Diversity-Oriented Synthesis of cis-3,4-Dihydroxylated Piperidine and Its Higher Saturated and Unsaturated Homologues from d-Ribose and Their Glycosidase-Inhibition Study^[1]

Abstract

The synthesis of six-, seven-, and eight-membered cis-dihydroxy azacycles has been accomplished from d-ribose using Vasella reductive amination as a key step and utilization of hydroboration–oxidation, Mitsunobu reaction, and ring-closing metathesis (RCM) reactions in a facile manner. These homologous dihydroxylated heterocyclic scaffolds were subjected to the glycosidase inhibition assays. However, only a moderate inhibitory activity for three out of five compounds was observed against α-glucosidases with a high degree of selectivity.

Key words

cis-dihydroxy azacycles - Vasella reductive amination - hydroboration–oxidation - Mitsunobu reaction - ring-closing metathesis - glycosidase inhibition.

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• 19 Synthesis of (3S,4R)-Piperidine-3,4-diol (6) To a solution of compound 15 (112 mg, 0.45 mmol) in 6 N methanolic HCl (3 mL) was added a catalytic amount of 10% Pd/C (10 mg). The reaction mixture was stirred under the H₂ (balloon) atmosphere at room temperature for 6 h. After completion of the reaction, Pd/C was removed by filtering through a short pad of Celite, and the filtrate was evaporated under vacuum to give a residue. It was washed again with Et₂O to get the pure compound 6 (48 mg, 91 %) as a white solid. R_f = 0.61 (MeOH–CH₂Cl₂, 1:9); mp 129–131 °C; [α]_D ²⁷ +10.0 (c 0.11, H₂O). ¹H NMR (400 MHz, D₂O): δ = 4.13 (brm, 1 H), 4.00–4.02 (m, 1 H), 3.34–3.39 (m, 2 H), 3.21–3.24 (m, 1 H), 3.10–3.16 (m, 1 H), 1.94–2.12 (m, 2 H). ¹³C NMR (100 MHz, D₂O): δ = 66.3, 65.2, 46.5, 41.4, 25.1. IR (KBr): 3400, 3020, 2926, 1403, 1216 cm^–1. ESI-HRMS: m/z [M + H]⁺ calcd for C₅H₁₂NO₂ ⁺: 118.0863; found: 118.0875.
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• 22 Synthesis of (3S,4R)-2,3,4,7-Tetrahydro-1H-azepine-3,4-diol (7) Compound 17 (89 mg, 0.33 mmol) was dissolved in 6 N methanolic HCl (3 mL) and stirred at room temperature for 2 h. After completion of the reaction, the solvent was removed under reduced pressure to obtain a solid residue, which was washed with Et₂O to get the pure compound 7 (43 mg, 96%) as a white solid. R_f = 0.59 (MeOH–CH₂Cl₂, 1:9); mp 135–139 °C; [α]_D ²⁵ –37.0 (c 0.21, MeOH). ¹H NMR (400 MHz, CD₃OD): δ = 5.98–6.01 (m, 1 H), 5.77–5.84 (m, 1 H), 4.58–4.59 (m, 1 H), 4.10–4.12 (m, 1 H), 3.71–3.84 (m, 2 H), 3.50–3.55 (m, 1 H), 3.41–3.44 (m, 1 H). ¹³C NMR (100 MHz, CD₃OD): δ = 140.2, 121.7, 73.2, 69.1, 51.7, 46.1. IR (KBr): 3683, 3399, 2927, 1476, 1216 cm^–1. ESI-HRMS: m/z [M + H]⁺ calcd for C₆H₁₂NO₂ ⁺: 130.0863; found: 130.0861.
• 23 Synthesis of (3S,4R)-Azepane-3,4-diol (8) Catalytic amount of Pd (10% on carbon, 15 mg) was added to a solution of 17 (121 mg, 0.45 mmol) in 6 N methanolic HCl (4 mL). The reaction mixture was degassed and left for stirring under a positive pressure of H₂ (balloon) for 3 h at room temperature. After completion of the reaction (TLC control), the reaction mixture was filtered and washed with MeOH. The filtrate was evaporated to dryness to give a solid compound which was washed with Et₂O to provide compound 8 as a white solid (54 mg, 92%). R_f = 0.62 (MeOH–CH₂Cl₂, 1:9); mp 142–144 °C; [α]_D ²⁵ +1.4 (c 0.21, MeOH). ¹H NMR (400 MHz, CD₃OD): δ = 4.11–4.12 (m, 1 H), 3.80–3.84 (m, 1 H), 3.18–3.36 (m, 4 H), 1.98–2.02 (m, 1 H), 1.78–1.94 (m, 3 H). ¹³C NMR (100 MHz, CD₃OD): δ = 74.3, 69.7, 46.9, 46.0, 30.0, 20.5. IR (KBr): 3393, 1386, 1219, 1061, 771 cm^–1. ESI-HRMS: m/z [M + H]⁺ calcd for C₆H₁₄NO₂ ⁺: 132.1019; found: 132.1014.
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• 27 Synthesis of (3S,4R,Z)-1,2,3,4,7,8-Hexahydroazocine-3,4-diol (9) Compound 21 (105 mg, 0.37 mmol) was dissolved in 6 N methanolic HCl (3 mL), and the reaction mixture was allowed to stir at room temperature for 2 h. After completion of the reaction, the organic solvent was evaporated under reduced pressure, and the resulting residue was washed with Et₂O to afford the azocine 9 (48 mg, 95%) as a white solid. R_f = 0.61 (MeOH–CH₂Cl₂, 1:9); mp 143–145 °C; [α]_D ²⁶ –8.6 (c 0.32, MeOH). ¹H NMR (400 MHz, CD₃OD): δ = 5.84–5.88 (m, 1 H), 5.66–5.72 (m, 1 H), 4.57 (d, 1 H, J = 4.09 Hz), 4.16 (d, 1 H, J = 4.33 Hz), 3.27–3.41 (m, 3 H), 3.16 (td, 1 H, J ₁ = 13.16 Hz, J ₂ = 2.75 Hz), 2.59–2.70 (m, 1 H), 2.37–2.40 (m, 1 H). ¹³C NMR (100 MHz, CD₃OD): δ = 138.4, 124.8, 71.9, 71.8, 48.2, 47.9, 23.6. IR (KBr): 3392, 3020, 1650, 1385, 1216, 1068, 771 cm^–1. ESI-HRMS: m/z [M + H]⁺ calcd for C₇H₁₄NO₂ ⁺: 144.1019; found: 144.1018.
• 28 Synthesis of (3S,4R)-Azocane-3,4-diol (10) To a solution of compound 21 (130 mg, 0.46 mmol) in 6 N methanolic HCl was added a catalytic amount of 10% Pd/C (20 mg), and the resulting reaction mixture was stirred under hydrogen atmosphere at room temperature for 3 h. After completion of the reaction, the catalyst was filtered, and the filtrate was concentrated under vacuum to obtain a residue, which was washed with Et₂O to attain pure azocane 10 (60 mg, 90%) as a white solid. R_f = 0.64 (MeOH–CH₂Cl₂, 1:9); mp 160–163 °C; [α]_D ²⁶ +5.4 (c 0.81, MeOH). ¹H NMR (400 MHz, CD₃OD): δ = 4.09–4.11 (m, 1 H), 3.91–3.94 (m, 1 H), 3.38–3.48 (m, 1 H), 3.22–3.30 (m, 2 H), 3.09–3.13 (m, 1 H), 2.00–2.08 (m, 1 H), 1.80–1.90 (m, 3 H), 1.69–1.72 (m, 2 H). ¹³C NMR (100 MHz, CD₃OD): δ = 74.2, 69.2, 48.2, 47.7, 31.0, 24.5, 21.8. IR (KBr): 3392, 2924, 1650, 1385, 1216, 1068, 770 cm^–1. ESI-HRMS: m/z [M + H]⁺ calcd for ­C₇H₁₆NO₂ ⁺: 146.1176, found: 146.1175.