Synthesis and Characterization of New Isatin Nucleosides

 

Thanaa M. Al-Mouamin¹, Omar Abdulateef Mohammed^1, *

¹Department of Chemistry, College of Science, University of Baghdad, Baghdad, Iraq

 

ABSTRACT:

In this research, a series of new nucleoside analogues 25-36 of substituted isatin as nucleobase were synthesized in three steps. The reaction sequence is started from the condensation of free sugar (D-glucose and L-rhamnose) with different anilines to afford the N-arylglycosylamines 1-12 which subsequently O-acetylated in the presence of acetic anhydride/pyridine. The resulting acetylated N-arylglycosylamines 13-24 were then subjected to an intramolecular cyclization with oxalyl chloride in the presence of anhydrous aluminum chloride to yield the target isatin nucleosides. The synthesized compounds were characterized by the FTIR, ¹H-NMR and¹³ C-NMR spectroscopy. The stereochemistry was established based on the coupling constants observed between vicinal hydrogens of the glycon that confirmed the β-configuration of the synthesized nucleosides with a ⁴C₁ conformation of the glucosides and a ¹C₄ conformation of the rhamnosides.

 

 

 

1. INTRODUCTION:

Nucleoside analogues play pivotal roles in medicinal chemistry as chemotherapeutic agents such as anticancer⁽¹⁾ and antiviral⁽²⁾. For instance, until 2016, there are 16 FDA-approved nucleoside analogues as anticancer drugs⁽³⁾. In addition, 90 drugs were formally approved to treat 9 different human viral diseases⁽⁴⁾, about 30% of them are nucleoside analogues^(5-8). Furthermore, nucleoside antibiotics, the naturally occurring nucleoside analogues, are known to possess many biological activities, including anticancer, antiviral, antibacterial, antifungal and antiparasitic activity^(9,10). Moreover, in biosensor technology, nucleoside analogues are implemented in a class of MOF (Micro-Structure Optical Fibers) using labeled DNA⁽¹¹⁾. However, despite of the above mentioned versatilities of nucleoside analogues, the development of newer agents with improved activities and properties is still in need to eliminate or suppress the problems of resistance, long-term toxicity, poor oral availability, etc.^(3,5,12)

 

These observations have prompted us to search for new nucleoside analogues with promising bioactivity to expand the range of available such compounds in chemotherapy study.

 

Isatin, as a unique heterocyclic molecule, represents one of the most resilient synthones in organic chemistry^(13-15). In addition, isatin and its derivatives have been found to exhibit a wide spectrum of pharmacological properties, including antitumor, antimicrobial, anti-inflammatory, antiviral, anticonvulsant, anti-HIV, and antitubercular activity^(16-20). However, the synthesis of isatin nucleosides is limited to only few reports in the literatures^(21-25). Our effort, therefore, is to synthesize a series of new nucleoside analogues of isatin as the nucleobase that diversely substituted with electron-donor and acceptor groups on the aromatic isatin ring.

 

Scheme 1: Synthetic route to the isatin nucleosides 25-36.

 

2. EXPERIMENTAL:

2. 1. General:

Melting points were measured on Gallenkamp capillary melting point apparatus and are uncorrected. Infrared spectra were recorded on a Shimadzu FTIR-8400S spectrophotometer, as KBr discs. NMR spectra were performed on a Bruker BioSpin AV 3400 spectrometer (¹H: 400 MHz, ¹³C: 100 MHz) in CDCl₃, DMSO-d₆, and C₆D₆ as solvents and tetramethylsilane as internal standard, chemical shifts δ in ppm, the following abbreviations are used: singlet (s), doublet (d), triplet (t), quadruplet (q), doubled doublet (dd), doubled triplet (dt), doubled doubled doublet (ddd),  multiplet (m). Thin layer chromatography (TLC) was performed on aluminum plates pre-coated with 0.25 mm layer of silica-gel 60 supplied by Merck and spots were detected with iodine vapor. Column chromatography was carried out with silica-gel 60 (Fluka). All chemicals used were supplied by Merck, Fluka, Sigma-Aldrich, Riedel-De Haen AG. Solvents and liquid reagents were purified and dried in the usual manner before being used.

 

2.2. Preparation of N-arylglycosylamines (1-12)^{(26, 27)}:

Two mole equivalents of the aromatic primary amine were added with stirring to a suspension of dry powdered sugar (1 mole equivalent) in absolute ethanol. The resulting mixture was refluxed until all the sugar had dissolved, and the solution was concentrated under vacuum to about one third of its original volume. The remaining solution was treated with ether and allowed to cool with the exclusion of moisture in the refrigerator overnight, whereupon the desired product was deposited as a solid mass. The product was filtered with suction, washed repeatedly with ether to remove the unreacted amine and dried. Recrystallization from absolute ethanol afforded the desired glycosylamine. Reaction time and some physical properties of compounds 1-12 are presented in table 1.

 

2.3. Preparation of O-acetylated N-arylglycopyranosylamines (13-24)⁽²⁸⁾:

Acetic anhydride (4ml) was gradually added with stirring to a cooled solution of N-arylglycosylamine (1g) in dry-freshly redistilled pyridine (4ml), so as the temperature of the reaction did not exceed 0°C. The resulting solution was kept for 24 hours at room temperature with the exclusion of moisture. The reaction mixture was then poured onto a large excess of crushed ice with stirring and kept for several hours. Within this time, the aqueous layer was decanted and a fresh ice-water was added until all of the viscous oil had changed into a hard solid mass. The resulting solid was crushed and collected on a Büchner funnel, washed repeatedly with cold water until the filtrate was neutral and dried. Recrystallization (if required) from alcohol-petroleum ether (40-60) afforded the O-acetylated glycosylamine. Some physical properties and characteristic IR spectral data are presented in table 2. NMR data and signal assignments of compounds 13-18 are listed in table 3.

 

2.4. General procedure for the synthesis of isatin nucleosides (25-36):

One mole equivalent of the O-acetylated N-arylglycosylamine was dissolved in about 7–8 mole equivalents of oxalyl chloride and the solution was left to stir at room temperature, with the exclusion of moisture, for 5 minutes. Anhydrous aluminum chloride (1.2mole equivalent) was added portion-wise and with stirring to the reaction mixture at 0 °C.  Upon completion of the addition, the mixture was slowly heated to 55-60° under reflux condenser and CaCl₂-drying tube. Heating and stirring were continued until TLC (2:1 EtOAc/hexane) had showed the completion of the reaction. The dark-brown reaction mixture was cooled down to 0°C and treated with ice water. The resulting mixture was extracted three times with ethyl acetate and the combined organic extracts were washed successively with saturated aqueous sodium bicarbonate solution and water, dried (Na₂SO₄), and filtered. The filtrate was evaporated under vacuum and the residue was purified either by column chromatography or recrystallization to yield the desired isatin-N-glycoside.

 

1-(2',3',4',6'-Tetra-O-acetyl-β-D-glucopyranosyl)-6,7-dimethylindoline-2,3-dione (25):

Starting with the glucoside tetraacetate 13 (2.2 mmole), the reaction was completed after about 3 hours, and the product was isolated as an orange solid in 52% yield. Recrystallization from ethyl acetate-heptane gave (42%) of 25 as a yellow solid, m.p. 104-106 °C, R_f = 0.83 (hexane-EtOAc, 1:2). FTIR (KBr): 1753 cm^-1 (νC=O), 1604 cm^-1 (νC=C_aromatic), 1230 cm^-1 (ν O=C–O). ¹H NMR (400 MHz, Chloroform-d) δ 7.45 (d, J = 7.5 Hz, 1H, H-4), 7.05 (d, J = 7.6 Hz, 1H, H-5), 5.87 (d, J = 9.9 Hz, 1H, H-1'), 5.54 (t, J = 9.8 Hz, 1H, H-2'), 5.32 (t, J = 9.2 Hz, 1H, H-3'), 5.26 (t, J = 9.6 Hz, 1H, H-4'), 4.31 (dd, J = 12.7, 4.6 Hz, 1H, H-6a'), 4.20 (dd, J = 12.2, 2.0 Hz, 1H, H-6b'), 4.02 (ddd, J = 10.2, 4.7, 2.3 Hz, 1H, H-5'), 2.60, 2.40 (2s, 6H, 2Me), 2.11–2.06 (m, 12H, 4xCH_3acetate). ¹³C NMR (101 MHz, CDCl₃) δ 181.37 (C-3), 170.50, 169.98, 169.58, 169.17 (4xC=O_acetate), 160.75 (C-2), 152.40, 149.60, 147.76, 127.15, 123.55, 118.71 (aromatic), 80.67 (C-1'), 74.79, 73.85, 68.64, 67.50 (C-2',C-3',C-4',C-5'), 61.50 (C-6'), 22.73, 16.47 (2Me), 20.78, 20.67, 20.66, 20.65 (4xCH_3acetate).

 

1-(2',3',4',6'-Tetra-O-acetyl-β-D-glucopyranosyl)-5,6-dimethylindoline-2,3-dione (26A) and its 4,6-dimethyl isomer (26B):

Starting with the glucoside tetraacetate 14 (2.2 mmole), the reaction was completed after about 4 hours, and the product was isolated in 96% yield. Column chromatography (EtOAc/hexane; 1:2) gave (55%) of inseparable mixture of 84A and 84B as a yellow solid, m.p. 114-130 °C. R_f = 0.81 and 0.82 (hexane-EtOAc, 1:2). FTIR (KBr): 1757 cm^-1 (νC=O), 1622 and 1604 cm^-1 (νC=C_aromatic), 1224 cm^-1(ν O=C–O). ¹H NMR (400 MHz, Chloroform-d) δ 7.39 (s, 1H, H-4), 7.33 (d, J = 8.1 Hz, 0H, H-6,84B), 7.03 (s, 1H, H-7), 6.98 (d, J = 8.0 Hz, 0H, H-7,84B), 5.65 (d, J = 9.4 Hz, 1H, H-1'), 5.53 (t, J = 9.4 Hz, 1H, H-2'), 5.39 (t, J = 9.4 Hz, 1H, H-3'), 5.26 (t, J = 9.8 Hz, 1H, H-4), 4.24 (dd, J = 13.1, 4.5 Hz, 1H, H-6a'), 4.18 (dd, J = 12.5, 2.2 Hz, 1H, H-6b'), 3.93 (ddd, J = 10.1, 4.4, 2.2 Hz, 1H, H-5'), 2.51, 2.38, 2.23 (3s, 6H, 2Me), 2.09, 2.08, 2.01, 1.90 (4s, 12H, 4xCH_3acetate). ¹³C NMR (101 MHz, CDCl₃) δ 182.63, 181.20 (C-3), 170.45, 169.86, 169.71, 169.56 (4xC=O_acetate), 158.33, 157.66 (C-2), 149.74, 146.63, 146.05, 140.81, 138.70, 134.18, 133.27, 126.48, 116.27, 116.12, 114.80, 110.56 (aromatic), 79.85 (C-1'), 77.16, 74.81, 73.16, 67.84, 67.81 (C-2',C-3',C-4',C-5'), 61.74 (C-6'), 20.79, 20.69, 20.64, 20.39 (4xCH_3acetate), 22.05, 19.38, 18.64, 14.71 (Me).

 

1-(2',3',4',6'-Tetra-O-acetyl-β-D-glucopyranosyl)-4,7-dimethylindoline-2,3-dione (27):

Starting with the glucoside tetraacetate 15 (2.2 mmole), the product was isolated after about 4 hours, and recrystallized from ethyl acetate-heptane to afford 27 as a yellow solid. Yield; (43%), m.p. 96-98 °C, R_f= 0.86 (hexane-EtOAc, 1:2). FTIR (KBr): 1755 cm^-1 (νC=O), 1585 cm^-1 (νC=C_aromatic), 1228 cm^-1 (ν O=C–O).

 

1-(2',3',4',6'-Tetra-O-acetyl-β-D-glucopyranosyl)-5-carbethoxyindoline-2,3-dione (28):

Starting with the glucoside tetraacetate 16 (1 mmole), the product was isolated after about 6 hours as deep brown solid in 54% yield. Column chromatography (EtOAc/hexane; 2:1) afforded the pure 28 as a yellowish brown solid. Yield (35%), m.p. 76-78 °C. R_f= 0.51 (hexane-EtOAc, 1:2). FTIR (KBr): 1751 cm^-1 (νC=O_acetate), 1714 cm^-1 (νC=O_benzoate), 1614 cm^-1 (νC=C_aromatic), 1226, 1274 cm^-1 (ν O=C–O). ¹H NMR (400 MHz, Chloroform-d) δ 8.35 (dd, J = 8.4, 1.8 Hz, 1H, H-6), 8.32 (d, J = 1.6 Hz, 1H, H-4), 7.37 (d, J = 8.4 Hz, 1H, H-7), 5.70 (d, J = 9.4 Hz, 1H, H-1'), 5.58 – 5.52 (m, 2H, H-2',H-3'), 5.43 (d, J = 9.4 Hz, 1H, H-4'), 4.25 – 4.20 (m, 2H, CH_{2 Et}), 4.19 – 4.13 (m, 2H, H-6'), 3.96 (ddd, J = 10.3, 4.4, 2.2 Hz, 1H, H-5'), 2.04, 2.03, 2.03, 2.02 (4s, 12H, 4xCH_3acetate), 1.19 (t, J = 7.1 Hz, 3H, CH_{3 Et}). ¹³C NMR (101 MHz, CDCl₃) δ 180.96 (C-3), 170.49, 170.02, 169.69, 169.64 (4xC=O_acetate), 164.79 (C=O_benzoate), 157.52 (C-2), 140.00, 131.50, 127.19, 117.48, 113.53, 113.31 (aromatic), 80.08 (C-1'), 75.08, 72.86, 67.93, 67.75 (C-2', C-3', C-4', C-5'), 61.62 (C-6'), 60.64 (CH_{2 Et}), 20.84, 20.69, 20.65, 20.38 (4xCH_3acetate), 14.42 (CH_{3 Et}).

 

1-(2',3',4',6'-Tetra-O-acetyl-β-D-glucopyranosyl)-5-methoxyindoline-2,3-dione (29):

Starting with the glucoside tetraacetate 17 (2.2 mmole), the product was isolated after about 4 hours as a dark brown solid in 70% yield. Column chromatography (hexane/EtOAc; 1:2) gave the pure 29 as a brick-red solid. Yield (47%), m.p. 80-82 °C. R_f= 0.58 (hexane-EtOAc, 1:2). FTIR (KBr): 1747 cm^-1 (νC=O_acetate), 1597 cm^-1 (νC=C_aromatic), 1224 cm^-1 (ν O=C–O). ¹H NMR (400 MHz, Chloroform-d) δ 7.21 – 7.16 (m, 2H, H-6, H-7), 7.14 (dd, J = 2.3, 1.0 Hz, 1H, H-4), 5.65 (d, J = 9.4 Hz, 1H, H-1'), 5.52 (t, J = 9.4 Hz, 1H, H-2'), 5.38 (t, J = 9.4 Hz, 1H, H-3'), 5.22 (t, J = 9.8 Hz, 1H, H-4'), 4.25 (dd, J = 12.5, 4.7 Hz, 1H, H-6a'), 4.18 (dd, J = 12.5, 2.3 Hz, 1H, H-6b'), 3.93 (ddd, J = 10.1, 4.6, 2.3 Hz, 1H, H-5'), 3.80 (s, 3H, O CH₃), 2.08, 2.07, 2.00, 1.90 (4s, 12H, 4xCH_{3 acetate}). ¹³C NMR (101 MHz, CDCl₃) δ 182.01 (C-3), 170.48, 169.86, 169.64, 169.58 (4xC=O _acetate), 157.88 (C-2), 156.96, 142.01, 125.58, 118.49, 114.81, 109.28 (aromatic), 79.90 (C-1'), 74.83, 73.06, 67.87, 67.77 (C-2',C-3',C-4',C-5'), 61.77 (C-6'), 56.00 (OCH₃), 20.80, 20.67, 20.63, 20.39 (4xCH_{3 acetate}).

 

1-(2',3',4',6'-Tetra-O-acetyl-β-D-glucopyranosyl)-6-acetylindoline-2,3-dione (30):

Starting with the glucoside tetraacetate 18 (1 mmole), the product was isolated after about 5 hours as a brown solid in (65%). Column chromatography (hexane-EtOAc; 1:2) gave the pure 30 as a light brown gum. Yield (35%). R_f= 0.67 (hexane-EtOAc, 1:2). FTIR (film): 1749 cm^-1 (νC=O_acetate), 1689cm^-1 (νC=O_acetyl), 1593 cm^-1 (νC=C_aromatic), 1222 cm^-1 (ν O=C–O).  ¹H NMR (400 MHz, Chloroform-d) δ 7.74 – 7.65 (m, 1H, H-5), 7.42 (dd, J = 8.1, 0.5 Hz, 1H, H-4), 7.27 (d, J = 0.6 Hz, 1H, H-7), 5.71 (d, J = 9.5 Hz, 1H, H-1'), 5.55 (t, J = 9.8 Hz, 1H, H-3'), 5.41 (t, J = 9.5 Hz, 1H, H-2'), 5.25 (t, J = 9.8 Hz, 1H, H-4'), 4.19 (dd, J = 12.6, 2.3 Hz, 1H, H-6a'), 4.14 (dd, J = 12.5, 4.9 Hz, 1H, H-6b'), 3.95 (ddd, J = 10.2, 4.8, 2.3 Hz, 1H, H-5'), 2.66 (s, 3H, CH_3acetyl), 2.10, 2.09, 2.04, 2.03 (4s, 12H, 4xCH_{3 acetate}). ¹³C NMR (101 MHz, CDCl₃) δ 200.18 (C=O _acetyl), 180.34 (C-3), 170.68, 170.02, 169.67, 169.61 (4xC=O _acetate), 156.26 (C-2), 148.40, 140.19, 138.74, 123.33, 115.86, 113.99 (aromatic), 79.99 (C-1'), 75.03, 73.04, 67.80, 67.55 (C-2',C-3',C-4',C-5'), 61.25 (C-6'), 30.25 (Me), 20.81, 20.76, 20.69, 20.44 (4xCH_{3 acetate}).

 

1-(2',3',4'-Tri-O-acetyl-β-L-rhamnopyranosyl)-4,7-dimethylindoline-2,3-dione (31):

Starting with the rhamnoside triacetate 19 (2.5 mmole), the product (70%) was isolated after about 4 hours heating. Recrystallization from EtOAc-heptane gave the pure 31 as a yellow solid. Yield (57%), m.p. 110-112 °C. R_f= 0.85 (hexane-EtOAc, 1:2). FTIR (KBr): 1751 cm^-1 (νC=O_acetate), 1585 cm^-1 (νC=C_aromatic), 1245, 1222 cm^-1 (ν O=C–O).

 

1-(2',3',4'-Tri-O-acetyl-β-L-rhamnopyranosyl)-6,7-dimethylindoline-2,3-dione (32):

Starting with the rhamnoside triacetate 20 (2.5 mmole), the product (73%) was isolated after about 4 hours heating. Recrystallization from EtOAc-heptane gave the pure 32 as a yellow solid. Yield (62%), m.p. 98-100 °C. R_f= 0.84 (hexane-EtOAc, 1:2).  FTIR (KBr): 1751 cm^-1 (νC=O_acetate), 1600 cm^-1 (νC=C_aromatic), 1220 cm^-1 (ν O=C–O).

 

1-(2',3',4'-Tri-O-acetyl-β-L-rhamnopyranosyl)-5,7-dimethylindoline-2,3-dione (33):

Starting with the rhamnoside triacetate 21 (2.5 mmole), the product (71%) was isolated after about 4 hours heating. Recrystallization from EtOAc-heptane afforded the pure 33 as a yellow solid. Yield (60%), m.p. 78-80 °C. R_f= 0.87 (hexane-EtOAc, 1:2). FTIR (KBr): 1751 cm^-1 (νC=O_acetate), 1620 cm^-1 (νC=C_aromatic), 1224 cm^-1 (ν O=C–O).

 

1-(2',3',4'-Tri-O-acetyl-β-L-rhamnopyranosyl)-5-methoxyindoline-2,3-dione (34):

Starting with the rhamnoside triacetate 22 (2.53 mmole), the product was isolated, after about 3.5 hours heating, as a reddish brown solid in 62% yield. Column chromatography (hexane-EtOAc; 1:2) gave pure 34 as deep red solid. Yield (44%), m.p. 88-90 °C. R_f= 0.6 (hexane-EtOAc, 1:2). FTIR (KBr): 1743 cm^-1 (νC=O_acetate), 1622, 1595 cm^-1 (νC=C_aromatic), 1245, 1220 cm^-1 (ν O=C–O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.49 (d, J = 8.9 Hz, 1H, H-7), 7.24 (dd, J = 8.9, 2.9 Hz, 1H, H-6), 7.09 (d, J = 2.8 Hz, 1H, H-4), 6.09 (d, J = 1.5 Hz, 1H, H-1'), 5.42 (dd, J = 10.2, 3.5 Hz, 1H, H-3'), 5.37 (dd, J = 3.5, 1.5 Hz, 1H, H-2'), 5.04 (t, J = 10.0 Hz, 1H, H-4'), 4.07 (td, J = 9.9, 6.3 Hz, 1H, H-5'), 3.76 (s, 3H, OCH₃), 2.09, 1.93, 1.79 (3s, 9H, 3xCH_{3 acetate}), 1.22 (d, J = 6.2 Hz, 3H, H-6'). ¹³C NMR (101 MHz, DMSO-D₆) δ 182.08 (C-3), 169.90, 169.75, 169.45 (3xC=O _acetate), 157.41 (C-2), 155.53, 142.85, 124.00, 118.64, 116.83, 107.90 (aromatic), 79.46 (C-1'), 72.13, 70.08, 70.02, 69.49 (C-2',C-3',C-4',C-5'), 55.78 (OCH₃), 20.64, 20.59, 20.48 (3xCH_{3 acetate}), 17.36 (C-6').

 

1-(2',3',4'-Tri-O-acetyl-β-L-rhamnopyranosyl)-5-carbethoxyindoline-2,3-dione (35):

Starting with the rhamnoside triacetate 23 (1.14 mmole), the product was isolated, after about 5 hours heating, as a brown solid in 60% yield. Column chromatography (hexane/EtOAc; 1:2) yielded (46%) of pure 35 as a yellow solid, m.p. 64-66 °C. R_f= 0.54 (hexane-EtOAc, 1:2). FTIR (KBr): 1749 cm^-1 (νC=O_acetate), 1718 cm^-1 (νC=O_benzoate) , 1618 cm^-1 (νC=C_aromatic), 1253, 1222 cm^-1 (ν O=C–O). ¹H NMR (400 MHz, Chloroform-d) δ 8.28 (dd, J = 8.2, 1.9 Hz, 1H, H-6), 8.25 (dd, J = 1.6, 0.7 Hz, 1H, H-4), 7.63 (dd, J = 8.3, 0.7 Hz, 1H, H-7), 5.87 (d, J = 1.5 Hz, 1H, H-1'), 5.58 (dd, J = 2.9, 1.5 Hz, 1H, H-2'), 5.36 (dd, J = 10.3, 3.5 Hz, 1H, H-3'), 5.07 (t, J = 10.0 Hz, 1H, H-4'), 4.37 (q, J = 7.1 Hz, 2H, CH_{2 Et}), 3.84 – 3.71 (m, 1H, H-5'), 2.05, 1.99, 1.98 (3s, 9H, 3xCH_{3 acetate}), 1.39 (t, J = 7.1 Hz, 3H, CH_{3 Et}), 1.21 (d, J = 6.3 Hz, 3H, H-6'). ¹³C NMR (101 MHz, CDCl₃) δ 181.25 (C-3), 170.32, 170.21, 169.91 (3xC=O _acetate), 165.05 (C=O _benzoate), 157.25 (C-2), 152.43, 139.25, 126.83, 126.72, 117.93, 115.73 (aromatic), 80.76 (C-1'), 71.37, 70.58, 70.48, 70.06 (C-2',C-3',C-4',C-5'), 61.83 (CH_{2 Et}), 21.06, 21.00, 20.73 (3xCH_{3 acetate}), 17.89 (C-6'), 14.50 (CH_{3 Et}).

 

1-(2',3',4'-Tri-O-acetyl-β-L-rhamnopyranosyl)-4-acetylindoline-2,3-dione (36):

Starting with the rhamnoside triacetate 24 (1.22 mmole), the product was isolated after 6 hours heating, as a brown solid in 41% yield. Column chromatography (hexane-EtOAc; 1:2) yielded (38%) of pure 36 as a yellowish brown gum. R_f= 0.52 (hexane-EtOAc, 1:2). FTIR (film): 1747 cm^-1 (νC=O_acetate), 1689 cm^-1 (νC=O_acetyl), 1614, 1591 cm^-1 (νC=C_aromatic), 1222 cm^-1 (ν O=C–O).  ¹H NMR (400 MHz, Chloroform-d) δ 7.72 (dd, J = 8.3, 1.9 Hz, 1H, H-5), 7.60 (t, J = 8.2 Hz, 1H, H-6), 7.17 (dd, J = 7.7, 2.0 Hz, 1H, H-7), 5.87 (d, J = 1.5 Hz, 1H, H-1'), 5.37 (dd, J = 10.1, 3.4 Hz, 1H, H-3'), 5.27 (dd, J = 3.4, 1.8 Hz, 1H, H-2'), 5.08 (t, J = 10.0 Hz, 1H, H-4'), 4.15 – 4.10 (m, 1H, H-5'), 2.65 (s, 3H, CH_{3 acetyl}), 2.15, 2.05, 1.99 (3s, 9H, 3xCH_{3 acetate}), 1.22 (d, J = 6.3 Hz, 3H, H-6').

 

3. RESULTS AND DISCUSSION:

Isatin nucleosides 25-36 were successfully synthesized, according to a published procedure^(21,22), from D-glucose and L-rhamnose in three steps, scheme 1. The reaction of free sugar with different anilines and subsequent acetylation with acetic anhydride/pyridine furnished the O-acetylated N-glycosylanilines 13-24, which in turn cyclized in the presence of oxalyl chloride/AlCl₃ to yield the title nucleosides  diversely substituted with electron-donor and acceptor groups on isatin aromatic ring.            The method of Hanaoka⁽²⁷⁾ was followed to prepare the starting N-arylglycosylamines 1-12, and some of their physical properties as well as reaction times are summarized in table 1. FTIR spectra and melting point were used to  characterize these known derivatives and the results obtained here were in accordance with the previously reported data^(27,29,30). FTIR measurements (e.g. Figure 1) revealed the presence of a strong and broad band at about (3250-3450) cm^-1 contributed to the stretching vibration of (O―H) bond of the sugar (which predominately mask the appearance of (N―H) stretching band of the amine). The appearance of two bands at about 1600 and 1440 cm^-1 for the aromatic (C―C) stretching within the ring, in addition to a frequently strong band around 1505-1530 cm^-1 attributed to the (N―H) bending of the secondary aromatic amine were good indications for success of the reaction. The spectra also showed strong bands in region of about 1100-1000 cm^-1 which assigned for the stretching of (C–O) bond of the pyranose ring and its alcohol groups, in addition to moderate bands between 1240-1360 cm^-1 attributed to the (O–H) bending and stretching of (C–N) bonds.

 

Figure 1: FTIR spectrum of compound 1.

 

Table 1: Reaction time and some physical properties of the prepared N-arylglycosylamines 1-12.

Compound Number	Reaction Time (h)	Molecular Formula	Physical Form	M.p. (°C)	Yield (%)
1	5	C14H21NO5	Off-white solid	147-150	69
2	4	C14H21NO5	White solid	106-108	79
3	3.5	C14H21NO5	Off-white solid	93-96	58
4	10	C15H21NO7	White solid	155-158	58
5	2.5	C13H19NO6	Light gray solid	128-130	88
6	20	C14H19NO6	Off-white solid	174-176	79
7	5	C14H21NO4	Off-white solid	128-131	57
8	5	C14H21NO4	White solid	166-168	65
9	5	C14H21NO4	Off-white solid	150-152	68
10	3.5	C13H19NO5	Light gray solid	130-132	75
11	12	C15H21NO6	Bright white solid	188-190	69
12	22	C14H19NO5	Off-white solid	180-182	85

 

The protection of sugar hydroxyls was smoothly accomplished following an authentic procedure⁽²⁸⁾, whereupon the desired per-O-acetylated N-arylglycopyranosylamines 13-24 obtained in high yield and anomeric purity. Some physical properties and characteristic IR absorption bands are presented in table 2. FTIR spectra of the products 13-24 showed  a strong absorption band at (1740-1750) cm^-1  for the (C=O) stretching vibration of acetate, broad and strong bands at about (1225-1260) cm^-1  and about (1030-1050) cm^-1  for (O=C–O) and (O=C–O–C) stretching respectively and strong band at about 1370 cm^-1  characteristic for (CH₃–C=O) bending. Conversely, (cf. figure 2 and figure 1), the absence of (O–H) stretching band at (3450-3250) cm^-1 and the appearance of a sharp and frequently strong (N–H) stretching band at (3360-3440) cm^-1, all indicated the success of the protection reaction.

 

Figure 2: FTIR spectrum of compound 13.

 

Table 2: Some physical properties and characteristic IR absorption bands of compounds 13-24.

Compound Number	Molecular Formula	Physical Form	M.p. (°C)	Yield (%)	Characteristic IR bands (cm-1)
					ν(N―H)	ν(C=O)	ν(C=C) aromatic
13	C22H29NO9	Off-white solid	120-124	86	3431	1743	1591
14	C22H29NO9	White solid	128-130	82	3390	1750	1618
15	C22H29NO9	Off-white solid	112-114	84	3421	1755	1618
16	C23H29NO11	White solid	110-112	88	3375	1751,1703	1608
17	C21H27NO10	Beige solid	128-130	72	3360	1747	1437
18	C22H27NO10	Off-white solid	138-140	92	3361	1751,1676	1599
19	C20H27NO7	Off-white solid	134-136	85	3439	1744	1585
20	C20H27NO7	White solid	150-152	92	3431	1745	1589
21	C20H27NO7	White solid	140-142	89	3425	1755	1620
22	C19H25NO8	Beige solid	126-128	75	3358	1745	1440
23	C21H27NO9	White solid	134-136	93	3387	1755,1697	1608
24	C20H25NO8	Off-white solid	136-138	81	3358	1749,1681	1600

 

The stereochemistry of some of the prepared per-O-acetylated N-arylglycosylamines was established by analyzing the ¹H-NMR data (table 3). The results showed that all vicinal glucosyl protons exhibited large coupling constant within 9-10 Hz which reflects the axial-axial orientation of these protons and hence, confirms the β-configuration at the anomeric carbon (C-1′) as well as the ⁴C₁ pyranose conformation⁽³¹⁾, (e.g.; figures 3 and 4).

 

 

Figure 3: 1H NMR spectrum of compound 13.

 

 

 

 

 

 

 

13-18                            25-30                                  31-36

Figure 4: Numbering of the atoms for NMR assignment

Table 3: 1H-NMR data and signal assignments of compounds 13-18.

Compound Number	R	1H-NMR data and signal assignments
13	2,3-diMe	1H NMR (400 MHz, Benzene-d6) δ 7.10 (t, J = 7.8 Hz, 1H, H-5), 6.76 (d, J = 7.5 Hz, 1H, H-4), 6.68 (d, J = 8.0 Hz, 1H, H-6), 5.51 (t, J = 9.5 Hz, 1H, H-3'), 5.27 (dd, J = 10.1, 9.3 Hz, 1H, H-4'), 5.15 (dd, J = 9.6, 8.5 Hz, 1H, H-2'), 4.64 – 4.50 (m, 2H, H-1', NH), 4.32 (dd, J = 12.2, 5.0 Hz, 1H, H-6a'), 3.95 (dd, J = 12.2, 2.3 Hz, 1H, H-6b'), 3.23 (ddd, J = 10.1, 4.9, 2.3 Hz, 1H, H-5'), 2.08, 1.85 (2s, 6H, 2xCH3), 1.73, 1.72, 1.72, 1.61 (4s, 12H, 4xCH3 acetate).
14	3,4-diMe	1H NMR (400 MHz, DMSO-d6) δ 6.87 (d, J = 8.1 Hz, 1H, H-5), 6.55 (d, J = 2.3 Hz, 1H, H-2), 6.47 (dd, J = 8.2, 2.4 Hz, 1H, H-6), 6.13 (d, J = 10.1 Hz, 1H, H-1'), 5.34 (t, J = 9.5 Hz, 1H, H-2'), 5.14 (t, J = 9.5 Hz, 1H, H-3'), 4.94 – 4.86 (m, 2H, H-4', NH), 4.15 (dd, J = 12.0, 5.1 Hz, 1H, H-6a'), 4.07 (ddd, J = 10.1, 5.1, 2.3 Hz, 1H, H-5'), 3.95 (dd, J = 12.0, 2.2 Hz, 1H, H-6b'), 2.12, 2.08 (2s, 6H, 2xCH3), 2.00, 1.96, 1.95, 1.94 (4s, 12H, 4xCH3 acetate).
15	2,5-diMe	1H NMR (400 MHz, DMSO-d6) δ 6.88 (d, J = 7.4 Hz, 1H, H-3), 6.59 (d, J = 1.7 Hz, 1H, H-6), 6.49 (dd, J = 7.5, 1.6 Hz, 1H, H-4), 5.41 (t, J = 9.1 Hz, 1H, H-3'), 5.32 (d, J = 9.0 Hz, 1H, H-1'), 5.14 – 5.02 (m, 2H, H-2',NH), 4.90 (t, J = 9.5 Hz, 1H, H-4'), 4.19 – 4.11 (m, 2H, H-6a',H-6b'), 4.05 – 3.98 (m, 1H, H-5'), 2.21, 2.01 (2s, 6H, 2xCH3), 1.98, 1.97 (2s, 12H, 4xCH3 acetate).
16	4-COOEt	1H NMR (400 MHz, Chloroform-d) δ 7.90 (dd, J = 8.7, 3.2 Hz, 2H, H-3,H-5), 6.64 (dd, J = 8.8, 3.2 Hz, 2H, H-2,H-6), 5.38 (t, J = 9.4 Hz, 1H, H-3'), 5.19 (d, J = 8.9 Hz, 1H, H-1'), 5.07 (dt, J = 10.0, 4.7 Hz, 2H, H-4',NH), 4.81 (t, J = 8.9 Hz, 1H, H-2'), 4.31 (dq, J = 11.2, 4.9, 4.1 Hz, 3H, H-6a',CH2 Et), 4.09 (dd, J = 12.4, 2.8 Hz, 1H, H-6b'), 3.85 (ddd, J = 10.1, 5.4, 3.1 Hz, 1H, H-5'), 2.05 (s, 12H, 4xCH3acetate), 1.36 (t, J = 7.2 Hz, 3H, CH3 Et).
17	4-OMe	1H NMR (400 MHz, DMSO-d6) δ 6.74 (d, J = 9.1 Hz, 2H, H-2,H-6), 6.68 (d, J = 9.1 Hz, 2H, H-3,H-5), 6.08 (d, J = 10.1 Hz, 1H, H-1'), 5.34 (t, J = 9.4 Hz, 1H, H-3'), 5.10 (t, J = 9.6 Hz, 1H, H-4'), 4.90 (m, 2H, H-2',NH), 4.16 (dd, J = 12.1, 4.9 Hz, 1H, H-6a'), 4.07 (ddd, J = 10.1, 5.0, 2.4 Hz, 1H, H-5'), 3.94 (dd, J = 12.1, 2.3 Hz, 1H, H-6b'), 3.65 (s, 3H, OCH3), 2.00, 1.96, 1.95, 1.95 (4s, 12H, 4xCH3 acetate).
18	3-Ac	1H NMR (400 MHz, Chloroform-d) δ 7.40 (d, J = 7.6 Hz, 1H, H-4), 7.31 – 7.23 (m, 2H, H-2,H-5), 6.85 (d, J = 8.2 Hz, 1H, H-6), 5.38 (t, J = 9.4 Hz, 1H, H-3'), 5.13 – 5.01 (m, 2H, H-4',NH), 4.96 (d, J = 9.0 Hz, 1H, H-1'), 4.83 (t, J = 9.0 Hz, 1H, H-2'), 4.27 (dd, J = 12.3, 5.6 Hz, 1H, H-6a'), 4.10 (dd, J = 12.3, 2.3 Hz, 1H, H-6b'), 3.92 – 3.82 (m, 1H, H-5'), 2.55 (s, 3H, CH3acetyl), 2.04 (s, 12H, 4xCH3 acetate).

 

Per-O-acetylated N-arylglycosylamines 13-24 were subjected to an intramolecular AlCl₃-mediated cyclization reaction with oxalyl chloride to afford the per-O-acetylated isatin nucleosides 25-36. The procedure was originally invented by Stolle'⁽³²⁾ to synthesize N-alkylisatin, and utilized later for the synthesis of N-glycosylisatin derivatives by three research groups^(21,33-35). Reaction times were ranged from 2-6 hours as monitored by TLC. The slower reactions ( as well as the low yield ) were observed for the derivatives substituted with carboxylate group and those with acetyl group, as a result of the deactivation character of such groups on aromatic ring towards electrophilic substitution. By comparing FTIR spectra of the products with those of starting N-arylglycosylamines, (cf. figures 5 and 2), it is easy  to distinguish the complete disappearance of (N–H) stretching band at (3440-3360) cm^-1 as well as the (N–H) bending band around (1510-1530) cm^-1 from all products spectra, which indicate, preliminarily, the success of cyclization reaction.

 

Figure 5: FTIR spectrum of compound 25.

Further evidence for the reaction success was extracted from ¹³ C NMR spectra of the products which exhibited two signals at δ(180-182) ppm and at δ(156-160) ppm for the carbonyl carbons of ketone and amide (C₃ and C₂ of isatin) respectively, (e.g.; figures 6 and 7).

 

Figure 6: ¹³C NMR spectrum of compound 29.

 

Figure 7: ¹³C NMR spectrum of 26.

In figure 7, the presence of extra number of carbon signals was expected, since there are two different sites on the aromatic ring available for cyclization as proposed in scheme 2, leading to form two isomers having different signals on the spectrum.

 

 

Scheme 2: The two probable cyclization patterns arising from the reaction of compound 14 with (COCl)₂/AlCl₃.

 

¹H-NMR spectrum of 26, figure 8, revealed two singlets at δ 7.39 and δ 7.03 ppm for H-4 and H-7 respectively of isomer 26A, as well as two doublets at δ 7.33 (³J_6,7 = 8.1 Hz) and at δ 6.98 (³J_7,6=8 Hz) for H-6 and H-7 respectively of isomer 26B. As shown in figure 8 , from the integration calculated for each aromatic proton signal, it can be said that the product 26 is a mixture of two isomers; 26A and 26B in (2:1) proportion. TLC of 26 showed a double spot with ∆R_f of (0.01) that could not be separated by column chromatography using different solvent mixtures with different proportions.

 

 

Figure 8: ¹H NMR spectrum of 26.

 

 

Figure 9: ¹H NMR spectrum of 30.

The same two probable cyclization patterns arising from the reaction of N-(3-acetylphenyl)glycosylamines 18 and 24 with (COCl)₂/AlCl₃ might be postulated as in scheme 3. The product obtained from 18 was constituted of a separable mixture of two components using column chromatography, by which the faster and major component (R_f = 0.67) was separated and characterized as 6-acetyl isomer 30, while the slower component (R_f = 0.41) was separated as a trace that could not be characterized. ¹H-NMR of 30 (figure 9), showed two para-coupled aromatic protons, (⁵J_4,7≈ 0.5 Hz), between a doubled doublet at  δ 7.42 ppm for (H-4) and a doublet at δ 7.27 ppm for (H-7) in addition to a multiplate at δ 7.74 ppm for (H-5). These findings gave a powerful indication that the separated component is 6-acetyl derivative and not 4-acetyl one, since the later do not have two para-aromatic protons.

 

An opposite results were obtained from the cyclization reaction of compound 24, in which the major component that have been separated from the reaction product by column chromatography was the 4-acetyl derivative 36 and not its 6-acetyl isomer, since there is no coupling constant magnitude corresponds to the dipara-protons coupling, (i.e. ⁵J ~ 0–1 Hz) in any of the three signals of aromatic protons of 36. Instead, characteristic meta-proton coupling constant of about (⁴J_5,7= 2 Hz) was appointed between H-5 and H-7 in addition to a further splitting of both two proton signals by the ortho proton (H-6) with (³J_5,6= 8.2 Hz) and (³J_6,7= 8 Hz). Therefore, there are three adjacent aromatic hydrogens at (C-5, C-6 and C-7) and the acetyl group should occupy the remaining 4-position of isatin benzene ring.

 

Scheme 3: The two probable cyclization patterns arising from the reaction of compounds 18 and 24 with (COCl)₂/AlCl₃.   

 

The stereochemistry of some of the synthesized isatin nucleosides can be determined by analyzing coupling constant magnitudes between vicinal protons of the glycosyl moiety. For the D-gluco drivatives 25-30, the observed coupling constant between H-1ʹ and H-2' (³J_1',2') is more than 9 Hz in all these derivatives which indicates the axial orientation of both hydrogens and hence confirmed the β-configuration at C-1'. Furthermore, the large coupling constant observed between each couple of vicinal protons (i.e.; ³J_1',2', ³J_2',3', ³J_3',4' and ³J_4',5') confirmed the ⁴C₁ chair conformation of all gluco derivatives^(31,36).

In the case of L-rhamno derivatives 31-36, the determination of anomeric configuration from ¹H-NMR is difficult, since the coupling constant observed between H-1' and H-2' ( ~ 1.5 Hz) can be assigned to both the β-anomer (³J_ae= 1.5-5.8 Hz) and to the α-anomer (³J_ee= 0.6-3.5 Hz), while the differentiation between them is possible only if the observed coupling lies outside the range of overlap of the two sets of values⁽³⁶⁾. However, the NMR spectral data obtained here for rhamnosides are identical with those reported by Langer and coworkers⁽³⁷⁾ for analogue derivatives, as they have proved the β-configuration of utilizing 2D-NMR and X-ray crystallography. Such agreement between results can therefore be exploited for deducing the configuration of the L-rhamno derivatives as β-L-rhamnopyranoside. On the other hand, the later derivatives can be proved to exist in the ¹C₄ conformation, as they comprised three axial arrangements of vicinal hydrogens at C-3', C-4' and C-5' with (³J_aa = 10 Hz) characteristic for the ¹C₄ conformation of the L-rhamno derivatives⁽³⁸⁾.

 

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Received on 15.02.2019           Modified on 18.04.2019

Accepted on 30.05.2019         © RJPT All right reserved