Efficient one-pot per-O-acetylation–thioglycosidation of native sugars, 4,6-O-arylidenation and one-pot 4,6-O-benzylidenation–acetylation of S-/O-glycosides catalyzed by Mg(OTf)₂

Abstract

A sequential one-pot per-O-acetylation–S-/O-glycosidation of native mono and disaccharides under solvent free conditions using 0.5 mole% of Mg(OTf)₂ as a non-hygroscopic, recyclable catalyst is reported. Regioselective 4,6-O-arylidenation of glycosides and thioglycosides with benzaldehyde or p-methoxybenzaldehyde dimethyl acetal is catalyzed by 10 mole% of Mg(OTf)₂ to produce the corresponding 4,6-O-arylidenated product in high yields. Mg(OTf)₂ can also mediate sequential one-pot benzylidenation–acetylation of mono and disaccharide based glycosides and thioglycosides in high yield.

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Introduction

The central principle of atom economy and green chemistry is the design of synthetic strategies that minimise waste by using stoichiometric reagents and catalytic promoters.^1a–d Advancement of synthetic carbohydrate chemistry demands extensive functional group transformation by means of suitable protection and deprotection of hydroxy groups.^1e In this context, per-O-acetylation of native sugars is the most commonly utilised functional group transformation as these readily made per-O-acetylated sugars can be easily activated by Lewis acids and transformed towards other glycosyl donors like glycosyl halides or thioglycosides.² The classical method for carrying out per-O-acetylation is via excess reagent like acetic anhydride or acetyl chloride in large excess of pyridine as base as well as solvent in spite of its well documented toxicity.³ The poor nucleophilicity of hydroxy groups in carbohydrates sometimes necessitates addition of pyridine derivatives like 4-dimethylaminopyridine (DMAP) or 4-pyrrolidino pyridine as co catalyst to activate the acetylating agents or accelerate the reaction.⁴ So far many reports have been made in this direction utilising acid or bases which include (i) bases like NaOAc,^5a NaOH/TBAB,^5b imidazole^5c and DABCO;^5d (ii) Lewis acids such as ZnCl₂,^6a FeCl₃,^6b BF₃·Et₂O,^6c Cu(OTf)₂,^6d Sc(OTf)₃,^6e In(OTf)₃,^6f Ce(OTf)₃,^6g SnCl₄,^6h LiClO₄ ⁶ⁱ and Fe₂(SO₄)₃;^6j (iii) protic acids such as H₂SO₄,^7a H₃BO₃/H₂SO₄ ^7b and p-TSA;^7c (iv) heterogeneous catalysts like montmorillonite K-10,^8a H-β-zeolite,^8b H₂SO₄–SiO₂,^8c HClO₄–SiO₂,^8d molecular sieves,^8e Al₂O₃,^8f sulphonic acid functionalised γ-Al₂O₃ ^8g and sulfamic acid.^8h Beside these few other catalysts like I₂,^9a,b N-bromosuccinimide,^9c Cu(ClO₄)₂·6H₂O^9d and even ionic liquids^9e and microwave condition^9f were also used. A few among the above catalysts such as Cu(OTf)₂,^6d SnCl₄,^6h p-TSA,^7c I₂,^9a,b and Cu(ClO₄)₂·6H₂O^9d have been employed previously in conjugation with BF₃·Et₂O for the one-pot sequential per-O-acetylation–thioglycosidation reaction. In spite of their effectiveness on many instances these catalysts even suffer from many flaws like use of large excess of acetic anhydride, environmentally hazardous volatile organic solvents (VOSs), expensive catalysts, moisture intolerance, requirement of catalyst preparation or incompatibility with carbohydrate derivatives carrying acid sensitive protecting group. In some instances, isomerized product mixture of furanose and pyranose are obtained during acetylation of native sugars.^6j,8i Therefore, there is strong need to search an effective catalyst that is mild, non-toxic, and economically viable yet allows just stoichiometric amount of the reagent and avoids use of toxic VOSs. Moreover that can be employed for undertaking more than one steps in one-pot in order to develop more efficient and expeditious transformations.

After smooth preparation of S- and/or O-glycosides, 4,6-O-benzylidene protection is of immense importance in the synthesis of complex carbohydrates^2g,h as these can be selectively transformed to the corresponding 6-deoxy sugars under oxidative condition.^10a–d These benzylidene acetals can either be selectively transformed under reductive conditions^11a–c to their corresponding 4-O-benzylated or 6-O-benzylated analogue leaving the alternate hydroxy group free to be used further as glycosyl acceptor during oligosaccharide synthesis or to produce the corresponding 4,6-diol.^11d–f In earlier days when benzaldehyde was employed as electrophile for 4,6-O-benzylidene protection, most of such transformations were catalysed by ZnCl₂,^12a H₂SO₄ ^12b or TsOH^12c and later when benzaldehyde dimethylacetal was proved to be a better reagent, transacetalations were carried out with Lewis acids [VO(OTf)₂]^13a or Brønsted acids like HBF₄,^13b CSA^13c,d and TfOH^13e including silica supported reagents (NaHSO₄–SiO₂,^14a H₂SO₄–SiO₂ ^14b and HClO₄–SiO₂ ^14c) or other reagents like I₂ ^15a–c or 2,4,6 trichloro-1,3,5-triazine.^15d However some of these catalysts suffer from limitations too like those having short shelf life, or often being corrosive and expensive or tough to handle due to moisture sensitivity.

In continuation of our research on complex oligosaccharide synthesis¹⁶ we needed to prepare a number of S- and O-glycosides and 4,6-O-benzylidenated carbohydrate derivatives and we sought to modify even our own developed method based on FeCl₃ ^16g with a more efficient, non-hygroscopic and recyclable one. Recently Mg(OTf)₂ has been used as highly stable, non-hygroscopic and recyclable catalyst^17a for many organic transformations like silylation of α-hydroxyphosphonates,^17b tetrahydroquinoline synthesis,^17c and 1,3-dipolar cycloaddition reaction.^17d For time and cost effectiveness and also due to environmental reasons minimisation of overall isolated steps during a total target synthesis is advisable. Sometimes this is managed by undertaking two or more reactions sequentially in one-pot. In this context we report herein Mg(OTf)₂ as an inexpensive, recyclable, eco-friendly and multi-functional potent catalyst for the extensive functional group manipulations of carbohydrate derivatives: For one-pot per-O-acetylation–S-/O-glycosidation of native sugars, for 4,6-O-arylidenation and also for one-pot 4,6-O-benzylidenation–acetylation of mono and disaccharide derivatives.

Result and discussion

For optimisation of reaction condition for one-pot acetylation–S-/O-glycosidation, D-glucose 1a was initially allowed to react with a varied quantity of acetic anhydride (1.5 to 1.0 equivalent per hydroxy group) in the presence of catalytic amount of Mg(OTf)₂ (0.1 to 0.001 equivalent) at room temperature under neat condition for acetylation step; and this was followed by in situ addition of 1.1 equivalent of thiophenol and 1.2 equivalent of BF₃·Et₂O at 0 °C for thiophenylation step. An exothermic reaction started immediately and a clear reaction mixture was obtained within few minutes resulting in a complete consumption of the starting material (checked by TLC). Proceeding through a number of such experiments 1.0 equivalent acetic anhydride per hydroxy group with 0.5 mol% (0.005 equivalent) of the catalyst at room temperature was found to be most effective for the per O-acetylation reaction in terms of time of per O-acetylation step (Table 1); then to this reaction mixture thiophenol followed by lowering of the temperature to 0 °C, BF₃. Et₂O was added and the reaction mixture was kept for 8 hours at room temperature to produce phenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyanoside 1b. The resulting thioglycoside was obtained as a single β anomer, due to neighbouring group participation by C-2 acetate.

Table 1 Optimisation of reaction condition of one-pot acetylation–thioglycosidation

Entry	Catalyst (mol%)	Ac2O equiv.	Time^a (min)	Yield^b (%)
a Time corresponds to acetylation step.b Isolated yield over two steps.
1	10	1.5 per OH	1 to 2	90
2	5	1.2 per OH	1 to 2	92
3	1	1.1 per OH	1 to 2	92
4	0.5	1.0 per OH	3	95
5	0.1	1.1 per OH	15	93
6	0.05	1.1 per OH	45	90

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In order to extend the scope of this reaction a series of native mono and disaccharides were subjected to per-O-acetylation followed by one pot S-/O-glycosidation, and the results are summarised in Table 2 and Scheme 1. Per O-acetylation of glucose 1a under this condition was completed at room temperature within 3 minutes (checked by TLC) and then sequential one-pot thioglycosidation separately with thiophenol, ethanethiol and thiocresol produced the corresponding thioglycosides 1b, 1c and 1d in 95%, 89% and 87% respective yields (entries 1, 2 and 3, Table 2). Scale up reaction using 5 g 1a produced 91% of phenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyanoside 1b; the yield is comparable with that of the pilot reaction (entry 1, Table 2). Similar sequential one-pot O-glycosidation using 4-methoxyphenol afforded the corresponding O-glycoside 1e in 85% yield (entry 4, Table 2).

Table 2 Sequential one-pot acetylation–S-or-O-glycosidation of native sugars

Entry	Product	Time^a (min)	Temperature^a	Yield^b (%)	Entry	Product	Time^a (min)	Temperature^a	Yield^b (%)
a Time and temperature corresponds to per-O-acetylation step.b Isolated yields over two steps.c Reaction was carried out in 5 g scale.d Reaction was carried out in 2 g scale.
1	1b	3	rt	95, 91^c	11	5b	3	Rt	84, 80^c
2	1c	3	rt	89	12	5c	3	rt	87
3	1d	3	rt	87	13	6b	3	rt	86
4	1e	3	rt	85	14	7b	15	80 °C	78
5	2b	3	rt	94, 89^c	15	7c	15	80 °C	73
6	2c	3	rt	84	16	8b	5	80 °C	77
7	2d	3	rt	86	17	9b	5	80 °C	85, 83^c
8	3b	3	rt	93, 87^c	18	10b	5	80 °C	91, 87^d
9	3c	3	rt	91	19	10c	5	80 °C	83
10	4b	3	rt	86

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Reaction sequence akin to the previous one with D-galactose 2a produced the corresponding S- and O-glycosides 2b, 2c and 2d in 94%, 84% and 86% yield, respectively (entries 5, 6 and 7, Table 2). The preparative scale reaction with 5 g of 2a produced phenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyanoside 2b in 89% yield (entry 5, Table 2). Per O-acetylation of D-mannose 3a underwent smoothly at room temperature within 3 minutes (checked by TLC) and then its sequential one-pot thioglycosidation separately using thiophenol and ethanethiol generated the corresponding α-thioglycosides in 93% and 91% yields, respectively (entries 8 and 9, Table 2). Phenyl 2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyanoside 3b was prepared in 87% yield starting from 5 g of D-mannose (entry 8, Table 2).

After successful per-O-acetylation followed by in situ stereoselective S-aryl/alkyl or O-aryl glycoside preparation of native hexoses we turned our attention to similar reactions of commonly used pentose sugars. Reaction of D-xylose 4a with 3 equivalent of Ac₂O, 0.5 mole% Mg(OTf)₂ followed by in situ addition of thiophenol and BF₃·Et₂O produced the corresponding phenyl 2,3,4-tri-O-acetyl-1-thio-β-D-xylopyranoside 4b in 86% yield (entry 10, Table 2). L-Rhamnose 5a after robust per-O-acetylation, in reaction separately with thiophenol and 4-methoxyphenol produced the corresponding S- and O-glycosides 5b and 5c in 84% and 87% respective yields (entries 11 and 12, Table 2). The efficiency of this protocol was supported by preparative scale reaction with 5 g of 5a which produced phenyl 2,3,4-tri-O-acetyl-1-thio-α-L-rhamnopyanoside 5b in 80% yield, comparable with the pilot reaction (entry 11, Table 2). p-Tolyl 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranoside 6b was prepared from L-fucose 6a via sequential one-pot per-O-acetylation–thioglycosidation in 86% overall yield (entry 13, Table 2). The reaction with 2-deoxy-2-phthalimido-D-glucose 7a was carried out at 80 °C for 15 minutes, and then sequential in situ thioglycosidation separately with thiophenol and thiocresol produced the corresponding β-D-thioglycosides 7b and 7c in 78% and 73% respective yields (entries 14 and 15, Table 2).

Scheme 1 Per-O-acetylation and their one-pot conversion to S-aryl/alkyl or O-aryl glycoside of native sugars.

This per O-acetylation followed by in situ S- or O-glycoside preparation was also successful for the disaccharides like cellobiose 8a, lactose 9a and maltose 10a. The per-O-acetylation for these native disaccharides were performed at 80 °C for 5 minutes and after full consumption of free sugar (checked by TLC); sequential one-pot thioglycosidation then produced the corresponding phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl-(1 → 4)-2,3,6-tri-O-acetyl-1-thio-β-D-glucopyranoside 8b in 77% yield (entry 16, Table 2). Similarly lactose produced the corresponding phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl-(1 → 4)-2,3,6-tri-O-acetyl-1-thio-β-D-galactopyranoside 9b in 85% overall yield, and its preparative scale reaction based on 2 g of 9a produced 9b in 83% overall yield (entry 17, Table 2). In case of maltose the corresponding S-/O-glycosides 10b and 10c were obtained in 91% and 83% overall yields, respectively (entries 18 and 19, Table 2). Preparative scale reaction with 2 g of native maltose produced phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl-(1 → 4)-2,3,6-tri-O-acetyl-1-thio-α-D-glucopyranoside 10b in 87% overall yield (entry 18, Table 2). All these products were characterized by melting point (mp) and spectral analysis; the data corresponded well with the literature values.

After completion of sequential one-pot per-O-acetylation–thioglycosidation the reaction mixture was poured into water. The aqueous phase was evaporated under reduced pressure and the Mg(II) salt was recovered as a white solid and reused after drying overnight over P₂O₅. This recycle protocol was repeated five times, and the percentage of the catalyst recovery was always more than 90% while the yields of the phenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside 2b and phenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranoside 3b were always more than 93% and 90%, respectively (Fig. 1).

Fig. 1 Recyclability of catalyst.

After efficient sequential one-pot per-O-acetylation–S-/O-glycosidation of native mono and disaccharides we turned our attention towards employment of Mg(OTf)₂ for preparation of 4,6-O-arylidinated carbohydrate derivatives. At the outset, phenyl 1-thio-β-D-glucopyranoside 11a was chosen as the substrate for optimization of reaction condition. 11a was treated with benzaldehyde dimethylacetal in the presence of Mg(OTf)₂ using CH₃CN as solvent (Table 3). After several trial experiments optimum reaction condition was established as 11a (1.0 equivalent) and benzaldehyde dimethylacetal (1.1 equivalent) in the presence of Mg(OTf)₂ (10 mol%) in dry CH₃CN at ambient temperature, which produced the corresponding 4,6-O-benzylidene acetal 11b in 87% yield. The reaction retains its productivity even after scale up based on 2 g of substrate (entry 1, Table 3) (Scheme 2).

Table 3 4,6-O-Arylidination of monosaccharides

Entry	Product	Time (h)	Yield^a (%)	Entry	Product	Time (h)	Yield^a (%)
a Isolated yields.b Reaction was carried out in 2 g scale.
1	11b	3	87, 82^b	11	20b	2.5	82
2	12b	3	80, 77^b	12	21b	3	85, 81^b
3	13b	3	82, 79^b	13	22b	2	87
4	11c	3	78	14	23b	3	88, 82^b
5	14b	3	82	15	24b	3	84, 80^b
6	15b	2.5	81	16	25b	2.5	84, 82^b
7	16b	3	83	17	26b	3.5	77
8	17b	3	83	18	27b	3.5	76
9	18b	3	85	19	28b	3	68
10	19b	2	88

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Scheme 2 4,6-O-Arylidenation of monosaccharides.

Under similar reaction condition, other phenyl thioglycosides of 2-NPhth-β-D-Glc, β-D-Gal and α-D-Man furnished the corresponding 4,6-O-benzylidene derivatives (20b, 23b, 25b and 28b) in 82%, 88% (for scale up 82%), 84% (for scale up 82%) and 68% respective yields (entries 11, 14, 16 and 19 respectively, Table 3). Efficient 4,6-O-benzylidenation was also possible for p-tolyl 1-thio-β-D-glycopyranosides 12a and 24a which produced 12b and 24b (entries 2 and 15, Table 3) and for ethyl 1-thio-β-D-glucopyranoside 13a that afforded 13b (entry 3, Table 3), in high yields. The efficacy of the present process was further established under scale-up condition for the preparation of 12b, 13b and 24b using 2 g starting material (77%, 79% and 80% yields, respectively; entries 2, 3 and 15, Table 3).

Among other substrates while methyl α-D-glucopyranoside derivatives 17a and 18a generated the corresponding 4,6-O-benzylidene glucopyranosides (17b and 18b) in 83% and 85% respective yields (entries 8 and 9, Table 3), p-methoxyphenyl, p-bromophenyl and 2-napthyl β-D-glucopyranosides furnished the corresponding desired products (14b, 15b and 16b) in high yields (82%, 81% and 83%, respectively, entries 5, 6 and 7, Table 3). Similarly preparation of 4,6-O-benzylidene of allyl, p-methoxyphenyl and 3-(N-benzyloxycarbonyl)propyl 2-deoxy-2-phthalimido glucosides was also found to be very efficient, and the desired derivatives 19b, 21b and 22b were obtained in 88%, 85% (81% for scale-up condition) and 87% respective yields (entries 10, 12 and 13, Table 3). Under similar condition p-methoxyphenyl and o-allylphenyl β-D-galactopyranosides 26a and 27a were converted to their corresponding 4,6-O-benzylidene products 26b and 27b in high yields (77% and 76%, respectively, entries 16 and 17, Table 3). The present arylidenation protocol was further applied for the synthesis of phenyl 4,6-O-(4-methoxybenzylidene)-1-thio-β-D-glucopyranoside 11c in 78% yield (entry 4, Table 3) using p-methoxybenzaldehyde dimethylacetal as the electrophile.

For further elaboration of the efficacy of Mg(OTf)₂ towards synthesis of some glycosyl acceptors and thioglycoside donors we set out for an one-pot benzylidenation-acetylation of some S-/O-glycosides based on mono and disaccharides. Using Mg(OTf)₂, preparation of 4,6-O-benzylidene acetal followed by one-pot acetylation of 2- and 3- hydroxy group of p-tolyl 1-thio-β-D-glucopyranoside 12a produced p-tolyl 2,3-di-O-acetyl-4,6-O-benzylidene-1-thio-β-D-glucopyranoside 29 in 77% overall yield at ambient temperature (entry 1, Table 4). 4,6-O-Benzylidenation followed by one pot acetylation of β-D-glucopranoside 40 produced methyl 2,3-di-O-acetyl-4,6-O-benzylidene-β-D-glucopranoside 41 in 77% overall yield (entry 7, Table 4).

Table 4 Benzylidenation acetylation of carbohydrates

Entry	Starting material	Product	Time (x + y) (h)	Yield^a (%)
a Isolated yield over two steps.
1			0.5 + 0.5	77%
2			(3.0 + 0.5)	73%
2			(2.0 + 0.5)	84%
4			(2.5 + 0.5)	78%
5			(3.0 + 0.5)	79%
6			(0.25 + 0.5)	79%
7			(0.5 + 0.5)	77%

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Lactose, maltose and cellobiose are common disaccharide units of many biologically important polysaccharides and glycoconjugates in which chain elongation of these units occur via their C-4′ or C-6′ hydroxy group.¹⁸ With this end in view S-and O-glycosides of cellobiose, lactose and maltose were next 4′,6′-O-benzylidenated followed by acetylation in one-pot reaction. High combined yields (over two steps) of the final products (31, 33, 35, 37 and 39 in 73%, 84%, 78%, 79%, and 79% respective yields, entries 2 to 6, Table 4) indicate that the yields of the individual steps are quite high.

Conclusions

In summary, we have demonstrated Mg(OTf)₂ as a mild, non-hygroscopic, recyclable and inexpensive bench-top catalyst for robust and convenient one-pot per-O-acetylation–S-/O-glycosidation of native mono and disaccharides. The catalyst retains its efficacy even after several cycles of reactions. Similarly the Mg(OTf)₂ catalyzed selective 4,6-O-arylidenation of monosaccharides and disaccharides was high yielding. These reactions are equally applicable under scale-up condition also. Moreover Mg(OTf)₂ is also able to mediate one-pot 4,6-O-benzylidenation-acetylation of various mono and disaccharide based S-/O-glycosides in high yields. Unlike many of the reported procedures glycosides or thioglycosides are not anomerized.

Experimental

Column chromatography was performed employing silica gel 60–120 (60–120 mesh). Thin-layer chromatography (analytical and preparative) was performed using Merck silica gel plates (60-F254) to monitor the reactions and visualized under UV (254 nm) and/or by charring with 5% ethanolic solution of sulfuric acid. ¹H and ¹³C NMR spectra were recorded on a Bruker DPX-300 (300 MHz), a Bruker DPX-400 (400 MHz), a Bruker DPX-500 (500 MHz). Optical rotations were measured using Jasco P-1020 digital polarimeter.

General experimental procedure for sequential one-pot per-O-acetylation–S-/O-glycosidation of native sugars

To a suspension of sugar (500 mg scale) and stoichiometric acetic anhydride (1.0 equivalent per –OH of sugar) was added Mg(OTf)₂ (0.5 mole % of sugar), and the reaction mixture was allowed to stir at ambient temperature (for disaccharides the same was carried out at 80 °C) for appropriate time as mentioned in Table 1. When the reaction was completed (checked by TLC), reaction mixture was cooled in ice bath, and to this thiol/thiophenol/phenol (1.1 equivalent) followed by BF₃·Et₂O (1.2 equivalent) were added, and the reaction mixture was kept on stirring for overnight (8 hours). When TLC showed complete conversion of starting material, the reaction mixture was diluted with ethyl acetate, and the mixture was washed subsequently with cold 5% NaOH solution followed by brine solution. The organic layer was dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and the crude product was passed through a short pad of silica to give pure S- or O-glycosides.

Compound characterization data.

Typical procedure for phenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside (1b)¹⁹. To a suspension of D-glucose 1a (500 mg, 2.8 mmol), and acetic anhydride (5 equivalent, 14.0 mmol, 143 mg), was added Mg(OTf)₂ (0.005 equivalent, 0.014 mmol, 4.5 mg), and the reaction mixture was allowed to stir at ambient temperature for 3 minutes. After the reaction was completed (checked by TLC), the mixture was cooled in ice bath and to this thiophenol (1.1 equivalent, 3.08 mmol, 0.4 ml) followed by BF₃·Et₂O (1.2 equivalent, 3.36 mmol, 0.44 ml) were added, and the reaction mixture was kept on stirring for overnight for completion (8 hours). The reaction mixture was then worked up as described under the general procedure. The crude product was passed through a short pad of silica to give pure product as white solid following elution of the column with 25% EA/PE; yield 1.16 g, 95% (scale up yield 11.1 g, 91% starting with 1a, 5 g, 27.8 mmol); mp (EA/PE) 122 °C, [α]²⁵_D −102.6 (c 1.00, CHCl₃), lit¹⁹ mp 124 °C and [α]²³_D −101.5 (c 1.00, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.98 (s, 3H, COCH₃), 2.01 (s, 3H, COCH₃), 2.07 (s, 3H, COCH₃), 2.08 (s, 3H, COCH₃), 3.74 (m, 1H, H₅), 4.15–4.21 (m, 2H, H₆, H₆), 4.70 (d, J = 9.9 Hz, 1H, H₁), 4.94–5.07 (m, 2H, H₂, H₃), 5.22 (apparent t, J = 9.1, 9.2 Hz, 1H, H₄), 7.32–7.49 (m, 5H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 20.6 (CH₃CO), 20.7 (CH₃CO), 62.1, 68.2, 69.9, 73.9, 75.7, 85.6 (C₁), 128.4, 128.9, 131.6, 133.1, 169.2 (C=O), 169.3 (C=O), 170.1 (C=O), 170.5 (C=O).

Ethyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside (1c)²⁰. Pure product 1b was isolated as white solid following elution of the column with 25% EA/PE; yield 0.97 g, 89% (starting from 1a, 500 mg, 2.8 mmol); mp (EA/PE) 82–84 °C, [α]²⁵_D −26.7 (c 1.3, CHCl₃), lit²⁰ mp 84–86 °C and [α]²³_D −27.3 (c 2.00, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.22–1.27 (m, 3H, CH₃), 1.98 (s, 3H, COCH₃), 1.99 (s, 3H, COCH₃), 2.03 (s, 3H, COCH₃), 2.05 (s, 3H, COCH₃), 2.64–2.75 (m, 2H, CH₂), 3.69 (m, 1H, H₅), 4.09–4.25 (m, 2H, H₆, H₆), 4.47 (d, J = 9.9 Hz, 1H, H₁), 4.97–5.09 (m, 2H, H₂, H₃), 5.19 (t, 1H, J = 9.3 Hz, H₄).

p-Tolyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside (1d)²¹. Pure product was isolated as white solid following elution of the column with 20% EA/PE; yield 1.09 g, 87% (starting from 1a, 500 mg, 2.8 mmol); mp (EA/PE) 114 °C, [α]²⁵_D −116.8 (c 1.00, CHCl₃), lit²¹ mp 116 °C and [α]²³_D −114.3(c 1.00, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.98 (s, 3H, COCH₃), 2.01 (s, 3H, COCH₃), 2.08 (s, 3H, COCH₃), 2.09 (s, 3H, COCH₃), 2.35 (s, 3H, CH₃), 3.70 (m, 1H, H₅), 4.19–4.20 (m, 2H, H₆, H₆), 4.62 (d, J = 10.0 Hz, 1H, H₁), 4.92 (t, J = 9.9 Hz, 1H, H₂), 5.01 (t, J = 9.8 Hz, 1H, H₃), 5.20 (t, J = 9.3 Hz, 1H, H₄), 7.01–7.14 (d, J = 7.9 Hz, 2H, ArH), 7.37–7.39 (d, J = 7.9 Hz, 2H, ArH).

p-Methoxyphenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside (1e)²². Pure product was isolated as white solid following elution of the column with 33% EA/PE; yield 1.07 g, 85% (starting from 1a, 500 mg, 2.8 mmol); mp 104–105 °C, [α]²⁵_D −9.3 (c 1.00, CHCl₃), lit²² mp 106–107 °C and [α]²⁵_D −8.4(c 1.00, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 2.08 (s, 3H, COCH₃), 2.09 (s, 3H, COCH₃), 2.12 (s, 3H, COCH₃), 2.13 (s, 3H, COCH₃), 3.81 (bs, 4H, OCH₃, H₅), 4.21 (d, J = 10.4 Hz, 1H, H₆), 4.34 (dd, J = 5.0, 12.2 Hz, 1H, H₆), 5.00 (d, J = 7.2 Hz, 1H, H₁), 5.21–5.33 (m, 3H, H₂, H₃, H₄), 6.84–6.88 (d, J = 8.9 Hz, 2H, ArH), 6.98–7.01 (d, J = 8.9 Hz, 2H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 20.60(CH₃CO), 20.62 (CH₃CO), 20.66 (CH₃CO), 20.7(CH₃CO), 55.6 (OCH₃), 61.9, 68.3, 71.2, 71.9, 72.7, 100.3 (C₁), 114.5, 118.7, 150.9, 155.8, 169.3 (C=O), 169.4 (C=O), 170.3 (C=O), 170.6 (C=O).

Phenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranoside (2b)²³. Pure product was isolated as white solid following elution of the column with 30% EA/PE; yield 1.14 g, 94% (starting from 2a, 500 mg, 2.8 mmol), scale up yield 10.8 g, 89% (starting with 2a, 5 g, 27.8 mmol); mp (EA/PE) 80–82 °C, [α]²⁵_D −82.9 (c 1.05, CHCl₃), lit²³ mp 81 °C and [α]²⁵_D −84 (c 1.0, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.97 (s, 3H, COCH₃), 2.04 (s, 3H, COCH₃), 2.09 (s, 3H, COCH₃), 2.12 (s, 3H, COCH₃), 3.94 (apparent t, J = 6.3, 6.4 Hz, 1H, H₅), 4.08–4.22 (m, 2H, H₆, H′₆), 4.71 (d, J = 9.9 Hz, 1H, H₁), 5.04 (dd, J = 3.2, 9.9 Hz, 1H, H₃), 5.24 (t, J = 9.9 Hz, 1H, H₂), 5.41 (d, J = 2.5 Hz, 1H, H₄), 7.31–7.51 (m, 5H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 20.5 (CH₃CO), 20.60 (CH₃CO), 2.63 (CH₃CO), 20.8 (CH₃CO), 61.6, 67.2, 71.9, 74.4, 76.7, 86.5 (C₁), 128.1, 128.9, 132.4, 132.5, 169.4 (C=O), 169.9 (C=O), 170.1 (C=O), 170.3 (C=O).

p-Tolyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranoside (2c)²¹. Pure product was isolated as white solid following elution of the column with 30% EA/PE; yield 1.05 g, 84% (starting from 2a, 500 mg, 2.8 mmol); mp (EA/PE) 110–112 °C, [α]²⁵_D −125.5 (c 1.05, CHCl₃). Lit²¹ mp 112 °C and [α]²²_D −127.0 (c 1.05, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.97 (s, 3H, COCH₃), 2.05 (s, 3H, COCH₃), 2.10 (s, 3H, COCH₃), 2.12 (s, 3H, COCH₃), 2.35 (s, 3H, CH₃), 3.92 (bt, J = 6.5 Hz, 1H, H₅), 4.12–4.19 (m, 2H, H₆, H₆), 4.65 (d, J = 9.9 Hz, 1H, H₁), 5.04 (dd, J = 3.2, 9.9 Hz, 1H, H₃), 5.22 (t, J = 9.9 Hz, 1H, H₂), 5.41 (d, J = 2.7 Hz, 1H, H₄), 7.12–7.14 (d, J = 7.8 Hz, 2H, ArH), 7.40–7.43 (d, J = 8.0 Hz, 2H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 20.58 (CH₃CO), 20.60 (CH₃CO), 20.63 (CH₃CO), 20.8 (CH₃CO), 21.1 (CH₃) 61.6, 67.2, 67.3, 72.0, 74.4, 86.9 (C₁), 128.6, 129.6, 133.1, 138.4, 169.4 (C=O), 170.0 (C=O), 170.2 (C=O), 170.3 (C=O).

p-Methoxyphenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranoside (2d)²². Pure product was isolated as white solid following elution of the column with 33% EA/PE; yield 1.08 g, 86% (starting from 2a, 500 mg, 2.8 mmol); mp 112–114 °C, [α]²⁵_D +3.5 (c 1.00, CHCl₃), lit²² 109–110 °C and [α]²⁵_D +3.2 (c 0.9, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.99 (s, 3H, COCH₃), 2.04 (s, 3H, COCH₃), 2.07 (s, 3H, COCH₃), 2.17 (s, 3H, COCH₃), 3.76 (s, 3H, OCH₃), 4.00 (apparent t, J = 6.4, 6.6 Hz, 1H, H₅), 4.11–4.25 (m, 2H, H₆, H₆), 4.91 (d, J = 7.9 Hz, 1H, H₁), 5.07 (dd, J = 3.2, 10.5 Hz, 1H, H₃), 5.42–5.47 (m, 2H, H₂, H₄), 6.79–6.82 (d, J = 8.9 Hz, 2H, ArH), 6.92–6.96 (d, J = 8.9 Hz, 2H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 20.58 (CH₃CO), 20.65 (CH₃CO), 20.7 (CH₃CO), 55.6 (OCH₃), 61.3, 66.9, 68.8, 70.8, 100.8 (C₁), 114.5, 118.6, 151.0, 155.7, 169.4 (C=O), 170.1 (C=O), 170.27 (C=O), 170.3 (C=O).

Phenyl 2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranoside (3b)^6c. Pure product was isolated as white solid following elution of the column with 22.5% EA/PE; yield 1.13 g, 93% (starting from 3a, 500 mg, 2.8 mmol), scale up yield 10.6 g, 87% (starting from 3a, 5 g, 27.8 mmol); mp (EA/PE) 84–86 °C, [α]²⁵_D +77.1 (c 1.2, CHCl₃), lit^6c mp 87 °C (Et₂O/PE) and [α]²²_D +74.4 (c 1.5, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 2.02 (s, 3H, COCH₃), 2.05 (s, 3H, COCH₃), 2.07 (s, 3H, COCH₃), 2.15 (s, 3H, COCH₃), 4.10 (dd, J = 2.0, 12.2 Hz, 1H, H₆), 4.30 (dd, J = 5.9, 12.2 Hz, 1H, H₆), 4.54 (m, 1H, H₅), 5.32–5.34 (m, 2H, H₃, H₄), 5.49 (m, 2H, H₁, H₂), 7.29–7.50 (m, 5H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 20.6 (CH₃CO), 20.7 (CH₃CO), 20.8 (CH₃CO), 62.5, 66.4, 69.4, 69.5, 70.9, 85.7 (C₁), 128.1, 129.2, 132.1, 132.6, 169.7 (C=O), 169.8 (C=O), 169.9 (C=O), 170.5 (C=O).

Ethyl 2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranoside (3c)²⁴. Pure product was isolated as white solid following elution of the column with 22.5% EA/PE; yield 0.99 g, 91% (starting from 3a, 500 mg, 2.8 mmol); mp (EA/PE) 160–162 °C, [α]²⁵_D −64.8 (c 1.00, CHCl₃), lit²⁴ mp 162–164 °C and [α]²³_D −64.3 (c 0.90, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.25 (bs, 3H, CH₃), 1.92 (s, 3H, COCH₃), 1.99 (s, 3H, COCH₃), 2.02 (s, 3H, COCH₃), 2.09 (s, 3H, COCH₃), 2.59 (bs, 2H, CH₂), 4.04 (bs, 1H), 4.32 (bs, 2H), 5.22 (bs, 4H); ¹³C-NMR (75 MHz, CDCl₃); δ 14.7, 20.5 (CH₃CO), 20.6 (CH₃CO), 20.8 (CH₃CO), 25.3, 62.4, 66.3, 68.8, 69.4, 71.1, 82.2 (C₁), 169.6 (C=O), 169.7 (C=O), 169.8 (C=O), 170.4 (C=O).

Phenyl 2,3,4-tri-O-acetyl-1-thio-β-D-xylopyranoside (4b)²⁵. Pure product was isolated as white solid following elution of the column with 20% EA/PE; yield 1.06 g, 86% (starting from 4a, 500 mg, 3.3 mmol); mp (EA/PE) 78–80 °C, [α]²⁵_D−56.8 (c 1.00, CHCl₃), lit²⁵ mp 74–76 °C and [α]²³_D −55.3 (c 1.00, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 2.04 (s, 3H, COCH₃), 2.05 (s, 3H, COCH₃), 2.09 (s, 3H, COCH₃), 3.43 (t, J = 11.5 Hz, 1H, H_5a), 4.27 (dd, J = 4.8, 11.6 Hz, 1H, H_5e), 4.79 (d, J = 8.3 Hz, 1H, H₁), 4.88–4.96 (m, 2H, H₃, H₄), 5.18 (apparent t, J = 7.9, 8.1 Hz, 1H, H₂) 7.31–7.32 (m, 3H, ArH), 7.46–7.48 (m, 2H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 20.7 (CH₃CO), 20.8 (CH₃CO), 65.2, 69.8, 72.0, 86.2 (C₁), 128.2, 129.0, 132.2, 132.7, 169.3 (C=O), 169.7 (C=O), 169.9 (C=O).

Phenyl 2,3,4-tri-O-acetyl-1-thio-α-L-rhamnopyranoside (5b)²⁶. Pure product was isolated as white solid following elution of the column with 30% EA/PE; yield 0.97 g, 84% (starting from 5a, 500 mg, 3.05 mmol), scale up yield 9.30 g, 80% (starting from 5a, 5 g, 30.5 mmol); mp (EA/PE) 120–122 °C, [α]²⁵_D −110.0 (c 1.5, CHCl₃), lit²⁶ mp 118 °C and [α]²⁵_D −107.0 (c 2.4, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.22 (d, J = 6.1 Hz, 3H, CH₃), 1.99 (s, 3H, COCH₃), 2.05 (s, 3H, COCH₃), 2.11 (s, 3H, COCH₃), 4.34 (m, 1H, H₅), 5.12 (t, 1H, J = 9.7 Hz, H₄), 5.26 (dd, J = 3.0, 9.9 Hz, 1H, H₃), 5.39 (s, 1H, H₁), 5.48 (bs, 1H, H₂), 7.27–7.46 (m, 5H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 17.3 (CH₃), 20.6 (CH₃CO), 20.8 (CH₃CO), 20.9 (CH₃CO), 67.8, 69.4, 71.1, 71.3, 85.7 (C₁), 127.9, 129.1, 131.8, 133.2, 169.8 (C=O), 169.9 (C=O), 170.2 (C=O).

p-Methoxyphenyl 2,3,4-tri-O-acetyl-1-thio-α-L-rhamnopyranoside (5c)²⁷. Pure product was isolated as white solid following elution of the column with 30% EA/PE; yield 1.05 g, 87% (starting from 5a, 500 mg, 3.05 mmol); mp (EA/PE) 116–118 °C, [α]²⁵_D −64.0 (c 1.5, CHCl₃), lit²⁷ mp 120 °C and [α]²⁵_D −65.0 (c 1.5, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.19 (d, J = 6.2 Hz, 3H, CH₃), 2.01 (s, 3H, COCH₃), 2.05 (s, 3H, COCH₃), 2.17 (s, 3H, COCH₃), 3.73 (s, 3H, OCH₃), 4.00 (m, 1H, H₅), 5.13 (t, J = 9.9 Hz, 1H, H₄), 5.33 (bs, 1H, H₁), 5.41 (bs, 1H, H₂), 5.48 (dd, J = 3.3, 10.0 Hz, 1H, H₃), 6.79–6.83 (d, J = 8.9 Hz, 2H, ArH), 6.97–7.00 (d, J = 8.9 Hz, 2H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 17.4 (CH₃), 20.7 (CH₃CO), 20.8 (CH₃CO), 20.9 (CH₃CO), 55.6 (OCH₃), 66.9, 68.9, 69.8, 71.0, 96.5 (C₁), 114.6, 117.6, 149.9, 155.2, 170.01 (C=O), 170.02 (C=O), 170.07 (C=O).

p-Tolyl 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranoside (6b)^6h. Pure product was isolated as white solid following elution of the column with 20% EA/PE; yield 1.04 g, 86% (starting from 5a, 500 mg, 3.05 mmol); mp (EA/PE) 110–112 °C, [α]²⁵_D −125.5 (c 1.05, CHCl₃); ¹H-NMR (300 MHz, CDCl₃) δ 1.20 (d, J = 6.3 Hz, 3H, CH₃), 1.95 (s, 3H, COCH₃), 2.06 (s, 3H, COCH₃), 2.11 (s, 3H, COCH₃), 2.32 (s, 3H, CH₃), 3.78 (m, 1H, H₅), 4.61 (d, J = 9.8 Hz, 1H, H₁), 5.01 (dd, J = 3.2, 9.8 Hz, 1H, H₃), 5.14–5.23 (m, 2H, H₂, H₄), 7.09–7.12 (d, J = 7.7 Hz, 2H, ArH), 7.38–7.40 (d, J = 7.9 Hz, 2H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 16.5 (CH₃), 20.62 (CH₃CO), 20.63 (CH₃CO), 20.9 (CH₃CO), 21.1 (CH₃), 67.4, 70.4, 72.5, 73.1, 86.8 (C₁), 129.1, 129.6, 132.9, 138.2, 169.5 (C=O), 170.1 (C=O), 170.6 (C=O).

Phenyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside (7b)²⁸. To a suspension of 7a (500 mg, 1.6 mmol) and acetic anhydride (4 equivalent, 6.5 mmol, 0.62 ml) was added Mg(OTf)₂ (0.005 equivalent, 0.008 mmol, 2.6 mg), and the reaction mixture was allowed to stir at 80 °C for 15 minutes. After the reaction was completed (checked by TLC), reaction mixture was cooled in ice bath and to this thiophenol (1.1 equivalent, 1.78 mmol, 0.19 ml) followed by BF₃·Et₂O (1.2 equivalent, 1.94 mmol, 0.25 ml) were added, and the reaction mixture was kept on stirring for overnight (8 hours) for complete conversion of starting material. The reaction mixture was then worked up as described under the general procedure. The crude product was passed through a short pad of silica to give pure product as white solid following elution of the column with 35% EA/PE; yield 0.67 g, 78%; mp (EA/PE) 144–146 °C, [α]²⁵_D +53.9 (c 1.00, CHCl₃), lit²⁸ mp 145–146 °C and [α]²⁵_D +53.0 (c 1.0, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.84 (s, 3H, COCH₃), 2.04 (s, 3H, COCH₃), 2.10 (s, 3H, COCH₃), 3.91 (m, 1H, H₅), 4.18–4.30 (m, 2H, H₆, H′₆), 4.35 (t, J = 3.4 Hz, 1H, H₂) 5.14 (apparent t, J = 9.6, 9.8 Hz, 1H, H₄), 5.71 (d, J = 10.6 Hz, 1H, H₁), 5.79 (d, J = 7.9 Hz, 1H, H₃), 7.26–7.88 (m, 9H, ArH).

p-Tolyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside (7c)^9d. Pure product was isolated as white solid following elution of the column with 33% EA/PE; yield 0.64 g, 73% (starting from 7a, 500 mg, 1.6 mmol); mp (EA/PE) 162–164 °C, [α]²⁵_D +40.9 (c 0.70, CHCl₃), lit^9d mp 160–162 °C and [α]²⁵_D +40.0 (c 0.60, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.83 (s, 3H, COCH₃), 2.01 (s, 3H, COCH₃), 2.09 (s, 3H, COCH₃), 2.32 (s, 3H, CH₃), 3.87 (m, 1H, H₅), 4.18–4.35 (m, 3H, H₂, H₆, H′₆), 5.11 (t, J = 9.8 Hz, 1H, H₄), 5.64 (d, J = 10.5 Hz, 1H, H₁), 5.77 (apparent t, J = 9.5, 9.9 Hz, 1H, H₃), 7.06–7.08 (d, J = 7.7 Hz, 2H, ArH), 7.28–7.31 (d, J = 7.9 Hz, 2H, ArH), 7.74–7.88 (m, 4H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 20.4 (CH₃CO), 20.6 (CH₃CO), 20.7 (CH₃CO), 21.2 (CH₃), 53.6, 62.2, 68.7, 71.7, 75.8, 83.1 (C₁), 123.7, 126.9, 129.7, 131.2, 131.6, 133.9, 134.3, 134.5, 138.7, 166.9 (C=O), 167.8 (C=O), 169.4 (C=O), 170.1 (C=O), 170.6 (C=O).

Typical procedure for phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl-(1 → 4)-2,3,6-tri-O-acetyl-1-thio-β-D-glucopyranoside (8b)²⁹. To a suspension of D-cellobiose 8a (500 mg, 1.46 mmol) and acetic anhydride (8 equivalent, 11.7 mmol, 1.1 ml) was added Mg(OTf)₂ (0.005 equivalent, 0.007 mmol, 2.4 mg) and the reaction mixture was allowed to stir at 80 °C for 5 minutes. After the reaction was completed (checked by TLC), reaction mixture was cooled in ice bath and to this thiophenol (1.1 equivalent, 1.6 mmol, 0.16 ml), followed by BF₃·Et₂O (1.2 equivalent, 1.75 mmol, 0.22 ml) were added, and the reaction mixture was kept on stirring for overnight (8 hours). When TLC showed complete conversion of starting material, the reaction mixture was diluted with ethyl acetate, and the mixture was washed subsequently with cold 5% NaOH solution followed by brine solution. The organic layer was dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and the crude product was passed through a short pad of silica to give the product. Pure product was isolated as white solid following elution of the column with 33% EA/PE; yield 0.82 g, 77%; mp (EA/PE) 214–216 °C, [α]²⁵_D −16.8 (c 1.00, CHCl₃), lit²⁹ mp 217 °C and [α]²⁰_D −13.2(c 1.05, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.96 (s, 3H, COCH₃), 1.99 (s, 6H, COCH₃), 2.00 (s, 3H, COCH₃), 2.05 (s, 3H, COCH₃), 2.06 (s, 3H, COCH₃), 2.09 (s, 3H, COCH₃), 3.62–3.74 (m, 3H, H_4, H_5, H′₅), 3.99–4.18 (m, 2H, H_6, H₆), 4.36 (dd, J = 3.7, 12.3 Hz, 1H, H′₆), 4.47–4.56 (m, 2H, H′_2, H′₆), 4.65 (d, J = 10.0 Hz, 1H, H₁), 4.86–4.92 (m, 2H, H_2, H′₁), 5.01–5.21 (m, 3H, H_3, H′₃, H′₄), 7.26–7.29 (m, 3H, ArH), 7.44–7.66 (m, 2H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 20.5 (CH₃CO), 20.6 (CH₃CO), 20.7 (CH₃CO), 20.8 (CH₃CO), 61.5, 62.0, 67.8, 70.2, 71.6, 71.9, 72.9, 73.6, 76.3, 85.5 (C₁), 100.7 (C′₁), 128.3, 128.9, 129.1, 131.7, 133.1, 168.9 (C=O), 169.3 (C=O), 169.5 (C=O), 169.7 (C=O), 170.1 (C=O), 170.2 (C=O), 170.4 (C=O).

Phenyl 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl-(1 → 4)-2,3,6-tri-O-acetyl-1-thio-β-D-glucopyranoside (9b)²⁹. Pure product was isolated as white solid following elution of the column with 33% EA/PE; yield 0.90 g, 85% (from D-lactose 9a, 500 mg, 1.46 mmol), scale up yield 3.5 g, 83% (from 9a, 2 g, 5.84 mmol); mp (EA/PE) 168–170 °C, [α]²⁵_D −15.3 (c 1.00, CHCl₃), lit²⁹ mp 169–170 °C and [α]²⁵_D −12.7 (c 1.00, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.95 (s, 3H, COCH₃), 2.03 (s, 9H, COCH₃), 2.08 (s, 3H, COCH₃), 2.09 (s, 3H, COCH₃), 2.14 (s, 3H, COCH₃), 3.65 (m, 1H, H₅), 3.74 (t, J = 9.3 Hz, 1H, H₄), 3.85 (bt, J = 6.7 Hz, 1H, H′₅), 4.02–4.12 (m, 3H, H_6, H₆/H′₆, H′₆), 4.45–4.54 (m, 2H, H₃, H₆/H′₆), 4.66 (d, J = 10.0 Hz, 1H, H₁), 4.86–4.96 (m, 2H H′_1, H′₃), 5.08 (apparent t, J = 9.3 Hz, 1H, H₂), 5.21 (t, J = 9.0 Hz, 1H, H′₂), 5.33 (d, J = 2.5 Hz, 1H, H′₄), 7.31–7.48 (m 5H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 20.5 (CH₃CO), 20.6 (CH₃CO), 20.7 (CH₃CO), 20.8 (CH₃CO), 60.8, 62.1, 66.6, 69.1, 70.2, 70.7, 70.9, 73.8, 76.1, 85.5 (C₁), 101.0 (C′₁), 128.3, 128.9, 131.7, 133.0, 162.3, 169.4 (C=O), 169.6 (C=O), 169.7 (C=O), 170.0 (C=O), 170.1 (C=O), 170.2 (C=O), 170.3 (C=O).

Phenyl 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-(1 → 4)-2,3,6-tri-O-acetyl-1-thio-β-D-glucopyranoside (10b)²⁹. Pure product was isolated as white solid following elution of the column with 33% EA/PE; yield 0.96 g, 91% (from D-maltose 10a, 500 mg, 1.46 mmol), scale up yield 3.7 g, 87% (from 10a, 2 g, 5.84 mmol); mp 90–92 °C, [α]²⁵_D +56.3 (c 1.00, CHCl₃), lit²⁹ mp 92–94 °C and [α]²⁵_D +57.0 (c 1.00, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.98 (s, 3H, COCH₃), 2.01 (s, 3H, COCH₃), 2.02 (s, 6H, COCH₃), 2.05 (s, 3H, COCH₃), 2.08 (s, 3H, COCH₃), 2.11 (s, 3H, COCH₃), 3.72 (m, 1H, H₅), 3.89–3.93 (m, 2H, H_4, H′₅), 4.03 (m, 1H, H₆/H′₆), 4.17–4.24 (m, 2H, H₆/H′₆, H′₆), 4.53 (m, 1H, H₆), 4.69–4.85 (m, 3H, H_1, H′₂, H′₃), 5.03 (t, J = 9.8 Hz, 1H, H₂), 5.24–5.33 (m, 2H, H_3, H′₄), 5.37 (d, J = 4.1 Hz, 1H, H′₁), 7.17–7.47 (m 5H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 20.57 (CH₃CO), 20.66 (CH₃CO), 20.7 (CH₃CO), 20.8 (CH₃CO), 20.9 (CH₃CO), 61.5, 62.8, 68.0, 68.5, 69.3, 69.9, 70.7, 72.5, 76.1, 76.4, 85.0 (C₁), 95.4 (C′₁), 128.5, 128.9, 129.0, 131.2, 133.4, 169.4 (C=O), 169.5 (C=O), 169.9 (C=O), 170.1 (C=O), 170.3 (C=O), 170.5 (C=O).

p-Methoxyphenyl 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-(1 → 4)-2,3,6-tri-O-acetyl-β-D-glucopyranoside (10c)³⁰. Pure product was isolated as white solid following elution of the column with 40% EA/PE; yield 0.89 g, 83% (from D-maltose 10a, 500 mg, 1.46 mmol); mp 130–132 °C, [α]²⁵_D +54.3 (c 1.00, CHCl₃), lit³⁰ mp 130–132 °C and [α]²⁴_D +49.8 (c 1.0, CHCl₃); ¹H-NMR (400 MHz, CDCl₃); δ 2.00 (s, 3H, COCH₃), 2.02 (s, 3H, COCH₃), 2.03 (s, 3H, COCH₃), 2.04 (s, 3H, COCH₃), 2.05 (s, 3H, COCH₃), 2.10 (s, 3H, COCH₃), 2.11 (s, 3H, COCH₃), 3.77 (s, 3H, OCH₃), 3.80 (m, 1H, H₅), 3.96 (m, 1H, H′₅), 4.05 (dd, J = 1.6, 12.0 Hz, 1H, H₆), 4.18 (t, J = 9.2 Hz, 1H, H₄), 4.23–4.28 (m, 2H, H′₆, H′₆), 4.48 (dd, J = 2.8, 12.0 Hz, 1H, H₆), 4.86 (dd, J = 3.8, 10.6 Hz, 1H, H′₂), 4.98 (d, J = 7.6 Hz, 1H, H₁), 5.02–5.08 (m, 2H, H_2, H′₃), 5.30 (m, 1H, H′₄), 5.36 (t, J = 10.0 Hz, 1H, H₃), 5.43 (d, J = 4.0 Hz, 1H, H′₁), 6.81–6.94 (m, 4H, ArH).

General procedure for 4,6-O-arylidenation of monosaccharides

To a solution of unprotected monosaccharide glycosides (200 mg) and benzaldehyde dimethylacetal or p-methoxybenzaldehyde dimethylacetal (1.1 equivalent with respect to sugr) in dry acetonitrile (10 ml), 10 mole % Mg(OTf)₂ was added at ambient temperature. After completion of reaction (indicated by TLC), the reaction mixture was diluted with ethyl acetate, and the mixture was washed subsequently with saturated NaHCO₃ followed by brine solution; finally the organic extract was dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure and the crude product was either crystallized or passed through a short pad of silica to give pure arylidenated product.

Typical procedure for phenyl 4,6-O-benzylidene-1-thio-β-D-glucopyranoside (11b)³¹. To a solution of 11a (200 mg, 0.74 mmol) and benzaldehyde dimethylacetal (1.1 equivalent, 0.81 mmol, 0.12 ml) in dry acetonitrile (10 ml), Mg(OTf)₂ (0.1 equivalent, 0.074 mmol, 23.8 mg) was added at ambient temperature. After completion of reaction (indicated by TLC), the reaction mixture was diluted with ethyl acetate, and the mixture was washed subsequently with saturated NaHCO₃ followed by brine solution; finally the organic extract was dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure. The crude material was crystallized from EtOH to isolate pure product as white solid. Yield 230 mg, 87% (2.17 g, 82%); mp (EtOH) 172–174 °C, [α]²²_D −28.1 (c 1.00, CHCl₃), lit³¹ 174 °C and [α]²⁵_D −26.9; ¹H-NMR (300 MHz, CDCl₃); δ 2.17 (bs, 2H, OH), 3.45–3.54 (m, 3H, H_2, H_3, H₅), 3.75–3.88 (m, 2H, H_4, H_6a), 4.38 (m, 1H, H_6e), 4.62 (d, J = 9.7 Hz, 1H, H₁), 5.54 (s, 1H, PhCH), 7.33–7.56 (m, 10H, ArH).

4-Tolyl 4,6-O-benzylidene-1-thio-β-D-glucopyranoside (12b)³². The crude product was crystallized from EtOH to isolate pure product as white solid. Yield 209 mg, 80% (starting from 12a, 200 mg, 0.699 mmol), scale up yield, 2.0 g, 77% (starting from 12a, 2.09 g, 6.99 mmol); mp 170–172 °C, [α]²⁵_D −40.1 (c 1.0, CHCl₃), lit³² mp 171–172 °C and [α]²⁵_D −34.4 (c 1.0, CHCl₃); ¹H-NMR (500 MHz, CDCl₃); δ 2.28 (s, 3H, CH₃), 2.61 (s, 1H, OH), 2.76 (s, 1H, OH), 3.35 (t, J = 9.0 Hz, 1H, H₃), 3.39–3.44 (m, 2H, H_2, H₅), 3.69 (m, 1H, H_6a), 3.75 (t, J = 8.5 Hz, 1H, H₄), 4.29 (dd, J = 4.3, 10.3 Hz, 1H, H_6e), 4.48 (d, J = 10 Hz, 1H, H₁), 5.44 (s, 1H, PhCH), 7.07–7.08 (d, J = 8.0 Hz, 2H, ArH), 7.28–7.31 (m, 3H, ArH), 7.35–7.40 (m, 4H, ArH); ¹³C-NMR (125 MHz, CDCl₃); δ 21.2, 68.6, 70.6, 72.5, 74.6, 80.2, 88.7 (C₁), 101.9 (PhCH), 126.3, 127.2, 128.4, 129.3, 129.9, 133.7, 136.9, 138.9.

Ethyl 4,6-O-benzylidene-1-thio-β-D-glucopyranoside (13b)³³. The crude product was crystallized from EtOH to isolate pure product as white solid. Yield 228 mg, 82% (starting from 13a, 200 mg, 0.89 mmol), scale up yield, 2.2 g, 79% (starting from 13a, 2.09 g, 8.9 mmol); mp 146–148 °C, [α]²²_D −64.0 (c 1.4, CHCl₃), lit³³ 145 °C, and [α]²⁵_D −65.0 (c 1.0, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.33–1.38 (t, J = 7.4 Hz, 3H, CH₃), 2.75–2.82 (q, J = 7.4 Hz, 3H, SCH_2, OH), 2.93 (bs, 2H, OH), 3.49–3.63 (m, 3H, H_2, H_3, H₅), 3.76–3.88 (m, 2H, H_4, H_6a), 4.37 (m, 1H, H_6e), 4.48 (d, J = 9.7 Hz, 1H, H₁), 5.56 (s, 1H, PhCH), 7.28–7.52 (m, 5H, ArH).

Phenyl 4,6-O-(4-methoxybenzylidene)-1-thio-β-D-glucopyranoside (11c)³⁴. 11c was isolated as white solid following elution of the column with 45% EA/PE; yield 224 mg, 78% (starting from 11a, 200 mg, 0.74 mmol); mp (EtOH) 170–172 °C, [α]²⁵_D −31.5 (c 1.0, CHCl₃), lit³⁴ mp(EtOH) 173–176 °C and [α]²⁵_D −38.8 (c 0.19, CHCl₃); ¹H-NMR (500 MHz, CDCl₃); δ 2.66 (s, 1H, OH), 2.82 (s, 1H, OH), 3.36–3.44 (m, 3H, H₂, H₃, H₅), 3.66–3.76 (m, 5H, OCH₃, H₄, H_6a), 4.27 (m, 1H, H_6e), 4.54 (d, J = 9.5 Hz, 1H, H₁), 5.40 (s, 1H, PhCH), 6.79–6.81 (d, J = 8.5 Hz, 2H, ArH), 7.26 (bs, 3H, ArH), 7.31–7.33 (d, J = 8.5 Hz, 2H, ArH), 7.46 (bs, 2H, ArH); ¹³C-NMR (125 MHz, CDCl₃); δ 55.3 (OCH₃), 68.6, 70.6, 72.6, 74.6, 80.2, 88.6 (C₁), 101.9 (PhCH), 113.8, 127.6, 128.5, 129.1, 129.4, 131.3, 133.4.

4-Methoxyphenyl 4,6-O-benzylidene-β-D-glucopyranoside (14b)³⁵. The crude material was crystallized from MeOH to isolate pure product as white solid. Yield 214 mg, 82% (starting from 14a, 200 mg, 0.699 mmol); mp 212 °C, [α]²⁵_D −28.1 (c 1.0, CH₃OH/CHCl₃ 1 : 1), lit³⁵ mp 213–214 °C and [α]²⁵_D −35.0 (c 1.0, DMF); ¹H-NMR (300 MHz, D₆-DMSO); δ 3.48 (d, J = 8.9 Hz, 1H), 3.57 (bs, 2H), 3.70 (s, 4H), 4.20 (d, J = 5.2 Hz, 1H), 4.97 (d, J = 7.3 Hz, 1H, H₁), 5.44 (d, J = 3.7 Hz, 1H), 5.59 (s, 1H, PhCH), 6.85–6.87 (d, J = 8.5 Hz, 2H, ArH), 6.98–7.00 (d, J = 8.4 Hz, 2H, ArH), 7.37–7.45 (m, 5H, ArH); ¹³C-NMR (75 MHz, D₆-DMSO); δ 55.8 (OCH₃), 66.2, 68.3, 73.3, 74.7, 80.9 (C₁), 101.2 (PhCH), 102.2 (C₁), 114.9, 118.3, 126.8, 128.5, 129.3, 138.2, 151.5, 154.9.

4-Bromophenyl 4,6-O-benzylidene-β-D-glucopyranoside (15b)^16g. The crude mass was crystallized from EtOH to isolate pure product as white solid. Yield 205 mg, 81% (starting from 15a, 200 mg, 0.66 mmol); mp 180–182 °C, [α]²⁵_D −38.7 (c 1.00, CHCl₃), lit^16g mp 182–184 °C and [α]²⁵_D −38.8 (c 0.89, CHCl₃); ¹H-NMR (400 MHz, CDCl₃); δ 2.71 (bs, 1H, OH), 2.84 (bs, 1H, OH), 3.49–3.67 (m, 2H, H₂/H₃, H₅), 3.77–3.84 (m, 2H, H₃/H₂, H_6a), 3.92 (m, 1H, H₄), 4.37 (m, 1H, H_6e), 4.99 (d, J = 7.6 Hz, 1H, H₁), 5.57 (s, 1H, PhCH), 6.93–6.95 (d, J = 8.8 Hz, 2H, ArH), 7.38–7.51 (m, 7H, ArH).

2′-Napthyl 4,6-O-benzylidene-β-D-glucopyranoside (16b)³⁶. The crude product was crystallized from EtOH to isolate pure product as white solid. Yield 214 mg, 83% (starting from 16a, 200 mg, 0.65 mmol); mp 202–204 °C, [α]²⁵_D −36.0 (c 1.00, CHCl₃), lit³⁶ mp 202–205 °C and [α]²⁵_D −37.1 (c 1.00, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 2.83 (bs, 1H, OH), 2.92 (bs, 1H, OH), 3.68–3.90 (m, 4H, H₂, H₃, H_5, H_6a), 3.95 (m, 1H, H₄), 4.44 (m, 1H, H_6a), 5.19 (d, J = 7.5 Hz, 1H, H₁), 5.59 (s, 1H, PhCH), 7.28–7.52 (m, 9H, ArH), 7.75–7.82 (m, 3H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 66.6, 68.6, 73.2, 74.4, 80.3, 101.3, 102.0, 111.6, 118.8, 124.7, 126.3, 126.6, 127.2, 127.7, 128.4, 129.4, 129.8, 130.2, 134.1, 136.8.

Methyl 2-O-benzyl-4,6-O-benzylidene-α-D-glucopyranoside (17b)³⁷. The pure product was isolated as white solid following elution of the column with 22.5% EA/PE; yield 217 mg, 83% (starting from 17a, 200 mg, 0.7 mmol); mp 126–128 °C, [α]²⁵_D +35.5 (c 5.0, CHCl₃), lit³⁷ mp 129–130 °C and [α]²⁵_D +35.0 (c 5.0, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 3.37 (s, 3H, OCH₃), 3.44–3.52 (m, 2H, H₂, H₃), 3.69 (apparent t, J = 10.1, 10.2 Hz, 1H, H_6a), 3.80 (m, 1H, H₅), 4.16 (t, J = 9.3 Hz, 1H, H₄), 4.26 (dd, J = 4.9, 9.9 Hz, 1H, H_6e), 4.61 (d, J = 3.1 Hz, 1H, H₁), 4.67–4.81 (m, 2H, BnH), 5.51 (s, 1H, PhCH), 7.30–7.39 (m, 8H, ArH), 7.49–7.53 (m, 2H, ArH).

Methyl 3-O-benzyl-4,6-O-benzylidene-α-D-glucopyranoside (18b)³⁷. The pure product was isolated as white solid following elution of the column with 22.5% EA/PE; yield 222 mg, 85% (starting from 18a, 200 mg, 0.7 mmol); mp 184–186 °C, [α]²⁵_D +77.8 (c 5.0, CHCl₃), lit³⁷ mp 185–187 °C and [α]²⁵_D +80.0 (c 5.0, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 3.46 (s, 3H, OCH₃), 3.58–3.89 (m, 5H, H₂, H_3, H_4, H_6a, H_6e), 4.33 (m, 1H, H₅), 4.80 (d, J = 3.7 Hz, 1H, H₁), 4.80–4.84 (m, 1H, BnH), 4.98 (dd, J = 3.1, 11.6 Hz, 1H, BnH), 5.59 (s, 1H, PhCH), 7.29–7.41 (m, 8H, ArH), 7.51–7.54 (m, 2H, ArH).

Allyl 4,6-O-benzylidene-2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside (19b)³⁸. Pure product was isolated as white solid following elution of the column with 33% EA/PE and crystallized from DCM and PE; yield 220 mg, 88% (starting from 19a, 200 mg, 0.57 mmol); mp 182–184 °C, [α]²⁵_D −39.0 (c 1.0, CHCl₃), lit³⁸ mp 185–187 °C and [α]²⁵_D −40.0 (c 1.0, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 2.89 (bs, 1H, OH), 3.58–3.60 (m, 2H), 3.81 (m, 1H, H₃), 4.00 (m, 1H, H₆), 4.23–4.39 (m, 3H, H_2, H_4, H₆), 4.61 (m, 1H, H₅), 5.02–5.16 (m, 2H, AllCH₂), 5.28 (d, J = 8.4 Hz, 1H, H₁), 5.56 (s, 1H, PhCH), 5.69 (m, 1H, AllCH), 7.36–7.37 (d, J = 3.0 Hz, 3H, ArH), 7.49–7.50 (d, J = 3.3 Hz, 2H, ArH), 7.69–7.71 (d, J = 2.9 Hz, 2H, ArH), 7.82–7.84 (m, 2H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 56.7, 66.2, 68.6, 68.7, 70.1, 82.2, 98.0 (C₁), 101.9 (PhCH), 117.6, 123.5, 126.4, 128.4, 129.3, 131.6, 133.4, 137.1, 168.1 (C=O), 168.2 (C=O).

Phenyl 4,6-O-benzylidene-2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside (20b)³⁹. Pure product was isolated as foam following elution of the column with 40% EA/PE; yield 200 mg, 82% (starting from 20a, 200 mg, 0.5 mmol); [α]²⁵_D +30.7 (c 1.0, CHCl₃), lit³⁹ [α]²⁵_D +34.2 (c 1.3, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 3.61 (m, 1H, H₃), 3.70 (m, 1H, H_6a), 3.83 (apparent t, J = 9.8, 10.1 Hz, 1H, H₂), 4.30–4.43 (m, 2H, H₄, H_6e), 4.64 (m, 1H, H₅), 5.56 (s, 1H, PhCH), 5.69 (d, J = 10.3 Hz, 1H, H₁), 7.17–7.89 (m, 14H, ArH).

4-Methoxyphenyl 4,6-O-benzylidene-2-deoxy-2-phthalimido-β-D-glucopyranoside (21b)⁴⁰. Pure product was isolated as foam following elution of the column with 33% EA/PE; yield 206 mg, 85% (starting from 21a, 200 mg, 0.48 mmol), scale up yield, 1.96 g, 81% (starting from 21a, 2.0 g, 4.8 mmol); [α]²⁵_D +12.3 (c 1.0, CHCl₃), lit⁴⁰ [α]²⁰_D +11.4 (c 0.67, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 3.67–3.69 (m, 2H), 3.72 (s, 3H, OCH₃), 3.87 (m, 1H), 4.39 (m, 1H), 4.50 (m, 1H), 4.70 (m, 1H), 5.59 (s, 1H, PhCH), 5.80 (d, J = 8.4 Hz, 1H, H₁), 6.72–6.75 (d, J = 9.0 Hz, 2H, ArH), 6.83–6.86 (d, J = 9.1 Hz, 2H, ArH), 7.37–7.86 (m, 9H, ArH).

3-(N-Carboxybenzyl)propyl 4,6-O-benzylidene-2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside (22b)^16e. Pure product was isolated as foam following elution of the column with 50% EA/PE; yield 205 mg, 87% (starting from 22a, 200 mg, 0.4 mmol); [α]²⁵_D −38.7 (c 1.2, CHCl₃), lit^16e [α]²⁰_D −39.8 (c 1.48, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 1.62–1.69 (m, 2H, CH₂), 2.87 (bs, 1H, OH), 3.02–3.12 (m, 2H, NCH₂), 3.47 (m, 1H), 3.59–3.65 (m, 3H, OCH_2, H₆), 3.75–3.87 (m, 2H, H₃, H₅), 4.23 (dd, J = 8.5, 10.4 Hz, 1H, H₂), 4.35 (dd, J = 3.7, 10.6 Hz, 1H, H₆), 4.60 (apparent t, J = 8.9, 9.1 Hz, 1H, H₄), 4.94 (m, 1H, NH), 5.01 (bs, 2H, BnH), 5.24 (d, J = 8.5 Hz, 1H, H₁), 5.54 (s, 1H, PhCH), 7.34–7.81 (m, 14H, ArH).

Phenyl 4,6-O-benzylidene-1-thio-β-D-galactopyranoside (23b)⁴¹. The crude product was crystallized from EtOH to isolate pure product as white solid; yield 233 mg, 88% (starting from 23a, 200 mg, 0.74 mmol), scale up yield, 2.25 g, 82% (starting from 23a, 2.0 g, 7.4 mmol); mp 116–118 °C, [α]²⁵_D −41.2 (c 1.0, CHCl₃), lit⁴¹ mp 118 °C and [α]²⁵_D −34.5 (c 1.2, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 3.55 (s, 1H, OH), 3.68–3.72 (m, 3H, H₂, H₃, H₅), 4.03 (d, J = 10.6 Hz, 1H, H₆), 4.21 (s, 1H, H₄), 4.38 (d, J = 12.4 Hz, 1H, H₆), 4.51 (d, J = 8.8 Hz, 1H, H₁), 5.51 (s, 1H, PhCH), 7.27–7.31 (m, 3H, ArH), 7.38 (bs, 5H, ArH), 7.68–7.70 (d, J = 6.3 Hz, 2H, ArH).

4-Tolyl 4,6-O-benzylidene-1-thio-β-D-galactopyranoside (24b)³². The crude mass was crystallized from EtOH to isolate pure product as white solid; yield 225 mg, 86% (starting from 24a, 200 mg, 0.699 mmol), scale up yield, 2.09 g, 80% (starting from 24a, 2.0 g, 6.9 mmol); mp 152–154 °C, [α]²⁵_D −65.1 (c 1.0, CHCl₃), lit³² mp 154–155 °C and [α]²⁵_D −72.8 (c 1.0, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 2.36 (s, 3H, CH₃), 2.96 (bs, 2H, OH), 3.44 (bs, 1H), 3.63–3.65 (m, 2H), 3.95 (d, J = 12.4 Hz, 1H, H₆), 4.12 (bs, 1H, H₄), 4.33 (d, J = 12.4 Hz, 1H, H₁), 4.43 (m, 1H, H₆), 5.47 (s, 1H, PhCH), 6.98–7.12 (d, J = 7.6 Hz, 2H, ArH), 7.37–7.39 (m, 5H, ArH), 7.58 (d, J = 7.9 Hz, 2H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 21.3, 68.7, 69.3, 69.9, 73.7, 75.5, 87.1 (C₁), 101.9 (PhCH), 126.6, 126.9, 128.2, 129.0, 129.3, 129.7, 129.8, 134.2, 134.5, 136.4, 137.7, 138.4.

Phenyl 3-O-benzyl-4,6-O-benzylidene-1-thio-β-D-galactopyranoside (25b). The crude mass was crystallized from DCM and PE to isolate pure product as white solid; yield 209 mg, 84% (starting from 25a, 200 mg, 0.55 mmol), scale up yield, 2.04 g, 82% (starting from 25a, 2.0 g, 5.5 mmol); mp 159–160 °C and [α]²⁵_D +13.1 (c 1.0, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 2.51 (bs, 1H, OH), 3.45 (bs, 1H, H₅), 3.52 (dd, J = 3.3, 9.3 Hz, 1H, H₃), 3.91–4.00 (m, 2H, H_2, H_6a), 4.15 (d, J = 3.2 Hz, 1H, H₄), 4.35 (dd, J = 1.4, 12.4 Hz, 1H, H_6e), 4.52 (d, J = 9.5 Hz, 1H, H₁), 4.72–4.77 (m, 2H, BnH), 5.43 (s, 1H, PhCH), 7.20–7.43 (m, 13H, ArH), 7.66–7.69 (m, 2H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 67.2, 69.4 70.1, 71.7, 73.3, 80.3, 87.1 (C₁), 101.1 (PhCH), 126.5, 127.9, 128.0, 128.1, 128.5, 128.9, 129.1, 129.8, 130.8, 132.6, 133.7, 137.9, 138.0.

4-Methoxyphenyl 4,6-O-benzylidene-β-D-galactopyranoside (26b)⁴². The crude mass was crystallized from MeOH to isolate pure product as white solid; yield 201 mg, 77% (starting from 26a, 200 mg, 0.699 mmol); mp 230–232 °C, [α]²⁵_D −79.8 (c 1.0, CH₃OH/CHCl₃ 1 : 1), lit⁴² mp 230–232 °C and [α]²⁵_D −80.4 (c 1.0, CH₃OH/CHCl₃ 1 : 1); ¹H-NMR (300 MHz, D₆-DMSO); δ 3.59 (bs, 2H, OH), 3.69 (s, 4H), 4.05 (bs, 2H), 4.12 (s, 1H), 4.83 (d, J = 5.9 Hz, 1H), 5.05 (s, 1H), 5.27 (s, 1H), 5.57 (s, 1H, PhCH), 6.84–6.87 (d, J = 8.9 Hz, 2H, ArH), 6.99–7.02 (d, J = 8.9 Hz, 2H, ArH), 7.36–7.46 (m, 5H, ArH); ¹³C-NMR (75 MHz, D₆-DMSO); δ 55.8 (OCH₃), 66.5, 68.9, 70.2, 72.2, 76.3, 101.2 (PhCH), 102.0 (C₁), 114.9, 118.1, 126.7, 128.4, 129.1, 139.1, 151.8, 154.8.

2-Allylphenyl 4,6-O-benzylidene-β-D-galactopyranoside (27b). The crude mass was crystallized from MeOH to isolate pure product as white solid. Yield 197 mg, 76% (starting from 27a, 200 mg, 0.68 mmol); mp 230–232 °C; ¹H-NMR (300 MHz, D₆-DMSO); δ 3.59–3.68 (m, 2H), 3.72 (bs, 2H, OH), 4.06 (s, 2H), 4.15 (s, 1H), 4.90 (d, J = 7.3 Hz, 1H, H₁), 4.99 (d, J = 9.9 Hz, 1H), 5.06–5.12 (m, 2H), 5.26 (d, J = 5.0 Hz, 1H), 5.58 (s, 1H, PhCH), 5.97–6.06 (m, 1H), 6.95 (m, 1H, ArH), 7.11–7.16 (m, 3H, ArH), 7.36–7.48 (m, 5H, ArH); ¹³C-NMR (75 MHz, D₆-DMSO); δ 66.5, 68.9, 70.4, 72.3, 76.3, 100.3 (C₁), 101.9 (PhCH), 115.6, 116.1, 122.4, 126.7, 127.7, 128.4, 129.1, 129.7, 129.9, 137.7, 139.1, 155.5.

Phenyl 4,6-O-benzylidene-1-thio-α-D-mannopyranoside (28b)⁴³. Isolated as white solid following elution of the column with EA and crystallized from CH₃OH; yield 180 mg, 68% (starting from 28a, 200 mg, 0.74 mmol); mp 210–212 °C, [α]²⁵_D +281.0 (c 1.0, CH₃OH/CHCl₃ 1 : 1), lit⁴³ mp 213–214 °C and [α]²⁰_D −289.0 (c 0.50, CH₃OH/CHCl₃ 1 : 1); ¹H-NMR (300 MHz, D₆-DMSO); δ 3.77–3.81 (m, 2H, 2OH), 3.93–4.08 (m, 4H, H₄, H₅, H_6a, H_6e), 5.24 (d, J = 6.0 Hz, 1H, H₃), 5.47 (s, 1H, H₂), 5.57 (d, J = 3.8 Hz, 1H, H₁), 5.63 (s, 1H, PhCH), 7.30–7.49 (m, 10H, ArH); ¹³C-NMR (75 MHz, D₆-DMSO); δ 65.8, 68.1, 68.6, 72.9, 78.9, 89.7 (C₁), 101.7 (PhCH), 126.9, 127.9, 128.5, 129.3, 129.7, 131.8, 134.1, 138.3.

General procedure for one-pot 4,6-O-benzylidation acetylation of carbohydrates

To a solution of unprotected glycosides (100 mg) and benzaldehyde dimethylacetal (1.1 mmol) in dry acetonitrile (5 ml), 10 mole % Mg(OTf)₂ was added at room temperature. After completion of reaction (indicated by TLC), solvent was concentrated in vacuum and in the same reaction vessel acetic anhydride (1.0 equivalent per hydroxyl group) was added. After completion of the reaction (indicated by TLC), the reaction mixture was diluted with ethyl acetate, and the mixture was washed subsequently with saturated NaHCO₃ followed by brine solution; the organic extract was finally dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure and the crude product was either crystallized or passed through a short pad of silica to give pure product.

Typical procedure for 4-tolyl 2,3-di-O-acetyl-4,6-O-benzylidene-1-thio-β-D-glucopyranoside (29)⁴⁴. To a solution of glycoside 12a (100 mg, 0.35 mmol) and benzaldehyde dimethylacetal (1.1 equivalent, 0.39 mmol, 0.06 ml) in dry acetonitrile (5 ml), Mg(OTf)₂ (0.1 equivalent, 0.4 mmol, 12.8 mg) was added at ambient temperature. After completion of reaction (indicated by TLC), solvent was concentrated in vacuum and in the same reaction vessel acetic anhydride (2.0 equivalent, 0.7 mmol, 0.06 ml) was added. After completion of the reaction (indicated by TLC), the reaction mixture was worked up as described under the general procedure, and the crude product was crystallized from EA and PE to isolate 29 as white solid; yield 123.4 mg, 77%; mp 170–172 °C, [α]²⁵_D −38.0 (c 1.00, CHCl₃), lit⁴⁴ mp 172–174 °C and [α]²⁵_D −34.1 (c 1.00, CHCl₃); ¹H-NMR (500 MHz, CDCl₃); δ 1.95 (s, 3H, COCH₃), 2.03 (s, 3H, COCH₃), 2.28 (s, 3H, CH₃), 3.48 (m, 1H, H₅), 3.56 (t, J = 9.5 Hz, 1H, H_6a), 3.70 (t, J = 10.0 Hz, 1H, H₄), 4.29 (dd, J = 5.0, 10.5 Hz, 1H, H_6e), 4.65 (d, J = 10.0 Hz, 1H, H₁), 4.89 (apparent t, J = 9.0, 10.0 Hz, 1H, H₂), 5.25 (apparent t, J = 9.0, 9.5 Hz, 1H, H₃), 5.42 (s, 1H, PhCH), 7.06–7.07 (d, J = 8.0 Hz, 2H, ArH), 7.26–7.35 (m, 7H, ArH);¹³C-NMR (125 MHz, CDCl₃); δ 20.7 (CH₃CO), 20.8 (CH₃CO), 21.2 (CH₃), 68.5, 70.6, 70.8, 72.9, 78.1, 86.8 (C₁), 101.5 (PhCH), 126.2, 127.7, 128.3, 129.2, 133.7, 136.8, 138.8, 169.5 (C=O), 170.1 (C=O).

Phenyl 2,3-di-O-acetyl-4,6-O-benzyledene-β-D-glucopyranosyl-(1 → 4)-2,3,6-tri-O-acetyl-1-thio-β-D-glucopyranoside (31)⁴⁵. The crude product was crystallized from EA and PE to isolate pure product as white solid; yield 123.2 mg, 73% (starting from 30, 100 mg, 0.23 mmol); mp 264–266 °C, [α]²⁵_D −42.5 (c 0.50, CHCl₃), lit⁴⁵ mp 267 °C and [α]²⁵_D −45.3 (c 1.00, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 2.01 (s, 3H, COCH₃), 2.02 (s, 3H, COCH₃), 2.04 (s, 3H, COCH₃), 2.08 (s, 3H, COCH₃), 2.11 (s, 3H, COCH₃), 3.47 (m, 1H, H₅), 3.62–3.77 (m, 4H, H_4, H′₆, H′_5, H′₆), 4.07 (dd, J = 5.0, 11.8 Hz, 1H, H₆), 4.33 (dd, J = 4.5, 10.0 Hz, 1H, H′₆), 4.48–4.59 (m, 2H, H_3, H′₄), 4.66 (d, J = 10.0 Hz, 1H, H₁) 4.85–4.94 (m, 2H, H′₁, H₂), 5.16–5.28 (m, 2H, H′₂, H′₃), 5.47 (s, 1H, PhCH), 7.26–7.48 (m, 10H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 20.6 (CH₃CO), 20.7 (CH₃CO), 20.8 (CH₃CO), 20.9 (CH₃CO), 30.9 (CH₃CO), 61.9, 62.2, 62.3, 66.4, 68.5, 69.2, 70.2, 70.3, 71.7, 71.9, 72.6, 74.2, 74.4, 75.8, 76.1, 76.3, 76.8, 77.9, 85.3, 100.5, 101.5, 126.1, 128.3, 128.9, 129.0, 129.8, 133.0, 133.3, 134.5, 136.6, 169.4 (C=O), 169.5 (C=O), 170.2 (C=O), 170.3 (C=O), 171.5 (C=O).

Phenyl 2,3-di-O-acetyl-4,6-O-benzylidene-β-D-galactopyranosyl-(1 → 4)-2,3,6-tri-O-acetyl-1-thio-β-D-glucopyranoside (33)⁴⁵. The crude product was crystallized from EA and PE to isolate pure product as white solid; yield 141.7 mg, 84% (starting from 32, 100 mg, 0.23 mmol); mp 254–256 °C, [α]²⁵_D +23.5 (c 0.50, CHCl₃), lit⁴⁵ mp 257 °C and [α]²⁵_D +24.5 (c 0.70, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 2.03 (s, 9H, COCH₃), 2.08 (s, 3H, COCH₃), 2.10 (s, 3H, COCH₃), 3.45 (s, 1H), 3.65–3.77 (m, 2H), 4.01–4.14 (m, 2H), 4.26–4.33 (m, 2H), 4.44 (d, J = 7.8 Hz, 1H, H₁), 4.56 (m, 1H), 4.68 (d, J = 10.0 Hz, 1H), 4.85–4.96 (m, 2H, H′₁), 5.19–5.28 (m, 2H), 5.46 (s, 1H, PhCH), 7.29–7.31 (m, 3H, ArH), 7.36–7.38 (m, 3H, ArH), 7.41–7.49 (m, 4H, ArH); ¹³C-NMR (75 MHz, CDCl₃); δ 20.6 (CH₃CO), 20.7 (CH₃CO), 20.8 (CH₃CO), 22.7 (CH₃CO), 29.7 (CH₃CO), 62.1, 62.4, 66.5, 68.1, 68.4, 69.0, 69.7, 70.1, 70.4, 72.1, 73.1, 73.4, 73.6, 74.4, 75.9, 76.9, 85.5, 101.1, 101.4, 126.5, 128.2, 128.9, 129.0, 129.2, 129.7, 131.9, 133.0, 134.5, 137.4, 168.9 (C=O), 169.4 (C=O), 169.6 (C=O), 170.2 (C=O), 170.3 (C=O), 170.4 (C=O), 170.7 (C=O).

Methyl 2,3-di-O-acetyl-4,6-O-benzylidene-β-D-galactopyranosyl-(1 → 4)-2,3,6-tri-O-acetyl-β-D-glucopyranoside (35)⁴⁶. The crude product was purified by column chromatography on silica gel and the white solid mass was crystallized from EtOH to give 35; yield 78% (starting from 34, 100 mg, 0.28 mmol); mp 220–222 °C, [α]²⁵_D +36.5 (c 1.46, CHCl₃), lit³² mp 225 °C and [α]²⁵_D +36.5 (c 0.70, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 2.03 (s, 12H, 4 × COCH₃), 2.11 (s, 3H, COCH₃), 3.45 (s, 1H), 3.47 (s, 3H, OCH₃), 3.59–3.63 (m, 1H), 3.79 (t, J = 9.5 Hz, 1H), 4.03 (d, J = 12.4 Hz, 1H), 4.12 (dd, J = 4.8,11.9 Hz, 1H), 4.27–4.33 (m, 2H), 4.39 (d, J = 7.9 Hz, 1H), 4.45–4.54 (m, 2H), 4.85–4.93 (m, 2H), 5.26 (d, J = 10.5 Hz 1H), 5.19 (d, J = 9.7 Hz, 1H), 5.46 (s, 1H, CHPh), 7.36–7.38 (m, 3H, ArH), 7.44–7.46 (m, 2H, ArH).

4-Methoxyphenyl 2,3-di-O-acetyl-4,6-O-benzylidene-α-D-glucopyranosyl-(1 → 4)-2,3,6-tri-O-acetyl-β-D-glucopyranoside (37)^16g. The crude product was purified by column chromatography on silica gel and the white solid mass was crystallized from EtOH to give 37; yield 131.5 mg, 79% (starting from 36, 100 mg, 0.35 mmol); mp 180–182 °C, [α]²⁵_D +25.5 (c 0.49, CHCl₃), lit^16g mp 182–184 °C and [α]²⁵_D +24.5 (c 0.60, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 2.04 (s, 3H, COCH₃), 2.05 (s, 3H, COCH₃), 2.05 (s, 3H, COCH₃), 2.06 (s, 3H, COCH₃), 2.08 (s, 3H, COCH₃), 3.64 (t, J = 9.5 Hz, 1H, H₄), 3.70–3.77 (m, 4H, OCH_3, H′₄), 3.80–3.91 (m, 2H, H′_5, H′₆), 4.08 (t, J = 9.4 Hz, 1H, H₃), 4.24–4.32 (m, 2H, H_5, H′₂), 4.54 (dd, J = 2.7, 12.5 Hz, 1H, H′₆), 4.89 (dd, J = 4.1, 10.1 Hz, 1H, H₆), 4.97 (d, J = 7.6 Hz, 1H, H₁), 5.06 (t, J = 7.7 Hz, 1H, H₂), 5.31 (t, J = 8.8 Hz, 1H, H₆), 5.38 (d, J = 4.1 Hz, 1H, H′₁), 5.43–5.50 (m, 2H, H′_3, PhCH), 6.79–6.84 (m, 2H, ArH), 6.90–6.95 (m, 2H, ArH), 7.33–7.36 (m, 3H, ArH), 7.40–7.44 (m, 2H, ArH);

2′-Azidoethyl 2,3-di-O-acetyl-4,6-O-benzylidene-α-D-glucopyranosyl-(1 → 4)-2,3,6-tri-O-acetyl-β-D-glucopyranoside (39)^16g. The crude product was purified by column chromatography on silica gel and the white solid mass was crystallized from EtOH to give 39; yield 135.8 mg, 79% (starting from 38, 100 mg, 0.24 mmol); mp 184–186 °C, [α]²⁵_D +2.3 (c 2.25, CHCl₃), lit^16g mp 186–188 °C and [α]²⁵_D +2.0 (c 2.25, CHCl₃); ¹H-NMR (400 MHz, CDCl₃); δ 2.01 (s, 3H, COCH₃), 2.02 (s, 3H, COCH₃), 2.04 (s, 3H, COCH₃), 2.05 (s, 3H, COCH₃), 2.11 (s, 3H, COCH₃), 3.26 (m, 1H, NCH), 3.47 (m, 1H, NCH), 3.60–3.76 (m, 4H), 3.83–3.89 (m, 1H), 3.97–4.05 (m, 2H), 4.22–4.27 (m, 2H, H₆), 4.57–4.61 (m, 2H, H₆, H′₃), 4.82–4.89 (m, 2H, H_1, H′₂), 5.26 (apparent t, J = 8.8, 9.2 Hz, 1H, H₂), 5.36 (d, J = 4.0 Hz, 1H, H′₁), 5.44 (d, J = 9.6 Hz, 1H, H₃), 5.48 (s, 1H, PhCH), 7.33–7.42 (m, 5H, ArH).

Methyl 2,3-di-O-acetyl-4,6-O-benzylidene-β-D-glucopyranoside (41)⁴⁷. The crude product was crystallized from EA and PE to isolate pure product as white solid; yield 145 mg, 77% (starting from 40, 100 mg, 0.52 mmol); mp 106–108 °C, [α]²⁸_D −100.6 (c 2.10, CHCl₃), lit⁴⁷ mp 110–112 °C and [α]²⁴_D −95.2 (c 5.24, CHCl₃); ¹H-NMR (300 MHz, CDCl₃); δ 2.05 (s, 3H, COCH₃), 2.07 (s, 3H, COCH₃), 3.52 (s, 3H, OCH₃), 3.56 (m, 1H, H₅), 3.70 (t, J = 9.5 Hz, 1H, H₄), 3.80 (t, J = 10.2 Hz, 1H, H₆), 3.83 (dd, J = 4.9, 10.5 Hz, 1H, H₆), 4.51 (d, J = 7.8 Hz, 1H, H₁), 4.99 (apparent t, J = 8.0, 9.0 Hz, 1H, H₂), 5.32 (apparent t, J = 9.4, 11.5 Hz, 1H, H₃), 5.51 (s, 1H, CHPh), 7.35–7.44 (m, 5H, ArH).

Acknowledgements

Financial support from DST-SERB (Scheme No. SR/S1/OC-61/2012), New Delhi, India to RG, from CAS-UGC and FIST-DST, India, to the Department of Chemistry, Jadavpur University are acknowledged. MMM (SRF) is grateful to UGC, India for fellowship.

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra23198e

‡ Present address: Department of Organic Chemistry, IACS, Jadavpur, Kolkata 700032, India.

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