Synthesis of 2-amino-6,7,8,9-tetrahydro-6-phenethyl-3H-pyrimido[4,5-e][1,4]diazepin-4(5H)-one: a model for a potential pyrimido[4,5-e][1,4]diazepine-based folate anti-tumor agent

Austin W. Gann 1  and Partha S. Ray 1
  • 1 Department of Chemistry, University of West Georgia, Carrollton, GA 30118, USA
Austin W. Gann and Partha S. Ray

Abstract

Reductive cyclization of 2-{N-[(2-amino-4,6-dichloropyrimidin-5-yl)methyl]-N-phenethylamino}acetonitrile (5) with Raney nickel and hydrogen gave the chloropyrimido[4,5-e][1,4]diazepine 3 which could not be converted to 2 via an attempted nucleophilic aromatic substitution with hydroxide. The title compound (2) was prepared, however, by the reductive cyclization of 2-{N-[(2-amino-4-chloro-6-methoxypyrimidin-5-yl)methyl]-N-phenethylamino}acetonitrile (13) followed by treatment with trimethyliodosilane.

Introduction

Based on the structure-activity relationships of inhibitors of glycinamide ribonucleotide formyltransferase (GARFT) as potential anti-tumor agents [1–3] we have, for some time, been interested in preparing pyrimido[4,5-e][1,4]diazepine-based folates, such as 1. In an earlier article we have described our rational for the design of these potential anti-cancer drugs [4]. In previous papers we have also reported on three strategies to these targets, none of which were successful [4–6]. Herein we report on establishing a synthetic methodology to the title compound 2, which should serve as a model for the eventual synthesis of our desired target 1 (Figure 1).

Figure 1
Figure 1

Structures of potential GARFT inhibitor 1 and model compound 2.

Citation: Heterocyclic Communications 21, 6; 10.1515/hc-2015-0216

Results and discussion

Our retrosynthetic analysis for the model compound 2 is shown in Scheme 1. It was envisioned that 2 could be obtained from the chloropyrimidodiazepine 3 by treatment with hydroxide and that 3 could arise from an intramolecular nucleophilic aromatic substitution reaction of the intermediate 4 obtained from reduction of the nitrile 5. Reaction of the trichloropyrimidine 6 with 2-(phenethylamino)acetonitrile (7) was expected to give 5 via straightforward alkylation chemistry.

Scheme 1
Scheme 1

Retrosynthetic analysis of model compound 2.

Citation: Heterocyclic Communications 21, 6; 10.1515/hc-2015-0216

In our previous communication we have reported the preparation of the trichloropyrimidine 6 from commercially available 2-amino-4,6-dihydroxypyrimidine 8 as shown in Scheme 2. Thus, 2-amino-4,6-dichloro-5-formylpyrimidine (9) was prepared from 8 using Vilsmeier-Haack conditions as reported by Bell [7]. The aldehyde 9 was reduced with sodium borohydride in anhydrous DMF to give the alcohol 10 which was treated with thionyl chloride under reflux, which provided the trichloropyrimidine 6 in 38% overall yield from 8 [5]. 2-(Phenethylamino) acetonitrile was prepared in 90% yield by adding chloroacetonitrile dropwise, to a well stirred mixture of phenethylamine (11) and triethylamine. A vigorous and exothermic reaction occurred giving largely the desired monoalkylated amine 7 and a minor amount (10%) of the dialkylated amine 12 which were easily separable by column chromatography. Next, compound 7 was allowed to react with the trichloropyrimidine 6 in the presence of triethylamine in refluxing ethanol which yielded the nitrile 5 in 68% yield. The fact that the desired reaction had taken place at the chloromethyl carbon of 6 as opposed to a nucleophilic aromatic substitution reaction was evident from both the 1H and 13C NMR data of 5. Thus, the signals for the chloromethyl hydrogens of 6 appear at δ 4.74 whereas the same protons in 5 resonate at δ 3.78 (both in DMSO-d6) which clearly indicates that the chloromethyl chlorine has been replaced with the amino nitrogen of 7. Also, the 13C NMR spectrum of 5 shows 7 sp2 carbons consistent with structure 5 in which the four and six carbons are equivalent. Reduction of the nitrile was achieved by hydrogenation in the presence of Raney nickel at 50 psi in DMF which provided the chloropyrimidodiazepine 3 in 60% yield after purification by column chromatography. Interestingly, the intermediate amine 4 (see Scheme 1) was not isolated as it reacted in situ via intramolecular nucleophilic aromatic substitution chemistry. It was expected that reaction of 3 with hydroxide ion would provide the desired model compound 2. However, an attempted reaction of 3 with sodium hydroxide in refluxing 1,4-dioxane or diglyme was not successful and the starting material 3 was recovered in high yield. Similarly, 3 failed to react with sodium methoxide and 2-mercaptoethanol in refluxing methanol. This method was used to convert 6-chloropurine nucleoside analogs to the corresponding 6-hydroxy derivatives [8, 9]. The reluctance of 3 to undergo nucleophilic aromatic substitution at the four position was unexpected. Consequently, compound 5 was treated with one equivalent of sodium methoxide in refluxing anhydrous methanol, and this reaction yielded the corresponding mono methoxy derivative 13 in 70% yield via a smooth nucleophilic aromatic substitution. Reduction of the nitrile group of 13 via hydrogenation in the presence of Raney nickel at 50 psi in DMF gave the amine 14 in 10% yield after purification by column chromatography. It is likely that much of the product was lost on the column (see below). Presumably, 14 did not cyclize in situ, as was the case with 4, due to the lowered electrophilicity of the pyrimidine carbon bearing the chlorine, compared to the same position in 4. Fortunately, 14 was easily cyclized to 15 by heating in DMF in the presence of potassium carbonate. Subsequently, the conversion 1315 was carried out without isolation of the intermediate amine 14 and product 15 was obtained in 61% overall yield (from 13) after purification by column chromatography. Finally, the methoxy group in 15 was cleaved by treatment with trifluoroacetic acid (three equivalents; which allows for protonation of the basic nitrogen atoms and thus preventing them from reacting with trimethyliodosilane) followed by addition of trimethyliodosilane (two equivalents). This procedure gave the desired model compound 2 in 23% yield as the HI salt. The proton NMR spectrum of the HI salt of 2 (where the most basic sp3 nitrogen is protonated) shows that the signals for the two heterocyclic ‘benzylic’ hydrogens (at C5) appear at δ 4.17 and 4.42 as a pair of doublets with a coupling constant of 13 Hz, which is consistent with these diastereotopic hydrogens. Having established the above methodology to the model compound, we are currently working on similar chemistry using methyl 4-(2-aminoethyl)benzoate in place of phenethylamine, which should provide the actual pyrimidodiazepine-based folate target 1, which we hope will be a potent anti-tumor agent via inhibition of GARFT.

Scheme 2
Scheme 2

Synthetic route to model compound 2.

Citation: Heterocyclic Communications 21, 6; 10.1515/hc-2015-0216

Experimental

Melting points were determined in open capillary tubes using a MELT-TEMP apparatus and are uncorrected. All 1H and 13C NMR spectra were recorded at 400 MHz and 100 MHz, respectively, on a Varian 400 MHz spectrometer. Column chromatography was performed on Merck silica gel 60 (240–400) mesh, and silica gel plates were used for TLC determinations. HR-MS data were obtained using liquid introduction field desorption ionization (LIFDI) on a Waters GCT Premiere mass spectrometer.

2-Amino-4,6-dichloro-5-hydroxymethylpyrimidine (10)

To a stirred, ice cooled suspension of 2-amino-4,6-dichloro-5-formylpyrimidine [7] (10.05 g, 52.3 mmol) in anhydrous DMF, sodium borohydride (2.38 g, 62.9 mmol) was added in portions over a 0.5 h period. The mixture was stirred for an additional 0.5 h at 0°C, treated with cold water (50 mL), slowly poured into 750 mL of more cold water, and the final mixture was stirred for an additional 1 h. The white solid was collected by vacuum filtration and dried in a vacuum desiccator to give 7.4 g (75%) of a white powder. This material was converted to 6 without further purification. For the mp and NMR data see ref. [5].

2-Amino-4,6-dichloro-5-chloromethylpyrimidine (6)

Thionyl chloride (25 mL) was carefully added to 2-amino-4,6-dichloro-5-hydroxymethylpyrimidine (7.45 g, 38.6 mmol) and the mixture was heated at reflux for 2 h and then concentrated under reduced pressure. The orange residue was cooled in an ice water bath and ice cold water (50 mL) was added very slowly to the residue. The mixture was stirred well, filtered and the collected solid was washed with water and dried in a vacuum desiccator to give 7.66 g (93%) of a white powder. For the mp and NMR data see [5]. Anal. Calcd for C5H4Cl3N3: C, 28.27; H, 1.90; N, 19.78. Found: C, 28.41; H, 2.03; N, 19.61.

2-(Phenethylamino)acetonitrile (7)

Chloroacetonitrile (6.26 mL, 99 mmol) was added dropwise to a stirred mixture of phenethylamine (12.4 mL, 99 mmol) and triethylamine (13.8 mL, 99 mmol). The mixture was stirred overnight at room temperature. The resulting orange oil was dissolved in dichloromethane (100 mL) and washed with water (30 mL). The organic layer was separated and dried with anhydrous Na2SO4, filtered and the solvent was removed by rotary evaporation. The orange residue was chromatographed on silica gel eluting with a 50:50 mixture of ethyl acetate and hexanes. The fractions with an Rf of 0.58 were combined, and the solvent evaporated to give 12 g (91%) of a yellow oil; 1H NMR (CDCl3): δ 2.83 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 6.8 Hz, 2H), 3.58 (s, 2H), 7.20–7.31 (m, 5H); 13C NMR (CDCl3): δ 35.77, 37.34, 49.79, 117.64, 128.54, 128.66, 138.88. HR-MS (LIFDI-TOF). Calcd for C10H12N2, [M.]+: m/z 160.0992. Found: m/z 160.1000. Reported mp of hydrochloride salt: 144°C [10].

2-{N-[(2-amino-4,6-dichloropyrimidin-5-yl)methyl]- N-phenethylamino}acetonitrile (5)

To a stirred mixture of 2-amino-4,6-dichloro-5-chloromethylpyrimidine (3.18 g, 15 mmol) and ethanol (20 mL) was added dropwise a mixture of 2-(phenethylamino)acetonitrile (2.66 g, 16.6 mmol), ethanol (10 mL) and triethylamine (2.1 mL, 15 mmol). The mixture was heated at reflux for 4 h and then the solvent removed by rotary evaporation to give a pale yellow solid which was washed with water, filtered and washed again with cold ethanol and dried in a vacuum desiccator to give 3.61 g (68%) of a colorless solid; mp 191–192°C; 1H NMR (CDCl3): δ 2.79 (t, J = 6.8 Hz, 2H), 2.94 (t, J = 6.8 Hz, 2H), 3.58 (s, 2H), 3.79 (s, 2H), 5.26 (s, 2H), 7.14–7.28 (m, 5H); 13C NMR (CDCl3): δ 33.79, 41.46, 52.11, 54.95, 115.11, 116.05, 126.33, 128.45, 128.54, 138.95, 160.52, 163.47. HR-MS (LIFDI-TOF). Calcd for C15H15Cl2N5, [M.]+: m/z 335.0705. Found: m/z 335.0706.

2-Amino-4-chloro-6-phenethyl-6,7,8,9-tetrahydro- 5H-pyrimido[4,5-e][1,4]diazepine (3)

A mixture of 5 (0.45 g, 1.34 mmol), DMF (7 mL), 2 m ammonia in methanol (3 mL), and Raney nickel (1 g, washed with methanol to remove most of the water) was allowed to react under 50 psi of hydrogen in a Parr shaker for 21 h. The reaction mixture was filtered through a pad of celite and washed well with methanol. The solvents were removed by rotary evaporation under reduced pressure and the residue was partitioned between dichloromethane and water. The organic layer was separated, dried with anhydrous sodium sulfate, filtered and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 10% methanol in chloroform. The fractions with an Rf of 0.5 were combined and the solvent removed to give 0.24 g (60%) of a colorless solid; mp 134–135°C; 1H NMR (CDCl3): δ 2.76–2.816 (m, 2H), 2.84–2.88 (m, 2H), 3.02 (m, 2H), 3.43 (m, 2H), 4.03 (s, 2H), 4.74 (br s, 2H), 5.08 (br s, 1H), 7.18–7.30 (m, 5H); 13C NMR (CDCl3): δ 34.46, 42.91, 50.22, 55.82, 57.02, 103.11, 126.11, 128.40, 128.71, 139.96, 160.16, 160.45, 167.39. HR-MS (LIFDI-TOF). Calcd for C15H18ClN5, [M.]+: m/z 303.1251. Found: m/z 303.1237.

2-{N-[(2-Amino-4-chloro-6-methoxypyrimidin-5-yl)methyl]-N-phenethylamino}acetonitrile (13)

A solution of 0.5 m sodium methoxide in methanol (16.7 mL, 8.33 mmol) was added dropwise to a stirred solution of 5 (2.8 g, 8.33 mmol) in anhydrous methanol (12 mL) under nitrogen. The mixture was stirred at room temperature to 10 min and then heated at reflux for 24 h. The solvent was removed by rotary evaporation under reduced pressure and the residue was triturated with water and the resultant solid was filtered under reduced pressure. This solid was further triturated with diethyl ether, filtered and dried in a vacuum desiccator to give 1.9 g (70%) of a colorless material; mp 158–159°C; 1H NMR (CDCl3): δ 2.83 (d, J = 7.6 Hz, 2H), 2.88 (d, J = 8 Hz, 2H), 3.52 (s, 2H), 3.68 (s, 2H), 3.90 (s, 3H), 5.07 (s, 2H), 7.18–7.27 (m, 5H); 13C NMR (CDCl3): δ 33.8, 41.7, 48.3, 54.5, 55.5, 104.5, 115.4, 126.2, 128.4, 128.6, 139.4, 160.9, 161.6, 170.1. HR-MS (LIFDI-TOF). Calcd for C16H18ClN5O, [M.]+: m/z 331.1200. Found: m/z 331.1220.

N1-[(2-Amino-4-chloro-6-methoxypyrimidin-5-yl)methyl]-N1-phenethylethane-1,2-diamine (14)

A mixture of 13 (0.5 g, 1.5 mmol), DMF (7 mL), 2 m solution of ammonia in methanol (3 mL), and Raney nickel (1 g, washed with methanol to remove most of the water) was allowed to react under 50 psi of hydrogen in a Parr shaker for 21 h. The reaction mixture was filtered through a pad of celite and washed well with DMF (5 mL). The solvent was removed by rotary evaporation under reduced pressure and the residue was triturated first with water and then with dichloromethane. The resultant solid material was chromatographed on silica gel eluting with 10% methanol in chloroform. The fractions with an Rf of 0.2 were combined and the solvent removed to give 0.1 g (10%) of a colorless solid; mp 82–83°C; 1H NMR (CDCl3): δ 2.77 (d, J = 4 Hz, 2H), 2.81 (m, J = 8 Hz, 2H), 2.92 (t, J = 4 Hz, 2H), 3.13 (t, J = 4 Hz, 2H), 3.54 (s, 2H), 3.86 (s, 3H), 5.05 (br s, 1H), 7.06–7.24 (m, 5H) 13C NMR (DMSO-d6): δ 31.9, 37.1, 47.5, 50.2, 54.1, 55.0, 103.4, 126.3, 128.7, 128.9, 140.7, 160.6, 161.7, 169.8. HR-MS (LIFDI-TOF). Calcd for C16H23ClN5O, [M.]+: m/z 336.1591. Found: m/z 336.1607.

2-Amino-4-methoxy-6-phenethyl-6,7,8,9-tetrahydro- 5H-pyrimido[4,5-e][1,4]diazepine (15)

This compound was prepared using the initial procedure described above for 14. The filtrate (after the removal of the Raney nickel) was treated with potassium carbonate (0.27 g, 2.0 mmol) and the mixture was heated at 100°C for 4 h. The solvent was re moved by rotary evaporation under reduced pressure and the residue was partitioned between water (30 mL) and chloroform (30 mL). The organic layer was washed with brine (30 mL) and dried over anhydrous sodium sulfate, filtered and the solvent removed by rotary evaporation. The residue was chromatographed on silica gel eluting with 10% methanol in chloroform. The fractions with an Rf of 0.53 were combined and the solvent removed to give 0.275 g (61%) of a colorless solid; mp 119–120°C; 1H NMR (CDCl3): δ 2.74 (m, 2H), 2.87 (m, 2H), 2.98 (m, 2H), 3.30 (m, 2H), 3.84 (s, 2H), 3.87 (s, 3H), 4.65 (br s, 2H), 4.79 (br s, 1H), 7.19–7.30 (m, 5H); 13C NMR (CDCl3): δ 34.2, 43.3, 47.4, 53.6, 56.7, 57.2, 90.4, 126.0, 128.4, 128.7, 140.3, 160.6, 167.7, 169.2. HR-MS (LIFDI-TOF). Calcd for C16H21N5O, [M.]+: m/z 299.1746. Found: m/z 299.1764.

2-Amino-6,7,8,9-tetrahydro-6-phenethyl-3H-pyrimido[4,5-e][1,4]diazepin-4(5H)-one (2), HI Salt

A mixture of 15 (0.261 g, 0.87 mmol), anhydrous DMF (5 mL) and trifluoroacetic acid (0.2 mL, 2.61 mmol) was heated to 60°C and stirred for 0.5 h. Trimethyliodosilane (0.248 mL, 1.74 mmol) was then added and the mixture was stirred for an additional 0.5 h, quenched with methanol (5 mL), cooled to room temperature and concentrated by rotary evaporation under reduced pressure. The residue was triturated with sodium bicarbonate solution and the solid collected by filtration at the pump was washed with ethanol and dried in a vacuum desiccator to give 0.082 g (23%) of a colorless product; mp 186–188°C; 1H NMR (DMSO-d6): δ 2.95 (m, 2H), 3.02 (m, 2H), 3.24 (m, 2H), 3.62 (m, 2H), 4.17 (d, J = 13 Hz, 1H), 4.42 (d, J = 13 Hz, 1H), 6.49 (br s, 2H), 6.74 (br s, 1H), 7.23–7.35 (m, 5H), 9.65 (br s, 1H), 10.30 (br s, 1H); 13C NMR (DMSO-d6): δ 30.6, 38.8, 45.7, 55.1, 78.1, 127.3, 129.1, 129.3, 137.3, 154.9, 163.5, 165.9. HR-MS (LIFDI-TOF). m/z: [M.]+ Calcd for C15H19N5O, [M.]+: m/z 285.1590. Found: m/z 285.1564.

Acknowledgments

We are grateful to the faculty research grant and the student research assistant programs at the University of West Georgia for financial support. We are also thankful for funding from the University of West Georgia Institutional STEM Excellence (UWISE) program, funded by Georgia Board of Regents STEM II Initiative. We thank Mr. Jesse McAtee in the Department of Chemistry and Biochemistry at the University of Delaware for the HRMS measurements.

References

  • [1]

    Baldwin, S. W.; Tse, A.; Gossett, L. S.; Taylor, E. C.; Rosowsky, A.; Shih, C.; Moran, R. G. Structural features of 5,10-dideaza-5,6,7,8-tetrahydrofolate that determine inhibition of mammalian glycinamide ribonucleotide formyltransferase. Biochemistry 1991, 30, 1997–2006.

  • [2]

    Taylor, E. C.; Dowling, J. E. Synthesis of a pyrimido[4,5-b]azepin analog of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF). Bioorg. Med. Chem. Lett. 1997, 7, 453–456.

  • [3]

    Read, M. W.; Miller, M. L.; Ray, P. S. Synthesis of N-{[4-(2-amino-4(3H)-oxo-5,6,7,8- tetrahydro-(9H)-pyrimido[4,5-b]azepin-6-yl)benzoyl}-L-glutamic acid and two of its conformationally-restricted analogs. Tetrahedron 1999, 55, 373–392.

  • [4]

    Parker, D. P.; Hughes, S. A.; Parker, D. L.; Ray, P. S. An unexpected dimer formation from a (2-aminoethylamino)-5-formylpyrimidine intermediate. Heterocycl. Commum. 2002, 8, 419–422.

  • [5]

    Huddleston, N. E.; Harris, J. L.; Nguyen, H. L.; Ray, P. S. Synthesis of 2-amino-4-chloro-6,9-bis-(2,4-dimethoxybenzyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e]diazepine: a potentially useful intermediate to pyrimido[4,5-e]diazepine-based folates. Heterocycl. Commum. 2004, 10, 405–406.

  • [6]

    Frick, M.; McAtee, D.; McAtee, J.; Wysocznski, C.; Ray, P. S. Synthesis of N 1-alky-1,4- diazepin-5-ones via Schmidt ring expansion chemistry. Heterocycl. Commum. 2011, 17, 17–19.

  • [7]

    Bell, L.; McGuire, H. M.; Freeman, G. A. Chemistry of 5-pyrimidinecarboxaldehydes. J. Heterocyclic Chem. 1983, 20, 41–44.

  • [8]

    Jeong, L. S.; Schinazi, R. F.; Beach, J. W.; Kim, H. O.; Nampalli, S.; Shanmuganathan, K.; Alves, A. J.; McMillan, A.; Chu, C. K.; Mathis, R. Asymmetric Synthesis and Biological Evaluation of b-L-(2R,5S)- and a-L-(2R,5R)-1,3-Oxathiolane-Pyrimidine and –Purine Nucleosides as Potential Anti-HIV Agents. J. Med. Chem. 1993, 36, 181–195.

  • [9]

    Wong, C-H.; Provencher, L.; Porco, J. A.; Jung, S-H.; Wang, Y-F.; Chen, L.; Wang, R.; Steensma, D. H. Synthesis and Evaluation of Homoazasugars as Glycosidase Inhibitors. J. Org. Chem. 1995, 60, 1492–1501.

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    Sidhu, G. S.; Thyagarajan, G.; Mazharuddin, M. Cyanomethylation with chloroacetonitrile. Indian J. Chem., 1964, 2, 170–172.

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  • [1]

    Baldwin, S. W.; Tse, A.; Gossett, L. S.; Taylor, E. C.; Rosowsky, A.; Shih, C.; Moran, R. G. Structural features of 5,10-dideaza-5,6,7,8-tetrahydrofolate that determine inhibition of mammalian glycinamide ribonucleotide formyltransferase. Biochemistry 1991, 30, 1997–2006.

  • [2]

    Taylor, E. C.; Dowling, J. E. Synthesis of a pyrimido[4,5-b]azepin analog of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF). Bioorg. Med. Chem. Lett. 1997, 7, 453–456.

  • [3]

    Read, M. W.; Miller, M. L.; Ray, P. S. Synthesis of N-{[4-(2-amino-4(3H)-oxo-5,6,7,8- tetrahydro-(9H)-pyrimido[4,5-b]azepin-6-yl)benzoyl}-L-glutamic acid and two of its conformationally-restricted analogs. Tetrahedron 1999, 55, 373–392.

  • [4]

    Parker, D. P.; Hughes, S. A.; Parker, D. L.; Ray, P. S. An unexpected dimer formation from a (2-aminoethylamino)-5-formylpyrimidine intermediate. Heterocycl. Commum. 2002, 8, 419–422.

  • [5]

    Huddleston, N. E.; Harris, J. L.; Nguyen, H. L.; Ray, P. S. Synthesis of 2-amino-4-chloro-6,9-bis-(2,4-dimethoxybenzyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e]diazepine: a potentially useful intermediate to pyrimido[4,5-e]diazepine-based folates. Heterocycl. Commum. 2004, 10, 405–406.

  • [6]

    Frick, M.; McAtee, D.; McAtee, J.; Wysocznski, C.; Ray, P. S. Synthesis of N 1-alky-1,4- diazepin-5-ones via Schmidt ring expansion chemistry. Heterocycl. Commum. 2011, 17, 17–19.

  • [7]

    Bell, L.; McGuire, H. M.; Freeman, G. A. Chemistry of 5-pyrimidinecarboxaldehydes. J. Heterocyclic Chem. 1983, 20, 41–44.

  • [8]

    Jeong, L. S.; Schinazi, R. F.; Beach, J. W.; Kim, H. O.; Nampalli, S.; Shanmuganathan, K.; Alves, A. J.; McMillan, A.; Chu, C. K.; Mathis, R. Asymmetric Synthesis and Biological Evaluation of b-L-(2R,5S)- and a-L-(2R,5R)-1,3-Oxathiolane-Pyrimidine and –Purine Nucleosides as Potential Anti-HIV Agents. J. Med. Chem. 1993, 36, 181–195.

  • [9]

    Wong, C-H.; Provencher, L.; Porco, J. A.; Jung, S-H.; Wang, Y-F.; Chen, L.; Wang, R.; Steensma, D. H. Synthesis and Evaluation of Homoazasugars as Glycosidase Inhibitors. J. Org. Chem. 1995, 60, 1492–1501.

  • [10]

    Sidhu, G. S.; Thyagarajan, G.; Mazharuddin, M. Cyanomethylation with chloroacetonitrile. Indian J. Chem., 1964, 2, 170–172.

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