Preparation of ribavirin analogues by copper- and ruthenium-catalyzed azide-alkyne 1,3-dipolar cycloaddition

Abstract

In this study, we described the synthesis of 1,4- and 1,5-disubstituted-1,2,3-triazolo-nucleosides from various alkynes with 1′-azido-2′,3′,5′-tri-O-acetylribose using either copper-catalyzed azide-alkyne cycloaddition (CuAAC) or ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC), respectively. Optimized RuAAC conditions were realized with the commercially available [Cp*RuCl(PPh₃)₂] under microwave heating, which allows a significant acceleration of the reaction times (from 6 h to 5 min). This reaction can work under water-containing system. RuAAC and CuAAC are useful tools for the synthesis of 1,2,3-triazolyl-nucleosides small libraries.

1. Introduction

In recent years, many nucleoside analogues have been successfully developed into DNA virus and retrovirus therapeutic agents,¹ against different human immunodeficiency virus (HIV) strains and viruses with related-polymerases such as hepatitis B (HBV) or C (HCV). In the case of HCV, the template and substrate specificity of HCV RNA-dependent RNA polymerase differs from the host DNA-dependent polymerase, increasing thus the probability of developing potent HCV-specific nucleoside chain terminator. Figure 1 shows some examples of anti-HCV nucleosides and some triazolo derivatives (Fig. 1). The first nucleoside to show a therapeutic effect in HCV infection was ribavirin² (1) whose mechanism of action is a subject of debate.

Figure 1.

Some anti-HCV triazolo-nucleosides and target compounds (12 and 13).

Stuyver et al.³ reported the activity of a N⁴-hydroxycytidine (NHC) analogue (2), meanwhile several reports⁴ describe the anti-HCV replicon activity of nucleosides modified at the 2′-position (3). Another approach to discover a potent anti-HCV compounds was reported by Smith et al.⁵ in which analogues of triciribine (4), a cyclic sangivamycin analog with anti-cancer and anti-viral activity was reported. The synthesis of various triazolo compounds has been reported by Schinazi et al. (for 5),⁶ Benhida et al. (for 6),⁷ and by our team (for 7).⁸ As part of our drug discovery program, we report herein the synthesis of new 1,4-disubstituted-1,2,3-triazolonucleosides through well established Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). We have then investigated the Ru(II)-catalyzed azide-alkyne cycloaddition (RuAAC) under microwave conditions for the synthesis of 1,5-regiomers. All obtained compounds were evaluated for their anti-HCV activity in vitro.

2. Results and discussion

The Huisgen 1,3-dipolar cycloaddition of alkynes and azides (AAC)⁹ to give substituted-1,2,3-triazoles has emerged as a powerful linking reaction in both uncatalyzed¹⁰ and copper (I)-catalyzed leading to the sole 1,4-regioisomers.¹¹ The copper-catalyzed version of the reaction (CuAAC) has proven to be popular in many conditions, ranging from drug discovery to surface science, where rapid and reliable bond formation is required. Such 1,4 selectivity has been already reported in a very similar system under microwave conditions by Benhida et al.⁷ Nevertheless, we have synthesized new compounds and evaluated them against HCV. Starting with the protected β-azido-ribose (8),¹² the synthesis of various protected 1,4-disubstituted-1,2,3-triazolyl-nucleosides (Scheme 1) was performed regioselectively with Cu(0)/CuSO₄ as catalyst precursor. The desired new compounds 9a–h were obtained in yields ranging from 83 to 93% (Table 1, entries 1–7) except for ethoxy-ethyne (Table 1, entry 8). This system has the advantage of being simple and the products can be obtained from the reaction mixture by simple extraction.

Scheme 1.

Table 1.

Survey of CuAAC and RuAAC reaction^a,b

Entry	Alkyne	R	1,4-Regioisomers (CuAAC) (%)	1,5-Regioisomers (RuAAC)b		Ratio 1,4/1,5
			Δ	Δ	MW yield % (Conv. %)
1		a	86	79	88 (93)	4:96
2		b	88	83	92 (100)	3:93
3		c	93	71	92 (100)	4:96
4		d	87	79	87 (100)	5:95
5		e	89	82	91 (96)	4:96
6		f	83	68	87 (100)	5:95
7		g	92	77	95 (100)	5:95
8		h	63	54	93 (100)	3:97

^aConditions: azide 1 (1 equiv), alkyne (1.1 equiv), Cu powder (4 equiv), CuSO₄·5H₂O (0.2 equiv), ^tBuOH/H₂O.

^bConditions: azide 1 (1 equiv, 0.1 M in THF), alkyne (1.5 equiv), Cp*RuCl(PPh₃)₂ (0.05 equiv), THF, thermal heating (Δ): 6 h, T=50 °C or microwave conditions (MW): 5 min, T=100 °C.

We then turn our attention to the ruthenium-catalyzed version of the reaction (RuAAC), which is less extensively described and led mainly to 1,5-regioisomers.¹³ Generally, the common approaches to 1,5-regioisomers were based on Grignard reagents,¹⁴ or 1-trimethylsilylalkynes;¹⁵ nevertheless, these approaches suffer from some limitations including the number of steps and the chemical behavior of some functional groups toward those conditions. Thus, under classical heating, the azido-ribose (8) was reacted with various alkynes and 5 mol % Cp*RuCl(PPh₃)₂ catalyst¹⁶ (11) in THF at 50 °C. After 6 h, the desired triazolo compounds 10a–h were obtained in moderate to good yield (54–83%), after purification by column chromatography. Except for the ethyl ethynyl ether derivative (54%), the yields of all other alynes are almost identical (from 71 to 83%) for the RuAAc reaction showing that the influence of the steric hindrance of alkyne is low.

During the RuAAC, 3 to 7% of the 1,4-regioisomers, separable by column chromatography on silica gel, were obtained. Their structures were unambiguously confirmed by NMR (e.g., δ_H1=6.44 ppm (for 1,4-isomer) and δ_H1=6.15 ppm (for 1,5-isomer)) and TLC comparison with those obtained under CuAAC conditions. It should be noted that some catalyst deactivation has been encountered during long heating times. Thus, to circumvent this limitation, we decided to work under microwave activation¹⁷ (Table 1). Microwave heating is known as powerful tool to promote a variety of chemical reactions.¹⁸ While yields and purities of the coupling products were comparable to heating conditions, microwave heating allows a significant acceleration of the reaction from 6 h to 5 min (Table 1).

Working in THF at 100 °C, we first investigated the optimal conditions for the cycloaddition of azido-ribose 8 and hexyne with different concentration of catalyst 11 (Table 2). A 95% conversion was obtained after only 3 min of reaction with 5% catalyst. The total conversion of starting azido-ribose was obtained after 10 min with 3.5% catalyst loading and in 5 min for 5% catalyst loading. For lower catalyst loading, conversion was not complete, even after 10 min reaction.

Table 2.

Optimization of RuAAC under microwave conditions for 11e

Catalyst loading (mol %)	Irradiation time
	3 min	5 min	10 min
1	—	—	36%
2	—	—	57%
3.5	—	84%	100%
5	94%	100%	—

Thus, 5 mol % catalyst and 1.5 equiv of alkyne in THF at 100 °C for 5 min under microwave irradiation allowed the isolation of the desired compound 10e. It is interesting to note that anhydrous conditions are not necessary (e.g., undistilled THF, or THF-containing 2 equiv of water can be used to run this RuAAC). With this optimized conditions in hand, we probed the scope of the reaction on protected azido-ribose (8) with various alkynes. The desired 1,5-disubstituted-1,2,3-triazolyl-nucleosides 10a–h were obtained in good yields (Table 1). In most examples (Table 1, entries 1–7), microwave irradiation had evident beneficial effects in terms of reaction time and yield. For example, using classical heating, sluggish reactions with ethyl ethynyl ether were observed (54% after 6 h), meanwhile under microwave irradiation, complete conversion was achieved with [Cp*RuCl(PPh₃)₂] after short reaction time (5 min). The deacylation of 1,4-regioisomers (9a–h) and 1,5-regioisomers (10a–h) was carried out using a 7 N solution of ammonia in methanol at 0 °C over 12 h and led quantitatively to the final 1,4-disubstituted-1,2,3-triazolo-nucleosides (12a–h) and 1,5-disubstituted-1,2,3-triazolo-nucleosides (13a–h), respectively (Scheme 2).

Scheme 2.

Cleavage of benzoyl protective group.

Finally, the scope of this reaction with respect to unprotected azido-ribose (14) was next investigated on the hexyne and after 5 min of irradiation with 5 mol % RuAAC catalyst, the desired product (13e) was obtained in 95% yield (Scheme 3). This result confirms the robustness of the RuACC reaction conditions.

Scheme 3.

RuAAC on deprotected azido-ribose under thermal heating.

3. Biological results

The biological activity and toxicity of the synthesized triazoles against HCV were investigated in a replicon system in Huh-7 cells, and these compounds did not exhibit any marked activity or toxicity. The anti-viral¹⁹ and cytotoxicity²⁰ assays were done as previously described.

4. Conclusion

In summary, we have used either the Cu(0)/CuSO₄ catalytic system for CuAAC or the Cp*RuCl(PPh₃)₂ (11) under microwave conditions for RuAAC to reach hitherto unknown 1,4- and 1,5-di-substituted-1,2,3-triazolyl-nucleosides. The cooperative effect of the catalyst 11 and the microwave activation afforded the desired compounds in a few minutes in high yields. This approach allows an easy access to a small library of 1,5-disubstituted-triazolo derivatives under RuAAC and 1,4-regioisomers under CuAAC.

5. Experimental

5.1. General

Commercially available chemicals were of reagent grade and used as received. THF was distilled from sodium/benzophenone ketyl; CH₂Cl₂ from CaH₂ immediately prior use and benzene over Na. The microwave was a Biotage AB Initiator EXP EU with a maximum power of 300 W. The vials used in the microwave were Emrys^™ process vials 0.5–2 mL. The reactions were monitored by thin layer chromatography (TLC) analysis using silica gel plates (Kieselgel 60F₂₅₄, E. Merck). Column chromatography was performed on Silica Gel 60M (0.040–0.063 mm, E. Merck). Melting points are uncorrected and were measured on a Kofler apparatus. The ¹H and ¹³C NMR spectra were recorded on a Bruker AVANCE DPX 250 and Varian Inova_Unity 400 spectrometer (¹H: 250 MHz, ¹³C: 100 MHz) in (d₄) methanol and CDCl₃, shift values in parts per million relative to SiMe₄ as internal reference, the ³¹P spectra were reported using aqueous phosphoric acid as external reference (³¹P: 161.97 MHz) in CD₃OD, unless otherwise stated; J in hertz. Evidence of purity has been done from a proton-decoupled ¹³C NMR spectrum with a signal-to-noise ratio sufficient to permit seeing peak with 5% of the intensity of the strongest peak.

5.2. General procedure under CuAAC condition

To a solution of selected alkyne (1.1 mmol) and azido-ribose (8) (1 mmol) in H₂O/^tBuOH (1 mL) were added Cu powder (4 mmol) and CuSO₄ (0.2 mmol). The resulting suspension was stirred overnight at room temperature, then the mixture was extracted twice with ethyl acetate (50 mL), and dried over MgSO₄. The solvents were removed under reduced pressure and the obtained residue was purified on silica gel (petroleum ether/ethyl acetate, 8:2, v/v) to give the desired compound.

5.2.1. 2′,3′,5′-Tri-O-benzoyl-1′-[4-phenyl-[1,2,3]triazol-1yl]ribofuranose (9a)

Prepared from compound 8 with the typical procedure described before to give 9a (86%) as an oil. IR: 1717, 1451, 1316, 1124, 1093,1040, 703 cm⁻¹; ¹H NMR (CDCl₃): δ 8.06 (d, J=7.2 Hz, 2H, H^Ar), 8.00–7.95 (m, 5H, H^Ar and H⁵), 7.65 (d, J=7.5 Hz, 2H, H^Ar), 7.58–7.50 (m, 3H, H^Ar), 7.41–7.30 (m, 9H, H^Ar), 6.53 (d, J=3.8 Hz, 1H, H^1′), 6.30 (dd, J=5.3, 3.8 Hz, 1H, H^2′), 6.18 (t, J=5.3 Hz, 1H, H^3′), 4.86–4.92 (m, 2H, H^4′ and H^5′), 4.62 (dd, J=12.0, 3.6 Hz, 1H, H^5′); ¹³C NMR (CDCl₃): δ 166.0 (C(O)), 165.1 (C(O)), 165.0 (C(O)), 148.2 (C⁴), 133.8 (C^Ar), 133.6 (C^Ar), 133.3 (C^Ar), 129.8 (2C, C^Ar), 129.7 (C^Ar), 129.6 (C^Ar), 129.2 (C^Ar), 128.6 (2C, C^Ar), 128.5 (2C, C^Ar), 128.4 (C^Ar), 128.4 (C^Ar), 128.3 (C^Ar), 125.7 (C^Ar), 118.4 (C⁵), 90.3 (C^1′), 81.1 (C^4′), 75.2 (C^2′), 71.5 (C^3′), 63.5 (C^5′); CAS: 26295-47-6; MS (ESI): m/z [M+Na]⁺ calcd for C₃₄H₂₇N₃NaO₇: 612.6, found: 612.5.

5.2.2. 2′,3′,5′-Tri-O-benzoyl-1′-[4–4-fluoro-3-methylphenyl-[1,2,3]triazol-1-yl]ribofuranose (9b)

Prepared from compound 8 with the typical procedure described before to give 9b (88%) as a slight yellow oil. IR: 1720, 1602, 1493, 1451, 1259, 1091, 1069, 1024, 799, 705 cm⁻¹; ¹H NMR (CDCl₃): δ 8.07 (d, J=8.3 Hz, 2H, H^Ar), 8.00 (d, J=8.3 Hz, 2H, H^Ar), 7.97 (d, J=8.3 Hz, 2H, H^Ar), 7.89 (s, 1H, H⁵), 7.61–7.50 (m, 4H, H^Ar), 7.44–7.37 (m, 7H, H^Ar), 6.98 (t, J=9.0 Hz, 1H, H^Ar), 6.53 (d, J=3.9 Hz, 1H, H^1′), 6.28 (dd, J=5.2, 3.9 Hz, 1H, H^2′), 6.15 (t, J=5.2 Hz, 1H, H^3′), 4.93–4.87 (m, 2H, H^4′ and H^5′), 4.62 (dd, J=13.2, 4.8 Hz, 1H, H^5′), 2.28 (d, J=1.7 Hz, 3H, CH₃); ¹³C NMR (CDCl₃): δ 166.1 (C(O)), 165.2 (C(O)), 165.1 (C(O)), 147.7 (C⁴), 133.9 (C^Ar), 133.8 (C^Ar), 133.5 (C^Ar), 129.9 (C^Ar), 129.8 (C^Ar), 129.7 (C^Ar), 129.2 (C^Ar), 129.0 (C^Ar), 128.9 (C^Ar), 128.7 (C^Ar), 128.6 (3C, C^Ar), 128.5 (C^Ar), 125.8 (2C, C^Ar), 125.4 (C^Ar), 125.2 (C^Ar), 124.9 (C^Ar), 124.8 (C^Ar), 118.0 (C⁵), 115.5 (C^Ar), 115.2 (C^Ar), 90.4 (C^1′), 81.3 (C^4′), 75.3 (C^2′), 71.6 (C^3′), 63.6 (C^5′), 14.6, 14.5 (CH₃); MS (ESI): m/z [M+Na]⁺ calcd for C₃₅H₂₈FN₃NaO₇: 644.6, found: 644.5.

5.2.3. 2′,3′,5′-Tri-O-benzoyl-1′-[4-benzyl-[1,2,3]triazol-1-yl]ribofuranose (9c)

Prepared from compound 8 with the typical procedure described before to give 9c (93%) as white solid. Mp: 158 °C (CHCl₃); IR: 1727, 1708, 1601, 1450, 1270, 1123, 1095, 1068, 710 cm⁻¹; ¹H NMR (CDCl₃): δ 8.09–7.96 (m, 6H, H^Ar), 7.64–7.56 (m, 3H, H^Ar), 7.50–7.38 (m, 7H, H^Ar and H⁵), 7.33–7.21 (m, 5H, H^Ar), 6.43 (d, J=3.1 Hz, H^1′), 6.28–6.25 (m, 1H, H^2′), 6.19 (t, J=5.5 Hz, 1H, H^3′), 4.95–4.88 (m, 1H, H^4′), 4.83 (dd, J=12.2, 3.3 Hz, 1H, H^5′), 4.63 (dd, J=12.2, 4.5 Hz, 1H, H^5′), 4.02–3.88 (m, 1H, CH₂Ph); ¹³C NMR (CDCl₃): δ 166.0 (C(O)), 165.6 (C(O)), 165.0 (C(O)), 138.4 (C⁴), 133.8 (C^Ar), 133.6 (C^Ar), 133.3 (C^Ar), 129.8 (C^Ar), 129.7 (2C, C^Ar), 129.2 (C^Ar), 128.7 (C^Ar), 128.6 (C^Ar), 128.5 (C^Ar), 128.4 (C^Ar), 126.5 (C⁵), 90.1 (C^1′), 81.0 (C^4′), 75.2 (C^2′), 71.6 (C^3′), 63.7 (C^5′), 32.1 (CH₂Ph); MS (ESI): m/z [M+Na]⁺ calcd for C₃₅H₂₉N₃NaO₇: 626.6, found: 626.5.

5.2.4. 2′,3′,5′-Tri-O-benzoyl-1′-[4-methylcyclopentyl-[1,2,3]triazol-1-yl]ribofuranose (9d)

Prepared from compound 8 with the typical procedure described before to give 9d (87%) as white solid. Mp: 121 °C (CHCl₃); IR: 1716, 1601, 1451, 1261, 1093, 1068, 1023, 803, 706 cm⁻¹; ¹H NMR (CDCl₃): δ 8.05 (d, J=8.2 Hz, 2H, H^Ar), 7.97 (d, J=8.2 Hz, 2H, H^Ar), 7.94 (d, J=8.2 Hz, 2H, H^Ar), 7.57–7.49 (m, 4H, H^Ar and H⁵), 7.44–7.31 (m, 6H, H^Ar), 6.46 (d, J=3.6 Hz, 1H, H^1′), 6.23 (dd, J=5.2, 3.6 Hz, 1H, H^2′), 6.15 (t, J=5.4 Hz, 1H, H^3′), 4.89–4.79 (m, 2H, H^4′ and H^5′), 4.59 (dd, J=12.1, 4.2 Hz, 1H, H^5′), 2.63 (d, J=6.9 Hz, 2H, CH₂–CHCH₂CH₂), 2.11–2.01 (m, 1H, CH₂–CHCH₂CH₂), 1.73–1.62 (m, 2H, CH₂–CHCH₂CH₂), 1.60–1.52 (m, 2H, CH₂–CHCH₂CH₂), 1.50–1.42 (m, 2H, CH₂–CHCH₂CH₂), 1.17–1.07 (m, 2H, CH₂–CHCH₂CH₂); ¹³C NMR (CDCl₃): δ 166.1 (C(O)), 165.2 (C(O)), 165.1 (C(O)), 148.6 (C⁴), 133.8 (C^Ar), 133.7 (C^Ar), 133.4 (C^Ar), 130.1 (C^Ar), 129.9 (C^Ar), 129.8 (2C, C^Ar), 129.3 (C^Ar), 128.7 (C^Ar), 128.6 (2C, C^Ar), 128.5 (C^Ar), 128.3 (C^Ar), 112.0 (C⁵), 90.2 (C^1′), 81.0 (C^4′), 75.2 (C^2′), 71.7 (C^3′), 63.8 (C^5′), 39.7 (CH₂–CHCH₂CH₂), 32.5 (2C, CH₂–CHCH₂CH₂), 31.6 (CH₂–CHCH₂CH₂), 25.1 (CH₂–CHCH₂CH₂); MS (ESI): m/z [M+Na]⁺ calcd for C₃₄H₃₃N₃NaO₇: 618.7, found: 618.5.

5.2.5. 2′,3′,5′-Tri-O-benzoyl-1′-[4-butyl-[1,2,3]triazol-1-yl]ribofuranose (9e)

Prepared from compound 8 with the typical procedure described before to give 9e (89%) as white solid. Mp: 98 °C (CHCl₃); IR: 1726, 1601, 1451, 1254, 1124, 1090, 1068, 1045, 706 cm⁻¹; ¹H NMR (CDCl₃): δ 8.05 (d, J=8.5 Hz, 2H, H^Ar), 7.99 (d, J=8.5 Hz, 2H, H^Ar), 7.95 (d, J=8.5 Hz, 2H, H^Ar), 7.58–7.52 (m, 3H, H^Ar), 7.49 (s, 1H, H⁵), 7.46–7.34 (m, 6H, H^Ar), 6.45 (d, J=3.6 Hz, 1H, H^1′), 6.23 (dd, J=5.3, 3.6 Hz, 1H, H^2′), 6.15 (t, J=5.3 Hz, 1H, H^3′), 4.90–4.80 (m, 2H, H^4′ and H^5′), 4.60 (dd, J=12.1, 4.2 Hz, 1H, H^5′), 2.64 (td, J=7.6, 2.3 Hz, 2H, CH₂CH₂CH₂CH₃), 1.59–1.50 (m, 2H, CH₂CH₂CH₂CH₃), 1.39–1.28 (m, 2H, CH₂CH₂CH₂CH₃), 0.89 (t, J=7.3 Hz, 3H, CH₂CH₂CH₂CH₃); ¹³C NMR (CDCl₃): δ 166.0 (C(O)), 165.0 (C(O)), 164.9 (C(O)), 148.9 (C⁴), 133.7 (C^Ar), 133.6 (C^Ar), 133.3 (C^Ar), 129.7 (2C, C^Ar), 129.6 (C^Ar), 129.2 (C^Ar), 128.6 (C^Ar), 128.5 (C^Ar), 128.4 (2C, C^Ar), 119.5 (C⁵), 90.0 (C^1′), 80.9 (C^4′), 75.1 (C^2′), 71.6 (C^3′), 63.6 (C^5′), 31.0 (CH₂CH₂CH₂CH₃), 25.1 (CH₂CH₂CH₂CH₃), 22.2 (CH₂CH₂CH₂CH₃), 13.7 (CH₂CH₂CH₂CH₃); MS (ESI): m/z [M+Na]⁺ calcd for C₃₂H₃₁N₃NaO₇: 592.6, found: 592.5.

5.2.6. 2′,3′,5′-Tri-O-benzoyl-1′-[4-(3-chloropropyl)-[1,2,3]triazol-1-yl]ribofuranose (9f)

Prepared from compound 8 with the typical procedure described before to give 9f (83%) as white solid. Mp: 132 °C (CHCl₃); IR: 1716, 1601, 1451, 1264, 1124, 1099, 1070, 1047, 702 cm⁻¹; ¹H NMR (CDCl₃): δ 8.03 (d, J=8.5 Hz, 2H, H^Ar), 7.98 (d, J=8.4 Hz, 2H, H^Ar), 7.94 (d, J=8.4 Hz, 2H, H^Ar), 7.58–7.52 (m, 4H, H^Ar and H⁵), 7.45–7.33 (m, 6H, H^Ar), 6.44 (d, J=3.5 Hz, 1H, H^1′), 6.24 (dd, J=5.4, 3.5 Hz, 1H, H^2′), 6.14 (t, J=5.4 Hz, 1H, H^3′), 4.90–4.79 (m, 2H, H4^′ and H^5′), 4.58 (dd, J=12.2, 4.3 Hz, 1H, H^5′), 3.51 (t, J=6.4 Hz, 2H, CH₂CH₂CH₂Cl), 2.79 (t, J=6.4 Hz, 2H, CH₂CH₂CH₂Cl), 2.07–2.00 (m, 2H, CH₂CH₂CH₂Cl); ¹³C NMR (CDCl₃): δ 165.9 (C(O)), 165.0 (C(O)), 164.9 (C(O)), 146.7 (C⁴), 133.7 (C^Ar), 133.6 (C^Ar), 133.3 (C^Ar), 129.7 (C^Ar), 129.6 (2C, C^Ar), 129.2 (C^Ar), 128.5 (2C, C^Ar), 128.4 (2C, C^Ar), 128.3 (C^Ar), 120.1 (C⁵), 90.0 (C^1′), 80.9 (C^4′), 75.1 (C^2′), 71.5 (C^3′), 63.5 (C^5′), 44.0 (CH₂CH₂CH₂Cl), 31.4 (CH₂CH₂CH₂Cl), 22.5 (CH₂CH₂CH₂Cl); MS (ESI): m/z [M+Na]⁺ calcd for C₃₁H₂₈ClN₃NaO₇: 612.6, found: 612.5.

5.2.7. 2′,3′,5′-Tri-O-benzoyl-1′-[4-terbutyl-[1,2,3]triazol-1-yl]ribofuranose (9g)

Prepared from compound 8 with the typical procedure described before to give 9g (92%) as white solid. Mp: 129 °C (CHCl₃); IR: 1718, 1600, 1450, 1265, 1094, 1069, 1037, 706 cm⁻¹; ¹H NMR (CDCl₃): δ 8.07 (d, J=8.0 Hz, 2H, H^Ar), 7.99 (d, J=8.3 Hz, 2H, H^Ar), 7.94 (d, J=8.3 Hz, 2H, H^Ar), 7.59–7.51 (m, 3H, H^Ar), 7.46–7.33 (m, 7H, H^Ar and H⁵), 6.46 (d, J=3.1 Hz, 1H, H^1′), 6.20–6.14 (m, 2H, H^2′ and H^3′), 4.90–4.80 (m, 2H, H^4′ and H^5′), 4.61 (dd, J=11.9, 4.1 Hz, 1H, H^5′), 1.27 (s, 9H, C(CH₃)₃); ¹³C NMR (CDCl₃): δ 166.1 (2C, C(O)), 165.1 (2C, C(O)), 158.2 (C⁴), 133.8 (C^Ar), 133.7 (C^Ar), 133.4 (C^Ar), 129.8 (C^Ar), 129.7 (2C, C^Ar), 129.3 (C^Ar), 128.6 (2C, C^Ar), 128.5 (3C, C^Ar), 117.4 (C⁵), 90.1 (C^1′), 81.0 (C^4′), 75.2 (C^2′), 71.8 (C^3′), 63.8 (C^5′), 30.7 (CHCH₃), 30.1 (CHCH₃); MS (ESI): m/z [M+Na]⁺ calcd for C₃₂H₃₁N₃NaO₇: 592.6, found: 592.0.

5.2.8. 2′,3′,5′-Tri-O-benzoyl-1′-[4-O-ethoxy-[1,2,3]triazol-1-yl]ribofuranose (9h)

Prepared from compound 8 with the typical procedure described before to give 9h (63%) as yellow solid. Mp: 117 °C (CHCl₃); IR: 1715, 1568, 1451, 1282, 1265, 1127, 1092, 1024, 701 cm⁻¹; ¹H NMR (CDCl₃): δ 8.06 (d, J=8.4 Hz, 2H, H^Ar), 7.98 (d, J=8.4 Hz, 2H, H^Ar), 7.95 (d, J=8.4 Hz, 2H, H^Ar), 7.60–7.53 (m, 3H, H^Ar), 7.48–7.34 (m, 6H, H^Ar), 7.16 (s, 1H, H⁵), 6.36 (d, J=3.8 Hz, 1H, H^1′), 6.22 (dd, J=5.3, 3.8 Hz, 1H, H^2′), 6.10 (t, J=5.3 Hz, 1H, H^3′), 4.88–4.79 (m, 2H, H^4′ and H^5′), 4.69 (dd, J=12.1, 4.2 Hz, 1H, H^5′), 4.12 (q, J=7.1 Hz, 2H, OCH₂CH₃), 1.35 (t, J=7.1 Hz, 3H, OCH₂CH₃); ¹³C NMR (CDCl₃): δ 166.0 (C(O)), 165.1 (C(O)), 165.0 (C(O)), 161.2 (C⁴), 133.8 (C^Ar), 133.7 (C^Ar), 133.4 (C^Ar), 129.8 (C^Ar), 129.7 (C^Ar), 128.6 (2C, C^Ar), 128.5 (2C, C^Ar), 104.5 (C⁵), 90.7 (C^1′), 81.1 (C^4′), 74.9 (C^2′), 71.6 (C^3′), 66.3 (OCH₂CH₃), 63.7 (C^5′), 14.7 (OCH₂CH₃); MS (ESI): m/z [M+Na]⁺ calcd for C₃₀H₂₇N₃NaO₈: 580.6, found: 580.5.

5.3. General procedure for the RuAAC reaction

In a microwave sealed reactor, a mixture of azido-ribose (8) (1 mmol), the selected alkyne (1.5 mmol), and Cp*RuCl(PPh₃)₂ (0.05 mmol) in THF (10 mL) was irradiated for 5 min at 100 °C (200 W, normal mode). The mixture was then evaporated under reduced pressure and the residue purified on silica gel (petroleum ether/ethyl acetate; 7:3) to give the desired product.

5.3.1. 2′,3′,5′-Tri-O-benzoyl-1′-[5-phenyl-[1,2,3]triazol-1-yl]ribofuranose (10a)

Prepared from compound 8 with the typical procedure described before to give 10a (see Table 1) as a slightly brown oil. IR: 1721, 1601, 1451, 1261, 1090, 1069, 704 cm⁻¹; ¹H NMR (CDCl₃): δ 8.05–7.90 (m, 6H, H^Ar), 7.74 (s, 1H, H⁴), 7.59–7.47 (m, 8H, H^Ar), 7.43–7.30 (m, 6H, H^Ar), 6.54–6.47 (m, 2H, H^2′ and H^3′), 6.15 (d, J=1.6 Hz, 1H, H^1′), 4.91 (m, 1H, H^4′), 4.78 (dd, J=12.12, 3.96 Hz, 1H, H^5′), 4.61 (dd, J=12.12, 5.13 Hz, 1H, H^5′); ¹³C NMR (CDCl₃): δ 166.2 (C(O)), 165.0 (2C, C(O)), 139.1 (C⁵), 133.7 (C^Ar), 133.5 (C^Ar), 133.1 (C^Ar), 133.0 (C⁵), 129.9 (C^Ar), 129.8 (2C, C^Ar), 129.4 (C^Ar), 129.2 (2C, C^Ar), 128.8 (C^Ar), 128.7 (C^Ar), 128.5 (C^Ar), 128.4 (C^Ar), 128.3 (C^Ar), 126.0 (C⁴), 88.2 (C^1′), 80.9 (C^4′), 75.6 (C^2′), 72.2 (C^3′), 63.7 (C^5′); MS (ESI): m/z [M+Na]⁺ calcd for C₃₄H₂₇N₃NaO₇: 612.6, found: 612.5.

5.3.2. 2′,3′,5′-Tri-O-benzoyl-1′-[5–4-fluoro-3-methylphenyl-[1,2,3]triazol-1-yl]ribofuranose (10b)

Prepared from compound 8 with the typical procedure described before to give 10b (see Table 1) as a slight brown oil. IR: 1720, 1602, 1492, 1451, 1253, 1084, 705 cm⁻¹; ¹H NMR (CDCl₃): δ 8.05–7.91 (m, 6H, H^Ar), 7.70 (s, 1H, H⁴), 7.60–7.48 (m, 3H, H^Ar), 7.44–7.30 (m, 9H, H^Ar), 7.16–7.08 (t, J=8.0 Hz, 1H, H^Ar), 6.51–6.45 (m, 2H, H^2′ and H^3′), 6.10 (d, J=1.2 Hz, 1H, H^1′), 4.93–4.89 (m, 1H, H^4′), 4.78 (dd, J=12.1, 3.9 Hz, 1H, H^5′), 4.61 (dd, J=12.1, 5.2 Hz, 1H, H^5′), 2.32 (d, J=1.8 Hz, 3H, CH₃); ¹³C NMR (CDCl₃): δ 166.2 (C(O)), 165.1 (C(O)), 165.0 (C^Ar), 163.5 (C^Ar), 161.0 (C^Ar), 138.4 (C^Ar), 133.8 (C^Ar), 133.5 (C^Ar), 133.2 (C^Ar), 132.9 (C^Ar), 132.6 (2C, C^Ar), 129.8 (3C, C^Ar), 129.4 (C^Ar), 128.7 (2C, C^Ar), 128.5 (C^Ar), 128.4 (C^Ar), 128.3 (C^Ar), 126.3 (C⁴), 126.1 (C⁴), 121.7 (C^Ar), 121.6 (C^Ar), 116.0 (C^Ar), 115.8 (C^Ar), 88.1 (C^1′), 80.8 (C^4′), 75.7 (C^2′), 72.1 (C^3′), 63.7 (C^5′), 14.5 (2C, CH₃); MS (ESI): m/z [M+Na]⁺ calcd for C₃₅H₂₈FN₃NaO₇: 644.6, found: 644.5.

5.3.3. 2′,3′,5′-Tri-O-benzoyl-1′-[5-methylbenzyl-[1,2,3]triazol-1-yl]ribofuranose (10c)

Prepared from compound 8 with the typical procedure described before to give 10c (see Table 1) as a slight brown oil. IR: 1720, 1577, 1451, 1261, 1091, 705 cm⁻¹; ¹H NMR (CDCl₃): δ 7.93–7.80 (m, 6H, H^Ar), 7.51–7.40 (m, 3H, H^Ar), 7.34–7.22 (m, 7H, H^Ar and H⁴), 7.21–7.09 (m, 3H, H^Ar), 7.09–7.04 (m, 2H, H^Ar), 6.35 (dd, J=5.2, 2.1 Hz, 1H, H^2′), 6.21 (dd, J=7.0, 5.2 Hz, 1H, H^3′), 6.07 (d, J=2.1 Hz, 1H, H^1′), 4.80–4.74 (m, 1H, H^4′), 4.65 (dd, J=12.1, 3.8 Hz, 1H, H^5′), 4.46 (dd, J=12.1, 5.1 Hz, 1H, H^5′), 4.03 (q, J=16.6 Hz, 2H, CH₂Ph); ¹³C NMR (CDCl₃): δ 166.1 (C(O)), 165.0 (2C, C(O)), 137.0, 135.6 (C^Ar and C⁵), 133.8 (C^Ar), 133.7 (C^Ar), 133.5 (C^Ar), 133.1 (C^Ar), 129.7 (2C, C^Ar), 129.3 (C^Ar), 128.9, 128.7, 128.6, 128.5, 128.4 (2C), 128.3 (C^Ar and C⁴), 127.2 (C^Ar), 88.0 (C^1′), 80.8 (C^4′), 75.1 (C^2′), 71.8 (C^3′), 63.6 (C^5′), 29.0 (CH₂Ph); MS (ESI): m/z [M+Na]⁺ calcd for C₃₅H₂₉N₃NaO₇: 626.6, found: 626.5.

5.3.4. 2′,3′,5′-Tri-O-benzoyl-1′-[5-methylcyclopentyl-[1,2,3]triazol-1-yl]ribofuranose (10d)

Prepared from compound 8 with the typical procedure described before to give 10d (see Table 1) as a slight brown oil. IR: 1721, 1601, 1580, 1451, 1262, 1091, 706 cm⁻¹; ¹H NMR (CDCl₃): δ 8.06–7.92 (m, 6H, H^Ar), 7.62–7.49 (m, 3H, H^Ar), 7.47 (s, 1H, H⁴), 7.46–7.32 (m, 6H, H^Ar), 6.48 (dd, J=5.2, 1.8 Hz, 1H, H^2′), 6.36 (dd, J=7.1, 5.2 Hz, 1H, H^3′), 6.20 (d, J=1.8Hz, 1H, H^1′), 4.93–4.87 (m, 1H, H^4′), 4.73 (dd, J=12.1, 3.9 Hz, 1H, H^5′), 4.53 (dd, J=12.1, 5.3 Hz, 1H, H^5′), 2.73 (d, J=7.4 Hz, 2H, CH₂–CHCH₂CH₂), 2.25–2.12 (m, 1H, CH₂–CHCH₂CH₂), 1.85–1.73 (m, 2H, CH₂–CHCH₂CH₂), 1.68–1.47 (m, 4H, CH₂–CHCH₂CH₂), 1.24–1.12 (m, 2H, CH₂–CHCH₂CH₂); ¹³C NMR (CDCl₃): δ 166.1 (C(O)), 165.1 (C(O)), 165.0 (C(O)), 138.0 (C⁵), 133.7 (C^Ar), 133.5 (C^Ar), 133.1 (C^Ar), 132.8 (C⁴), 129.8 (C^Ar), 129.7 (C^Ar), 129.3 (C^Ar), 128.8 (C^Ar), 128.7 (C^Ar), 128.5 (C^Ar), 128.4 (C^Ar), 128.3 (C^Ar), 87.8 (C^1′), 80.8 (C^4′), 75.4 (C^2′), 72.1 (C^3′), 63.8 (C^5′), 38.7 (CH₂–CHCH₂CH₂), 32.5 (2C, CH₂–CHCH₂CH₂), 28.9 (CH₂–CHCH₂CH₂), 25.0 (CH₂–CHCH₂CH₂); MS (ESI): m/z [M+Na]⁺ calcd for C₃₄H₃₃N₃NaO₇: 618.7, found: 618.5.

5.3.5. 2′,3′,5′-Tri-O-benzoyl-1′-[5-butyl-[1,2,3]triazol-1-yl]ribofuranose (10e)

Prepared from compound 8 with the typical procedure described before to give 10e (see Table 1) as a brown oil. IR: 1721, 1602, 1451, 1261, 1092, 706 cm⁻¹; ¹H NMR (CDCl₃): δ 8.05–7.93 (m, 6H, H^Ar), 7.62–7.50 (m, 3H, H^Ar), 7.46 (s, 1H, H⁴), 7.45–7.33 (m, 6H, H^Ar), 6.46 (dd, J=5.2, 1.8 Hz, 1H, H^2′), 6.35 (dd, J=7.2, 5.2 Hz, 1H, H^3′), 6.19 (d, J=1.8 Hz, 1H, H^1′), 4.92–4.88 (m, 1H, H^4′), 4.73 (dd, J=12.1, 3.9 Hz, 1H, H^5′), 4.54 (dd, J=12.1, 5.5 Hz, 1H, H^5′), 2.73 (t, J= 7.8 Hz, 2H, CH₂CH₂CH₂CH₃), 1.71–1.62 (m, 2H, CH₂CH₂CH₂CH₃), 1.44–1.33 (m, 2H, CH₂CH₂CH₂CH₃), 0.96–0.89 (t, J=7.4 Hz, 3H, CH₂CH₂CH₂CH₃); ¹³C NMR (CDCl₃): δ 166.1 (C(O)), 165.2 (C(O)), 165.0 (C(O)), 138.4 (C⁵), 133.8 (C^Ar), 133.5 (C^Ar), 133.2 (C^Ar), 132.4 (C⁴), 129.8 (2C, C^Ar), 129.4 (C^Ar), 128.8 (2C, C^Ar), 128.6 (C^Ar), 128.4 (C^Ar), 128.3 (C^Ar), 87.9 (C^1′), 80.8 (C^4′), 75.4 (C^2′), 72.0 (C^3′), 63.8 (C^5′), 30.2 (CH₂CH₂CH₂CH₃), 22.6 (CH₂CH₂CH₂CH₃), 22.2 (CH₂CH₂CH₂CH₃), 13.6 (CH₂CH₂CH₂CH₃); MS (ESI): m/z [M+Na]⁺ calcd for C₃₂H₃₁N₃NaO₇: 592.6, found: 592.5.

5.3.6. 2′,3′,5′-Tri-O-benzoyl-1′-[5-(3-chloropropyl)-[1,2,3]triazol-1-yl]ribofuranose (10f)

Prepared from compound 8 with the typical procedure described before to give 10f (see Table 1) as a brown oil. IR: 1719, 1602, 1451, 1260, 1092, 706 cm⁻¹; ¹H NMR (CDCl₃): δ 8.05–7.94 (m, 6H, H^Ar), 7.61–7.50 (m, 3H, H^Ar), 7.50 (s, 1H, H⁴), 7.39 (m, 6H, H^Ar), 6.50 (dd, J=5.2, 1.8 Hz, 1H, H^2′), 6.34 (dd, J=7.2, 5.2 Hz, 1H, H^3′), 6.25 (d, J=1.8 Hz, 1H, H^1′), 4.94–4.90 (m, 1H, H^4′), 4.74 (dd, J=12.2, 3.8 Hz, 1H, H^5′), 4.53 (dd, J=12.2, 5.1 Hz, 1H, H^5′), 3.60–3.48 (m, 2H, CH₂CH₂CH₂Cl), 3.03–2.88 (m, 2H, CH₂CH₂CH₂Cl), 2.20–2.09 (m, 2H, CH₂CH₂CH₂Cl); ¹³C NMR (CDCl₃): δ 166.0 (C(O)), 165.1 (C(O)), 165.0 (C(O)), 136.7 (C⁵), 133.7 (C^Ar), 133.5 (C^Ar), 133.1 (C^Ar), 132.6 (C⁴), 129.7 (C^Ar), 129.6 (C^Ar), 129.2 (C^Ar), 128.6 (2C, C^Ar), 128.5 (C^Ar), 128.3 (2C, C^Ar), 87.8 (C^1′), 80.8 (C^4′), 75.2 (C^2′), 71.8 (C^3′), 63.5 (C^5′), 43.4 (CH₂CH₂CH₂Cl), 30.7 (CH₂CH₂CH₂Cl), 19.9 (CH₂CH₂CH₂Cl); MS (ESI): m/z [M+Na]⁺ calcd for C₃₁H₂₈ClN₃NaO₇: 612.6, found: 612.5.

5.3.7. 2′,3′,5′-Tri-O-benzoyl-1′-[5-tert-butyl-[1,2,3]triazol-1-yl]ribofuranose (10g)

Prepared from compound 8 with the typical procedure described before to give 10g (see Table 1) as a brown oil. IR: 1721, 1602, 1451, 1250, 1092, 1069, 706 cm⁻¹; ¹H NMR (CDCl₃): δ 8.09 (d, J=8.5 Hz, 2H, H^Ar), 8.01 (d, J=8.5 Hz, 2H, H^Ar), 7.97 (d, J=8.5 Hz, 2H, H^Ar), 7.61–7.54 (m, 3H, H^Ar), 7.47–7.36 (m, 7H, H^Ar and H⁴), 6.45 (d, J=3.1 Hz, 1H, H^2′), 6.19–6.15 (m, 2H, H^3′ and H^1′), 4.89–4.80 (m, 2H, H^4′ and H^5′), 4.61 (dd, J=11.9, 4.1 Hz, 1H, H^5′), 1.27 (s, 9H, C(CH₃)₃); ¹³C NMR (CDCl₃): δ 166.1 (C(O)), 165.1 (C(O)), 165.0 (C(O)), 146.5 (C⁵), 133.7 (C^Ar), 133.4 (C^Ar), 133.0 (C^Ar), 131.2 (C⁴), 129.8 (C^Ar), 129.7 (C^Ar), 129.4 (C^Ar), 128.8 (2C, C^Ar), 128.5 (C^Ar), 128.4 (C^Ar), 128.3 (C^Ar), 117.4 (C⁴), 89.2 (C^1′), 80.7 (C^4′), 72.4 (C^2′), 63.8 (C^5′), 30.3 (C(CH₃)₃), 30.1 (C(CH₃)₃); MS (ESI): m/z [M+Na]⁺ calcd for C₃₂H₃₁N₃NaO₇: 592.6, found: 592.0.

5.3.8. 2′,3′,5′-Tri-O-benzoyl-1′-[5-O-ethoxy-[1,2,3]triazol-1-yl]ribofuranose (10h)

Prepared from compound 8 with the typical procedure described before to give 10h (see Table 1) as a brown oil. IR: 1720, 1577, 1451, 1261, 1091, 1026, 705 cm⁻¹; ¹H NMR (CDCl₃): δ 8.07–7.98 (m, 4H, H^Ar), 7.96–7.90 (m, 2H, H^Ar), 7.55 (m, 3H, H^Ar), 7.44–7.31 (m, 6H, H^Ar), 7.07 (s, 1H, H⁴), 6.34 (dd, J=5.3, 2.4 Hz, 1H, H^2′), 6.30–6.25 (m, 2H, H^3′ and H^1′), 4.88–4.82 (m, 1H, H^4′), 4.72 (dd, J=12.0, 4.1 Hz, 1H, H^5′), 4.60 (dd, J=12.0, 5.4 Hz, 1H, H^5′), 4.23–4.16 (dq, J=7.1, 1.4 Hz, 2H, OCH₂CH₃), 1.46 (t, J=7.1 Hz, 3H, OCH₂CH₃); ¹³C NMR (CDCl₃): δ 166.2 (C(O)), 165.0 (2C, C(O)), 152.0 (C⁵), 133.7 (C^Ar), 133.5 (C^Ar), 133.1 (C^Ar), 129.8 (C^Ar), 129.7 (C^Ar), 129.4 (C^Ar), 128.7 (2C, C^Ar), 128.5 (C^Ar), 128.4 (C^Ar), 128.3 (C^Ar), 113.8 (C⁴), 86.7, 80.2, 74.5, 71.8, 69.3, 63.9, 14.4; MS (ESI): m/z [M+Na]⁺ calcd for C₃₀H₂₇N₃NaO₈: 580.6, found: 580.5.

5.4. General procedure for sugar deprotection

To the protected compounds (9a–h and 10a–h) was added a solution of 7 N NH₃/MeOH. The reaction was followed by TLC. After evaporation of the solvent under reduced pressure, the crude product was purified by liquid chromatography on silica gel (methanol/ethyl acetate, 1:9, v/v) to give the desired pure product.

5.4.1. 1′-[4-Phenyl-[1,2,3]triazol-1-yl]ribofuranose (12a)

Prepared from compound 9a with the typical procedure described above to give 12a (>98%) as an oil. IR: 3368, 1661, 1447, 1191, 1135, 799, 723 cm⁻¹; ¹H NMR (CD₃OD): δ 8.58 (s, 1H, H⁵), 7.82 (d, J=8.3 Hz, 2H, H^Ar), 7.43 (t, J=7.5 Hz, 2H, H^Ar), 7.35 (t, J=7.4 Hz, 1H, H^Ar), 6.09 (d, J=4.0 Hz, 1H, H^1′), 4.57 (t, J=4.5 Hz, 1H, H^2′), 4.37 (t, J=5.1 Hz, 1H, H^3′), 4.17 (m, 1H, H^4′), 3.86 (dd, J=12.3, 3.2 Hz, 1H, H^5′), 3.73 (dd, J=12.3, 4.2 Hz, 1H, H^5′); ¹³C NMR (CD₃OD): δ 149.0 (C⁴), 131.6 (C^Ar), 130.0 (C^Ar), 129.5 (C^Ar), 126.7 (C^Ar), 120.9 (C⁵), 94.5 (C^1′), 87.2 (C^4′), 77.1 (C^2′), 71.9 (C^3′), 62.8 (C^5′); HRMS (ESI): m/z [M+H]⁺ calcd for C₁₃H₁₆N₃NO₄: 278.1141, found: 278.1148. Known product CAS: 26295-54-5.

5.4.2. 1′-[4–4-Fluoro-3-methylphenyl-[1,2,3]triazol-1-yl]ribofuranose (12b)

Prepared from compound 9b with the typical procedure described above to give 121b (>98%) as white solid. Mp: 158 °C (MeOH); IR: 3344, 2929, 1493, 1233, 1082, 1043, 817 cm⁻¹; UV (MeOH) λ_max: 241 nm; ${\left[\alpha \right]}_{\text{D}}^{20}$ −76.4 (c 1.45, MeOH); ¹H NMR (CD₃OD): δ 8.53 (s, 1H, H⁵), 7.71 (d, J=7.3 Hz, 1H, H^Ar), 7.67–7.62 (m, 1H, H^Ar), 7.10 (t, J=9.1 Hz, 1H, H^Ar), 6.08 (d, J=4.0 Hz, 1H, H^1′), 4.55 (t, J=4.5 Hz, 1H, H^2′), 4.35 (t, J=5.0 Hz, 1H, H^3′), 4.18–4.13 (m, 1H, H^4′), 3.85 (dd, J=12.2, 3.2 Hz, 1H, H^5′), 3.71 (dd, J=12.2, 4.2 Hz, 1H, H^5′), 2.32 (s, 3H, CH₃); ¹³C NMR (CDCl₃): δ 148.3 (C⁴), 130.0 (C^Ar), 126.1 (C^Ar), 120.7 (C⁵), 116.6 (C^Ar), 116.4 (C^Ar), 94.6 (C^1′), 87.3 (C^4′), 77.2 (C^2′), 71.9 (C^3′), 62.9 (C^5′), 14.6 (CH₃); HRMS (ESI): m/z [M+H]⁺ calcd for C₁₄H₁₇FN₃O₄: 310.1203, found: 310.1218.

5.4.3. 1′-[4-Methylbenzen-[1,2,3]triazol-1-yl]ribofuranose (12c)

Prepared from compound 9c with the typical procedure described above to give 12c (>98%) as white solid. Mp: 100 °C (MeOH); IR: 3355, 2928, 2360, 1454, 1230, 1047, 725 cm⁻¹; UV (MeOH) λ_max: 212 nm; ${\left[\alpha \right]}_{\text{D}}^{20}$ −58.0 (c 0.59, MeOH); ¹H NMR (CD₃OD): δ 7.97 (s, 1H, H⁵), 7.30–7.16 (m, 5H, H^Ar), 6.00 (d, J=4.1 Hz, 1H, H^1′), 4.48 (t, J=4.6 Hz, 1H, H^2′), 4.30 (t, J=5.0 Hz, 1H, H^3′), 4.14–4.09 (m, 1H, H^4′), 4.04 (s, 2H, CH₂Ph), 3.79 (dd, J=12.2, 3.2 Hz, 1H, H^5′), 3.67 (dd, J=12.2, 4.3 Hz, 1H, H^5′); ¹³C NMR (CD₃OD): δ 148.6 (C⁴), 140.3 (C^Ar), 129.6 (2C, C^Ar), 127.5 (C^Ar), 122.6 (C⁵), 94.8 (C^1′), 87.1 (C^4′), 77.0 (C^2′), 71.9 (C^3′), 62.9 (C^5′), 32.6 (CH₂Ph); HRMS (ESI): m/z [M+H]⁺ calcd for C₁₄H₁₈N₃O₄: 292.1297, found: 292.1283.

5.4.4. 1′-[4-Methylcyclopentyl-[1,2,3]triazol-1-yl]ribofuranose (12d)

Prepared from compound 9d with the typical procedure described above to give 12d (>98%) as a white solid. Mp: 87 °C (MeOH); IR: 3349, 1298, 2868, 1452, 1228, 1048 cm⁻¹; UV (MeOH) λ_max: 223 nm; ${\left[\alpha \right]}_{\text{D}}^{20}$ −51.5 (c 1.37, MeOH); ¹H NMR (CD₃OD): δ 8.00 (s, 1H, H⁵), 6.00 (d, J=4.0 Hz, 1H, H^1′), 4.47 (t, J=4.5 Hz, 1H, H^2′), 4.30 (t, J=5.1 Hz, 1H, H^3′), 4.15–4.09 (m, 1H, H^4′), 3.81 (dd, J=12.2, 3.2 Hz, 1H, H^5′), 3.69 (dd, J=12.2, 4.3 Hz, 1H, H^5′), 2.70 (d, J=7.4 Hz, 2H, CH₂–CHCH₂CH₂), 2.24–2.12 (m, 1H, CH₂–CHCH₂CH₂), 1.82–1.72 (m, 2H, CH₂–CHCH₂CH₂), 1.71–1.62 (m, 2H, CH₂–CHCH₂CH₂), 1.61–1.51 (m, 2H, CH₂–CHCH₂CH₂), 1.31–1.18 (m, 2H, CH₂–CHCH₂CH₂); ¹³C NMR (CD₃OD): δ 148.9 (C⁴), 122.2 (C⁵), 94.3 (C^1′), 87.1 (C^4′), 77.1 (C^2′), 71.9 (C^3′), 62.9 (C^5′), 41.3 (CH₂–CHCH₂CH₂), 33.4 (CH₂–CHCH₂CH₂), 32.4 (CH₂–CHCH₂CH₂), 26.1 (CH₂–CHCH₂CH₂); HRMS (ESI): m/z [M+H]⁺ calcd for C₁₃H₂₂N₃O₄: 284.1610, found: 284.1608.

5.4.5. 1′-[4-Butyl-[1,2,3]triazol-1-yl]ribofuranose (12e)

Prepared from compound 9e with the typical procedure described above to give 12e (>98%) as a white solid. Mp: 105 °C (MeOH); IR: 3316, 2930, 2870, 1456, 1043, 826 cm⁻¹; UV (MeOH) λ_max: 223 nm; ${\left[\alpha \right]}_{\text{D}}^{20}$ −50.7 (c 0.56, MeOH); ¹H NMR (CD₃OD): δ 8.00 (s, 1H, H⁵), 6.00 (d, J=4.1 Hz, 1H, H^1′), 4.48 (t, J=4.5 Hz, 1H, H^2′), 4.32 (t, J=5.0 Hz, 1H, H^3′), 4.15–4.11 (m, 1H, H^4′), 3.82 (dd, J=12.2, 3.2 Hz, 1H, H^5′), 3.70 (dd, J=12.2, 4.3 Hz, 1H, H^5′), 2.71 (t, J=7.6 Hz, 2H, CH₂CH₂CH₂CH₃), 1.70–1.61 (m, 2H, CH₂CH₂CH₂CH₃), 1.45–1.34 (m, 2H, CH₂CH₂CH₂CH₃), 0.95 (t, J=7.4 Hz, 3H, CH₂CH₂CH₂CH₃); ¹³C NMR (CD₃OD): δ 149.4 (C⁴), 121.8 (C⁵), 94.3 (C^1′), 87.1 (C^4′), 77.0 (C^2′), 71.9 (C^3′), 62.9 (C^5′), 32.7 (CH₂CH₂CH₂CH₃), 26.0 (CH₂CH₂CH₂CH₃), 23.3 (CH₂CH₂CH₂CH₃), 14.2 (CH₂CH₂CH₂CH₃); HRMS (ESI): m/z [M+Na]⁺ calcd for C₁₁H₁₉N₃NaO₄: 280.1273, found: 280.1269.

5.4.6. 1′-[4-(3-Chloropropyl)-[1,2,3]triazol-1-yl]ribofuranose (12f)

Prepared from compound 9f with the typical procedure described above to give 12f (>98%) as colorless crystals. Mp: 91 °C (MeOH); IR: 3316, 2928, 2361, 1546, 1229, 1048 cm⁻¹; UV (MeOH) λ_max: 223 nm; ${\left[\alpha \right]}_{\text{D}}^{20}$ −46.7 (c 0.89, MeOH); ¹H NMR (CD₃OD): δ 8.05 (s, 1H, H⁵), 6.01 (d, J=4.1 Hz, 1H, H^1′), 4.49 (t, J=4.5 Hz, 1H, H^2′), 4.31 (t, J=5.0 Hz, 1H, H^3′), 4.15–4.11 (m, 1H, H^4′), 3.81 (dd, J=12.2, 3.2 Hz, 1H, H^5′), 3.69 (dd, J=12.2, 4.3 Hz, 1H, H^5′), 3.61 (t, J=6.5 Hz, 2H, CH₂CH₂CH₂Cl), 2.87 (t, J=7.5 Hz, 2H, CH₂CH₂CH₂Cl), 2.17–2.08 (m, 2H, CH₂CH₂CH₂Cl); ¹³C NMR (CD₃OD): δ 147.9 (C⁴), 122.2 (C⁵), 94.3 (C^1′), 87.1 (C^4′), 77.0 (C^2′), 71.9 (C^3′), 62.9 (C^5′), 44.8 (CH₂CH₂CH₂Cl), 33.3 (CH₂CH₂CH₂Cl), 23.6 (CH₂CH₂CH₂Cl); HRMS (ESI): m/z [M+H]⁺ calcd for C₁₀H₁₇ClN₃O₄: 278.0908, found: 278.0902.

5.4.7. 1′-[4-tert-Butyl-[1,2,3]triazol-1-yl]ribofuranose (12g)

Prepared from compound 9g with the typical procedure described above to give 12g (>98%) as a white solid. Mp: 114 °C (MeOH); IR: 3355, 2964, 2361, 1461, 1365, 1232, 1104, 1047 cm⁻¹; UV (MeOH) λ_max: 221 nm; ${\left[\alpha \right]}_{\text{D}}^{20}$ −55.7 (c 0.88, MeOH); ¹H NMR (400 MHz, CD₃OD): δ 8.01 (s, 1H, H⁵), 6.00 (d, J=4.2 Hz, 1H, H^1′), 4.49 (t, J=4.6 Hz, 1H, H^2′), 4.30 (t, J=5.0 Hz, 1H, H3^′), 4.14–4.09 (m, 1H, H^4′), 3.82 (dd, J=12.2, 3.2 1H, Hz, H^5′), 3.69 (dd, J=12.2, 4.3 Hz, 1H, H^5′), 1.34 (s, 9H, C(CH₃)₃); ¹³C NMR (101 MHz, CD₃OD): δ 158.7 (C⁴), 119.9 (C⁵), 94.2 (C^1′), 87.1 (C^4′), 77.0 (C^2′), 71.9 (C^3′), 62.9 (C^5′), 31.7 (C(CH₃)₃), 30.7 (C(CH₃)₃); HRMS (ESI): m/z [M+H]⁺ calcd for C₁₁H₂₀N₃O₄: 258.1454, found: 258.1457.

5.4.8. 1′-[4-O-Ethoxy-[1,2,3]triazol-1-yl]ribofuranose (12h)

Prepared from compound 9h with the typical procedure described above to give 12h (>98%) as colorless crystals. Mp: 127 °C (MeOH); IR: 3348, 2927, 2361, 1667, 1571, 1381, 1340, 1045 cm⁻¹; UV (MeOH) λ_max: 233 nm; ${\left[\alpha \right]}_{\text{D}}^{20}$ −63.1 (c 1.12, MeOH); ¹H NMR (400 MHz, CD₃OD): δ 7.71 (s, 1H, H⁵), 5.91 (d, J=4.1 Hz, 1H, H^1′), 4.46 (t, J=4.6 Hz, 1H, H^2′), 4.29 (t, J=5.0 Hz, 1H, H3^′), 4.17 (q, J=7.1 Hz, 2H, OCH₂CH₃), 4.13–4.09 (m, 1H, H^4′), 3.81 (dd, J=12.2, 3.2 Hz, 1H, H^5′), 3.69 (dd, J=12.2, 4.2 Hz, 1H, H^5′), 1.38 (t, 3H, J=7.1 Hz, OCH₂CH₃); ¹³C NMR (101 MHz, CD₃OD): δ 162.4 (C⁴), 106.4 (C⁵), 95.0 (C^1′), 87.2 (C^4′), 76.9 (C^2′), 71.9 (C^3′), 67.9 (OCH₂CH₃), 62.8 (C^5′), 15.1 (OCH₂CH₃); HRMS (ESI): m/z [M+Na]⁺ calcd for C₉H₁₅N₃NaO₅: 268.0909, found: 268.0915.

5.4.9. 1′-[5-Phenyl-[1,2,3]triazol-1-yl]ribofuranose (13a)

Prepared from compound 10a with the typical procedure described above to give 13a (>98%) as a white solid. Mp: 151 °C (MeOH); IR: 3332, 2930, 1486, 1454, 1243, 1058, 765, 699 cm⁻¹; UV (MeOH) λ_max: 242 nm; ${\left[\alpha \right]}_{\text{D}}^{20}$ −116.5 (c 0.83, MeOH); ¹H NMR (CD₃OD): δ 7.84 (s, 1H, H⁴), 7.64–7.60 (m, 2H, H^Ar), 7.58–7.52 (m, 3H, H^Ar), 5.81 (d, J=3.7 Hz, 1H, H^1′), 4.91 (dd, J=5.1, 3.7 Hz, 1H, H^2′), 4.51 (t, J=5.1 Hz, 1H, H^3′), 4.16–4.12 (m, 1H, H^4′), 3.80 (dd, J=12.1, 3.9 Hz, 1H, H^5′), 3.66 (dd, J=12.1, 5.8 Hz, 1H, H^5′); ¹³C NMR (CD₃OD): δ 141.2 (C⁵), 133.4 (C^Ar), 131.0 (C^Ar), 130.3 (2C, C^Ar), 127.4 (C⁴), 91.4 (C^1′), 87.3 (C^4′), 75.9 (C^2′), 72.6 (C^3′), 63.7 (C^5′); HRMS (ESI): m/z [M+H]⁺ calcd for C₁₃H₁₆N₃O₄: 278.1141, found: 278.1142.

5.4.10. 1′-[5–4-Fluoro-3-methylphenyl-[1,2,3]triazol-1-yl]ribofuranose (13b)

Prepared from compound 10b with the typical procedure described above to give 13b (>98%) as yellow crystals. Mp: 69 °C (MeOH); IR: 3332, 2929, 1493, 1243, 1124, 1059, 824 cm⁻¹; UV (MeOH) λ_max: 243 nm; ${\left[\alpha \right]}_{\text{D}}^{20}$ −91.3 (c 0.67, MeOH); ¹H NMR (CD₃OD): δ 7.86 (s, 1H, H⁴), 7.57–7.49 (m, 2H, H^Ar), 7.30–7.23 (t, J=9.0 Hz, 1H, H^Ar), 5.83 (d, J=3.7 Hz, 1H, H^1′), 4.95 (dd, J=4.9, 3.8 Hz, 1H, H^2′), 4.55 (t, J=5.2 Hz, 1H, H^3′), 4.22–4.17 (m, 1H, H4^′), 3.84 (dd, J=12.1, 3.8 Hz, 1H, H^5′), 3.70 (dd, J=12.1, 5.9 Hz, 1H, H^5′), 2.40 (d, J=1.8 Hz, 3H, CH₃); ¹³C NMR (CD₃OD): δ 164.8 (C^Ar), 162.4 (C^Ar), 140.4 (C⁵), 133.7 (2C, C^Ar), 133.5 (C^Ar), 129.9 (C^Ar), 129.8 (C^Ar), 127.4 (C⁴), 127.2 (C⁴), 123.4 (2C, C^Ar), 116.9 (C^Ar), 116.7 (C^Ar), 91.3 (C^1′), 87.4 (C^4′), 75.9 (C^2′), 72.6 (C^3′), 63.7 (C^5′), 14.4 (2C, CH₃); HRMS (ESI): m/z [M+H]⁺ calcd for C₁₄H₁₇FN₃O₄: 310.1203, found: 310.1216.

5.4.11. 1′-[5-Benzyl-[1,2,3]triazol-1-yl]ribofuranose (13c)

Prepared from compound 10c with the typical procedure described above to give 13c (>98%) as an yellow oil. IR: 3341, 2928, 2361, 1455, 1242, 1058, 720. UV (MeOH) λ_max: 214 nm; ${\left[\alpha \right]}_{\text{D}}^{20}$ −50.6 (c 0.51, MeOH); ¹H NMR (CD₃OD): δ 7.38 (s, 1H, H⁴), 7.36–7.31 (m, 2H, H^Ar), 7.29–7.21 (m, 3H, H^Ar), 5.88 (d, J=3.6 Hz, 1H, H^1′), 4.82 (dd, J=5.0, 3.6 Hz, 1H, H^2′), 4.42 (t, J=5.2 Hz, 1H, H^3′), 4.18 (d, J=2.7 Hz, 2H, CH₂Ph), 4.13–4.08 (m, 1H, H^4′), 3.74 (dd, J=12.1, 3.7 Hz, 1H, H^5′), 3.58 (dd, J=12.1, 5.6 Hz, 1H, H^5′); ¹³C NMR (CD₃OD): δ 139.8 (C⁵), 137.8 (C^Ar), 134.1 (C⁴), 129.9 (C^Ar), 129.7 (C^Ar), 128.2 (C^Ar), 91.5 (C^1′), 87.2 (C^4′), 75.7 (C^2′), 72.3 (C^3′), 63.6 (C^5′), 29.6 (CH₂Ph); HRMS (ESI): m/z [M+H]⁺ calcd for C₁₄H₁₈N₃O₄: 292.1297, found: 292.1298.

5.4.12. 1′-[5-Methylcyclopentyl-[1,2,3]triazol-1-yl]ribofuranose (13d)

Prepared from compound 10d with the typical procedure described above to give 13d (>98%) as an yellow oil. IR: 3315, 2946, 2867, 1449, 1241, 1050, 830 cm⁻¹; UV (MeOH) λ_max: 221 nm; ${\left[\alpha \right]}_{\text{D}}^{20}$ −62.1 (c 1.04, MeOH); ¹H NMR (CD₃OD): δ 7.55 (s, 1H, H⁴), 5.89 (d, J=4.0 Hz, 1H, H^1′), 4.83 (dd, J=5.0, 4.0 Hz, 1H, H^2′), 4.43 (t, J=5.0 Hz, 1H, H^3′), 4.14–4.10 (m, 1H, H^4′), 3.74 (dd, J=12.0, 3.9 Hz, 1H, H^5′), 3.60 (dd, J=12.0, 5.6 Hz, 1H, H^5′), 2.79 (d, J=7.5 Hz, 2H, CH₂–CHCH₂CH₂), 2.29–2.16 (m, 1H, CH₂–CHCH₂CH₂), 1.88–1.77 (m, 2H, CH₂–CHCH₂CH₂), 1.75–1.64 (m, 2H, CH₂–CHCH₂CH₂), 1.64–1.53 (m, 2H, CH₂–CHCH₂CH₂), 1.31–1.19 (m, 2H, CH₂–CHCH₂CH₂); ¹³C NMR (CD₃OD): δ 140.4 (C⁵), 133.3 (C⁴), 91.1 (C^1′), 87.4 (C^4′), 75.9 (C^2′), 72.5 (C^3′), 63.6 (C^5′), 40.3 (CH₂–CHCH₂CH₂), 33.5 (CH₂–CHCH₂CH₂), 29.7 (CH₂–CHCH₂CH₂), 26.0 (CH₂–CHCH₂CH₂); HRMS (ESI): m/z [M+H]⁺ calcd for C₁₃H₂₂N₃O₄: 284.1610, found: 284.1600.

5.4.13. 1′-[5-Butyl-[1,2,3]triazol-1-yl]ribofuranose (13e)

Prepared from compound 10e with the typical procedure described above to give 13e (>98%) as an yellow oil. IR: 3331, 2932, 2871, 1428, 1243, 1056, 832 cm⁻¹; UV (MeOH) λ_max: 221 nm; ${\left[\alpha \right]}_{\text{D}}^{20}$ −64.4 (c 0.70, MeOH); ¹H NMR (CD₃OD): δ 7.53 (s, 1H, H⁴), 5.88 (d, J=3.9 Hz, 1H, H^1′), 4.84 (dd, J=5.0, 3.9 Hz, 1H, H^2′), 4.33 (t, J=5.0 Hz, 1H, H^3′), 4.14–4.11 (m, 1H, H^4′), 3.74 (dd, J=12.1, 3.8 Hz, 1H, H^5′), 3.59 (dd, J=12.1, 5.6 Hz, 1H, H^5′), 2.79 (t, J=7.8 Hz, 2H, CH₂CH₂CH₂CH₃), 1.73–1.64 (m, 2H, CH₂CH₂CH₂CH₃), 1.48–1.39 (m, 2H, CH₂CH₂CH₂CH₃), 0.98 (t, J=7.4 Hz, 3H, CH₂CH₂CH₂CH₃); ¹³C NMR (CD₃OD): δ 140.9 (C⁵), 132.9 (C⁴), 91.1 (C^1′), 87.3 (C^4′), 75.8 (C^2′), 72.5 (C^3′), 63.7 (C^5′), 31.7 (CH₂CH₂CH₂CH₃), 23.3 (2C, CH₂CH₂CH₂CH₃ and CH₂CH₂CH₂CH₃), 14.0 (CH₂CH₂CH₂CH₃); HRMS (ESI): m/z [M+H]⁺ calcd for C₁₁H₂₀N₃O₄: 258.1454, found: 2258.1448.

5.4.14. 1′-[5-(3-Chloropropyl)-[1,2,3]triazol-1-yl]ribofuranose (13f)

Prepared from compound 10f with the typical procedure described above to give 13f (>98%) as an yellow oil. IR: 3315, 2927, 2360, 1717, 1446, 1276, 1242, 1058, 833 cm⁻¹; UV (MeOH) λ_max: 220 nm; ${\left[\alpha \right]}_{\text{D}}^{20}$ −50.5 (c 0.39, MeOH); ¹H NMR (CD₃OD): δ 7.59 (s, 1H, H⁴), 5.91 (d, J=3.9 Hz, 1H, H^1′), 4.88 (dd, J=5.0, 3.9 Hz, 1H, H^2′), 4.43 (t, J=5.0 Hz, 1H, H^3′), 4.15–4.10 (m, 1H, H^4′), 3.73 (dd, J=12.1, 3.8 Hz, 1H, H^5′), 3.67–3.60 (m, 2H, CH₂CH₂CH₂Cl), 3.58 (dd, J=12.1, 5.6 Hz, 1H, H^5′), 3.01–2.95 (t, J=7.6 Hz, 2H, CH₂CH₂CH₂Cl), 2.20–2.11 (m, 2H, CH₂CH₂CH₂Cl); ¹³C NMR (CD₃OD): δ 139.5 (C⁵), 133.2 (C⁴ ), 91.2 (C^1′), 87.3 (C^4′), 75.7 (C^2′), 72.4 (C^3′), 63.6 (C^5′), 44.6 (CH₂CH₂CH₂Cl), 32.4 (CH₂CH₂CH₂Cl), 21.0 (CH₂CH₂CH₂Cl); HRMS (ESI): m/z [M+H]⁺ calcd for C₁₀H₁₇ClN₃O₄: 278.0908, found: 278.0892.

5.4.15. 1′-[5-tert-Butyl-[1,2,3]triazol-1-yl]ribofuranose (13g)

Prepared from compound 10g with the typical procedure described above to give 13g (>98%) as an yellow oil. IR: 3346, 2969, 2360, 1371, 1057 cm⁻¹; UV (MeOH) λ_max: 221 nm; ${\left[\alpha \right]}_{\text{D}}^{20}$ −70.9 (c 1.21, MeOH); ¹H NMR (CD₃OD): δ 7.49 (s, 1H, H⁴), 6.20 (d, J=3.8 Hz, 1H, H^1′), 4.85 (dd, J=5.0, 3.8 Hz, 1H, H^2′), 4.47 (t, J=5.1 Hz, 1H, H^3′), 4.16–4.08 (m, 1H, H^4′), 3.76 (dd, J=12.0, 4.0 Hz, 1H, H^5′), 3.64 (dd, J=12.0, 5.7 Hz, 1H, H^5′), 1.44 (d, J=6.2 Hz, 9H, C(CH₃)3); ¹³C NMR (CD₃OD): δ 148.7 (C⁵), 131.5 (C⁴), 92.4 (C^1′), 87.4 (C^4′), 76.5 (C^2′), 72.6 (C^3′), 63.8 (C^5′), 31.4 (C(CH₃)₃), 30.5 (C(CH₃)₃); HRMS (ESI): m/z [M+H]⁺ calcd for C₁₁H₂₀N₃O₄: 258.1454, found: 258.1451.

5.4.16. 1′-[5-O-Ethoxy-[1,2,3]triazol-1-yl]ribofuranose (13h)

Prepared from compound 10h with the typical procedure described above to give 13h (>98%) as a white solid (MeOH). Mp: 149 °C; IR: 3357, 2936, 1579, 1458, 1325, 1056, 982 cm⁻¹; UV (MeOH) λ_max: 231 nm; ${\left[\alpha \right]}_{\text{D}}^{20}$ −56.2 (c 0.55, MeOH); ¹H NMR (CD₃OD): δ 7.24 (s, 1H, H⁴), 5.83 (d, J=3.9 Hz, 1H, H^1′), 4.68 (dd, J=5.0, 3.9 Hz, 1H, H^2′), 4.39 (t, J=5.0 Hz, 1H, H^3′), 4.25 (q, J=7.5 Hz, 2H, OCH₂CH₃), 4.10–4.05 (m, 1H, H^4′), 3.75 (dd, J=12.0, 3.9 Hz, 1H, H^5′), 3.62 (dd, J=12.0, 5.8 Hz, 1H, H^5′), 1.45 (t, J=7.5 Hz, 3H, OCH₂CH₃); ¹³C NMR (CD₃OD): δ 153.9 (C⁵), 114.8 (C⁴), 90.9 (C^1′), 86.9 (C^4′), 75.2 (C^2′), 72.3 (C^3′), 70.6 (OCH₂CH₃), 63.7 (C^5′), 14.8 (OCH₂CH₃); HRMS (ESI): m/z [M+Na]⁺ calcd for C₉H₁₅N₃NaO₅: 268.0909, found: 268.0909.