First noscapine glycoconjugates inspired by click chemistry

Abstract

A number of novel 7-O-noscapine glycoconjugates have been synthesized starting from noscapine, an alkaloid found in the opium plant, via two successive steps. The first step is a selective 7-O-demethylation of noscapine and the next is a subsequent propargylation which affords 7-O-propargyl noscapine (3) in good yield. The structure was confirmed by extensive spectroscopic data including single crystal X-ray data. The 1,3-dipolar cycloaddition of the developed noscapine derivative 3 with glycosyl azides 6a–m was investigated to give the triazole-linked second-generation noscapine analogs in their glycoconjugate forms (8a–m) to augment the therapeutic efficacy of noscapine.

---

Introduction

Natural products and their derivatives are now well established biologically relevant moieties and participate in critical roles in modern drug discovery and development.¹ Alkaloids obtained from nature are the most potent and pharmaceutically interesting scaffolds.² One member of this group, noscapine (‘a phthalideisoquinoline alkaloid’), has a benzofuranone ring attached to the hetero ring of isoquinoline. Noscapine is available in about 7% abundance during opium harvesting.³ It has been used as an antitussive agent for several decades because of its favourable toxicity profile. Recently, it was found to bind tubulin and alter its conformation and properties, and alter microtubule dynamics.^4,5 Additionally, noscapine has also shown the successful inhibition of various neoplasms in vitro as well as in vivo, such as leukaemia and lymphoma,^6–8 along with melanoma,⁹ ovarian cancer,¹⁰ gliomas,¹¹ and breast,¹² lung¹³ and colon¹⁴ cancers. Recently, Joshi et al. have assessed the mechanistic path of this anticancer effect after performing several studies where they found that noscapine can perturb tubulin dynamics.¹⁵ Recent literature has revealed that chemical modifications at its 7-position via selective demethylation on the benzofuranone ring system has been achieved and showed that the O-alkylated derivatives, including the 7-hydroxyl compounds, were 100-fold more effective than the parent noscapine.^16,17 This strongly suggests that the presence and modification of the benzofuranone ring in the parent molecule has a significant impact on its biological activity (Fig. 1).

Fig. 1 Structure of noscapine (1a) and its potent biologically active 7-O-analogs (1b, 1c), against tubulin polymerization.

Carbohydrates and their diverse saccharide forms (mono to poly) always attract synthetic chemists for their utilization in medicinal chemistry because their use yields effective control over biological functions.¹⁸ Additionally, the multivalent nature of carbohydrate molecules is frequently used to enhance their affinities for targets in different biological processes, such as the binding of bacteria, bacterial toxins, galectins and other lectins.¹⁹ Although the carbohydrates alone demonstrate no therapeutic action, their presence in synthetic and naturally occurring molecules creates a prominent change in their physical, chemical and biological properties. This also influences the biological activity of most of the drugs which incorporate them.²⁰

The Cu(I)-catalysed click reaction^21,22 is a precise tool for the joining of two dissimilar moieties having azide and terminal alkyne functionalities and has emerged as an important strategy for the discovery and optimization of leads. This strategy is also being used in the exploration of effective drug candidates against various therapeutic strains.^23–28 Based upon this impetus and with our previous experience,^29–32 herein we have successfully incorporated a terminal alkyne functionality in naturally occurring α-noscapine at its C-7 position. This strategy afforded novel 7-O-analogs which were further utilized for developing second-generation noscapine derivatives in their glycoconjugate forms using Cu(I)-catalyzed click chemistry. We hope this will satisfy the increasing demand for more potent analogs of this molecule to modulate microtubules more effectively.

Results and discussion

Our strategy started with the demethylation of the parent compound noscapine. Sodium azide and sodium iodide in dimethylformamide (DMF) were used to cleave the methyl group selectively at position 7 of the benzofuranone ring.^17b Briefly, noscapine was dissolved in anhydrous DMF along with sodium azide and sodium iodide followed by stirring at 140 °C for 4 h to obtain 7-hydroxy noscapine 2 (Scheme 1). Compound 2 was then propargylated at its hydroxyl moiety using K₂CO₃ in refluxing acetone at 80 °C to afford 7-O-propargylated noscapine 3 in 75% yield (Scheme 1). Surprisingly, this reaction did not occur in DMF at room temperature using the same base. Compound 3 served as a scaffold to synthesize various C-7-modified derivatives of noscapine 8a–m in their glycoconjugate form. The structures of the new C-7 analogs of noscapine 3 were deduced from their extensive spectral studies (IR, NMR, and MS). Single crystal X-ray analysis of compound 3 confirmed the selective demethylation of the parent molecule at the C-7 position.

Scheme 1 Synthesis of 7-O-propargyl noscapine derivative via selective demethylation and subsequent propargylation.

The ¹H NMR spectrum of compound 3 exhibited one singlet signal at δ 2.62, merged with the 3 protons of N–Me, which was assigned to the acetylene proton. Shifting of the ortho-coupled aromatic protons from δ 5.11 (d, J = 8.4 Hz) to 6.10 (d, J = 8.4 Hz) for C-9 and from δ 6.44 (d, J = 8.4 Hz) to 6.96 (d, J = 8.4 Hz) for C-10 also confirmed the substitution at the 7-hydroxy group. In addition to other signals, the appearance of a multiplet at δ 5.05 attributed to OCH₂ finally confirmed the addition of the propargyl group, leading to the formation of compound 3. In the ¹³C NMR, two new resonances were observed at δ 81.9 and δ 75.4 which were assigned to both acetylene carbons. The molecular structure of compound 3 was also confirmed by single crystal X-ray analysis (Fig. 2, see ESI Table 1†).

Fig. 2 Molecular structure of 3. Thermal ellipsoids of C, N, and O are set at 40% probability.

Once we achieved the second generation (C-7) noscapine analogue 3, having one terminal alkyne, we attempted the synthesis of various sugar azides for glycoconjugation of the novel noscapine derivative. We prepared sugar azides with the economical and readily available monosaccharides, i.e. D-glucose, D-galactose, D-xylose and a disaccharide, lactose, which, after processing through a number of high-yielding steps involving protections and diverse modifications, afforded deoxy-azido sugars 6a–j in good yields.³³ The sugar azides 6k–m were synthesised via a substitution reaction on the orthogonally protected carbohydrate with epichlorohydrin in the presence of NaH in dry DMF at 0 °C–r.t., which afforded a diastereoisomeric mixture of glycosyl epoxides 5k–m. These epoxides, on reaction with NaN₃ and NH₄Cl in EtOH/H₂O at 65 °C, afforded their respective O-substituted glycosyl azido alcohols 6k–m (Scheme 2).

Scheme 2 Synthesis of glycosyl azido alcohols 6k–m using orthogonally protected sugars and epichlorohydrin.

All the developed azidosugars 6a–m underwent glyco-conjugation using compound 3 via the copper-catalyzed azide–alkyne click reaction. Generally, copper-catalyzed azide–alkyne click reactions require the presence of Cu(I) species which may be provided directly or in situ depending on the catalyst. Hence, we carried out the reaction using both methods, first using CuI/DIPEA in dichloromethane and then CuSO₄·5H₂O/sodium ascorbate in aqueous medium. We preferred the former reaction system due to its better yield and shorter reaction time (Scheme 3). Hence, the click reaction of deoxy-azido sugar 6a (0.19 mmol) with 3 (0.16 mmol) in the presence of CuI (0.08 mmol) and DIPEA (0.16 mmol) was carried out in anhydrous CH₂Cl₂ under argon atmosphere at ambient temperature to afford 7-O-noscapine triazolyl glycoconjugate 8a regioselectively in 95% yield. The regioisomeric nature of compound 8a was established based on its spectroscopic data (IR, MS, ¹H NMR and ¹³C NMR) and the purity (evidenced by HRMS) is in close agreement with calculated values.

Scheme 3 Optimization of reaction medium and Cu(I) catalyst for CuAAC reaction of 3 and 6a.

In the ¹H NMR spectrum, two doublets and one singlet of the aromatic protons resonated at δ 6.95 (d, J = 8.4 Hz), 6.07 (d, J = 8.4 Hz) and δ 6.30, along with a triazolyl proton singlet observed at δ 8.25. The anomeric proton of the glucopyranose sugar resonated as a doublet at δ 5.86 (J = 9.6 Hz), while four other sugar protons, along with one noscapine and two oxymethylene protons, appeared at their usual chemical shift values, i.e. between δ 5.60–5.22. Two singlets of methyl protons appeared at δ 4.03, 3.84 and were established as the methoxy signals present at the aromatic rings of noscapine and another singlet at δ 2.54 was established as the N–Me protons of the hetero carbon ring. The twelve protons of the acetyl moieties on the sugar scaffold were observed as four singlets having three protons each at δ 2.10, 2.07, 2.04 and 1.85. A total of seven remaining protons of noscapine were assigned at δ 5.93 (s, 2H), 4.40 (d, J = 3.9 Hz, 1H), 2.33 (m, 2H), one merged with the acetyl protons and the last one with the N-methyl protons. One of the remaining sugar protons in compound 8a resonated at δ 4.28 (dd, J = 4.8 & 12.6 Hz) and the next one appeared as a multiplet at δ 4.16, which confirms the structure.

Further, having established the reaction conditions for the regioselective cycloaddition of the 7-O-propargyl noscapine 3, we explored the scope of other sugar azides in this cycloaddition and prepared a library of 7-O-noscapine triazolyl glycoconjugates 8b–m in efficient yields (Table 1). Using extensive spectral studies (IR, MS, ¹H, and ¹³C NMR), the structures of all the developed noscapine glycoconjugates 8a–m were elucidated.

Table 1 Synthesis of 7-O-Noscapine glycoconjugates 8a–m via Cu-catalyzed click chemistry

Entry	Sugar azides (6a–m)^a	Noscapine glycoconjugates (8a–m)^b	Time (h)	Yield^c (%)
a Molar ratios: deoxy-azido sugar (1.0 equiv.), 7-O-propargylated noscapine (1.0 equiv.), CuI (0.5 equiv.) and DIPEA (1.0 equiv.).b Noscapine glycoconjugates.c Isolated yield by column chromatography (SiO2).
1			14	95
2			12	90
3			12	84
4			16	88
5			12	94
6			14	85
7			15	90
8			13	86
9			12	85
10			12	80
11			14	82
12			14	84
13			15	90

---

Weak interactions in compound 3 and their biological importance via stabilisation of geometrical conformations

Noncovalent inter- and intramolecular interactions play a subtle role in molecular recognition and conformational stabilization within the crystal lattice for biological assays.^34,35 Therefore, it is important to quantify the various interactions within the molecules in the crystal structures. Compound 3 is rich in C–H donors and O, π acceptors. In the isoquinoline ring, the N-methyl hydrogens, methylene hydrogens and also the acetylene acidic hydrogen act as a donor whenever oxygen atoms and the π-electron ring system act as acceptors. Intramolecular and intermolecular CH⋯O and CH⋯π interactions stabilize the geometry of the molecule and show their effects in the relative changes in the geometrical conformations of compound 3.

These weak interactions generate a number of six member ring systems which were known for their crucial role in biological activities.³⁵ Intramolecular interactions have been shown with two six member ring along with a CH⋯π ring system.

Out of various types of intramolecular interactions (Fig. 3), three of them that cause conformational changes have been presented. A CH⋯O (I) interaction between the N-methyl hydrogens and furanone ring oxygen, with a measured distance of 2.538 Å, and a CH⋯π (III) interaction between the methylene hydrogen of quinoline and aromatic system fused with the lactone ring, with a measured distance of 2.977 Å, are attempting to place both of the fused ring systems in parallel planes, but the repulsion between the oxygen lone pairs of both fused ring systems pushes them to their maximum distances and overcomes the effect of a possible π⋯π interaction between both of the benzene rings. One of the CH⋯O (II) interactions, with a measured distance of 2.37 Å, generates a six-membered ring system. All these weak interactions confirm the efficacy of the developed molecules in a biological system due to the presence of a number of interacting sites, which create the effect of interacting with problematic enzymes and proteins to reduce their activities during clinical treatment.³⁶ Also, intermolecular interactions within the crystal packing have an effect on geometrical conformations and form dimeric structures. The dimeric structures (IV, V, VI) appeared in three forms depending on the type of interactions and the positions of their sites (Fig. 4).

Fig. 3 Intramolecular CH⋯O and CH⋯π interactions. Weak interactions are represented by broken light green lines. Carbon atoms are colored brown, hydrogen atoms green, oxygen atoms red, and nitrogen atoms blue.

Fig. 4 Intermolecular CH⋯O and CH⋯π interactions. Weak interactions are represented by broken light green lines. Carbon atoms are brown, hydrogen atoms green, oxygen atoms red, and nitrogen atoms blue.

Substitution at the C-7 position in the parent noscapine scaffold creates new interaction sites, such as CH⋯O, with measured distances of 2.503 Å (IV) and 2.587 Å (VI), between the acetylene and methylene hydrogens of the adjoining part and the oxygen of the parent molecule. An intermolecular CH⋯π (2.503 Å, V) interaction has effects on the conformations in the crystal packing. Thus, the creation of new binding sites in noscapine C-7 analog 3 is evidenced for the well-known potency towards modulating tublin polymerization. Furthermore, because of the multivalent nature of carbohydrates,¹⁸ their introduction to noscapine is envisaged to provide more binding sites and could result in increased efficacy; however, continued efforts are required for the conclusive investigation to this end.

Conclusion

In conclusion, a number of sugar azides were prepared and further subjected to a Cu(I)-catalyzed azide alkyne cycloaddition reaction (click) with 7-O-propargylated noscapine. We have developed thirteen second generation noscapine triazolyl glycoconjugates at the C-7 position in good to excellent yields. Also, the role of weak interactions has been correlated with the biological action of noscapine analogs. The methodology is efficient for the preparation of modified conjugates of noscapine to improve its therapeutic efficacy and its pharmacological properties. Further research into the development of noscapine glycoconjugates as potential anti-cancer agents is in progress in our laboratory.

Experimental

General methods

All of the reactions were performed in anhydrous solvents (where required) under an argon atmosphere in oven dried glassware at 100 °C. All reagents and solvents were of pure analytical grade. Thin-layer chromatography (TLC) was performed on 60 F₂₅₄ silica gel, pre-coated on aluminum plates, and revealed with either a UV lamp (λ_max = 254 nm), a specific colour reagent (Draggendorff reagent or iodine vapour) or by spraying with methanolic-H₂SO₄ solution and subsequent charring by heating at 100 °C. ¹H and ¹³C NMR were recorded at 300 and 75 MHz, respectively. Chemical shifts are given in ppm downfield from internal TMS; J values are in Hz. The high resolution mass spectrometry (HRMS) was carried out using electrospray ionization mass spectrometry. The infrared spectra were recorded as Nujol mulls on KBr plates. Single-crystal X-ray data were collected on an Xcalibur Eos (Oxford) CCD-diffractometer.

General procedure for synthesis of sugar azides (6a–g). The compounds 6a–g were prepared from readily available carbohydrates (D-glucose, D-galactose, and D-ribose etc.) using standard protection and modification methodologies.³³

General procedure for the synthesis of glycosyl epoxides (5k–m). A solution of orthogonally protected sugar 4k–m having one free hydroxyl group (1.0 mmol) in anhydrous DMF was cooled to 0 °C and sodium hydride (2.0 equiv.) was added portion-wise. The reaction mixture was stirred at 0 °C under argon atmosphere for 20 minutes. Epichlorohydrin (1.2 mmol) was added at 0 °C and allowed to stir for 12 hour at room temperature. Upon completion of the reaction, the remaining sodium hydride was quenched with water; the solvent was removed under reduced pressure followed by extraction with ethyl acetate. The combined organic layer was washed with brine solution, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to get the crude product. Purification using flash chromatography (ethyl acetate/n-hexane) afforded the desired glycosyl epoxide 5k–m.

General procedure for the synthesis of glycosyl azido alcohols 6k–m. A solution of glycosyl epoxide 5k–m in EtOH–H₂O (1 : 1) was treated with NaN₃ and NH₄Cl at 65 °C for 8 h. Upon completion of the reaction, the solvent was removed under reduced pressure, and extracted with ethyl acetate and water. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum, followed by flash chromatography (ethyl acetate/hexane) affording the desired glycosyl azido alcohol 6k–m in good yield.

General procedure for 7-O-propargyl noscapine 3. To a stirring solution of compound 2 (1.0 g, 2.5 mmol) in dry acetone (25 mL), propargyl bromide (0.291 mL, 3.2 mmol) and K₂CO₃ (690 mg, 5.0 mmol) were added at room temperature. The reaction was fitted with a water condenser and refluxed at 80 °C under inert conditions for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated in vacuo, extracted with CH₂Cl₂ (2 × 50 mL) and washed with H₂O (10 mL). The organic layer was separated and dried over anhydrous Na₂SO₄, and the solvent evaporated under reduced pressure followed by purification (flash column chromatography using gradient mixtures of n-hexane/ethyl acetate) to afford compound 3 as a yellowish solid (819 mg, yield 75%). IR (KBr) ν_max: 2949, 2850, 1753, 1622, 1514, 1497, 1479, 1362, 1243, 1033 cm⁻¹; MS: m/z 457 [M + Na]; ¹H NMR (300 MHz, CDCl₃): δ 6.97 (d, J = 8.4 Hz, 1H), 6.29 (s, 1H), 6.10 (d, J = 8.1 Hz, 1H), 5.93 (s, 2H), 5.58 (d, J = 4.2 Hz, 1H), 5.05 (s, 2H), 4.39 (d, J = 4.2 Hz, 1H), 4.03 (s, 3H), 3.86 (s, 3H), 2.62–2.54 (m, 4H), 2.40–2.30 (m, 3H), 1.90–1.86 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 168.0, 152.7, 148.3, 140.9, 140.4, 133.9, 132.1, 120.8, 118.5, 118.4, 118.1, 117.0, 102.3, 102.2, 100.7, 81.9, 81.8, 75.4, 62.5, 61.2, 60.7, 56.9, 49.9, 46.2, 27.9 ppm.

General procedure for the synthesis of noscapine glycoconjugates (8a–m).
Noscapine glycoconjugate 8a. To a stirring solution of compound 3 (70 mg, 0.16 mmol) and azido-sugar 6a (71 mg, 0.19 mmol) in anhydrous CH₂Cl₂ (10 mL), CuI (15 mg, 0.08 mmol) and DIPEA (0.027 ml, 0.16 mmol) were added and stirring was continued at room temperature for 14 h under argon atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated in vacuo to obtain a crude residue which was purified using silica gel (230–400 mesh) column chromatography (ethyl acetate/n-hexane) to afford the desired noscapine glycoconjugate 8a as a brown solid (124 mg, yield 95%); R_f = 0.35 (60% ethyl acetate/n-hexane); IR (KBr) cm⁻¹: 2960, 2854, 1756, 1622, 1497, 1479, 1377, 1225, 1037; ¹H NMR (300 MHz, CDCl₃): δ 8.25 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.30 (s, 1H), 6.07 (d, J = 8.1 Hz, 1H), 5.93–5.84 (m, 3H), 5.60–5.24 (m, 7H), 4.40 (d, J = 3.9 Hz, 1H), 4.28 (dd, J = 4.8 and 12.6 Hz, 1H), 4.16–4.08 (m, 1H), 4.03 (m, 3H), 3.84 (s, 3H), 2.54 (m, 4H), 2.33 (m, 2H), 2.10–2.03 (m, 10H), 1.85 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 170.5, 170.0, 169.2, 168.6, 168.2, 152.3, 148.3, 145.4, 140.8, 140.4, 132.1, 133.4, 122.6, 120.6, 118.2, 118.1, 116.9, 102.3, 102.2, 100.8, 85.5, 81.8, 74.9, 72.8, 70.2, 67.6, 67.6, 60.8, 60.6, 59.3, 56.6, 50.0, 46.3, 28.1, 20.6, 20.5, 20.4, 20.1 ppm; HRMS: calcd for C₃₈H₄₃N₄O₁₆ [M + H]: 811.2674; found 811.2671.
Noscapine glycoconjugate 8b. Compound 3 (50 mg, 0.11 mmol), on treatment with azido-sugar 6b (51 mg, 0.13 mmol), DIPEA (0.018 ml, 0.13 mmol) and CuI (10 mg, 0.05 mmol) in dry CH₂Cl₂ (10 mL) at room temperature under argon atmosphere for 12 h and workup as described in the general procedure, afforded compound 8b as a brown solid (80 mg, yield 90%); R_f = 0.3 (60% ethyl acetate/n-hexane); IR (KBr) cm⁻¹: 3454, 2924, 2853, 1755, 1622, 1498, 1479, 1460, 1371, 1218; ¹H NMR (300 MHz, CDCl₃): δ 8.22 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.23 (s, 1H), 6.02 (d, J = 8.1 Hz, 1H), 5.86 (s, 2H), 5.76 (d, J = 9.3 Hz, 1H), 5.61–5.22 (m, 4H), 5.19–5.15 (m, 2H), 4.34 (d, J = 3.6 Hz, 1H), 4.14–4.05 (m, 3H), 3.94 (s, 3H), 3.77 (s, 3H), 2.47 (m, 4H), 2.26–2.18 (m, 4H), 1.98–1.94 (m, 7H), 1.79 (m, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 170.2, 170.1, 169.8, 168.7, 168.1, 152.4, 148.3, 145.2, 140.8, 140.3, 133.9, 132.0, 122.6, 120.6, 118.1, 116.7, 102.3, 102.1, 100.7, 86.2, 81.9, 73.8, 70.9, 67.7, 67.5, 66.7, 61.2, 60.6, 59.2, 56.5, 49.8, 46.1, 27.9, 20.6, 20.5, 20.4, 20.1 ppm; HRMS: calcd for C₃₈H₄₃N₄O₁₆ [M + H]: 811.2674; found 811.2670.
Noscapine glycoconjugate 8c. Compound 3 (50 mg, 0.11 mmol), on treatment with azido-sugar 6c (90 mg, 0.13 mmol), DIPEA (0.018 ml, 0.13 mmol) and CuI (10 mg, 0.05 mmol) in dry CH₂Cl₂ (10 mL) at room temperature under argon atmosphere for 12 h and workup as described in the general procedure, afforded compound 8c as a brown solid (101 mg, yield 84%); R_f = 0.3 (80% ethyl acetate/n-hexane); IR (KBr) cm⁻¹: 3472, 2955, 2925, 2853, 1755, 1622, 1498, 1480, 1456, 1371, 1227, 1046; MS: m/z 1122 [M + Na]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.27 (s, 1H), 6.97 (d, J = 8.1 Hz, 1H), 6.30 (s, 1H), 5.93 (s, 2H), 5.82 (d, J = 9.0 Hz, 1H), 5.63 (d, J = 3.3 Hz, 1H), 5.48–5.37 (m, 6H), 5.17–5.11 (m, 1H), 4.98 (dd, J = 3.3 Hz, 10.8 Hz, 1H), 4.55–4.46 (m, 3H), 4.17–4.08 (m, 3H), 4.02 (m, 1H), 3.98 (s, 3H), 3.93–3.88 (m, 2H), 3.85 (s, 3H), 2.67–2.55 (m, 4H), 2.46–2.38 (m, 3H), 2.16, 2.12, 2.09, 2.06, 2.04, 1.97, 1.84 (each s, 21H); ¹³C NMR (75 MHz, CDCl₃): 170.3, 170.0, 169.5, 169.0, 168.8, 152.4, 148.7, 145.2, 140.2, 133.9, 131.9, 122.8, 120.2, 118.4, 115.3, 102.3, 102.2, 100.9, 100.8, 85.4, 75.7, 75.6, 72.73, 70.8, 70.7, 70.7, 69.0, 67.5, 66.5, 61.7, 60.7, 60.6, 56.7, 48.9, 45.0, 20.6, 20.6 ppm.
Noscapine glycoconjugate 8d. Compound 3 (50 mg, 0.11 mmol), on treatment with azido-sugar 6d (80 mg, 0.13 mmol), DIPEA (0.018 ml, 0.13 mmol) and CuI (10 mg, 0.05 mmol) in dry CH₂Cl₂ (10 mL) at room temperature under argon atmosphere for 16 h and workup as described in the general procedure, afforded compound 8d as a brown solid (102 mg, yield 88%); R_f = 0.25 (60% ethyl acetate/n-hexane); MS: m/z 1081 [M + Na]⁺; IR (KBr) cm⁻¹: 3444, 3065, 2925, 2852, 2798, 1738, 1621, 1584, 1496, 1452, 1269; ¹H NMR (300 MHz, CDCl₃): δ 8.34 (s, 1H), 8.01 (d, J = 7.2 Hz, 2H), 7.92 (d, J = 7.2 Hz, 2H), 7.82 (d, J = 7.2 Hz, 2H), 7.73 (d, J = 7.2 Hz, 2H), 7.54–7.35 (m, 9H), 7.30–7.28 (m, 3H), 6.85 (d, J = 8.1 Hz, 1H), 6.32–6.23 (m, 2H), 6.09–6.06 (m, 3H), 5.92–5.82 (m, 3H), 5.60 (m, 1H), 5.49–5.36 (m, 2H), 4.62–4.41 (m, 4H), 4.00 (s, 3H), 3.71 (s, 3H), 2.54 (m, 4H),2.33 (m, 2H), 1.88 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 168.2, 166.0, 165.5, 165.0, 164.3, 152.3, 148.3, 145.4, 140.9, 140.3, 133.9, 133.5, 133.4, 133.3, 133.1, 132.0, 129.8, 129.7, 129.2, 128.4, 128.3, 128.3, 128.1, 122.6, 120.6, 118.2, 116.9, 102.2, 100.7, 86.0, 81.8, 75.4, 73.1, 70.9, 68.8, 67.6, 62.7, 60.7, 59.3, 56.6, 49.9, 46.2, 28.0 ppm.
Noscapine glycoconjugate 8e. Compound 3 (70 mg, 0.16 mmol), on treatment with azido-sugar 6e (58 mg, 0.19 mmol), DIPEA (0.027 mL, 0.16 mmol) and CuI (15 mg, 0.07 mmol) in dry CH₂Cl₂ (10 mL) at room temperature under argon atmosphere for 12 h and workup as described in the general procedure, afforded compound 8e as a brown solid (111 mg, yield 94%); R_f = 0.3 (60% ethyl acetate/n-hexane); IR (KBr) cm⁻¹: 3425, 2928, 2797, 1759, 1622, 1497, 1479, 1376, 1271; ¹H NMR (300 MHz, CDCl₃): δ 7.97 (s, 1H), 7.35 (m, 5H), 6.94 (d, J = 8.4 Hz, 1H), 6.28 (s, 1H), 6.06 (d, J = 8.1 Hz, 1H), 5.96–5.92 (m, 3H), 5.58–5.29 (m, 3H), 4.74–4.39 (m, 7H), 4.01–3.99 (m, 4H), 3.82 (s, 3H), 2.25 (m, 4H), 2.34–2.31 (m, 2H), 1.89–1.85 (m, 1H), 1.42, 1.30 (each s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 168.1, 152.4, 148.2, 145.4, 144.4, 140.6, 140.2, 136.8, 133.9, 132.0, 128.5, 128.1, 127.9, 125.0, 124.9, 120.6, 118.0, 116.7, 111.9, 105.0, 102.2, 102.1, 100.6, 81.8, 81.6, 81.3, 78.7, 71.8, 67.6, 60.7, 60.5, 59.3, 56.5, 49.8, 48.9, 46.1, 27.9, 26.5, 26.0 ppm; HRMS: calcd for C₃₉H₄₂N₄NaO₁₁ [M + Na]: 765.2748; found 765.2742.
Noscapine glycoconjugate 8f. Compound 3 (90 mg, 0.20 mmol), on treatment with azido-sugar 6f (120 mg, 0.24 mmol), DIPEA (0.034 mL, 0.2 mmol) and CuI (19 mg, 0.1 mmol) in dry CH₂Cl₂ (10 mL) at room temperature under argon atmosphere for 12 h and workup as described in the general procedure, afforded compound 8f as a brown solid (157 mg, yield 85%); R_f = 0.35 (60% ethyl acetate/n-hexane); MS: m/z 927 [M + H]⁺; IR (KBr) cm⁻¹: 2963, 2926, 2855, 1760, 1621, 1496, 1454, 1401, 1261, 1095; ¹H NMR (300 MHz, CDCl₃): δ 7.97 (s, 1H), 7.25–7.23 (m, 15H), 6.88 (d, J = 8.4 Hz, 1H), 6.21 (s, 1H), 6.07 (d, J = 8.1 Hz, 1H), 5.83 (s, 2H), 5.54 (m, 1H), 5.40–5.27 (m, 2H), 4.92–4.37 (m, 11H), 3.95–3.75 (m, 8H), 3.40 (d, J = 9.6 Hz, 1H), 3.10 (m, 3H), 2.58–1.81 (m, 7H); ¹³C NMR (75 MHz, CDCl₃): δ 168.1, 152.5, 148.4, 145.6, 144.4, 140.7, 140.3, 138.4, 137.9, 133.9, 131.7, 128.4, 128.3, 128.1, 127.9, 127.8, 127.5, 125.4, 120.4, 118.4, 116.3, 102.2, 100.7, 97.8, 81.8, 81.6, 79.9, 77.9, 75.6, 74.8, 73.3, 69.0, 67.7, 60.7, 59.2, 56.7, 55.2, 50.6, 49.5, 45.8, 27.5 ppm.
Noscapine glycoconjugate 8g. Compound 3 (50 mg, 0.13 mmol), on treatment with azido-sugar 6g (46 mg, 0.16 mmol), DIPEA (0.022 mL, 0.13 mmol) and CuI (12 mg, 0.06 mmol) in dry CH₂Cl₂ (10 mL) at room temperature under argon atmosphere for 14 h and workup as described in the general procedure, afforded compound 8g as a brown solid (89 mg, yield 90%); R_f = 0.25 (60% ethyl acetate/n-hexane); MS: m/z 745 [M + Na]⁺; IR (KBr) cm⁻¹: 2988, 2934, 2876, 1764, 1624, 1500, 1479, 1382, 1274; ¹H NMR (300 MHz, CDCl₃): δ 7.98 (s, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.22 (s, 1H), 6.01 (d, J = 8.1 Hz, 1H), 5.85 (s, 2H), 5.51–5.31 (m, 4H), 4.56–4.10 (m, 7H), 3.92 (s, 3H), 3.77 (s, 3H), 2.45 (s, 3H), 2.29–2.26 (m, 2H), 1.98 (d, J = 3.3 Hz, 1H), 1.82–1.77 (m, 1H), 1.43, 1.31, 1.29, 1.20 (each s, 12H); ¹³C NMR (75 MHz, CDCl₃): δ 168.1, 152.2, 148.3, 144.0, 140.8, 140.3, 133.9, 132.0, 125.3, 120.6, 118.2, 116.7, 109.7, 108.9, 102.3, 102.2, 100.7, 96.0, 81.8, 71.0, 70.6, 70.2, 67.5, 67.0, 60.7, 59.2, 56.6, 50.3, 49.7, 46.1, 27.8, 25.9, 25.9, 24.8, 24.3 ppm.
Noscapine glycoconjugate 8h. Compound 3 (100 mg, 0.23 mmol), on treatment with azido-sugar 6j (93 mg, 0.28 mmol), DIPEA (0.039 mL, 0.23 mmol) and CuI (21 mg, 0.12 mmol) in dry CH₂Cl₂ (10 mL) at room temperature under argon atmosphere for 13 h and workup as described in the general procedure, afforded compound 8h as a brown solid (152 mg, yield 86%); R_f = 0.24 (60% ethyl acetate/n-hexane); MS: m/z 795 [M + Na]⁺; IR (KBr) cm⁻¹: 3416, 2926, 2854, 1759, 1711, 1622, 1497, 1479, 1457, 1376, 1271; ¹H NMR (300 MHz, CDCl₃): δ 7.96 (s, 1H), 7.28–7.19 (m, 5H), 6.87 (d, J = 8.4 Hz, 1H), 6.20 (s, 1H), 5.98 (d, J = 8.4 Hz, 1H), 5.87–5.84 (m, 3H), 5.47 (d, J = 3.6 Hz, 1H), 5.37–5.22 (m, 4H), 4.73–4.53 (m, 5H), 4.27–4.23 (m, 2H), 3.93 (s, 3H), 3.78 (s, 3H), 2.40 (s, 3H), 2.29–2.19 (m, 2H), 2.10 (m, 1H), 1.79–1.71 (m, 1H), 1.38, 1.24 (each s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 168.4, 152.6, 148.3, 145.0, 143.9, 140.5, 137.2, 133.8, 132.0, 128.5, 127.9, 125.7, 120.9, 118.0, 116.7, 111.9, 105.1, 102.3, 102.1, 100.7, 82.2, 81.6, 80.9, 80.5, 72.4, 67.7, 67.1, 60.6, 59.2, 56.4, 54.2, 49.7, 46.1, 27.7, 26.7, 26.2 ppm.
Noscapine glycoconjugate 8i. Compound 3 (60 mg, 0.14 mmol), on treatment with azido-sugar 6i (48 mg, 0.17 mmol), DIPEA (0.022 mL, 0.13 mmol) and CuI (12 mg, 0.06 mmol) in dry CH₂Cl₂ (10 mL) at room temperature under argon atmosphere for 12 h and workup as described in the general procedure, afforded compound 8i as a brown solid (80 mg, yield 85%); R_f = 0.25 (60% ethyl acetate/n-hexane); MS: m/z 747 [M + Na]⁺; IR (KBr) cm⁻¹: 3416, 2926, 2854, 1759, 1711, 1622, 1497, 1479, 1457, 1376, 1271; ¹H NMR (300 MHz, CDCl₃): δ 8.06 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.33–6.17 (m, 2H), 5.95–5.92 (m, 3H), 5.61 (d, J = 7.8 Hz, 1H), 5.44–5.31 (m, 2H), 4.73 (d, J = 11.7 Hz, 1H), 4.57 (m, 1H), 4.42–4.31 (m, 3H), 4.02–3.86 (m, 8H), 3.59–3.48 (m, 3H), 2.55–2.51 (m, 4H), 2.41–2.38 (m, 2H), 2.07–1.94 (m, 1H), 1.64–157 (m, 2H), 1.46, 1.32 (each s, 6H), 0.91 (t, J = 7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 158.8, 152.6, 148.4, 145.1, 143.9, 140.5, 140.3, 133.9, 125.8, 118.5, 118.1, 116.8, 111.8, 105.2, 102.3, 102.2, 100.7, 82.2, 82.0, 81.6, 80.4, 72.4, 68.0, 67.1, 60.6, 59.2, 56.5, 54.2, 49.6, 45.9, 27.6, 26.7, 26.2, 22.9, 10.5.
Noscapine glycoconjugate 8j. Compound 3 (100 mg, 0.23 mmol), on treatment with azido-sugar 6j (88 mg, 0.28 mmol), DIPEA (0.039 mL, 0.23 mmol) and CuI (21 mg, 0.12 mmol) in dry CH₂Cl₂ (10 mL) at room temperature under argon atmosphere for 12 h and workup as described in the general procedure, afforded compound 8j as a brown solid (138 mg, yield 80%); R_f = 0.25 (60% ethyl acetate/n-hexane); MS: m/z 775 [M + Na]⁺; IR (KBr) cm⁻¹: 3416, 2928, 2854, 1759, 1717, 1622, 1497, 1479, 1460, 1376, 1271; ¹H NMR (300 MHz, CDCl₃): δ 8.06 (s, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.29–6.20 (m, 2H), 5.93–5.90 (m, 3H), 5.62 (d, J = 3.3 Hz, 1H), 5.45–5.31 (m, 2H), 4.77 (d, J = 12.6 Hz, 1H), 4.56–4.25 (m, 5H), 3.98–3.86 (m, 7H), 3.68–3.49 (m, 3H, OH, OCH₂), 2.68–2.40 (m, 5H), 2.20–2.12 (m, 1H), 1.69–1.61 (m, 2H), 1.51–1.46 (m, 4H), 1.32 (s, 3H), 0.89 (d, J = 7.6 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 168.1, 152.6, 148.7, 145.2, 144.0, 140.3, 140.3, 133.9, 125.6, 118.6, 118.3, 111.8, 105.2, 105.1, 102.3, 100.8, 82.3, 82.1, 80.4, 69.1, 67.4, 67.3, 60.8, 60.6, 56.7, 54.1, 38.4, 26.8, 26.7, 26.2, 24.9, 22.5, 22.4 ppm.
Noscapine glycoconjugate 8k. Compound 3 (65 mg, 0.15 mmol), on treatment with azido-sugar 6k (64 mg, 0.18 mmol), DIPEA (0.025 mL, 0.14 mmol) and CuI (15 mg, 0.08 mmol) in dry CH₂Cl₂ (10 mL) at room temperature under argon atmosphere for 14 h and workup as described in the general procedure, afforded compound 8k as a brown solid (97 mg, yield 82%); R_f = 0.2 (80% ethyl acetate/n-hexane); MS: m/z 820 [M + Na]⁺; IR (KBr) cm⁻¹: 3426, 2987, 2937, 2926, 1759, 1622, 1497, 1479, 1382, 1271; ¹H NMR (300 MHz, CDCl₃): δ 7.; ¹³C NMR (75 MHz, CDCl₃): δ 168.1, 152.5, 152.4, 148.3, 148.3, 145.3, 145.2, 144.3, 144.1, 140.5, 140.4, 140.2, 133.8, 131.8, 131.6, 125.7, 125.2, 120.5, 118.2, 116.5, 116.3, 111.7, 109.3, 109.2, 105.5, 105.3, 102.1, 100.6, 83.8, 83.1, 82.2, 81.6, 81.3, 81.1, 81.0, 72.7, 72.5, 72.2, 71.0, 69.3, 68.6, 67.6, 67.5, 60.5, 59.2, 56.5, 53.3, 52.6, 52.3, 49.6, 49.3, 46.0, 45.7, 27.6, 27.1, 26.6, 26.0, 25.0, 25.0 ppm.
Noscapine glycoconjugate 8l. Compound 3 (90 mg, 0.21 mmol), on treatment with azido-sugar 6l (89 mg, 0.25 mmol), DIPEA (0.035 mL, 0.2 mmol) and CuI (19 mg, 0.1) in dry CH₂Cl₂ (10 mL) at room temperature under argon atmosphere for 14 h and workup as described in the general procedure, afforded compound 8l as a brown solid (140 mg, yield 84%); R_f = 0.2 (80% ethyl acetate/n-hexane); MS: m/z 820 [M + Na]⁺; IR (KBr) cm⁻¹: 3439, 2988, 2925, 2853, 1759, 1622, 1497, 1461, 1384, 1272, 1069; ¹H NMR (300 MHz, CDCl₃): δ 8.04 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.22 (s, 1H), 6.02 (m, 1H), 5.85 (s, 2H), 5.51–5.22 (m, 5H), 4.52–4.00 (m, 7H), 3.92 (s, 3H), 3.78 (s, 3H), 3.61–3.47 (m, 5H), 2.44–2.27 (m, 5H), 1.96–1.80 (m, 2H), 1.46–1.26 (merge 4 s, 12H); ¹³C NMR (75 MHz, CDCl₃): δ 168.2, 152.6, 148.4, 145.3, 140.6, 140.3, 133.9, 131.9, 131.5, 125.4, 120.6, 118.3, 118.2, 109.3, 108.6, 102.3, 102.2, 100.7, 96.2, 81.6, 81.1, 72.7, 72.2, 71.0, 70.5, 70.1, 69.2, 67.4, 66.8, 60.6, 60.8 59.3, 56.6, 52.9, 49.6, 49.0, 46.0, 45.5, 27.6, 26.6, 26.0, 25.9, 24.8, 24.4 ppm.
Noscapine glycoconjugate 8m. Compound 3 (50 mg, 0.11 mmol), on treatment with azido-sugar 6m (50 mg, 0.13 mmol), DIPEA (0.018 mL, 0.14 mmol) and CuI (10 mg, 0.05 mmol) in dry CH₂Cl₂ (10 mL) at room temperature under argon atmosphere for 15 h and workup as described in the general procedure, afforded compound 8m as a brown solid (80 mg, yield 90%); R_f = 0.2 (80% ethyl acetate/n-hexane); MS: m/z 817 [M + H]⁺; IR (KBr) cm⁻¹: 3417, 2926, 1759, 1622, 1497, 1479, 1456, 1272; ¹H NMR (300 MHz, CDCl₃): δ 8.08 (s, 1H), 7.30 (m, 5H), 6.96 (d, J = 8.1 Hz, 1H), 6.30 (s, 1H), 6.11 (d, J = 5.7 Hz, 1H), 5.93 (s, 2H), 5.49–5.29 (m, 2H), 4.70–4.30 (m, 7H), 4.13–3.51 (m, 13H), 2.51–2.35 (m, 5H), 2.04–1.93 (m, 2H), 1.49, 1.32 (each s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 168.2, 152.7, 148.5, 144.2, 140.4, 140.2, 137.3, 128.5, 127.9, 127.6, 125.8, 120.5, 118.4, 118.2, 111.7, 105.0, 102.2, 102.2, 100.7, 82.1, 81.7, 81.1, 79.1, 72.5, 71.8, 69.3, 67.2, 60.7, 60.4, 59.3, 56.6, 53.3, 53.0, 49.6, 48.9, 45.9, 45.4, 27.6, 26.8, 26.5, 26.2 ppm.

Acknowledgements

The authors gratefully acknowledge the Council of Scientific & Industrial Research, New Delhi (grant no. 02(0173)/13/EMR-II) for funding and CISC, Banaras Hindu University and RSIC, Central Drug Research Institute, Lucknow for providing the spectroscopic data of the developed molecules.

References

1. (a) B. B. Mishra and V. K. Tiwari, Eur. J. Med. Chem., 2011, 46, 4769; (b) G. Jurjens, A. Kirschning and D. A. Candito, Nat. Prod. Rep., 2015, 32, 723–737.
2. (a) P. M. Checchi, J. H. Nettles, J. Zhou, J. P. Snyder and H. C. Joshi, Trends Pharmacol. Sci., 2003, 24, 361; (b) M. A. Jordan and L. Wilson, Nat. Rev. Cancer, 2004, 4, 253.
3. C. Warolin and P. J. Robiquet, Rev. Hist. Pharm., 1999, 47, 97.
4. B. Dahlstrom, T. Mellstrand, C. G. Lofdahl and M. Johansson, Eur. J. Clin. Pharmacol., 1982, 22, 535.
5. K. Ye, Y. Ke, N. Keshava, J. Shanks, J. A. Kapp, R. R. Tekmal, J. Petros and H. C. Joshi, Proc. Natl. Acad. Sci. U. S. A., 1998, 95, 1601.
6. K. Ye, Y. Ke, N. Keshava, J. Shanks, J. A. Kapp and R. R. Tekmal, et al., Proc. Natl. Acad. Sci. U. S. A., 1998, 95, 1601.
7. Y. Ke, K. Ye, H. E. Grossniklaus, D. R. Archer, H. C. Joshi and J. A. Kapp, Cancer Immunol. Immunother., 2000, 49, 217.
8. B. Sung, K. S. Ahn and B. B. Aggarwal, Cancer Res., 2010, 70, 3259.
9. J. W. Landen, R. Lang, S. J. McMahon, N. M. Rusan, A. M. Yvon and A. W. Adams, Cancer Res., 2002, 62, 4109.
10. J. Zhou, K. Gupta, J. Yao, K. Ye, D. Panda and P. Giannakakou, J. Biol. Chem., 2002, 277, 39777.
11. J. W. Landen, V. Hau, M. Wang, T. Davis, B. Ciliax and B. H. Wainer, Clin. Cancer Res., 2004, 10, 5187.
12. R. Aneja, M. Lopus, J. Zhou, S. N. Vangapandu, A. Ghaleb and J. Yao, Cancer Res., 2006, 66, 3782.
13. T. Jackson, M. B. Chougule, N. Ichite, R. R. Patlolla and M. Singh, Cancer Chemother. Pharmacol., 2008, 63, 117.
14. R. Aneja, A. M. Ghaleb, J. Zhou, V. W. Yang and H. C. Joshi, Cancer Res., 2007, 67, 3862.
15. (a) K. Ye, Y. Ke, N. Keshava, J. Shanks, J. A. Kapp, R. R. Tekmal, J. Petros and H. C. Joshi, Proc. Natl. Acad. Sci. U. S. A., 1998, 95, 1601; (b) H. C. Joshi and J. Zhou, Drug News Perspect., 2000, 13, 543; (c) Y. Ke, K. Ye, H. E. Grossniklaus, D. R. Archer, H. C. Joshi and J. A. Kapp, Cancer Immunol. Immunother., 2000, 49, 217.
16. J. T. Anderson, A. E. Ting, S. Boozer, K. Brunden, C. Crumrine and J. Danzig, J. Med. Chem., 2005, 48, 7096.
17. (a) J. T. Anderson, A. E. Ting, S. Boozer, K. R. Brunden, J. Danzig and T. Dent, J. Med. Chem., 2005, 48, 2756; (b) R. C. Mishra, P. Karna, S. R. Gundala, V. R. Pannu, A. Stanton, K. K. Gupta, M. H. Robinson, M. Lopus, L. Wilson, M. Henary and R. Aneja, Biochem. Pharmacol., 2011, 82, 110.
18. (a) S. Dedola, S. A. Nepogodiev and R. A. Field, Org. Biomol. Chem., 2007, 5, 1006; (b) V. K. Tiwari, R. C. Mishra, A. Sharma and R. P. Tripathi, Mini-Rev. Med. Chem., 2012, 12, 1497.
19. (a) T. K. Dam and C. F. Brewer, Glycobiology, 2010, 20, 270; (b) A. Imberty, E. P. Mitchell and M. Wimmerova, Curr. Opin. Struct. Biol., 2005, 15, 525.
20. B. J. J. Davis, J. Chem. Soc., Perkin Trans. 1, 1999, 3215.
21. H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem., Int. Ed., 2001, 40, 2004.
22. (a) R. Huisgen, Angew. Chem., Int. Ed., 1963, 2, 565; (b) C. W. Meldal, C. Tornoe and M. Meldal, J. Org. Chem., 2002, 67, 3057; (c) V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2596.
23. (a) J. E. Hein and V. V. Fokin, Chem. Soc. Rev., 2010, 39, 1302; (b) M. Meldal and C. W. Tornoe, Chem. Rev., 2008, 108, 2952.
24. H. C. Kolb and K. B. Sharpless, Drug Discovery Today, 2003, 8, 1128.
25. F. Amblard, J. H. Cho and R. F. Schinazi, Chem. Rev., 2009, 109, 4207.
26. G. C. Tron, T. Pirali, R. A. Billington, P. L. Canonico, G. Sorba and A. A. Genazzani, Med. Res. Rev., 2008, 28, 278.
27. (a) A. Dumont, A. Malleron, M. Awwad, S. Dukan and B. Vauzeilles, Angew. Chem., Int. Ed., 2012, 51, 3143; (b) A. Niederwieser, A. K. Späte, L. D. Nguyen, C. Jüngst, W. Reutter and V. Wittmann, Angew. Chem., Int. Ed., 2013, 52, 4265; (c) A. Pathigoolla, R. G. Gonnade and K. M. Sureshan, Angew. Chem., Int. Ed., 2012, 51, 4362.
28. P. Thirumurugan, D. Matosiuk and K. Jozwiak, Chem. Rev., 2013, 113, 4905.
29. (a) D. Kumar, A. Mishra, B. B. Mishra, S. Bhattacharya and V. K. Tiwari, J. Org. Chem., 2013, 78, 899; (b) D. Kumar, B. B. Mishra and V. K. Tiwari, J. Org. Chem., 2014, 79, 251.
30. (a) V. K. Tiwari, A. Kumar and R. R. Schmidt, Eur. J. Org. Chem., 2012, 2945; (b) V. Prasad, R. R. Kale, B. B. Mishra, D. Kumar and V. K. Tiwari, Org. Lett., 2012, 14, 2936.
31. (a) P. Dwivedi, K. B. Mishra, B. B. Mishra, N. Singh, R. K. Singh and V. K. Tiwari, Glycoconjugate J., 2015, 32, 127–140; (b) D. Kushwaha, P. Pandey, R. R. Kale and V. K. Tiwari, Trends Carbohydr. Res., 2012, 4(3), 45; (c) K. B. Mishra and V. K. Tiwari, J. Org. Chem., 2014, 79, 5752.
32. (a) D. Kushwaha and V. K. Tiwari, J. Org. Chem., 2013, 78, 8184; (b) K. B. Mishra and V. K. Tiwari, J. Org. Chem., 2014, 79, 5752; (c) A. Mishra and V. K. Tiwari, J. Org. Chem., 2015, 80, 4869; (d) A. Mishra, B. B. Mishra and V. K. Tiwari, RSC Adv., 2015, 5, 41520.
33. D. Kumar, K. B. Mishra, B. B. Mishra, S. Mondal and V. K. Tiwari, Steroids, 2014, 80, 71.
34. S. K. Rai, S. Khanam, R. S. Khanna and A. K. Tewari, Cryst. Growth Des., 2015, 15, 1430.
35. G. R. Desiraju, Crystal Engineering: The Design of Organic Solids, Elsevier, Amsterdam, 1989.
36. (a) G. R. Desiraju, J. Am. Chem. Soc., 2013, 135, 9952; (b) G. R. Desiraju, Angew. Chem., Int. Ed., 2007, 46, 8342.

---

Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra of all the new compounds and single crystal X-ray data of 3 have been provided. CCDC 1022189. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra07321a

---