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

The click concept refers ease, e ﬃ cient, 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.


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 (Ki = 8 − −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].
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).
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, 2,6lutidine and N,N-diisopropylethylamine (DIPEA).

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).
More recently, Diot et al. reported the synthesis of several iminosugars from a click chemistry reaction between oligoethylene scaffolds and N-substituted DNJ derivative.
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).
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.
From the data presented in Table 1, it was noticed that the compounds (9) are prepared in yields ranging from 60% to 84%.

Identification of Products.
The structure elucidation of compounds 9 (a-e) achieved on the basis of their 1 H NMR, 13 C NMR and masse spectra.
The 1 H and 13 C NMR spectra showed the formation of the 1,2,3-triazole ring.
For the products 7 (a-e), the signal for the H 5 proton of the pyrrolidine cycle is around 4.11 ppm to 4.71 ppm.
In the 13 C NMR of the compounds 9 (a-e), characteristic (C=O) appeared at around 169.78 to 173.82. The 13 C 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].

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.

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 CH 2 Cl 2 (3 × 20 mL). The organic layer was dried over Na 2 SO 4 , concentrated and purified by column (CH 2 Cl 2 /MeOH, 95/5). The characterization of each compound obtained by means of NMR and mass spectrometry as reported below.