One-pot synthesis of oxazolidine-2-thione and thiozolidine-2-thione from sugar azido-alcohols

Carbohydrate Research 450 (2017) 1e9

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One-pot synthesis of oxazolidine-2-thione and thiozolidine-2-thione from sugar azido-alcohols Kunj B. Mishra a, b, Anand K. Agrahari b, Vinod K. Tiwari b, * a b

Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, India Department of Chemistry, Indian Institute of Technology (IIT), Banaras Hindu University, Varanasi 221005, India

a r t i c l e i n f o

a b s t r a c t

Article history: Received 27 June 2017 Received in revised form 2 August 2017 Accepted 2 August 2017 Available online 4 August 2017

A controlled and facile synthesis of various glycosyl 1,3-oxazolidine-2-thiones and 1,3- thiozolidine-2thiones has been accomplished from corresponding sugar azido alcohols utilizing Staudinger reaction (PPh3 and CS2) via isothiocynate route. A series of reactions were performed to investigate the effects of CS2 and PPh3 on the selectivity of product formed. The excessive addition of CS2 with PPh3(1.2 equiv) afforded oxazolidine-2-thione alone, while the solitary addition of PPh3 for 30 min followed by addition of CS2 to the reaction mixture resulted both the products in different ratios, which were successfully isolated using column chromatography (SiO2). Furthermore, synthesis of 1,3-oxathiolan-2-imine from glycosyl epoxide has also been attempted. Structures of all the developed compounds have been elucidated using extensive spectroscopic techniques including IR, NMR and MS analysis. © 2017 Elsevier Ltd. All rights reserved.

Keywords: Glycoconjugates PPh3 Isothiocynate 1,3-Oxazolidine-2-thiones 1,3-Thiazolidine-2-thiones Staudinger reaction

1. Introduction In past decade, combinatorial chemistry has provided the path to achieve an assembly of privileged structures [1], particularly by incorporating heterocyclic scaffolds which found remarkable applications in medicinal chemistry as well as in chiral synthesis [2e4]. Numerous heterocyclic systems with two hetero atoms in the ring, such as, piperazine, morpholine, oxazole, thiazole etc. have been considered as biologically relevant scaffolds [5]. Similarly, five-membered heterocyclic ring systems like thiozolidine, thiozolidine-2-thione and oxazolidine-2-thiones have been identified as a vital scaffolds in medicinal chemistry and displayed a wide variety of biological activities such as D-fructose transporter inhibitors [6], antithyroid [7], antifertility [8], antibacterial [9], insecticidal [10], etc. Some representative biologically relevant thiozolidine-based molecules include antithyroid Epigoitrin (I) [11], dopamine b-hydroxylase inhibitor (II) [12], antifungal Fezatione (III) [13], herbicidal (IV) [14] and antiviral 20 ,30 -thiocarbamatebased ribonucleoside (V) [15] (Fig. 1). Carbohydrate moiety, due to its poly-functional nature, rigidity and chirality, possesses many unique stereo-chemical and

* Corresponding author. E-mail address: [email protected] (V.K. Tiwari). http://dx.doi.org/10.1016/j.carres.2017.08.002 0008-6215/© 2017 Elsevier Ltd. All rights reserved.

functional aspects that are considered as essential features for the induction of selectivity and chiral discrimination in various chemical, metabolic and recognition processes [16e22]. Hence, functionality and structural variations are the key features due to which sugar molecules have appeared as the effective scaffolds for stereoselective synthesis and thus considered as nature's valuable gift to synthetic chemists [23]. A versatile synthetic intermediate ‘isothiocyanate’ has ability to undergo nucleophilic addition reactions and delivering a variety of interesting products of chemotherapeutic values [24]. Particularly, glycosyl isothiocyanates play crucial role in the synthesis of a wide spectrum of glycoconjugates and it has been found useful for the synthesis of glycosyl thiourea [25e27], although rarely used for the synthesis of 1,3-oxazolidine2-thione. Incorporation of such scaffolds on carbohydrate moieties has been considered as an essential requirement in chemical biology [28,29], however development of a facile protocol is still challenging. Absence of direct precursors on natural sugars makes such creation difficult; yet their mechanical construction is not an easy task. Amino alcohols are found as suitable precursors for non carbohydrate derivatives, but use of azido alcohols for this purpose is limited [30]. Some common approaches for the synthesis of 1,3oxazolidine-2-thiones is depicted in Scheme 1. The aziridine derivative, for example, 7-methyl-6-phenyl-7-azabicyclo[4,1,0]he [tan-2-ol, on refluxing with 1,1-thiocarbonyl diimidazole in

2

K.B. Mishra et al. / Carbohydrate Research 450 (2017) 1e9

Therefore, in continuation of our previous experience on conjugation of sugars with diverse scaffolds [37e48], herein we report a one-pot facile, controlled and selective synthesis of oxazolidine-2-thiones and thiazolidine-2-thiones from the corresponding glycosyl azides expecting for the notable efficacy for problematic bacteria, viruses and enzymes.

2. Results and discussion

Fig. 1. Structure of some biologically relevant thiozolidine-based molecules.

Although 1,3-oxazolidine-2-thiones can be accessed in good yield from corresponding amino alcohols, but usually requires multi-steps reactions, low reaction yield, difficult purification process and thus incorporation of this bi-functionality on carbohydrates is still a challenge. Therefore, we bestowed our effort for the desired synthesis by utilizing glycosyl azido alcohols which is easy to prepare without any problematic issue from readily available starting material and moreover known for their excellent reactivity with triphenylphosphene. Our synthetic strategy begins with common monosaccharides (D-glucose, DMannose and D-Galactose) which were converted to corresponding sugar azido-alcohols (3a-c) via straightforward and high-yielding synthetic steps including isopropylidene protections followed by reacting with epichlorohydrin and their respective azidation [44e46]. To get a series of an another related sugar-based azido alcohols (3d-l), D-glucose and D-Mannose, both were subjected first isopropylidene protection followed by selective deprotection, then selective tosylation and finally their respective azidation reaction under standard reaction conditions (Scheme 2) [46]. The resulting glycosyl 1,2-azidoalcohols (3a-l) having both azido and hydroxyl functionality at vicinal carbons were obtained as a most suitable precursors for the required synthesis of 1,3oxazolidine-2-thione (4a-l) via in situ formation of glycosyl isothiocyanate intermediate. For establishing the reaction condition, initially we treated compound 3a (1.0 equiv) with PPh3 (1.2

Scheme 1. Common approaches for the synthesis of 1,3-oxazolidine-2-thiones.

dichloromethane afforded the cyclic oxazolidine-2-thione alongwith the expected thiocarbonylimidazolide analog [31]. However, the method is little explored for an easy access of biologically relevant 1,3-oxazolidine-2-thiones [15,32,33]. In another way, amino alcohols, on treatment with CS2, either under standard heating or under microwave (MW), have also been utilized to achieve good yields of respective oxazolidine-2-thiones [34,35]. Interestingly, related amino alcohols, on reacting with CSCl2, afforded respective novel oxazolidine-2-thiones [36], however method has some serious limitations, notably the high toxicity of thiophosgene used in the reaction. Considering the above mentioned facts, there is a paramount interest to develop a practical and convenient synthesis for sugar-based oxazolidine-2thiones under mild reaction condition.

Scheme 2. Synthesis of glycosylated azido alcohols 3a-l from various monosaccharides (D-Glucose, D-Mannose and D-Galactose).

K.B. Mishra et al. / Carbohydrate Research 450 (2017) 1e9

3

Table 1 Optimization table to achieve the best reaction condition for compound 4a.

Scheme 3. Synthesis of oxazolidine-2-thione 4a using glycosyl azido alcohol 3a.

equiv) and CS2 (10 equiv) in toluene at 110  C for 5 h (Scheme 3). After the purification process (SiO2), compound 4a was isolated in 58% yield and structure was elucidated by its 1H and 13C NMR, and MS data. Further, we make detailed optimization to improve the reaction yield of oxazolidine-2-thione 4a. In repetitive reaction of azido alcohol 3a with PPh3 (1.2 equiv.) and CS2 (10.0 equiv.) under similar reaction condition, we noticed the appearance of another spot on thin layer chromatography (TLC) along with the expected oxazolidine-2-thione 4a. The new product 1,3-thiazolidine-2-thione 5a was isolated by column chromatography (SiO2) in considerable yield (36%). Both the oxa/thiozolidine-2-thione derivatives 4a and 5a have been characterized by their extensive spectral analysis (Scheme 4). The 1H NMR spectrum of compound 4a is exhibited a singlet at d 8.05 (bs, 1H) assigned for N-H proton which confirmed for the precedence of thermal cyclization leading to 1,3-oxazolidine-2thione. In addition to other signals, the appearance of a singlet at d 5.89 attributed for anomeric proton. Remaining six carbohydrate's protons, two O-methylene protons, two N-methylene protons and one tertiary proton of developed cyclic scaffold were resonated among 5.04e3.64. In 13C NMR, a resonance observed at d 189.5 was assigned to the carbon of thiocarbonyl. A shifting in the signal of CH2N3 from d 53.0 to d 45.8 corroborated the formation of desired cyclised heterocyclic molecule. The purity of compound 4a, was evidenced by MS spectra which displayed a molecular ion peak at 375 [MþH]þ. Likewise, the distinction between 4a and 5a was confirmed via 13C NMR where a carbon peak corresponding to C-S double bond attributed at d 200.7 in spectra of 4a and at 189.5 in spectra of 5a. In 1H NMR of 5a, a singlet is observed at 7.75 assigned for the one N-H proton. MS spectra displayed a molecular ion peak at 392 [MþH]þ. In order to get the detail investigation of reactions and effects of reagent concentration on products yield, we further performed the same reaction via different manners keeping changes in concentration of reagents. First, we put the variations in concentration of carbon disulfide in the reaction medium. Reactions separately with three, five and ten equivalents of CS2, did not exhibit remarkable change in the formation of compound 4a but showed a particular increase in yield of 5a (Table 1, entry 1e3). Further rising in CS2 concentration with twenty equivalents, found to be in favour of 4a yielded 90% product. Also, carbondisulfide with toluene in 1:1 ratio (by volume) gave clean single product 4a in remarkable yield (95%, Table 1, entry 4/5). Further, we varied the concentration of triphenylphosphene in similar reaction condition by using twenty

Scheme 4. Investigation of model reaction to identify the reaction products 4a and 5a.

S. No.

CS2 (equiv)

PPh3 (equiv)

Timec (h)

1 2 3 4 5 6b 7b 8b 9b

3 5 10 20 40 20 20 20 20

1.2 1.2 1.2 1.2 1.2 0.2 0.4 0.6 1.2

5 5 5 2 3 2 2 2 2

a b c d

Yieldd (%) (4a)

(5a)

52 54 58 90 95 e e e e

20 25 36 Traces Nd e e e e

Conversion (3a) a >78% >85% >90% >95% >95% >15% >45% >65% >95%

Conversion of 3a to 4a and 5a. Conversion of 3a to intermediate. Time in hour. Isolated yields of 4a and 5a after column chromatography (SiO2).

equivalents of CS2. A concentration less than one equivalent was unable to consume complete starting material, although the CS2 was taken in excess. We proceeded the reaction using PPh3 in 0.2, 0.4, 0.6 and 1.2 equivalents with 3a (1 equiv) and CS2 (20 equiv); we got increase consumption of 3a and this formation of 4a respectively (Table 1, entry 6e9). After the detailed optimization, we came to conclusion that the reaction of azido alcohol (3a, 1.0 equiv) with excess of CS2 and PPh3 (1.2 equiv) for 3 h (entry fifth, Table 1) identified as the best optimized condition for respective 1,3-oxazolidine-2-thione (4a, 95% yield). Having the various sugar azido alcohols, we now look forward the use of these compounds to get their respective carbohydrate based 1,3-oxazolidine-2-thiones. Thus, under the above optimized reaction conditions, we successfully explored the possibilities of different sugar azido alcohols (3a-l) and prepared a library of novel carbohydrate based 1,3-oxazolidine-2-thiones (4a-l) in good to excellent yields (Table 2). All the developed 1,3oxazolidine-2-thiones were characterized by spectroscopic data's including 1H NMR, 13C NMR, IR and MS. We furthermore attempted the selective synthesis of 5a and investigated a competitive study between CS2 and PPh3 to confirm the primary and the secondary role of the both reagents in reaction system and much more participation in synthesis of thiozolidinon2-thione. For this purpose, we put a set of reactions. Reaction of azidoalcohol 3a (1.0 equiv) with carbon disulfide (20.0 equiv) in toluene at 110  C exhibited no changes in reaction, even after 4 h, where starting material 3a was remained left in the reaction mixture and recovered as such (Table 1, entry 10) after column chromatography (SiO2). This result predicted for none of the interaction between secondary hydroxyl group and CS2 and indeed no formation of thiol was achieved, which was expected a reason for the formation of compound 5a through intramolecular attack of sulphur to the isothiocynate carbon. Although, subsequent addition of PPh3 furnishes good yield of compound 4a (Scheme 5, reaction II). Also, reaction was performed with one equivalent of 3a and 1.2 equivalents of PPh3 in CS2/toluene (1:1) and left it for over-night at 110  C, but selectivity for the formation of 4a was retarded the concept of CS2 attack on the tertiary carbon of oxazolidine-2-thione

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Table 2 Developed 1,3-oxazolidine-2-thiones by utilizing Scheme 3.

Entrya

Substrate (3)

Yield (%)b

Product (4)

1

90

3a

4a 88

2 4

3 b

b 85

3 3c

4c

4

90

3d

4d

5 88 3e

4e

6

95 3f 4f

7 90 3g

4g

K.B. Mishra et al. / Carbohydrate Research 450 (2017) 1e9

5

8 85 3h

4h

9 88 3i

4i

10 90 3j

4j

11 82 3k

4k

12 86 3l

4l Molar ratio of Sugar azidoalcohols & PPh3 (1:1.2) and volume ratio CS2: Toluene (1:1); bIsolated yield after column chromatography (SiO2).

a

scaffold for breaking it via releasing COS and subsequent cycloaddition by attack of resulted NH-group (Entry 5, Table 1). Further, the reaction of PPh3 with 3a in toluene displayed complete consumption of starting material confirms its primary attack on azide functionality and indicates for synthesis of intermediates (Scheme 5, reaction III) [15,34]. Subsequent addition of CS2, although in excess amount afforded mixture of 4a and 5a. With these results, we presume about the role of PPh3 in formation of compound 5a which is possible in stepwise addition of PPh3 and CS2 in reaction medium. First aid of PPh3 gave iminophosphorane within 1 h and absence of CS2 or its moderate concentration provide it time to convert in amino alcohols in diminutive quantity which is accountable for the synthesis of compound 5a [32]. Thus, utilizing the optimized reaction conditions (Scheme 3), a series of novel sugar-based thiozolidinone-2-thiones (5a-d, 5i) has been developed in 30e40% yield from the corresponding glycosyl azido alcohols (3a-d, 5i) (Table 3). All the developed 1,3-oxazolidine-2thiones were characterized by extensive spectroscopic analysis including NMR, IR and MS. We further tried for the formation of carbohydrate-based 1,3oxazolidine-2-thione via treating glycosyl epoxide 6 with KSCN and MgSO4 in aqueous medium at 100  C (Scheme 6). We

successfully isolated the reaction product using column chromatography (SiO2) and by extensive spectroscopic analysis, identified as a isomeric mixture of 1,3-oxathiolan-2-imine 7. Further work in this direction is under progress in our laboratory. Although a detailed investigation is required to establish the concern reaction mechanism for the formation of 4, however, we envisaged that the reaction may first involve the formation of iminophosphorane I by treatment of azide functionality of carbohydrate with triphenylphosphene. Then after, intermediate iminophosphorane I reacts with an excess of CS2 to generate an intermediate isothiocyanate II, which suffers intramolecular attack of vicinal hydroxyl group to afford the corresponding five membered heterocyclic rings comprising with carbohydrate that is glycosylated oxazolidinethione 4 [33] (Scheme 7). In conclusion, we have developed a new, short and practical strategy for the synthesis of diverse 1,3-oxazolidine thiones in excellent yield along with the 1,3-thiazolidinethiones in considerable yield, respectively on C-5 and C-6 position of some monosaccharides including D-glucose, D-galactose and D-Mannose. Synthesis of 1,3-oxathiolan-2-imine has also been attempted from glycosyl epoxide and found satisfactory. The protocol exhibits some important advantages, including wide substrate scope, uses of

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Scheme 6. An attempt towards synthesis of target oxazolidine-2-thione that exclusively resulted to 1,3-oxathiolan-2-imine 7.

Scheme 5. Set of reactions I-IV to investigate the path for the synthesis of 5a.

Table 3 Developed thiozolidinone-2-thione 5a-d and 5i using Scheme 3. Entrya

Substrate (3)

1

3a

Product (5)

Yield (%)b 36 Scheme 7. Proposed reaction mechanism.

5a 2

3b

3

3c

40

5b 38

cheap and readily available reagents, easy to perform, and high reaction yields. Interestingly, the protocol has been explored to generate some rare and biologically relevant heterocyclic-based glycohybrid molecules which may be recognized as a precise tool in drug discovery and development, where further work in this direction is under progress in our laboratory.

3. Experimental 3.1. General methods

5c 4

3d

5

3i

35

5d 30

5i a b

Molar ratio of Sugar azidoalcohols, PPh3, CS2 (1:1.2:10). Isolated Yield after column chromatography (SiO2).

All the reactions were performed in anhydrous solvents under an argon atmosphere in 1 h oven dried glassware at 100  C. All reagents and solvents were of pure analytical grade. Thin layer chromatography (TLC) was performed on Merk 60 F254 silica gel, pre-coated on aluminium plates and revealed with either a UV lamp (lmax ¼ 254 nm) or a specific colour reagent (Draggendorff reagent or iodine vapours) or by spraying with methanolic-H2SO4 solution and subsequent charring by heating at 100  C. NMR spectra were obtained by JEOL AL300 FT-NMR spectrometer (300 MHz for 1H NMR and 75 MHz for 13C NMR) in CDCl3. Chemical shifts given in ppm downfield from internal TMS and J values in Hz. Infrared spectra recorded as Nujol mulls in KBr plates by a PerkinElmer RX-1 (4000-450 cm1) spectrometer. The mass spectra of compounds were recorded on Jeol SX-102(EI/CI/FAB) mass spectrometry. Column chromatography was carried out on silica gel 234e400 mesh, E-Merck using n-hexane and ethyl acetate as eluent.

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3.2. General procedure for the synthesis of glycosyl azido-alcohols (3a-l)

109.3, 108.6, 96.2, 81.1, 72.6, 71.0, 70.5, 70.4, 70.4, 66.6, 44.6, 26.0, 25.8, 24.8, 24.2 ppm.

Sugar azido-alcohols 3d-l have been developed from commercial available D-mannose and D-glucose, which after isopropylidene protection gave mono-hydroxyl group bearing protected sugars. Subsequent substitution on 3-O and 1-O positions followed by selective 5,6-isopropylidene deprotection in acidic condition gave sugar diol's. These were treated with tosyl chloride and changed to tosyl sugars which were finally subjected under azidation by treating with NaN3 in DMF under inert condition. The rest of azido-alcohols were synthesized through the substitution reaction of protected sugars 1 with epichlorohydrin to furnish sugar linked epoxies 2a-c. The developed epoxides on azidation in ethanol/water using ammoniumchloride and sodium azide gave 3a-c (See Supporting information).

3.3.4. 5-(6-Methoxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol5-yl)oxazolidine-2-thione, 4d Glycosyl azidoalcohol 3d (90 mg, 0.34 mmol) and PPh3 (109 mg, 0.41 mmol) were reacted in CS2 (1.0 ml) and toluene (1.0 ml) to give compound 4d (84 mg, 90%). White solid; Rf ¼ 0.3 (35% ethyl acetate/ n-hexane); MS: m/z 276 [MþH]þ; IR (KBr) cm1 3229, 2988, 2925, 2854, 1639, 1479, 1375, 1264, 1124, 1075; 1H NMR (300 MHz, CDCl3): d 8.22 (s, 1H), 5.88e5.85 (m, 1H), 5.07 (d, J ¼ 6.1 Hz, 1H), 4.58e4.38 (m, 2H), 3.82e3.73 (m, 3H), 3.5 (s, 3H), 1.43, 1.26 (each s, 6H); 13C NMR (75 MHz, CDCl3): d 188.8, 112.1, 105.0, 83.1, 81.1, 79.4, 79.3, 57.7, 45.9, 26.5, 26.9 ppm.

3.3. General procedure for synthesis of glycosyl 1,3-oxazolidine-2thione (4a-l) A solution of glycosyl azidoalcohols (1.0 mmol) and PPh3 (1.2 mmol) in CS2/Toluene (1:1) was refluxed at 110  C. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure. Crude reaction was proceeded for purification through column chromatography using Silica gel234-400 mesh in ethyl acetate: hexane which afforded desired glycosyl 1,3-oxazolidine-2-thione 4 selectively.

3.3.5. 5-(6-Ethoxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5yl)oxazolidine-2-thione, 4e Glycosyl azidoalcohol 3e (100 mg, 0.37 mmol) and PPh3 (96 mg, 0.44 mmol) were reacted in CS2 (1.0 ml) and toluene (1.0 ml) to give compound 4e (94 mg, 88%). Brownish semi solid; Rf ¼ 0.3 (35% ethyl acetate/n-hexane); MS: m/z 290 [MþH]þ; IR (KBr) cm1 3275, 2925, 2854, 1745, 1638, 1465, 1261, 1166, 1087; 1 H NMR (300 MHz, CDCl3): d 8.08 (s, 1H), 5.92 (d, J ¼ 3.0 Hz, 1H), 5.19e5.11 (m, 1H), 4.58e4.45 (m, 2H), 3.97 (d, J ¼ 2.7 Hz, 1H), 3.92e3.79 (m, 2H), 3.76e3.66 (m, 1H), 3.58e3.48 (m, 1H), 1.50 (s, 3H), 1.32 (s, 3H), 1.19 (t, J ¼ 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 189.1, 112.2, 105.4, 82.1, 81.6, 79.5, 65.9, 46.0, 26.6, 26.1, 14.9 ppm.

3.3.1. 5-(((1,2:5,6-Di-O-isopropylidene-a-D-glucofuranos)oxy) methyl)oxazolidine-2-thione, 4a Glycosyl azidoalcohol 3a (125 mg, 0.35 mmol) and PPh3 (110 mg, 0.42 mmol) were reacted in CS2 (1.0 ml) and toluene (1.0 ml) to give compound 4a (124 mg, 95%). Yellowish semi solid; Rf ¼ 0.25 (60% ethyl acetate/n-hexane); MS: m/z 376 [MþH]þ; IR (KBr) cm1 3308, 2985, 2933, 1729, 1531, 1474, 1454, 1374, 1310, 1213, 1083; 1H NMR (300 MHz, CDCl3): d 8.05 (s, 1H), 5.89 (s, 1H), 5.04 (m, 1H), 4.59 (dd, J ¼ 3.0 Hz, 15.3 Hz, 1H), 4.30e4.24 (m, 1H), 4.21e3.80 (m, 7H), 3.78e3.64 (m, 1H), 1.49, 1.42, 1.35, 1.32 (each s, 12H); 13C NMR (75 MHz, CDCl3): d 189.5, 111.9, 109.1, 105.2, 83.3, 82.3, 81.0, 80.6, 72.2, 70.0, 67.1, 45.8, 26.6, 26.0, 25.1 ppm.

3.3.6. 5-(6-(Benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3] dioxol-5-yl)oxazolidine-2-thione, 4f Glycosyl azidoalcohol 3f (100 mg, 0.30 mmol) and PPh3 (94 mg, 0.36 mmol) were reacted in CS2 (1.0 ml) and toluene (1.0 ml) to give compound 4f (102 mg, 95%). White solid; Rf ¼ 0.3 (35% ethyl acetate/n-hexane); MS: m/z 352 [MþH]þ; cm1 3395, 2962, 2925, 2854, 1710, 1674, 1455, 1375, 1261, 1079; 1H NMR (300 MHz, CDCl3): d 7.30e7.19 (m, 6H), 5.86 (d, J ¼ 3.6 Hz, 1H), 5.08 (dd, J ¼ 6.9 Hz, 15.6 Hz, 1H), 4.62e4.51 (m, 3H), 4.47e4.38 (m, 1H), 4.06 (d, J ¼ 3.3 Hz, 1H), 3.85e3.67 (m, 2H), 1.42, 1.25 (each s, 6H); 13C NMR (75 MHz, CDCl3): d 189.4, 136.9, 128.7, 128.3, 127.8, 112.4, 105.5, 82.0, 81.4, 79.6, 72.4, 46.0, 26.7, 26.0 ppm.

3.3.2. 5-(((3-O-Benzyl-1,2-O-isopropylidene-a-D-xylofuranos)oxy) methyl)oxazolidine-2-thione, 4b Glycosyl azidoalcohol 3b (100 mg, 0.26 mmol) and PPh3 (82 mg, 0.31 mmol) were reacted in CS2/Toluene (1 ml:1 ml) to give compound 4b (92 mg, 88%). Colorless liquid; Rf ¼ 0.25 (60% ethyl acetate/n-hexane); MS: m/z 396 [MþH]þ; IR (KBr) cm1 3316, 2985, 2924, 1643, 1531, 1474, 186, 1317, 1215, 1077; 1H NMR (300 MHz, CDCl3): d 7.39e7.30 (m, 6H), 5.93 (d, J ¼ 3.6 Hz, 1H), 5.02e4.95 (m, 1H), 4.71e4.46 (m, 3H), 4.35 (m, 1H), 3.95 (d, J ¼ 2.7 Hz, 1H), 3.83e3.53 (m, 6H), 1.49, 1.32 (each s, 6H); 13C NMR (75 MHz, CDCl3): d 189.7, 137.4, 132.2, 128.5, 127.7, 111.8, 105.1, 82.1, 81.8, 81.1, 79.0, 71.8, 70.6, 69.4, 45.6, 26.7, 26.1 ppm.

3.3.7. 5-(2,2-Dimethyl-6-propoxytetrahydrofuro[2,3-d][1,3]dioxol5-yl)oxazolidine-2-thione, 4g Glycosyl azidoalcohol 3g (110 mg, 0.36 mmol) and PPh3 (114 mg, 0.43 mmol) were reacted in CS2 (1.0 ml) and toluene (1.0 ml) to give compound 4g (98 mg, 90%). White solid; Rf ¼ 0.3 (35% ethyl acetate/ n-hexane); MS: m/z 304 [MþH]þ; IR (KBr) cm1 3311, 3067, 2963, 2926, 2873, 1749, 1543, 1457, 1386, 1224, 1085; 1H NMR (300 MHz, CDCl3): d 7.52 (s, 1H), 5.83 (d, J ¼ 3.6 Hz, 1H), 5.12e5.04 (m, 1H), 4.49e4.36 (m, 2H), 3.90e3.68 (m, 3H), 3.54e3.34 (m, 2H), 1.54e1.47 (m, 2H), 1.42, 1.25 (each s, 6H), 0.84 (t, J ¼ 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 189.2, 112.2, 105.3, 81.9, 81.7, 79.6, 79.5, 72.1, 46.0, 26.7, 26.1, 22.7, 10.3 ppm.

3.3.3. 5-(((1,2:3,4-di-O-isopropylidene-a-D-galactopyranos)oxy) methyl)oxazolidine-2-thione, 4c Glycosyl azidoalcohol 3c (106 mg, 0.3 mmol) and PPh3 (82 mg, 0.36 mmol) were reacted in CS2 (1.0 ml) and toluene (1.0 ml) to give compound 4c (101 mg, 85%). Viscous liquid; Rf ¼ 0.25 (60% ethyl acetate/n-hexane); MS: m/z 376 [MþH]þ; IR (KBr) 3385, 2923, 2936, 1750, 1638, 1531, 1438, 1382, 1259, 1061; 1H NMR (300 MHz, CDCl3): d 7.55 (s, 1H), 5.53 (m, 1H), 5.06e4.99 (m, 1H), 4.60 (d, J ¼ 7.8 Hz, 1H), 4.31e4.20 (m, 2H), 3.96 (m, 1H), 3.78e3.61 (m, 6H), 1.53, 1.44, 1.40, 1.33 (each s, 12H); 13C NMR (75 MHz, CDCl3): d 189.7,

3.3.8. 5-(6-(Isopentyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3] dioxol-5-yl)oxazolidine-2-thione, 4h Glycosyl azidoalcohol 3h (90 mg, 0.28 mmol) and PPh3 (89 mg, 0.34 mmol) were reacted in CS2 (1.0 ml) and toluene (1.0 ml) to give compound 4h (78 mg, 85%). White solid; Rf ¼ 0.3 (35% ethyl acetate/n-hexane); MS: m/z 332 [MþH]þ; IR (KBr) cm1 3317, 2959, 2931, 2870, 1747, 1547, 1473, 1386, 1288, 1227, 1116, 1085; 1H NMR (300 MHz, CDCl3): d 8.03 (s, 1H), 5.91 (d, J ¼ 3.0 Hz, 1H), 5.13 (dd, J ¼ 6.9 Hz, 15.0 Hz, 1H), 4.57e4.44 (m, 2H), 3.96e3.45 (m, 5H), 1.66e1.64 (m, 1H), 1.49e1.43 (m, 5H), 1.32 (s, 3H), 0.90 (d, J ¼ 6.3 Hz,

8

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6H); 13C NMR (75 MHz, CDCl3): d 189.2, 112.2, 105.3, 81.9, 79.7, 79.5, 68.9, 45.9, 38.2, 26.7, 26.6, 24.8, 22.3 ppm. 3.3.9. 5-(6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol4-yl)oxazolidine-2-thione, 4i Glycosyl azidoalcohol 3i (110 mg, 0.42 mmol) and PPh3 (132 mg, 0.5 mmol) were reacted in CS2 (1.0 ml) and toluene (1.0 ml) to afford compound 4i (101 mg, 88%). Yellowish semi solid; Rf ¼ 0.3 (35% ethyl acetate/n-hexane); MS: m/z 276 [MþH]þ; IR (KBr) cm1 3276, 2925, 2853, 1745, 1639, 1467, 1262, 1162, 1098; 1H NMR (300 MHz, CDCl3): d 8.38 (s, 1H), 7.61e7.37 (m, 5H), 5.08e4.73 (m, 2H), 4.72e4.28 (m, 5H), 3.72e3.63 (m, 2H), 1.33, 1.19 (each s, 6H); 13 C NMR (75 MHz, CDCl3): d 188.7, 136.9, 131.9, 128.4, 128.0, 112.6, 105.5, 84.6, 80.2, 78.9, 78.6, 69.2, 45.3, 25.3, 23.8 ppm. 3.3.10. 5-(6-(Benzyloxy)-2,2-dimethyltetrahydrofuro[3,4-d][1,3] dioxol-4-yl)oxazolidine-2-thione, 4j Glycosyl azidoalcohol 3j (100 mg, 0.3 mmol) and PPh3 (93 mg, 0.35 mmol) were reacted in CS2 (1.0 ml) and toluene (1.0 ml) to give compound 4j (94 mg, 90%). White solid; Rf ¼ 0.3 (35% ethyl acetate/ n-hexane); MS: m/z 352 [MþH]þ; IR (KBr) cm1 3325, 3142, 2989, 2922, 2854, 1711, 1525, 1476, 1454, 1378, 1303, 1174, 1087; 1H NMR (300 MHz, CDCl3): d 8.25 (s, 1H), 5.23e5.17 (m, 1H), 4.95 (s, 1H), 4.81e4.78 (m, 1H), 4.58 (d, J ¼ 5.7 Hz, 1H), 4.34 (s, 1H), 3.97e3.76 (m, 2H), 3.34 (s, 3H), 1.42, 1.28 (each s, 6H); 13C NMR (75 MHz, CDCl3): d 188.9112.7, 107.3, 84.6, 80.4, 78.9, 78.4, 54.7, 45.3, 25.3, 23.7 ppm. 3.3.11. 5-(2,2-Dimethyl-6-propoxytetrahydrofuro[3,4-d][1,3]dioxol4-yl)oxazolidine-2-thione, 4k Glycosyl azidoalcohol 3k (95 mg, 0.33 mmol) and PPh3 (104 mg, 0.40 mmol) were reacted in CS2/Toluene (1 ml: 1 ml) to give compound 4k (81 mg, 82%).Oily liquid; Rf ¼ 0.3 (35% ethyl acetate/ n-hexane); MS: m/z 304 [MþH]þ; IR (KBr) cm1 3311, 3060, 2958, 2926, 2875, 1740, 1553, 1455, 1386, 1224, 1081; 1H NMR (300 MHz, CDCl3): d 8.21 (s, 1H), 5.24e4.95 (m, 2H), 4.75e4.52 (m, 2H), 4.28 (d, J ¼ 3.3 Hz, 1H), 3.89e3.69 (m, 2H), 3.54 (dd, J ¼ 6.6 Hz, 15.9 Hz, 1H), 3.27 (dd, J ¼ 6.6 Hz, 15.9 Hz, 1H), 1.50e1.33 (m, 5H), 1.21 (s, 3H), 0.83 (t, J ¼ 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 188.9, 112.6, 106.0, 84.6, 80.3, 78.9, 78.3, 69.2, 45.4, 25.2, 23.7, 22.3, 10.2 ppm. 3.3.12. 5-(6-(Isopentyloxy)-2,2-dimethyltetrahydrofuro[3,4-d][1,3] dioxol-4-yl)oxazolidine-2-thione, 4l Glycosyl azidoalcohol 3l (108 mg, 0.34 mmol) and PPh3 (107 mg, 0.41 mmol) were reacted in CS2 (1.2 ml) and toluene (1.2 ml) to give compound 4l (96 mg, 86%).White solid; Rf ¼ 0.3 (35% ethyl acetate/ n-hexane); MS: m/z 332 [MþH]þ; IR (KBr) cm1 3319, 2928, 2872, 1743, 1684, 1587, 1531, 1469, 1376, 1210, 1083; 1H NMR (300 MHz, CDCl3): d 8.34 (s, 1H), 5.23e5.16 (m, 1H), 5.04 (s, 1H), 4.80 (dd, J ¼ 3.9 Hz, 5.7 Hz, 1H), 4.59 (d, J ¼ 5.7 Hz, 1H), 4.34 (t, J ¼ 3.6 Hz, 1H), 3.95e3.45 (m, 3H), 3.42e3.31 (m, 1H), 1.70e1.62 (m, 1H), 1.46e1.42 (m, 5H), 1.28 (s, 3H), 0.89 (d, J ¼ 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3): d 188.9, 112.6, 106.2, 84.7, 80.4, 78.9, 78.3, 66.0, 45.4, 37.8, 25.2, 24.7, 23.7, 22.3, 22.2 ppm. 3.4. General procedure for synthesis of glycosyl 1,3-oxazolidine-2thione (5a-e) A solution of glycosyl azidoalcohols (1.0 mmol), PPh3 (1 mmol) and CS2 (10 mmol) in anhydrous toluene (5 ml) was refluxed at 110  C. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure which afforded viscous crude. Reaction crude was purified using column chromatography in ethyl acetate/n-hexane gave desired glycosyl 1,3thiazolidine-2-thione as minor reaction product.

3.4.1. 5-(((1,2:5,6-Di-O-isopropylidene-a-D-glucofuranos)oxy) methyl)thiazolidine-2-thione, 5a (98 mg, 36% Yield), Oily Viscous liquid; Rf ¼ 0.4 (60% ethyl acetate/n-hexane); MS: m/z 392 [MþH]þ; IR (KBr) cm1 1 3298, 2987, 2934, 1629, 1531, 1474, 1375, 1313, 1215, 1073; 1H; 1H NMR (300 MHz, CDCl3): d 7.75 (s, 1H), 5.86 (t, J ¼ 3.6 Hz, 1H), 4.53 (d, J ¼ 3.3 Hz, 1H), 4.25e4.21 (m, 1H), 4.19e3.83 (m, 7H), 3.80e3.72 (m, 2H), 1.49, 1.41, 1.35, 1.31 (each s, 12H); 13C NMR (75 MHz, CDCl3): d 200.7, 112.1, 109.3, 105.3, 83.0, 82.3, 81.1, 72.2, 71.5, 67.5, 52.7, 48.6, 26.7, 26.6, 26.1, 25.3 ppm. 3.4.2. 5-(((3-O-Benzyl-1,2-O-isopropylidene-a-D-xylofuranos)oxy) methyl)thiazolidine-2-thione, 5b (87 mg, 40% Yield), Oily liquid; Rf ¼ 0.4 (60% ethyl acetate/nhexane); MS: m/z 412 [MþH]þ; IR (KBr) cm1 3251, 2986, 2931, 1708, 1629, 1579, 1488, 1383, 1258, 1069; 1H NMR (300 MHz, CDCl3): d 7.34e7.16 (m, 6H), 5.93 (d, J ¼ 2.7 Hz, 1H), 4.71e4.62 (m, 2H), 4.46 (d, J ¼ 11.7 Hz, 1H), 4.33 (m, 1H), 3.96e3.52 (m, 8H), 1.49, 1.32 (each s, 6H); 13C NMR (75 MHz, CDCl3): d 200.6, 137.3, 128.6, 128.1, 127.8, 127.7, 111.8, 105.1, 82.0, 81.7, 79.1, 72.1, 71.8, 69.1, 52.8, 48.6, 26.7, 26.1 ppm. 3.4.3. 5-(((1,2:3,4-di-O-isopropylidene-a-D-galactopyranos)oxy) methyl)thiazolidine-2-thione, 5c (65 mg, 38% Yield), Brownish solid; Rf ¼ 0.4 (60% ethyl acetate/nhexane); MS: m/z 392 [MþH]þ; IR (KBr) cm1 3314, 2923, 2936, 1716, 1640, 1532, 1438, 1385, 1226, 1073; 1H NMR (300 MHz, CDCl3): d 8.13 (s, 1H), 5.46 (d, J ¼ 3.6 Hz, 1H), 4.57e4.17 (m, 4H), 3.90 (d, J ¼ 5.7 Hz, 1H), 3.63e3.45 (m, 5H), 3.22e3.12 (m, 1H), 1.48, 1.39, 1.32, 1.27 (each s, 12H); 13C NMR (75 MHz, CDCl3): d 200.8, 109.4, 108.6, 96.1, 72.2, 71.3, 70.8, 70.4, 69.2, 66.5, 63.4, 62.3, 34.5, 25.8, 25.7, 24.7, 24.2 ppm. 3.4.4. 5-(6-Methoxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol5-yl)thiazolidine-2-thione, 5d (40 mg, 35% Yield), Brownish solid; Rf ¼ 0.25 (35% ethyl acetate/ n-hexane); MS: m/z 292 [MþH]þ; IR (KBr) cm1 3321, 3088, 2989, 2961, 2906, 1749, 1525, 1471, 1386, 1262, 1178, 1056; 1H NMR (300 MHz, CDCl3): d 7.62 (s, 1H), 5.94 (d, J ¼ 3.6 Hz, 1H), 4.63e4.46 (m, 2H), 4.29e4.26 (m, 1H), 3.81 (d, J ¼ 3.3 Hz, 1H), 3.54e3.44 (m, 5H), 1.50, 1.34 (each s, 6H); 13C NMR (75 MHz, CDCl3): d 200.9, 112.2, 105.1, 84.6, 81.1, 80.0, 63.0, 57.6, 35.1, 26.6, 26.0 ppm. 3.4.5. 5-(6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol4-yl)thiazolidine-2-thione, 5i (36 mg, 30% Yield), Brownish semi solid; Rf ¼ 0.25 (35% ethyl acetate/n-hexane); MS: m/z 292 [MþH]þ; IR (KBr) cm1 3270, 2928, 2845, 1750, 1645, 1470, 1260, 1167, 1095; 1H NMR (300 MHz, CDCl3): d 7.69 (m, 1H), 4.95 (s, 1H), 4.80e4.72 (m, 1H), 4.62e4.50 (m, 2H), 4.04 (dd, J ¼ 3.6 Hz, 7.2 Hz, 1H), 3.69e3.66 (m, 1H), 3.45e3.34 (m, 4H), 1.49, 1.30 (each s, 6H); 13C NMR (75 MHz, CDCl3): d 201.2, 113.3, 107.3, 85.2, 80.0, 79.0, 63.3, 54.9, 34.9, 25.8, 24.3 ppm. 3.5. General procedure for synthesis of glycosyl 1,3-oxathiolan-2imine (7) A suspension of glycosyl epoxide 6 (1.0 mmol), KSCN (1.0 mmol) and MgSO4 (10 mmol) in water (5 ml) was refluxed. After completion of the reaction (monitored by TLC), reaction mixture was extracted with ethyl acetate and water. Organic layer was dried with MgSO4 and evaporated under reduced pressure which afforded viscous crude. Reaction crude was purified using column chromatography (SiO2) in ethyl acetate/n-hexane afforded compound 7. White Solid, 30%, Rf ¼ 0.25 (35% ethyl acetate/n-hexane); MS: m/z 252 [MþH]þ; IR (KBr) cm1 3420, 2918, 2833, 1645, 1473,

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1254, 1160, 1090; 1H NMR (300 MHz, CDCl3): 7.26e7.24 (m, 6H), 5.98 (s, 0.56 H), 5.83 (d, J ¼ 3.0 Hz, 1H), 4.82e4.79 (m, 66 H), 4.61e4.48 (m, 3.36H), 4.29e4.27 (m, 0.77 H), 4.02 (s, 1.67 H), 3.59e3.57 (m, 1.58), 1.41 (s, 3H), 1.24 (s, 3H); 13C NMR (75 MHz, CDCL3) d 159.6, 137.1, 128.5, 128.0, 127.7, 112.1, 105.2, 82.2, 81.5, 80.2, 80.1, 73.1, 72.9, 72.4, 42.8, 26.6, 26.0 ppm. Acknowledgments VKT sincerely thanks Science and Engineering Research Board (SERB), Department of Science & Technology, New Delhi (Grant No. EMR/2016/001123) for the funding. KBM gratefully acknowledge DST-SERB, New Delhi for National Post Doctoral Fellowship (NPDF/ 2016/001709) and his NPDF guide Dr J. Kandasamy, IIT-BHU for the valuable support. Authors gratefully acknowledge CISC, Department of Chemistry, Banaras Hindu University (BHU) and SAIF, CSIR-Central Drug Research Institute, Lucknow for providing the spectroscopic studies of developed molecules. Appendix A. Supporting information Supplementary data associated with this article can be found, in the online version, at https://dx.doi.org/10.1016/j.carres.2017.08. 002. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]

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