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DOI: 10.1055/s-2008-1042898
Cope-House Cyclization Strategy for the Synthesis of Pyrrolizidines: An Expedient Route to 5-epi-Hyacinthacine A3 and 5-epi-Hyacinthacine A5
Publication History
Publication Date:
11 March 2008 (online)
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
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References and Notes
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.
13Spectral 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.
15General 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.
16Spectral 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.