Appel-reagent-mediated transformation of glycosyl hemiacetal derivatives into thioglycosides and glycosyl thiols

Abstract

A series of glycosyl hemiacetal derivatives have been transformed into thioglycosides and glycosyl thiols in a one-pot two-step reaction sequence mediated by Appel reagent (carbon tetrabromide and triphenylphosphine). 1,2-trans-Thioglycosides and β-glycosyl thiol derivatives were stereoselectively formed by the reaction of the in situ generated glycosyl bromides with thiols and sodium carbonotrithioate. The reaction conditions are reasonably simple and yields were very good.

Introduction

Thioglycosides (1-thiosugar) are widely used glycosyl donors in glycosylation reactions [1–5]. Due to their thermal and chemical stability, they have been used as stable intermediates for functional-group transformations as well as stereoselective glycosylations. Thioglycosides can be transformed into various other glycosyl donors [6–10] (e.g., sulfoxide, sulfone, fluoride, bromide, hemiacetal, etc.) and hence the thio functionality is often used as a temporary anomeric protecting group. Thioglycosides can act as a glycosyl donor as well as glycosyl acceptor depending on the reaction conditions (orthogonal glycosylations) [11–12]. Due to their stability towards enzymatic hydrolysis, several thioglycosides have been evaluated as enzyme inhibitors [13–14]. As a consequence a large number of reports have appeared in the past for the preparation of thioglycosides. Conventionally, thioglycosides are prepared by the reaction of glycosyl acetates with thiols or trimethylsilylthiols in the presence of a Lewis acid (borontrifluoride diethyletherate, stannic chloride, trimethylsilyl trifluoromethanesulfonate, etc.) [15–20]. Other methods for the synthesis of thioglycosides include (a) reduction of disulfides using metallic salts [21–22] or nonmetallic reducing agents (triphenylphosphine or combination of triethylsilane and BF₃·OEt₂) followed by the reaction of the in situ generated thiolate ions with glycosyl bromides under phase-transfer conditions [23] or in ionic liquids [24]; (b) reaction of glycosyl bromides with thiols under phase-transfer conditions [25]; and (c) conversion of glycosyl acetates and bromides to isothiouronium salts followed by hydrolytic alkylation of isothiouronium salts with alkyl halide in the presence of a base [26–27]. Most of the reactions have several shortcomings, which include formation of an anomeric mixture of the products, instability of the starting materials (glycosyl bromides, etc.), multiple steps, unsatisfactory yields, use of metallic salts, use of expensive reagents, pregeneration of glycosyl isothiouronium salts, etc. Similar to thioglycosides, glycosyl thiol derivatives are useful intermediates for the synthesis of various thiooligosaccharides, glycoproteins and glycolipids [28–32]. The anomeric configurations of glycosyl thiols mostly remain unaffected in comparison to the glycosyl hemiacetal derivatives during their synthetic transformations [4]. Glycosyl thiol derivatives act as precursors for the preparation of several glycosyl donors such as thioglycosides [33–34], glycosyl sulfenamides [35] and sulfonamides [36], glycosyl disulfides [37], glycosyl thionolactones [38], etc. A number of reports are available for the preparation of glycosyl thiols, which include (a) a two-step reaction of glycosyl halide or acetate with thiourea or thioacetate and hydrolysis of the resulting intermediates [26–27]; (b) reaction of hydrogen sulfide gas with glycosyl halides in hydrogen fluoride [39]; (c) treatment of the glycosyl hemiacetal derivatives with Lawesson’s reagent [40] and (d) treatment of 1,6-anhydro sugar derivative [41] and glycosyl trichloroacetimidate derivatives [42] with bis(trimethylsilyl) sulfide. However, most of the reactions have several inherent shortcomings, such as the use of reactive starting materials, longer reaction time, multiple steps, unsatisfactory yield, formation an isomeric mixture, use of expensive reagents, use of hazardous gases, etc. Therefore, the development of convenient reaction conditions for the stereoselective preparation of thioglycosides and glycosyl thiols that are nonhazardous is pertinent. Recently, we reported the stereoselective preparation of β-glycosyl thiol derivatives by the treatment of glycosyl bromide derivatives with the in situ generated sodium carbonotrithioate (a combination of CS₂ and Na₂S·9H₂O) [43]. Although, the reaction is highly stereoselective and high yielding it involves the handling of unstable glycosyl bromide. Therefore, as an extension of the earlier report [43], it was envisioned that the treatment of a stable glycosyl hemiacetal derivative with Appel reagent (carbon tetrabromide (CBr₄) and triphenylphosphine (PPh₃)) [44] could generate the glycosyl bromide in situ, [45–46] which, on reaction with thiol or sodium carbonotrithioate (generated in situ from CS₂ and Na₂S·9H₂O) [43] in one-pot, could furnish thioglycosides and glycosyl thiol derivatives stereoselectively. We report herein, our findings on the Appel-reagent-mediated transformation of glycosyl hemiacetal derivatives to thioglycosides and glycosyl thiol derivatives (Scheme 1).

Scheme 1.

Appel-reagent-mediated transformation of glycosyl hemiacetal derivatives into thioglycosides and β-glycosyl thiol derivatives in one pot.

Results and Discussion

Initially, 2,3,4,6-tetra-O-acetyl-α,β-D-glucopyranose (1; 1.0 mmol) was treated with a mixture of CBr₄ (1.5 mmol) and PPh₃ (1.5 mmol) in CH₂Cl₂ (5 mL) at room temperature. The starting material was consumed in 6 h to give a faster-moving product (acetobromo-α-D-glucose). To the reaction mixture were added thiophenol (1.0 mmol), 10% aq Na₂CO₃ (5 mL) and tetrabutylammonium bromide (TBAB, catalytic) and the reaction mixture was stirred at room temperature for another 4 h. Aqueous work up of the biphasic reaction mixture furnished phenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside (10) in 80% yield. After a series of experimentation it was observed that the use of 2.0 equiv each of CBr₄ and PPh₃ led to the full consumption of compound 1 in 4 h, and addition of 1.5 equiv thiophenol and 10% aq Na₂CO₃ under phase-transfer reaction conditions led to the formation of compound 10 in 88% yield in an additional 4 h (Scheme 1). The reaction was carried out in a set of commonly used organic solvents (e.g., toluene, EtOAc, CH₃OH, CH₃CN, THF, DMF, DMSO, etc.) and it was observed that the reaction proceeds smoothly in CH₂Cl₂ and DMF in a similar fashion to the first step. Since CH₂Cl₂ is a low-boiling-point solvent and can be used directly in the next step, this solvent was chosen in the first step of the reaction (Table 1). Increasing the quantity of the reagents (CBr₄ and PPh₃) did not change the reaction time and yield significantly. However, reducing the quantity of reagents led to a low yield of conversion in a longer reaction time (Table 2). Under the optimized reaction conditions a series of 1,2-trans-thioglycosides were prepared from various glycosyl hemiacetals in excellent yield (Table 3). A large-scale (5 g) preparation of compound 10 was also achieved under the reaction conditions in similar yield.

Table 1.

Screening of solvents for the in situ conversion of glycosyl hemiacetal to glycosyl bromide.

Entry	Solvent	Time (h)	Conversion (%)
1	CH2Cl2	4	90
2	CH3CN	10	40a
3	THF	10	40a
4	DMF	4	85
5	EtOAc	12	20a
6	Toluene	12	10a
7	DMSO	5	80
8	CH3OH	4	–b

^aThe rest of the starting material remained unreacted; ^bthe starting material was degraded.

Table 2.

Optimization of the in situ conversion of glycosyl hemiacetal to glycosyl bromide.

Entry	CBr4 (equiv)	PPh3 (equiv)	Time (h)	Conversion (%)
1	2.5	2.5	3.5	90
2	2.0	2.0	4	90
3	1.5	1.5	6	75a
4	1.0	1.0	7	50a

^aThe rest of the starting material remained unreacted.

Table 3.

Appel-reagent-mediated transformation of glycosyl hemiacetal derivatives to the thioglycosides at room temperature.

Entry	Glycosyl hemiacetal	Thioglycoside	Time (h)a	Yield (%)	Ref
1	1	10	4	88	[49]
2	1	11	4	90	[50]
3	1	12	4	86	[51]
4	1	13	8	82	[52]
5	1	14	6	80	[23]
6	2	15	4	90	[53]
7	2	16	4	88	[51]
8	2	17	8	84	–
9	2	18	8	77	[54]
10	2	19	6	80	[23]
11	3	20	8	76	–
12	3	21	4	88	[53]
13	4	22	4	90	[55]
14	4	23	8	88	–
15	5	24	4	92	[56]
16	6	25	6	85	[57]
17	7	26	4	88	[25]
18	7	27	4	85	[50]
19	8	28	4	88	[25]
20	9	29	4	85	[25]

^aTime for the second steps after the formation of glycosyl bromides in situ.

In another experiment, compound 1 (1.0 mmol) was treated with a mixture of CBr₄ (2.0 mmol) and PPh₃ (2.0 mmol) in CH₂Cl₂ (5 mL) at room temperature for 4 h. Addition of a red-colored solution of CS₂ (2.0 mmol) and Na₂S·9H₂O (2.0 mmol) (sodium carbonotrithioate) in DMF (2 mL, prepared separately) to the reaction mixture furnished 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose (30) in 90% yield instantly. After optimization of the reaction condition it was observed that the best yield of compound 30 can be achieved by using CS₂ (1.5 mmol) and Na₂S·9H₂O (2.0 mmol) at room temperature. On reduction of the quantity of CS₂ and Na₂S·9H₂O, the rate of the reaction became very slow and a considerable amount of undesired byproducts were formed. The optimized reaction conditions were applied for the preparation of a series of glycosyl thiols in excellent yield in a stereoselective manner (Table 4). The reaction conditions have several notable features, which include (a) excellent yield; (b) exceptionally high stereoselectivity; (c) one-pot two-step reaction conditions; (d) applicability for scaled-up synthesis. It is worth mentioning that 1,2-trans-thioglycosides and exclusively β-glycosyl thiols were formed under these conditions. The reaction conditions have been applied successfully for the preparation of thioglycosides and glycosyl thiols from D- and L-sugars as well as disaccharides. The stereochemistry of the anomeric centers of the thioglycosides and glycosyl thiols were confirmed from their NMR spectral analysis (coupling constant of the H-1 (J_1,2)). Appearance of the coupling constant of the H-1 (J_1,2) = 8–10 Hz and coupling constant of the SH group (J_H-1,SH) = 9–10 Hz in the ¹H NMR spectra of the glycosyl thiols confirmed the exclusive formation of β-glycosyl thiols. In the case of D-mannose and L-rhamnose, exclusive formation of β-products were unambiguously confirmed from the coupling constant at the anomeric center (J_C-1,H-1) in the gated ¹H coupled ¹³C NMR spectra. Coupling constant (J_C-1,H-1) = 143 Hz and 142 Hz (less than 160 Hz) in the gated ¹H coupled ¹³C NMR spectra of compounds 32 and 33 confirmed the exclusive formation of β-products [47–48]. It is presumed that the reaction of the glycosyl hemiacetal derivative with the combination of CBr₄ and PPh₃ furnished α-glycosyl bromide in the first step. Interconversion of the α-glycosyl bromide to the reactive β-glycosyl bromide in the presence of a catalytic bromide ion derived from TBAB, led to the formation of a 1,2-oxocarbonium ion by participation of the neighboring group, which finally furnished 1,2-trans-thioglycoside by the reaction of thiols under reasonably slow biphasic reaction conditions. The thioglycoside formation became very slow without the addition of TBAB and the same product was obtained in a poor yield over a much longer period of time. In contrast, rapid S_N2-substitution of the bromide ion at the anomeric center in α-glycosyl bromide with a carbonotrithioate ion (derived from the reaction of CS₂ and Na₂S·9H₂O) in homogeneous solution led to the exclusive formation of the β-glycosyl thiol derivative (Scheme 2).

Table 4.

Appel-reagent-mediated transformation of glycosyl hemiacetal derivatives to glycosyl thiol derivatives at room temperature.

Entry	Glycosyl hemiacetal	Glycosyl thiol	Timea (min)	Yield (%)	Ref
1	1	30	5	90	[41]
2	2	31	5	92	[58]
3	3	32	5	85	[59]
4	4	33	5	90	[60]
5	5	34	5	88	[41]
6	7	35	15	86	[61]
7	8	36	15	85	[62]

^aTime for the second steps after formation of glycosyl bromides in situ.

Scheme 2.

Plausible mechanistic pathways for the formation of 1,2-trans-thioglycoside and β-glycosyl thiol.

Conclusion

In summary, treatment of glycosyl hemiacetal derivatives with Appel reagent followed by reaction with thiols and sodium carbonotrithioate (derived from the reaction of CS₂ and Na₂S·9H₂O) furnished thioglycosides and glycosyl thiols in excellent yield with high stereoselectivity in a two-step, one-pot reaction condition. The reaction condition is operationally simple, mild, reproducible, high-yielding, highly stereoselective, and can be scaled up for large-scale preparation. These reaction conditions may be considered as a valuable addition to those existing in this area.

Experimental

General methods: All reactions were monitored by thin-layer chromatography over silica-gel-coated TLC plates. The spots on TLC were visualized by warming ceric sulfate (2% Ce(SO₄)₂ in 2 N H₂SO₄) sprayed plates on a hot plate. Silica gel 230–400 mesh was used for column chromatography. ¹H and ¹³C NMR spectra were recorded on Bruker Avance 500 MHz by using CDCl₃ as solvent and TMS as internal standard, unless stated otherwise. Chemical shift values are expressed as δ in parts per million. ESIMS were recorded on a Micromass mass spectrometer. Commercially available grades of organic solvents of adequate purity were used in all reactions.

General experimental conditions for the preparation of thioglycosides

To a solution of glycosyl hemiacetal (1.0 mmol) in dry CH₂Cl₂ (5 mL) were added CBr₄ (2.0 mmol) and PPh₃ (2.0 mmol) and the reaction mixture was stirred at room temperature for 4 h. After consumption of the starting material (TLC, hexane–EtOAc 2:1), thiophenol (1.5 mmol), 10% aq. Na₂CO₃ (5 mL) and TBAB (20 mg) were added to the reaction mixture, and it was stirred for the appropriate time mentioned in Table 3. The reaction mixture was diluted with water and extracted with CH₂Cl₂ (50mL). The organic layer was washed with water, dried (Na₂SO₄) and concentrated to give the crude product, which was purified over SiO₂ by using hexane–EtOAc as eluant to give the pure product. Known compounds gave spectral data identical to the data reported in the cited references.

1-Phenyl-1H-tetrazol-5-yl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranoside (17): Yellow oil; [α]_D²⁵ +15 (c 1.2, CHCl₃); IR (neat): 3114, 2842, 1612, 1522, 1467, 912, 699 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.58–7.52 (m, 5H, Ar-H), 5.80 (d, J = 10.0 Hz, 1H, H-1), 5.46 (d, J = 3.0 Hz, 1H, H-4), 5.34 (t, J = 10.0 Hz each, 1H, H-2), 5.17 (dd, J = 10.0, 3.5 Hz, 1H, H-3), 4.12–4.10 (m, 2H, H-5, H-6_a), 4.08–4.06 (m, 1H, H-6_b), 2.15, 2.05, 2.01, 1.99 (4 s, 12H, 4 COCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 170.1, 169.9, 169.6, 169.5 (4 COCH₃), 133.3–124.1 (Ar-C), 84.2 (C-1), 75.2 (C-3), 71.6 (C-4), 67.1 (C-5), 67.0 (C-2), 60.9 (C-6), 20.7, 20.6, 20.5, 20.4 (4 COCH₃); ESIMS (m/z): 531.1 [M + Na]⁺; Anal. calcd for C₂₁H₂₄N₄O₉S (508.12): C, 49.60; H, 4.76; found: C, 49.45; H, 4.94.

1-Phenyl-1H-tetrazol-5-yl 2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranoside (20): Yellow oil; [α]_D²⁵ −2 (c 1.2, CHCl₃); IR (neat): 3104, 2838, 1610, 1520, 1472, 916, 697 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.61–7.50 (m, 5H, Ar-H), 6.12 (br s, 1H, H-1), 5.68 (d, J = 2.5 Hz, 1H, H-2), 5.27 (t, J = 10.0 Hz each, 1H, H-4), 5.19 (dd, J = 10.0, 3.0 Hz, 1H, H-3), 4.31 (dd, J = 12.5, 5.5 Hz, 1H, H-6_a), 4.13 (d, J = 12.5 Hz, 1H, H-6_b), 3.91–3.88 (m, 1H, H-5), 2.19, 2.07, 2.05, 1.99 (4 s, 12H, 4 COCH₃); ¹³C NMR (125 MHz, CDCl₃) δ 170.1, 170.0, 169.7, 169.6 (4 COCH₃), 130.5–124.1 (Ar-C), 82.6 (C-1), 77.2 (C-3), 71.5 (C-4), 70.1 (C-5), 65.0 (C-2), 62.0 (C-6), 20.7, 20.6, 20.5, 20.4 (4 COCH₃); ESIMS (m/z): 531.1 [M + Na]⁺; Anal. calcd for C₂₁H₂₄N₄O₉S (508.12): C, 49.60; H, 4.76; found: C, 49.42; H, 4.97.

1-Phenyl-1H-tetrazol-5-yl 2,3,4-tri-O-acetyl-1-thio-α-L-rhamnopyranoside (23): Yellow oil; [α]_D²⁵ +19 (c 1.2, CHCl₃); IR (neat): 3106, 2836, 1600, 1502, 1457, 916, 699 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.59–7.50 (m, 5H, Ar-H), 6.10 (d, J = 1.0 Hz, 1H, H-1), 5.66 (d, J = 3.5, 1.0 Hz, 1H, H-2), 5.13 (dd, J = 10.0, 3.0 Hz, 1H, H-3), 5.06 (t, J = 9.5 Hz each, 1H, H-4), 3.80–3.75 (m, 1H, H-5), 2.18, 2.07, 1.97 (3 s, 9H, 3 COCH₃), 1.28 (d, J = 6.0 Hz, 3H, CH₃); ¹³C NMR (125 MHz, CDCl₃) δ 170.1, 170.0, 169.9 (3 COCH₃), 130.4–124.1 (Ar-C), 82.4 (C-1), 75.6 (C-5), 71.4 (C-3), 70.5 (C-4), 69.8 (C-2), 20.7, 20.6, 20.5 (3 COCH₃), 17.6 (CH₃); ESIMS (m/z): 473.1 [M + Na]⁺; Anal. calcd for C₁₉H₂₂N₄O₇S (450.12): C, 50.66; H, 4.92; found: C, 50.47; H, 5.15.

General experimental condition for the preparation of glycosyl thiol derivatives

To a solution of glycosyl hemiacetal (1.0 mmol) in dry CH₂Cl₂ (5 mL) were added CBr₄ (2.0 mmol) and PPh₃ (2.0 mmol), and the reaction mixture was stirred for 4 h at room temperature. After completion of the reaction (TLC; hexane–EtOAc 2:1), a red premixed solution of CS₂ (1.5 mmol) and Na₂S·9H₂O (2.0 mmol) in DMF (2 mL) was added to the reaction mixture and it was stirred for the appropriate time mentioned in Table 4. The reaction mixture was diluted with water and extracted with CH₂Cl₂ (50 mL). The organic layer was washed with water, dried (Na₂SO₄) and concentrated to give the crude product, which was purified over SiO₂ by using hexane–EtOAc as eluant to give the pure product. Known compounds gave spectral data identical to the data reported in the cited references.

Supporting Information

File 1

Analytical data of compounds 10–16, 18, 19, 21, 22, 24-36 and ¹H NMR, ¹³C NMR spectra of compounds 17, 20, and 23.