HETEROCYCLES

Short Paper | Regular issue | Vol. 83, No. 12, 2011, pp. 2865-2872
Received, 16th September, 2011, Accepted, 20th October, 2011, Published online, 27th October, 2011.
DOI: 10.3987/COM-11-12362

■ One-Pot Synthesis of 2-Nitrooxyalkoxylated Inosine Analogs Using Cyclic Ether and Isoamyl Nitrite

Norikazu Sakakibara, Masahiro Komatsu, and Tokumi Maruyama*

Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki City, Kagawa, 769-2193, Japan

Abstract

An O6-methylguanosine derivative (1) was treated with isoamyl nitrite in the presence of a cyclic ether such as trimethylene oxide, tetrahydrofuran, or tetrahydropyran to give the corresponding 2-nitrooxyalkoxy-6-methoxypurine riboside derivatives (2a–c).

To date, 2-substituted inosine analogs, many of which form important intermediates of physiologically active substances, have been synthesized from appropriate nucleoside derivatives with an amino group at the 2-position via the diazonium salts using isoamyl nitrite.1-3 For example, purin-2-yl carboxylate was synthesized in our laboratory using an O6-methylguanosine derivative treated with sodium nitrite or isoamyl nitrite in the presence of a carboxylic acid.4,5 Recently, we developed a method for the conversion of the 2-amino group of O6-methylguanosine derivatives to a 2-alkoxy group via non-aqueous diazotization–dediazoniation reactions.6 This process was exploited for our synthesis of 2-methoxyadenosine (spongosine),6 which is known for its prominent bioactivity.7-10 Herein, by applying the above methods,4-6 we report a one-pot de novo nitrooxyalkoxylation at the 2-position of the purine skeleton using cyclic ethers and isoamyl nitrite. This is the first example of the synthesis of 2-nitrooxyalkoxylated nucleosides (2a–c, 5a–c) via nucleophilic attack by a cyclic ether at the 2-position of purine nucleoside analog followed by further attack at the α-position of the cyclic ether by the nitrate ion, which results in cleavage of the cyclic ether ring. New methods for the preparation of nitrooxylated compounds are important because nitrooxylated aspirin derivatives have been found to be useful as anti-inflammatory agents with low gastrointestinal and general toxicity due to the release of nitric monoxide (NO) from the nitrooxylated moiety.11,12 Hence, the compounds described in this report could also act as NO-donor reagents.
The isoamyl nitrite-promoted substitution of the 2-amino group of O6-methylguanosine derivative 14,5 was carried out in three different solvent, trimethylene oxide (n = 1), THF (n = 2) or THP (n = 3),

and the results are summarized in Table 1. First, compound 1 was treated with isoamyl nitrite in trimethylene oxide (n = 1) to give the O6-methylinosine analog (2a) nitrooxypropoxylated at the 2-position of the purine system, in a 23% yield. The reaction also yielded a non-substituted O6-methylinosine derivative (3), an O6-methylxanthosine analog (4), and an inosine analog (2d) a result of 3-[3-(nitrooxy)propoxy]- propoxylation of the 2-position, as by-products in 20, 43, and 12% yields, respectively (Table 1, entry 1). The structures of 2a, 3, 4, and 2d were identified by HR-MS (ESI), 1H NMR spectroscopy, and 1H-1H COSY spectroscopy. Similarly, compound 1 was treated in THF (n = 2) with isoamyl nitrite to give the 2-nitrooxybutoxylated compound 2b in a 30% yield and by-products 3 and 4 in 26 and 43% yields, respectively (Table 1, entry 2). In THP (n = 3), the reaction resulted in the production of 2-nitrooxypentoxylated derivative 2c and undesired products 3 and 4 in 24, 19, and 39% yields, respectively (Table 1, entry 3). The reaction times for these analogs decreased with the reduction of the cyclic ether ring size: the six- (n = 3), five- (n = 2), and four- (n = 1) membered ring systems required 4, 3, and 1 day(s), respectively, for completion of the reaction. These results may be due to the higher ring strain in the smaller ring systems. Especially trimethylene oxide (n = 1) has the most strained ring, therefore, is so reactive to produce double-reacted product 2-{3-[3-(nitrooxy)propoxy]propoxy}purine analog (2d) in 12% yield.
Deprotective reactions of the TBS groups at the 2', 3', and 5'-position of the ribose moieties of 2a–c were carried out in high yields using conventional methods to provide compounds 5a–c (Scheme 1). The molecular formulae of 5a–c were determined by HRMS (ESI) and 1H NMR, 1H-1H COSY, and FT-IR spectroscopy. In particular, the nitrate ester structures (RONO2) of 5a–c were confirmed by their IR spectra (5a: 1602, 1275, 859 cm-1, 5b: 1602, 1279, 864 cm-1, 5c: 1597, 1277, 861 cm-1).
While we synthesized compound 5b through an alternative method (Scheme 2). The O6-methylguanosine derivative (1) was treated with isoamyl nitrite in the presence of 15.0 equivalents of

4-nitrooxybutan-1-ol (6) in benzene to obtain the desired 2-nitrooxybutoxylated product (2b) in a relatively low yield (13%) and the by-product O6-methylxanthosine analog 4 in a 32% yield. Moreover, compound 2b was treated with tetrabutylammonium fluoride to obtain the desilylated product (5b) in an 86% yield. The 1H NMR and HRMS data of 2b and the 1H NMR, 1H-1H COSY, 13C NMR, HRMS, and FT-IR data of 5b were found to be in identical with the corresponding synthesized products (2b in Table 1 and 5b in Scheme 1).
The plausible reaction mechanism to obtain the 2-nitrooxybutoxyinosine (2b), inosine (3), and xanthosine analogs (4) is described in Scheme 3.4-6 In the presence of isoamyl nitrite, compound 1 underwent substitution, as in the Sandmeyer reaction, to give one water molecule and the corresponding diazonium salt (Ia) as the reaction intermediate.13 The diazo group at the 2-position of compound Ia was then nucleophilically attacked by the oxygen atom of THF, which simultaneously replaced the counter anion isoamyl oxide ion with the nitrate ion that is generated in the reaction system to providing the nitrogen-eliminated intermediate Ib. Then, nitrate esterification at the α-position of the THF moiety of Ib with the use of a nitrate ion occurred to afford the nitrooxybutoxylated product, 2b. If diazonium salt Ia was attacked by a water molecule, the xanthosine derivative 4 was formed.6 When intermediate Ia underwent the thermal homolysis, Ia was converted to the transient species, purine-2-yl radical, followed by the production of the inosine analog 3 as previously reported by Nair et al.14 The production of nitrate ions in the reactive system can be explained based on the Ostwald process.15,16 As shown in Scheme 3, the NO radical, which is derived from isoamyl nitrite, reacts with oxygen to produce NO2. The resulting NO2 reacts with water, which is produced during diazonium salt formation via compound 1 and isoamyl nitrite, to give nitric acid (HNO3) and NO. Then, the HNO3 molecule is ionized by a reaction with an isoamyl oxide ion to provide a nitrate ion (NO3−). We consider the reactions to provide compounds 2b, 3, and 4 to be competitive; therefore, the yields of the desired products (2a–c) are relatively low. Further research on the effective synthesis of 2-nitrooxyalkoxylinosine analogs is necessary.

EXPERIMENTAL
Instrumentation
1H NMR spectra were taken with a UltrashieldTM 400 Plus FT NMR System (BRUKER). Chemical shifts and coupling constants (J) were given in δ and Hz, respectively. High-resolution mass spectrometry was performed on a APEX IV mass spectrometer (BRUKER) with electrospray ionization mass spectroscopy (ESI-MS).

6-Methoxy-2-[3-(nitrooxy)propoxy]-9-(2,3,5-tri-O-tert-butyldimetylsilyl-β-D-ribofuranosyl)-9H-purine (2a), 6-Methoxy-2-{3-[3-(nitrooxy)propoxy]propoxy}-9-(2,3,5-tri-O-tert-butyldimetylsilyl-β-D-ribofuranosyl)-9H-purine (2d), 6-Methoxy-9-(2,3,5-tri-O-tert-butyldimetylsilyl-β-D-ribofuranosyl)-9H-purine (3) and 1,9-dihydro-6-methoxy-9-(2,3,5-tri-O-tert-butyldimetylsilyl-β-D-ribofuranosyl)-2H-purin-2-one (4)
Compound 1 (320.0 mg, 0.50 mmol) was dissolved in dry trimethylene oxide (8.0 mL) and isoamyl nitrite (489.7 μL, 3.75 mmol) was added to the solution at 0 °C, and then stirred for 1 day at 50 °C. The mixture was evaporated, and the residue was purified by silica gel column chromatography (25% AcOEt in hexane) to give 3 as oil (61.4 mg, 0.10 mmol, 20%). Evaporation of second fraction gave 2a as oil (86.3 mg, 0.12 mmol, 23%). Then, evaporation of third fraction gave 2d as oil (47.1 mg, 0.06 mmol, 12%) and finally fourth fraction gave 4 as oil (137.2 mg, 0.22 mmol, 43%). 3: 1H NMR (400 MHz, CDCl3): δ 8.51 (1H, s, H-8), 8.42 (1H, s, H-2), 5.99 (1H, d, J = 4.8, H-1'), 4.52 (1H, m, H-2'), 4.22 (1H, m, H-3'), 4.10 (3H, s, 6-OCH3), 4.06 (1H, m, H-4'), 3.94 (1H, dd, J = 11.6 and 4.0, H-5' a), 3.76 (1H, dd, J = 11.2 and 2.0, H-5' b), 0.88 (9H, s, OTBS), 0.83 (9H, s, OTBS), 0.71 (9H, s, OTBS), 0.08 (3H, s, OTBS), 0.07 (3H, s, OTBS), 0.04 (3H, s, OTBS), 0.03 (3H, s, OTBS), -0.11 (3H, s, OTBS), -0.33 (3H, s, OTBS); HRMS (ESI) Calcd for C29H57N4O5Si3 [M+Na]+: 647.34507. Found 647.33660. 2a: 1H-NMR (400 MHz, CDCl3): δ 8.20 (1H, s, H-8), 6.02 (1H, d, J = 4.8, H-1'), 4.68 (2H, m, 2-OCH2CH2CH2ONO2), 4.51 (1H, m, H-2'), 4.48 (2H, m, 2-OCH2CH2CH2ONO2), 4.31 (1H, m, H-3'), 4.15 (3H, s, 6-OCH3), 4.11 (1H, m, H-4'), 3.99 (1H, dd, J = 11.6 and 3.6, H-5´ a), 3.81 (1H, dd, J = 11.6 and 2.4, H-5´ b), 2.28 (2H, m, 2-OCH2CH2CH2ONO2), 0.95 (9H, s, OTBS), 0.92 (9H, s, OTBS), 0.81 (9H, s, OTBS), 0.14 (3H, s, OTBS), 0.13 (3H, s, OTBS), 0.12 (3H, s, OTBS), 0.11 (3H, s, OTBS), -0.03 (3H, s, OTBS), -0.40 (3H, s, OTBS); HRMS (ESI) Calcd for C33H64N5O9Si3 [M+H]+: 744.38498. Found 744.38499. 2d: 1H-NMR (400 MHz, CDCl3): δ 8.18 (1H, s, H-8), 6.02 (1H, d, J = 4.8, H-1'), 4.57 (2H, m, 2-OCH2CH2CH2OCH2CH2CH2ONO2), 4.48(1H, m, H-2'), 4.42 (2H, m, 2-OCH2CH2CH2OCH2CH2CH2ONO2), 4.31 (1H, m, H-3'), 4.15 (3H, s, 6-OCH3), 4.11 (1H, m, H-4'), 3.99 (1H, dd, J = 11.6 and 4.0, H-5' a), 3.81 (1H, dd, J = 11.2 and 2.4 , H-5' b), 3.62 (2H, m, 2-OCH2CH2CH2OCH2CH2CH2ONO2), 3.54 (2H, m, 2-OCH2CH2CH2OCH2CH2CH2ONO2), 2.11 (2H, m, 2-OCH2CH2CH2OCH2CH2CH2ONO2), 1.97 (2H, m, 2-OCH2CH2CH2OCH2CH2CH2ONO2), 0.96 (9H, s, OTBS), 0.93 (9H, s, OTBS), 0.83 (9H, s, OTBS), 0.18 (3H, s, OTBS), 0.15 (3H, s, OTBS), 0.13 (3H, s, OTBS), 0.12 (3H, s, OTBS), -0.03 (3H, s, OTBS), -0.19 (3H, s, OTBS); HRMS (ESI) Calcd for C35H67N5NaO10Si3 [M+Na]+: 824.40879. Found 824.40789. 4: 1H-NMR (400 MHz, CDCl3): δ 7.56 (1H, s, H-8), 5.70 (1H, d, J = 7.6, H-1'), 4.61 (1H, m, H-2'), 4.30 (1H, dd, J = 7.6 and 4.4, H-3'), 4.16 (1H, m, H-4'), 4.13 (3H, s, 6-OCH3) 4.05 (1H, dd, J = 12.0 and 2.0, H-5' a), 3.88 (1H, dd, J = 12.0 and 1.6, H-5' b), 1.00 (9H, s, OTBS), 0.95 (9H, s, OTBS), 0.80 (9H, s, OTBS), 0.27 (3H, s, OTBS), 0.21 (3H, s, OTBS), 0.14 (3H, s, OTBS), 0.12 (3H, s, OTBS), -0.03 (3H, s, OTBS), -0.40 (3H, s, OTBS); HRMS (ESI) Calcd for C29H57N4O6Si3 [M+H]+: 641.35846. Found 641.35804.
6-Methoxy-2-[4-(nitrooxy)butoxy]-9-(2,3,5-tri-O-tert-butyldimetylsilyl-β-D-ribofuranosyl)-9H-purine (2b), 6-Methoxy-9-(2,3,5-tri-O-tert-butyldimetylsilyl-β-D-ribofuranosyl)-9H-purine (3) and 1,9-dihydro-6-methoxy-9-(2,3,5-tri-O-tert-butyldimetylsilyl-β-D-ribofuranosyl)-2H-purin-2-one (4)
Compound 1 (1280.1 mg, 2.00 mmol) was dissolved in dry tetrahydrofuran (60.0 mL) and isoamyl nitrite (1999.0 μL, 15.0 mmol) was added to the solution at 0 °C, and then stirred for 3 days at 50 °C. The mixture was evaporated, and the residue was purified by silica gel column chromatography (25% AcOEt in hexane) to give 3 as oil (329.7 mg, 0.52 mmol, 26%). Evaporation of second fraction gave 2b as oil (458.7 mg, 0.60 mmol, 30%). Then, evaporation of third fraction gave 4 as oil (547.0 mg, 0.86 mmol, 43%). 2b: 1H-NMR (400 MHz, CDCl3): δ 8.06 (1 H, s, H-8), 5.89 (1H, d, J = 4.8, H-1'), 4.43 (2H, m, 2-OCH2CH2CH2CH2ONO2), 4.35 (1H, m, H-2'), 4.27 (2H, m, 2-OCH2CH2CH2CH2ONO2), 4.18 (1H, m, H-3'), 4.01 (3H, s, 6-OCH3), 3.98 (1H, m, H-4'), 3.86 (1H, dd, J = 11.2 and 3.2, H-5' a), 3.68 (1H, m, H-5' b), 1.82 (4H, m, 2-OCH2CH2CH2CH2ONO2), 0.85 (9H, s, OTBS), 0.82 (9H, s, OTBS), 0.67 (9H, s, OTBS), 0.05 (3H, s, OTBS), 0.04 (3H, s, OTBS), 0.00 (3H, s, OTBS), -0.01 (3H, s, OTBS), -0.13 (3H, s, OTBS), -0.34 (3H, s, OTBS); HRMS (ESI) Calcd for C33H63N5NaO9Si3 [M+Na]+: 780.38258. Found 780.37893.
6-Methoxy-2-[4-(nitrooxy)pentoxy]-9-(2,3,5-tri-O-tert-butyldimetylsilyl-β-D-ribofuranosyl)-9H-purine (2c), 6-Methoxy-9-(2,3,5-tri-O-tert-butyldimetylsilyl-β-D-ribofuranosyl)-9H-purine (3) and 1,9-dihydro-6-methoxy-9-(2,3,5-tri-O-tert-butyldimetylsilyl-β-D-ribofuranosyl)-2H-purin-2-one (4)
Compound 1 (640.05 mg, 1.00 mmol) was dissolved in dry tetrahydrofuran (16.0 mL) and isoamyl nitrite (1000.0 μL, 7.5 mmol) was added to the solution at 0 °C, and then stirred for 4 days at 50 °C. The mixture was evaporated, and the residue was purified by silica gel column chromatography (25% AcOEt in hexane) to give 3 as oil (118.6 mg, 0.19 mmol, 19%). Evaporation of second fraction gave 2c as oil (192.3 mg, 0.24 mmol, 24%). Then, evaporation of third fraction gave 4 as oil (248.9 mg, 0.39 mmol, 39%). 2c: 1H-NMR (400 MHz, CDCl3): δ 8.18 (1H, s, H-8), 6.02 (1H, d, J = 5.2, H-1'), 4.49 (1H, m, H-2'), 4.48 (2H, m, 2-OCH2CH2CH2CH2CH2ONO2), 4.38 (2H, m, 2-OCH2CH2CH2CH2CH2ONO2), 4.31 (1H, m, H-3'), 4.15 (3 H, s, 6-OCH3), 4.11 (1H, m, H-4'), 3.99 (1 H, dd, J = 11.6 and 3.6, H-5' a), 3.81 (1H, dd, J = 11.6 and 2.4, H-5' a), 1.91 (2H, m, 2-OCH2CH2CH2CH2CH2ONO2), 1.81 (2H, m, 2-OCH2CH2CH2CH2CH2ONO2), 1.65 (2H, m, 2-OCH2CH2CH2CH2CH2ONO2), 0.95 (9H, s, OTBS), 0.93 (9H, s, OTBS), 0.81 (9H, s, OTBS), 0.14 (3H, s, OTBS), 0.13 (3H, s, OTBS), 0.12 (3H, s, OTBS), 0.11 (3H, s, OTBS), -0.03 (3H, s, OTBS), -0.20 (3H, s, OTBS); HRMS (ESI) Calcd for C34H65N5NaO9Si3 [M+Na]+: 794.39823. Found 794.39869.
6-Methoxy-2-[3-(nitrooxy)propoxy]-9-(β-D-ribofuranosyl)-9H-purine (5a)
Compound 2a (86.3 mg, 0.12 mmol) was dissolved in THF (2.0 mL), and 1.0 M tetrabutylammonium fluoride-THF solution (0.6 mL) was added to the solution, and then stirred for 15 min at room temperature. The mixture was evaporated, and was purified by silica gel column chromatography (10% MeOH in AcOEt) to give needle crystals 5a (33.7 mg, 0.08 mmol, 72%). 1H-NMR (400 MHz, CD3OD): δ 8.21 (1H, s, H-8), 5.87 (1H, d, J = 5.6, H-1'), 4.61 (1H, m, H-2'), 4.60 (2H, m, 2-OCH2CH2CH2ONO2), 4.42 (2H, m, 2-OCH2CH2CH2ONO2), 4.25 (1H, dd, J = 5.2 and 3.6, H-3'), 4.04 (3H, s, 6-OCH3), 4.02 (1H, m, H-4'), 3.77 (1H, dd, J = 12.4 and 3.2, H-5' a), 3.65 (1H, dd, J = 12.4 and 3.6, H-5' b), 2.15 (2H, m, 2-OCH2CH2CH2ONO2); 13C-NMR (100MHz, CD3OD): δ 163.3, 162.4, 154.2, 142.4, 118.4, 90.6, 87.4, 75.5, 72.1, 71.5, 65.3, 63.1, 55.0, 27.7; HRMS (ESI) Calcd for C14H19N5NaO9 [M+Na]+: 424.10750. Found 424.10650; FT-IR (Nujol) cm-1: 1602, 1275, 859.
6-Methoxy-2-[3-(nitrooxy)butoxy]-9-(β-D-ribofuranosyl)-9H-purine (5b)
Compound 2b (153.7 mg, 0.20 mmol) was dissolved in THF (2.0 mL), and 1.0 M tetrabutylammonium fluoride-THF solution (1.0 mL) was added to the solution, and then stirred for 15 min at room temperature. The mixture was evaporated, and was purified by silica gel column chromatography (10% MeOH in AcOEt) to give needle crystals 5b (64.7 mg, 0.15 mmol, 77%). 1H-NMR (400 MHz, CD3OD): δ 8.19 (1H, s, H-8), 5.85 (1H, d, J = 5.6, H-1'), 4.61 (1H, m, H-2'), 4.48 (2H, m, 2-OCH2CH2CH2CH2ONO2), 4.34 (2H, m, 2-OCH2CH2CH2CH2ONO2), 4.25 (1H, dd, J = 5.2 and 3.6, H-3'), 4.03 (3H, s, 6-OCH3), 4.02 (1H, m, H-4'), 3.78 (1H, dd, J = 12.4 and 3.2, H-5' a), 3.65 (1H, dd, J = 12.4 and 3.2, H-5' b), 1.78- 1.87 (4H, m, 2-OCH2CH2CH2CH2ONO2); 13C-NMR (100 MHz, CD3OD): δ 163.2, 162.6, 154.2, 142.3, 118.3, 90.6, 87.4, 75.4, 74.4, 72.2, 68.6, 63.1, 55.0, 26.4, 24.8; HRMS (ESI) Calcd for C15H21N5NaO9 [M+Na]+: 438.12315. Found 438.12253; FT-IR (Nujol) cm-1: 1602, 1279, 864.
1H-NMR (400 MHz, CD3OD): δ 8.18 (1H, s, H-8), 5.85 (1H, d, J = 5.6, H-1'), 4.62 (1H, m, H-2'), 4.41 (2H, J = 6.8, 2-OCH2CH2CH2CH2CH2ONO2), 4.31 (2H, J = 6.0, 2-OCH2CH2CH2CH2CH2ONO2), 4.26 (1H, m, H-3'), 4.02 (3H, s, 6-OCH3), 4.01 (1H, m, H-4'), 3.77 (1H, dd, J = 12.4 and 2.8, H-5' a), 3.65 (1H, dd, J = 12.4 and 2.2, H-5' b), 1.66-1.80 (4H, m, 2-OCH2CH2CH2CH2CH2ONO2), 1.45-1.55 (2H, m, 2-OCH2CH2CH2CH2CH2ONO2); 13C-NMR (100 MHz, CD3OD): δ 163.2, 162.7, 154.2, 142.3, 118.3, 90.6, 87.4, 75.4, 74.6, 72.2, 68.9, 63.1, 55.0, 29.6, 27.6, 23.5; HRMS (ESI) Calcd for C16H23N5NaO9 [M+Na]+: 452.13880. Found 452.13777; FT-IR (Nujol) cm-1: 1597, 1277, 861.
6-Methoxy-2-[4-(nitrooxy)butoxy]-9-(2,3,5-tri-O-tert-butyldimetylsilyl-β-D-ribofuranosyl)-9H-purine (2b) and 1,9-dihydro-6-methoxy-9-(2,3,5-tri-O-tert-butyldimetylsilyl-β-D-ribofuranosyl)-2H-purin-2-one (4)
Compound 1 (236.5 mg, 0.37 mmol) and 4-nitrooxybutan-1-ol (6) (748.9 mg, 5.54 mmol) were dissolved in dry benzene (5.9 mL) and isoamyl nitrite (369.8 μL, 2.78 mmol) was added to the solution at 0 °C, and then stirred for 1 day at 50 °C. The mixture was evaporated, and the residue was purified by silica gel column chromatography (25% AcOEt in hexane) to give 2b as oil (34.9 mg, 0.05 mmol, 13%). Then, evaporation of second fraction gave 4 as oil (75.1 mg, 0.12 mmol, 32%).
6-Methoxy-2-[3-(nitrooxy)butoxy]-9-(β-D-ribofuranosyl)-9H-purine (5b)
Compound 2b (30.4 mg, 0.04 mmol) was dissolved in THF (2.0 mL), and 1.0 M tetrabutylammonium fluoride-THF solution (0.2 mL) was added to the solution, and then stirred for 15 min at room temperature. The mixture was evaporated, and was purified by silica gel column chromatography (10% MeOH in AcOEt) to give crystals 5b (14.4 mg, 0.03 mmol, 86%).

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