. Materials and Equipments

Chemicals were purchased from Aldrich, Acros, and Fluka and used without further purification. Solvents distilled with appropriate drying agents. All reactions performed under anhydrous conditions employing routine drying techniques unless otherwise indicated. Reactions were monitored by thin-layer chromatography (TLC) performed on E. Merck glass plates silica gel sheets (Silica Gel F₂₅₄) and stained with vanillin acid-aqueous H₂SO₄ solution. Column chromatography carried out on silica gel (E. Merck 230–400 mesh). Nuclear magnetic Resonance (NMR) data (¹H or ¹³C) were obtained on a AC-Brucker 300 machine chemical shifts are reported in parts per million relative to tetramethylsilane in deuterated solvents. Assignments of ¹H and ¹³C were assisted by 2D ¹H COSY and 2D ¹H–¹³C CORR experiments. Optical rotations were determined with a Jasco Dip 370 electronic micropolarimeter (10 cm cell). Low resolution electrospray mass spectra (ESIMS) in the positive ion mode were obtained on a Waters-Micromass ZQ quadrupole instrument, equipped with an electrospray (Z-spray) ion source (Waters-Micromass, Manchester, UK). High-resolution electro spray mass spectra (ESI-HRMS) in the positive ion mode were obtained on a Q-TOF Ultima Global hybrid quadrupole time-of-flight instrument (Waters-Micromass), equipped with a pneumatically assisted electro spray (Z-sprayl) ionization source and an additional sprayer (Lock Spray) for the reference compound. The compound (8) is synthesized as described in the literature [15].

4.2. General Procedure for Synthesis of Azide: RN₃

The alkyl or benzyl chloride (1.0 equiv) was suspended in water at concentration of 1.5 M. Sodium azide (3.0 equiv) and ammonium chloride (2.0 equiv) were added, and the reaction was heated at 80°C for 48 h with vigorous stirring. The aqueous layer was extracted with diethyl ether, dried with MgSO₄ and solvent was evaporated to yield pure azide [16].

Benzyl azide: 97%, 3-azido-propane-1-ol: 92%: 3-azido-propionitrile: 82%, 1,4 bis (azidomethyl) benzene: 45%, 1,3 bis (azidomethyl) benzene: 45%.

4.3. General Procedure for Synthesis of 1,2,3-triazoles-Iminosugars (9)

A mixture of alkyne 11 (0.43 mmol) and the appropriate azide (1.73 mmol) were dissolved in a solution of water and t-BuOH (1 : 1). To this solution was added DIEA (diisopropyl ethylamine) (0.26 mmol) and CuI (0.17 mmol). The reaction was stirred at room temperature overnight. After, the water (20 mL) was added to dilute the solution and the mixture was then extracted with CH₂Cl₂ ( mL). The organic layer was dried over Na₂SO₄, concentrated and purified by column (CH₂Cl₂/MeOH, 95/5). The characterization of each compound obtained by means of NMR and mass spectrometry as reported below.

4.3.1. N-(1-(3-hydroxypropyl)1H-1,2,3-triazol-4-methyl)-3.4-O-isopropylidendioxy-5-(3-hydroxypropyl)1H-1,2,3-triazol-4-yl)methylamino)pyrrolidin-2-one (9a)

Colorless syrup. = + 1.33 (C = 0.53, MeOH), NMR ¹H (300 MHz, CDCl ₃): δ 1.41(s, 3H); 1.44 (s, 3H); 2.08–2.17 (m, 4H); 3.58–3.64 (m, 4H); 4.02–4.07 (d, 1H,  Hz); 4.13–4.18 (d, 1H,  Hz); 4.45–4.60 (m, 7H), 4.69–4.74 (d, 1H,  Hz); 4.76–4.78 (m, 1H,  Hz); 7.66 (s, 1H, CH–N–N=N); 7.89 (s, 1H, CH–N–N=N). NMR ¹³C (75 MHz, CDCl ₃): δ 25.95; 27.05; 32.44; 34.54; 41.54; 47.04; 58.38–58.53; 71.06; 73.01; 77.28; 112.97; 123.15 (C–N–N=N); 123.71 (C–N–N=N); 143.16 (C–N=N–N); 146.49 (C–N=N–N); 169.92 (C=O). HRMS (m/z) [M + Na] ⁺ calcd for C₁₉H₃₀N₈O₅Na = 473.2237, found: 473.2226.

4.3.2. N-1-(2-cyanoeth)1H-1,2,3-triazol-4-methyl)-3.4-O-isopropylidendioxy-5-(2-cyanoethyl)-1H-1,2,3-triazol-4-yl))methylamino)pyrrolidin-2-one (9b)

Yellow gum, = +0.83 (C = 0.22, MeOH), NMR ¹H  (300 MHz, CDCl ₃): δ 1.36 (s, 3H); 1.1.40 (s, 3H); 3.1–3.01 (m, 4H); 3.9–4.03 (d, 1H,  Hz); 4.1–4.15 (d, 1H,  Hz); 4.29–4.72 (m, 9H), 7.79 (s, 1H, CH–N–N=N); 7.91 (s, 1H, CH–N–N=N); NMR ¹³C (75 MHz, CDCl ₃): δ 19.25; −19.33; 25.91; 257.01; 34.46; 41.54; 45.50–45.56; 71.28; 73.16; 77.30; 112.90; 116.91–117.00; 123.09 (C–N–N=N); 123.77 (C–N–N=N); 143.56 (C–N=N–N); 147.18 (C–N=N–N); 169.78 (C=O). HRMS (m/z) [M+Na] ⁺ calcd for C₁₉H₂₄N₁₀O3 Na: 463.1931, found: 463.1920.

4.3.3. N1-(1-benzyl-1H-1,2,3-triazol-4-yl)methyl-3,4-O-isopropylidendioxy-5-(1-benzyl-1H-1,2,3-triazol-4-yl)methylamino)pyrrolidin-2-one (9c)

Yellow solid, Mp = 149-150°C. +1.16 (C = 0.22, MeOH). NMR ¹H (300 MHz, CDCl ₃): δ 1.33 (s, 6H); 3.92–3.97 (d, H,  Hz); 3.92–3.97 (d, H,  Hz); 4.49 (m, 2H), 4.58 (d, 1H,  Hz); 4.65 (m, 1H,  Hz); 4.72 (m, 1H); 5.79–5.52 (m, 4H); 7.24–7.26 (m, H-aromatic); 7.55–7.56 (2s, 2H, CH–N). NMR ¹³C (75 MHz, CDCl ₃): δ 25.64; 26.71; 34.61; 41.51; 71.82; 73.41; 77.38; 112.72; 123.53 (C–N–N=N); 124.35 (C–N–N=N); 128.3–129.00 (C-aromatic); 134.77–134.96 (C-aromatic); 143.28 (C–N=N–N); 147.11 (C–N=N–N); 170.43 (C=O).HRMS (m/z) [M+Na] ⁺ calcd for C₂₇H₃₀N₈O3 Na: 537.2336, found: 537.2316.

4.3.4. N1-(4-((1H-1,2,3-triazol-1-yl)methyl)benzyl)-3,4-O-isopropylidendioxy-5-(1H-1,2,3-triazol-4-yl)methylamino)pyrrolidin-2-one (9d)

Yellow gum, +1.5 (C = 0.19, MeOH). NMR ¹H (300 MHz, CDCl ₃): δ 1.38–1.40 (s, 6H); 4.09–4.09 (d, 1H,  Hz); 4.15–4.20 (d, 1H,  Hz); 4.38 (m, 2H), 4.54–4.56 (m, 3H,  Hz); 4.70 (m, 2H); 5.47–5.56 (m, 2H); 7.30–7.37 (m, H-aromatic); 7.51 (s, 1H, CH–N); 7.72 (s, 1H, CH–N). NMR ¹³C (75 MHz, CDCl ₃): δ 24.97; 26.09; 34.34; 41.08; 53.24–53.74; 71.90; 73.53; 77.45; 112.47; 122.98 (C–N–N=N); 123.49 (C–N–N=N); 128.21–128.62 (C-aromatic); 135.23 (C–N=N–N); 136.24 (C–N=N–N); 170.84 (C=O). HRMS (m/z) [M+Na] ⁺ calcd for C₂₇H₃₀N₈O₃ Na 437.2050, found 437.2064.

4.3.5. N1-(3-((1H-1,2,3-triazol-1-yl)methyl)benzyl)3,4-O-isopropylidendioxy-5-(1H-1,2,3-triazol-4-yl)methylamino)pyrrolidin-2-one (9e)

Marrow syrup, = 3.0 (C = 0.22, MeOH). NMR ¹H (300 MHz, CDCl ₃): δ 1.45 (s, 3H); 1.53 (s, 3H); 1.62–1.71 (NH); 4.11–4.13 (m, 3H); 4.44–4.49 (d, 1H,  Hz); 4.67–4.69 (d, 1H,  Hz); 4.80–4.84 (m, 1H,  Hz); 5.09–5.14 (d, 1H,  Hz); 5.47–5.69 (m, 2H); 7.36–7.42 (m, H-aromatic); 7.52 (s, 1H, CH–N); 7.60 (s, 1H, CH–N); 7.78–7.83 (m, H-aromatic). NMR 13C (75 MHz, CDCl ₃): δ 27.87; 29.00; 36.53–42.27; 56.65–56.96; 71.52; 74.97; 80.03; 115.44; 124.54 (C–N–N=N); 124.75 (C–N–N=N); 126.43 (C-aromatic); 141.10 (C-aromatic); 143.96 (C–N=N–N); 148.96 (C–N=N–N); 156.64 (C-aromatic); 173.82 (C=O). HRMS (m/z) [M+Na] ⁺ calc for C₂₀H₂₃N₉O₃Na: 460.1822,found: 460.1814.

4.3.6. N-1-(2-propynyl)-3,4-O-isopropylidendioxy-5-(2-propynylamino)pyrrolidin-2-one (8)

This compound was obtained as a method described in the literature [14]. Colorless syrup. −2.43 (C = 0.55, MeOH); NMR ¹H (CDCl ₃):  δ 4.91 (m, 1H, H-4,  Hz). 4.75 (m, 2H, H-5, H-3,  Hz); 4.42 (dd, 1H, –CH2–, , 2.51 Hz); 3.89 (dd, 1H, –CH2–, , 2.5 Hz); 3.33 (m, 2H, –CH2–); 2.24–2.26 (m, 2H, –CH–); 1.37 (s, 6H, CH₃). NMR ¹³C (CDCl ₃) δ 168.76 (C=O); 112.92; 82.12; 77.64; 73.39; 72.01; 71.21–71.78; 36.15; 28.79; 26.06–26.97. HRMS (m/z) [M+Na] ⁺ calcld for C₁₃H₁₆N₂O₃Na 271.1059, found:271.1065.

Acknowledgments

C. Benhaoua thanks the Scientific Ministry for Higher Education and Research of Algeria for fellowships and thanks Dr D. Turki for helping in the English correction of the paper.

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