Stereoselective Approach for the Synthesis of 2-epi-Hyacinthacine A₂, (–)-7a-epi-Hyacinthacine A₁, 1-Deoxy-d-altro-homonojirimycin, and Some Pyrrolidine Iminosugars

Abstract

A divergent approach has been developed for the synthesis of some important iminosugars by stereoselective allylation of the lyxosylamine derived from d-lyxose and intramolecular 5-exo-tet ring opening of the epoxide. The strategy described in this paper will be useful for the synthesis of some other biologically active iminosugars for the drug-discovery program.

Key words

azasugar - Grignard addition - glycosidase - glycosyltransferase - hyacianthacine - 5-exo-tet epoxide ring opening

• References and Notes

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A little variation in the spectral data of compound 16 is observed with reported data, see:
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• 24 Synthetic Procedure and Spectroscopic Data for Compound 3 Tosyl compound 19 (0.1 g, 0.16 mmol) was subjected to hydro­genolysis using Pd/C (10 mg), NaHCO₃ (5 mg) under H₂ atmosphere and stirred for 6 h. Then 6 M HCl (1 mL) was added, and the reaction mixture stirred for a further 6 h. The catalyst was filtered through the pad of Celite^®, and the filtrate was neutralized with aq NaOH. The solvent was removed in vacuo, and the crude product was purified by ion-exchange resin (DOWEX 50WX8) to give the title compound 1-deoxy-d-altro-homonojirimycin (3) as a yellow oil (27 mg, 91%). [α]_D ²⁶ +27.2 (c 0.95, MeOH) {lit.¹⁰ [α]_D ²⁵ +26.7 (c 0.68, MeOH)}. IR (neat, KBr): ν_max = 1067, 1466, 2925, 3415 cm^–1. ¹H NMR (300 MHz, D₂O): δ = 1.50–1.85 (m, 4 H), 2.82 (m, 1 H), 2.92–3.21 (m, 2 H), 3.64 (t, 2 H, J = 5.2 Hz), 3.78 (1 H, dd, J = 2.7, 9.0 Hz), 3.87–4.07 (m, 2 H). ¹³C NMR (75 MHz, D₂O): δ = 26.27, 27.83, 44.53, 55.45, 61.59, 68.50, 69.15, 69.74. ESI-HRMS (Orbitrap): m/z calcd for C₈H₁₈O₄N [M + H]⁺: 192.12303; found: 192.12305.
• 25 Synthetic Procedure and Spectroscopic Data for Compound 6 To a stirred solution of epoxy alcohol 22 (80 mg, 0.17 mmol) in CH₂Cl₂ (1 mL), Et₃N (0.1 mL, 0.26 mmol), methanesulfonyl chloride (0.1 mL, 0.21 mmol) followed by catalytic amount of DMAP were added at 0 °C under N₂ atmosphere. After 30 min, brine solution was added and aqueous phase was extracted by CH₂Cl₂ (2 × 2 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure to obtain the mesylated crude product. Without further purification, the resulting crude product was subjected to catalytic hydrogenolysis in MeOH (1 mL) using 10% Pd/C, NaHCO₃ (5 mg) under H₂ atmosphere and stirred for 6 h. Then 6 M HCl (1 mL) was added, and the reaction mixture stirred for a further 6 h. The catalyst was filtered through the pad of Celite^®, and the filtrate was neutralized with aq NaOH. Solvent was removed in vacuo, and the crude product was purified by ion-exchange resin (DOWEX 50WX8) to give the title compound 6 as a solid (27 mg, 90% yield); mp 166–168 °C {lit.^16b mp 165–167 °C); [α]_D ²⁶ –30.5 (c 2.0, H₂O) {lit.^16a [α]_D ²² –26.5 (c 2.0, H₂O). IR (neat, KBr): ν_max = 1042, 1114, 2923, 3377 cm^–1. ¹H NMR (300 MHz, D₂O): δ = 1.70–2.02 (m, 4 H), 2.71 (m, 1 H), 2.80–3.02 (m, 2 H), 3.38 (m, 1 H), 3.67 (dd, 1 H, J = 6.5, 11.0 Hz), 3.83 (m, 1 H), 3.91 (dd, 1 H, J = 4.1, 8.8 Hz), 4.25 (dd, 1 H, J = 1.6, 3.3 Hz). ¹³C NMR (75 MHz, D₂O): δ = 26.95, 31.67, 56.78, 62.59, 69.33, 71.34, 75.94, 79.34. HRMS: m/z calcd for C₈H₁₆NO₃ [M + H]⁺: 174.11247; found: 174.11245.
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• 27 Synthetic Procedure and Spectroscopic Data for Compound 9 The title compound 9 (18 mg, 90% as a yellow oil) was prepared from 21 (50 mg) by the general procedure described in ref. 24. [α]_D ²⁶ +60.6 (c 0.89, MeOH) {lit.¹⁸ [α]_D ²⁶ +62.3 (c 1.0, MeOH)}. IR (neat, KBr): ν_max = 1106, 1633, 2926, 3449 cm^–1. ¹H NMR (300 MHz, D₂O): δ = 0.95 (t, 3 H, J = 7.2 Hz), 1.32–1.58 (m, 2 H) 1.62–1.95 (m, 2 H), 3.53 (m, 1 H), 3.78 (m, 1 H), 3.88 (dd, 1 H, J = 8.1, 11.9 Hz), 3.99 (dd, 1 H, J = 5.1, 11.9 Hz), 4.11 (dd, 1 H J = 4.0, 9.3 Hz), 4.31 (t, 1 H, J = 3.4 Hz). ¹³C NMR (125 MHz, D₂O): δ = 15.59, 21.84, 34.89, 60.35, 63.00, 64.13, 72.86, 78.00. ESI-HRMS (Orbitrap): m/z calcd for C₈H₁₈O₃N [M + H]⁺: 176.12812; found: 176.12805.
• 28 Synthetic Procedure and Spectroscopic Data for Compound 10 The title compound 10 (22 mg, 89% as a yellow oil) was prepared from 11 (80 mg) by the general procedure described in ref. 25. IR (neat. KBr): ν_max = 1078, 1378, 2932, 3380 cm^–1. ¹H NMR (300 MHz, D₂O): δ = 0.85 (t, 3 H, J = 7.3 Hz), 1.26–141 (m, 2 H), 1.55–174 (m, 2 H), 3.42 (m, 1 H), 3.52 (dd, 1 H, J = 5.8, 9.6 Hz), 3.72 (dd, 1 H, J = 5.9, 12.5 Hz), 3.82 (dd, 1 H, J = 3.8, 12.6 Hz), 3.95 (m, 1 H), 4.09 (m, 1 H). ¹³C NMR (75 MHz, D₂O): δ = 13.68, 19.82, 32.58, 59.21, 63.56, 64.93, 71.10, 74.28. ESI-HRMS (Orbitrap): m/z calcd for C₈H₁₈O₃N [M + H]⁺: 176.12812; found: 176.12796.