En Route to Novel Furanoside Mimics through Stereoselective Zinc-Mediated Propargylation of N-Benzyl Glycofuranosylamines Using Ultrasound Activation

Abstract

Preliminary results on a novel zinc-mediated, ultrasound-promoted chain extension of glycofuranosylamines with a propargyl group are reported. The procedure was applied to d-arabino and d-xylo substrates to give, via Cram-chelate transition states, 1-C-1-(3-trimethylsilyl-2-propynyl)-1-benzylamino pentionols in moderate to good yields and acceptable stereoselectivities (syn/anti ≥4:1). To apply the reaction to the synthesis of galactofuranoside mimics, the d-xylo intermediate was cyclized to afford a 1-C-1-(2-propynyl)-1,4-dideoxy-1,4-imino-l-arabinitol derivative in excellent yield. This building block was used in three examples of CuAAC click reactions with azide compounds to provide the corresponding galactofuranoside mimics.

Key words

propargylation - N-benzyl glycofuranosylamines - stereoselective synthesis - iminosugars - Huisgen cycloaddition - furanoside mimics

• References and Notes

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• 24 Procedure A: In a 10-mL round-bottom flask under an argon atmosphere were added zinc dust (96.2 mg, 1.47 mmol) and iodine (11.2 mg, 0.04 mmol). The flask was placed under vacuum and the vessel was heated with a heat gun during 5 min. The vessel was filled with argon and allowed to reach r.t. The cycle was repeated once and anhyd THF (2 mL) was then added followed by 3-bromo-1-trimethylsilyl-1-propyne at 0 °C (53 μL, 0.32 mmol; mixture A). The reaction mixture was allowed to warm to r.t. and stirred for a further 2 h. In parallel, a solution of the N-benzyl-2,3,5-tri-O-benzyl-α/β-furanosylamine (0.10 mmol) in anhyd THF (2 mL) under argon was prepared in a 10-mL round-bottom flask (mixture B). Solution A was added to solution B via cannula, avoiding transferring too much zinc powder into solution B. The reaction mixture was stirred under ultrasonication for 48 h (45 °C, 42 kHz, 0.47 W/cm²). The resulting mixture was then filtered through Celite^® and the residue was washed with EtOAc. The organic phase was washed with H₂O, aq NH₄Cl, sat. aq NaHCO₃ and dried over MgSO₄. The organic phase was filtered and concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether–EtOAc, 8:2) to give the corresponding propargylated pentitols as a mixture of two diastereomers.
• 25 Procedure B: In a 10-mL round-bottom flask under an argon atmosphere were added zinc dust (96.2 mg, 1.47 mmol) and iodine (11.2 mg, 0.04 mmol). The flask was placed under vacuum and the vessel was heated with a heat gun during 5 min. The vessel was filled with argon and allowed to reach r.t. The cycle was repeated once and anhyd THF (4 mL) was then added followed by 3-bromo-1-trimethylsilyl-1-propyne (53 μL, 0.32 mmol) and the N-benzyl-2,3,5-tri-O-benzyl-α/β-furanosylamine (0.10 mmol) under argon atmosphere. The reaction mixture was stirred under ultrasonication for 48 h (45 °C, 42 kHz, 0.47 W/cm²). The resulting mixture was then filtered through Celite^® and washed with EtOAc. The organic phase was washed with H₂O, aq NH₄Cl, sat. aq NaHCO₃ and dried over MgSO₄. The organic phase was filtered and concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether–EtOAc, 8:2) to give the corresponding propargylated pentitols as a mixture of two diastereomers.
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• 27 Diastereomers of compound 6 could not be separated on regular silica gel column chromatography and were thus further processed as a mixture of isomers.
• 28 Spectroscopic Data for Selected Compounds:(1R)- and (1S)-1-C-(3-Trimethylsilyl-2-propynyl)-2,3,5-tri-O-benzyl-1-benzylamino-1-deoxy-d-xylitol [(1R)-6 and (1S)-6]: colorless oil; (1R)-6 and (1S)-6 were obtained as a 8:2 mixture of diastereomers; [α]_D ²⁰ −17.3° (CHCl₃, c = 0.5). ¹H NMR (400 MHz, CDCl₃/TMS): δ = 7.19–7.36 (m, 20 H), 4.34–4.71 (m, 6 H), 4.12 (d, J = 6.5 Hz, 0.8 H), 4.08–4.11 (dd, J = 8.2, 5.8 Hz, 0.8 H), 4.00–4.06 (m, 0.2 H), 3.88 (d, J = 12.5 Hz, 0.2 H), 3.85 (d, J = 12.1 Hz, 0.8 H), 3.80–3.82 (m, 0.2 H), 3.78 (br d, J = 6.6 Hz, 0.8 H), 3.62–3.70 (m, 1 H), 3.48–3.62 (m, 2.2 H), 3.33 (dd, J = 9.4, 3.6 Hz, 0.8 H), 3.08 (dd, J = 12.0, 4.0 Hz, 0.2 H), 2.71–2.84 (m, 1 H), 2.63–2.70 (m, 0.2 H), 2.48 (dd, J = 16.7, 9.5 Hz, 0.8 H), 0.06–0.19 (m, 9 H). ¹³C NMR (101 MHz, CDCl₃/TMS): δ = 139.1, 138.7, 138.6, 138.5, 138.4, 138.2, 138.1, 137.9, 127.5–128.8, 104.2, 103.7, 88.0, 87.5, 79.0, 78.9, 77.9, 75.3, 73.9, 73.7, 73.6, 73.2, 73.7, 73.2, 73.0, 71.1, 70.8, 68.0, 66.4, 57.3, 53.9, 50.6, 50.6, 22.5, 20.9, 0.1–0.5. IR (film): 3030, 2862, 2171, 1496, 1453, 1360, 1249, 1207, 1071, 1027, 907, 841, 726, 696, 645 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₉H₄₈NO₄Si: 622.334712; found: 622.334699.(1R)- and (1S)-1-C-(3-Trimethylsilyl-2-propynyl)-N-benzyl-2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-imino-l-arabinitol (7): light yellow oil; 8:2 mixture of diastereomers (1R)-7 and (1S)-7; [α]_D ²⁰ −14.5° (CHCl₃, c = 0.4). ¹H NMR (400 MHz, CDCl₃/TMS): δ = 7.14–7.39 (m, 20 H), 4.22–4.60 (m, 6 H), 4.06–4.12 (m, 0.4 H), 3.97 (d, J = 10.9 Hz, 0.8 H), 3.95 (br s, 0.8 H), 3.91–3.94 (m, 0.2 H), 3.88 (br s, 0.8 H), 3.76 (d, J = 13.9 Hz, 0.8 H), 3.71 (d, J = 14.6 Hz, 0.2 H), 3.53–3.58 (m, 0.4 H), 3.27–3.38 (m, 1.8 H), 3.20–3.26 (m, 0.2 H), 3.07–3.16 (m, 1.6 H), 2.56 (dd, J = 16.6, 9.3 Hz, 0.8 H), 2.44–2.59 (m, 0.2 H), 2.34 (br s, 0.2 H), 2.40 (dd, J = 16.6, 5.1 Hz, 0.8 H), 0.05–0.19 (m, 9 H). ¹³C NMR (101 MHz, CDCl₃/TMS): δ = 139.6, 139.5, 138.7, 138.5, 125.4–129.2, 106.0, 105.2, 86.8, 86.3, 86.0, 85.4, 83.5, 82.7, 73.3, 73.0, 72.7, 71.7, 71.6, 71.0, 72.0, 70.6, 69.7, 66.5, 65.2, 63.8, 59.0, 51.4, 20.8, 19.5, 0.3. IR (film): 3029, 2858, 2172, 1495, 1453, 1363, 1248, 1205, 1097, 1071, 1027, 908, 839, 731, 695, 645 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₉H₄₆NO₃Si: 604.324147; found: 604.324106.(1R)-1-C-[1-(3-Hydroxypropyl)triazol-4-ylmethyl]-2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-imino-l-arabinitol [(1R)-10a]: amber oil; [α]_D ²⁰ –4.24° (CHCl₃, c = 1.1). ¹H NMR (400 MHz, CDCl₃/TMS): δ = 7.15–7.35 (m, 21 H), 6.83 (s, 1 H), 4.55 (d, J = 12.2 Hz, 1 H), 4.46 (d, J = 12.3 Hz, 1 H), 4.45 (d, J = 12.0 Hz, 1 H), 4.38 (d, J = 12.0 Hz, 1 H), 4.30 (dt, J = 6.7, 2.2 Hz, 2 H), 4.25 (d, J = 12.1 Hz, 1 H), 4.21 (d, J = 11.9 Hz, 1 H), 4.01 (d, J = 12.0 Hz, 1 H), 3.93 (br s, 1 H), 3.71–3.78 (m, 2 H), 3.52 (t, J = 5.8 Hz, 2 H), 3.43 (dt, J = 9.2, 4.5 Hz, 1 H), 3.35 (dd, J = 12.0, 8.0 Hz, 1 H), 3.03–3.17 (m, 3 H), 2.92 (dd, J = 14.4, 4.4 Hz, 1 H), 1.97 (p, J = 6.5 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃/TMS): δ = 145.7, 139.4, 138.7, 138.5, 138.3, 127.7–129.4, 122.1, 82.4, 82.1, 73.0, 71.4, 70.8, 71.9, 69.1, 66.6, 59.0, 58.8, 46.7, 32.6, 25.1. IR (neat): 3342, 2919, 2861, 1453, 1097, 1068 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₉H₄₅N₄O₄: 633.343529; found: 633.343532.(1R)-1-C-[1-(3-Hydroxypropyl)triazol-4-ylmethyl]-1,4-dideoxy-1,4-imino-l-arabinitol [(1R)-11a]: yellow oil; [α]_D ²⁰ –4.24° (CHCl₃, c = 1.1). ¹H NMR (400 MHz, CD₃OD/TMS): δ = 7.79 (s, 1 H), 4.47 (t, J = 7.0 Hz, 2 H), 3.86 (dd, J = 3.7, 1.6 Hz, 1 H), 3.78 (dd, J = 4.0, 1.6 Hz, 1 H), 3.68 (dd, J = 10.8, 4.4 Hz, 1 H), 3.65 (dd, J = 11.2, 4.8 Hz, 1 H), 3.57 (t, J = 6.4 Hz, 2 H), 3.44 (dt, J = 7.3, 4.0 Hz, 1 H), 3.02 (dd, J = 14.7, 7.1 Hz, 1 H), 2.96 (br q, J = 4.8 Hz, 1 H), 2.88 (dd, J = 14.6, 7.5 Hz, 1 H), 2.09 (p, J = 6.5 Hz, 2 H). ¹³C NMR (101 MHz, CD₃OD/TMS): δ = 146.6, 124.2, 81.2, 79.1, 68.4, 63.5, 62.5, 59.3, 48.2, 34.0, 26.1. IR (neat): 3265, 2922, 1652, 1557, 1429, 1216, 1060 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₂₀N₄O₄: 273.155732; found: 273.155429