Cope-House Cyclization Strategy for the Synthesis of Pyrrolizidines: An Expedient Route to 5-epi-Hyacinthacine A₃ and 5-epi-Hyacinthacine A₅

Abstract

An expedient Cope-House cyclization strategy is reported here for the synthesis of several polyhydroxy pyrrolizidine alkaloids starting from sugar-derived nitrones.

Key words

nitrone - Grignard reaction - Cope-House cyclization - hydrogenation - hyacinthacine

References and Notes

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12

General Procedure for the Cope-House Cyclization: To a stirred solution of nitrone (1.2 mmol) in anhyd THF (20 mL), a previously prepared (4.8 mmol of 4-bromobutene and 7.2 mmol Mg in 15 mL anhyd THF) Grignard solution was slowly added under a nitrogen atmosphere at -78 °C and allowed to come to r.t. Then the reaction mixture was quenched by sat. NH₄Cl solution and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over Na₂SO₄, washed with brine and filtered. The filtrate was evaporated under vacuum to afford the hydroxylamine. Without further purification, the hydroxylamine was dissolved in CHCl₃ (15 mL) and stirred for 24 h at r.t. to provide the cyclized product which upon purification by silica gel column chromatography (MeOH in CHCl₃) afforded the product.

13

Spectral data for selected compounds: Compound 20: R _f 0.65 (CHCl₃-MeOH, 3:0.5); [α]_D ²⁵ 8.4 (c = 1.00, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.22-7.36 (m, 15 H), 4.42-4.61 (m, 6 H), 4.35 (t, J = 3.9 Hz, 1 H), 4.24 (dd, J = 5.8, 10.1 Hz, 1 H), 4.07-4.12 (m, 1 H), 3.86 (dd, J = 6.4, 10.1 Hz, 1 H), 3.76 (dd, J = 3.4, 6.4 Hz, 1 H), 3.66-3.73 (m, 1 H), 3.61 (dd, J = 5.8, 10.4 Hz, 1 H), 2.36-2.41 (m, 1 H), 2.03-2.09 (m, 2 H), 1.71-1.95 (m, 1 H), 1.32 (d, J = 6.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 137.5, 136.8, 128.1, 128.0, 127.7, 127.6, 127.5, 127.4, 127.3, 86.7, 83.5, 83.4, 74.3, 73.0, 72.5, 72.0, 71.5, 65.9, 29.5, 26.2, 12.7. IR (neat): 3063, 3031, 2933, 2868, 1650, 1496, 1454, 1367, 1107, 1027, 740, 699 cm^-1. HRMS (ESI-TOF): m/z [M + 1]⁺ calcd for C₃₀H₃₆NO₄: 474.2644; found: 474.2632. Compound 22: R _f 0.63 (CHCl₃-MeOH, 3:0.5); [α]_D ²⁵ -13.6 (c = 1.00, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.24-7.36 (m, 15 H), 4.78-4.81 (m, 2 H), 4.52-4.69 (m, 5 H), 4.36 (t, J = 3.6 Hz, 1 H), 4.14 (dd, J = 5.8, 10.4 Hz, 1 H), 3.83-3.93 (m, 3 H), 3.43-3.45 (m, 1 H), 2.01-2.28 (m, 2 H), 1.96-1.99 (m, 1 H), 1.69-1.71 (m, 1 H), 1.31 (d, J = 6.4 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 137.8, 137.6, 137.1, 128.3, 128.2, 128.1, 127.8, 127.7, 127.6, 127.5, 83.3, 82.1, 78.3, 77.5, 76.2, 73.8, 73.1, 72.3, 64.2, 32.2, 25.5, 11.7. IR (neat): 3064, 3031, 2936, 2873, 1650, 1497, 1454, 1368, 1153, 1073, 1028, 748, 698 cm^-1. HRMS (ESI-TOF): m/z [M + 1]⁺ calcd for C₃₀H₃₆NO₄: 474.2644; found: 474.2641. Compound 24: R _f 0.63 (CHCl₃-MeOH, 2:1); [α]_D ²⁵ -1.6 (c = 1.00, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 4.78 (q, J = 6.4 Hz, 1 H), 4.44 (dd, J = 4.9, 6.7 Hz, 1 H), 4.15-4.19 (m, 1 H), 3.99 (dd, J = 6.7, 13.1 Hz, 1 H), 3.70 (dd, J = 6.1, 12.8 Hz, 1 H), 3.06-3.15 (m, 1 H), 2.51-2.60 (m, 1 H), 2.15-2.25 (m, 1 H), 2.05-2.13 (m, 1 H), 1.85-1.93 (m, 1 H), 1.60 (s, 3 H), 1.39 (d, J = 6.4 Hz, 3 H), 1.32 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 114.7, 85.1, 84.4, 76.3, 71.9, 68.7, 30.0, 27.0, 25.1, 24.9, 12.2. IR (neat): 2988, 2934, 1659, 1460, 1385, 1214, 1160, 1054, 992, 854, 758 cm^-1. HRMS (ESI-TOF): m/z [M + 1]⁺ calcd for C₁₁H₂₀NO₃: 214.1443; found: 214.1435. Compound 26: R _f 0.67 (CHCl₃-MeOH, 2:1); [α]_D ²⁵ -8.1 (c = 1.00, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.24-7.39 (m, 10 H), 4.44-4.58 (m, 4 H), 4.30-4.35 (m, 1 H), 4.27 (d, J = 5.8 Hz, 1 H), 3.94 (dd, J = 6.1, 13.4 Hz, 1 H), 3.82 (br d, J = 3.4 Hz, 1 H), 3.66-3.77 (m, 2 H), 2.37-2.45 (m, 1 H), 2.14-2.25 (m, 1 H), 1.98-2.03 (m, 1 H), 1.68-1.78 (m, 1 H), 1.37 (d, J = 6.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 136.7, 136.4, 128.4, 128.3, 128.1, 127.8, 127.6, 127.5, 86.7, 86.3, 81.8, 72.9, 71.8, 71.4, 68.1, 30.7, 26.8, 11.9. IR (neat): 3060, 3027, 2925, 2851, 1660, 1495, 1454, 1368, 1113, 1026, 753, 700 cm^-1. HRMS (ESI-TOF): m/z [M + 1]⁺ calcd for C₂₂H₂₈NO₃: 354.2069; found: 354.2081. Compound 28: R _f 0.60 (CHCl₃-MeOH, 3:0.5); [α]_D ²⁵ -9.4 (c = 1.00, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.22-7.36 (m, 15 H), 4.42-4.61 (m, 6 H), 4.36 (t, J = 3.9 Hz, 1 H), 4.26 (dd, J = 5.5, 10.1 Hz, 1 H), 4.16-4.21 (m, 1 H), 3.87 (dd, J = 6.4, 10.1 Hz, 1 H), 3.76 (dd, J = 3.4, 6.4 Hz, 1 H), 3.66-3.72 (m, 1 H), 3.62 (dd, J = 5.8, 10.4 Hz, 1 H), 2.36-2.44 (m, 1 H), 2.00-2.15 (m, 2 H), 1.69-1.78 (m, 1 H), 1.33 (d, J = 6.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 137.7, 136.9, 36.9, 128.3, 128.2, 128.1, 127.9, 127.8, 127.6, 127.5, 127.4, 86.9, 83.5, 83.4, 74.5, 73.2, 72.6, 72.1, 71.6, 66.0, 29.6, 26.3, 12.8. IR (neat): 3060, 3030, 2928, 2867, 1655, 1496, 1454, 1367, 1105, 1028, 740, 698 cm^-1. HRMS (ESI-TOF): m/z [M + 1]⁺ calcd for C₃₀H₃₆NO₄: 474.2644; found: 474.2658.

15

General Procedure for Hydrogenation: To a solution of N-oxide (0.65 mmol) in a mixture of MeOH and THF (4:1, 20 mL) was added 10% Pd/C (111 mg). After the reaction flask was purged with H₂, 10 drops of 6 N HCl were added and the reaction mixture was stirred for 3 d at r.t. under a H₂ atmosphere. The mixture was then filtered through a pad of Celite, and the filtrate was concentrated under vacuum. The residue was dissolved in minimum amount of H₂O and stirred with IRA450 resin (OH^- form) until pH 11. After filtration, the filtrate was concentrated in vacuo to give the pure pyrrolizidine.

16

Spectral data for selected compounds: Compound 13: R _f 0.46 (CHCl₃-MeOH, 2:1); [α]_D ²⁵ 24.8 (c = 1.00, H₂O). ¹H NMR (300 MHz, D₂O): δ = 3.89-3.94 (m, 2 H), 3.81 (dd,
J = 4.4, 12.2 Hz, 1 H), 3.72 (dd, J = 6.3, 12.6 Hz, 1 H), 3.57-3.64 (m, 1 H), 3.36-3.42 (m, 1 H), 3.11-3.15 (m, 1 H), 2.10-2.27 (m, 2 H), 1.83-1.95 (m, 1 H), 1.55-1.68 (m, 1 H), 1.20 (d, J = 6.3 Hz, 3 H). ¹³C NMR (100 MHz, D₂O): δ = 79.2, 77.1, 70.0, 68.5, 65.1, 60.0, 32.5, 27.9, 17.4. HRMS (ESI-TOF): m/z [M + 1]⁺ calcd for C₉H₁₈NO₃: 188.1287; found: 188.1277. Compound 23: R _f 0.44 (CHCl₃-MeOH, 2:1); [α]_D ²⁵ -8.0 (c = 1.00, H₂O). ¹H NMR (300 MHz, D₂O): δ = 4.34 (t, J = 3.7 Hz, 1 H), 4.08 (dd, J = 3.7, 8.4 Hz, 1 H), 3.82-3.98 (m, 3 H), 3.40-3.66 (m, 2 H), 2.11-3.31 (m, 2 H), 1.83-1.94 (m, 1 H), 1.66-1.78 (m, 1 H), 1.24 (d, J = 6.6 Hz, 3 H). ¹³C NMR (100 MHz, D₂O): δ = 75.6, 72.5, 69.5, 68.7, 65.2, 5.3, 31.8, 26.8, 17.2. HRMS (ESI-TOF): m/z [M + 1]⁺ calcd for C₉H₁₈NO₃: 188.1287; found: 188.1287. Compound 25: R _f 0.42 (CHCl₃-MeOH, 2:1); [α]_D ²⁵ 32.5 (c = 1.00, H₂O). ¹H NMR (300 MHz, D₂O): δ = 4.43 (d, J = 3.4 Hz, 1 H), 4.11 (br m, 1 H), 3.90-3.92 (m, 1 H), 3.18-3.43 (m, 3 H), 2.15-2.28 (m, 2 H), 1.64-1.86 (m, 2 H), 1.27 (d, J = 6.3 Hz, 3 H). ¹³C NMR (75 MHz, D₂O): δ = 77.7, 73.6, 72.1, 68.0, 57.8, 35.5, 29.9, 18.3. HRMS (ESI-TOF): m/z [M + 1]⁺ calcd for C₈H₁₆NO₂: 158.1181; found: 158.1186. Compound 27: R _f 0.46 (CHCl₃-MeOH, 2:1); [α]_D ²⁵ -33.5 (c = 1.00, H₂O). ¹H NMR (400 MHz, D₂O): δ = 4.34 (dd, J = 3.1, 7.3 Hz, 1 H), 4.17 (t, J = 2.7 Hz, 1 H), 3.89-3.94 (m, 1 H), 3.52-3.61 (m, 2 H), 3.22 (dd, J = 2.7, 12.9 Hz, 1 H), 2.56-2.33 (m, 1 H), 2.17-2.23 (m, 1 H), 1.96-2.06 (m, 1 H), 1.59-1.69 (m, 1 H), 1.33 (d, J = 6.2 Hz, 3 H). ¹³C NMR (100 MHz, D₂O): δ = 81.2, 79.6, 76.2, 69.8, 58.5, 36.2, 31.1, 18.6. HRMS (ESI-TOF): m/z [M + 1]⁺ calcd for C₈H₁₆NO₂: 158.1181; found: 158.1176. Compound 29: R _f 0.59 (CHCl₃-MeOH, 2:1); [α]_D ²⁵ -22.0 (c = 1.00, H₂O). ¹H NMR (400 MHz, D₂O): δ = 3.98-4.04 (m, 2 H), 3.89 (dd, J = 3.9, 12.4 Hz, 1 H), 3.78-3.85 (m, 2 H), 3.36-3.64 (m, 1 H), 3.33-3.34 (m, 1 H), 2.21-2.35 (m, 2 H), 1.97-2.04 (m, 1 H), 1.67-1.87 (m, 1 H), 1.31 (d, J = 6.6 Hz, 3 H). ¹³C NMR (100 MHz, D₂O): δ = 81.2, 78.9, 73.1, 72.3, 68.9, 61.2, 35.1, 30.5, 19.1. HRMS (ESI-TOF): m/z [M + 1]⁺ calcd for C₉H₁₈NO₃: 188.1296; found: 188.1287.