A Synthesis of (±)-Stemoamide Using the Intramolecular Propargylic Barbier Reaction

Abstract

A diastereoselective synthesis of the alkaloid stemo­amide has been achieved using the intramolecular propargylic ­Barbier reaction to construct the seven-membered ring.

alkaloids - Barbier reaction - allenes - indium - cyclisations

References and Notes

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Preparation of Acetal 6
A mixture of 4-bromobutanal (prepared by DIBAL-H reduction of methyl 4-bromobutyrate; 3.5 g, 23.1 mmol), ethylene glycol (3.9 mL, 69.5 mmol), and PTSA (440 mg, 2.3 mmol) in toluene (40 mL) was heated at reflux for 1.5 h using a Dean-Stark trap. The mixture was cooled to r.t. Toluene was removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel (150 g, 4% EtOAc-hexane) to give acetal (6, 3.3 g, 73%) as a colourless liquid. ^¹H NMR (500 MHz, CDCl₃):
δ = 4.9 (t, J = 4.5 Hz, 1 H), 3.98-3.93 (m, 2 H), 3.88-3.81 (m, 2 H), 3.45 (t, J = 6.8 Hz, 2 H), 2.0 (quint, J = 7.1 Hz, 2 H), 1.85-1.78 (m, 2 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 103.7, 64.9 (2 C), 33.6, 32.3, 27.1.
Preparation of Lactam 7
n-BuLi (36.8 mL of a 1.6 M solution in hexane, 59.0 mmol) was slowly added to a solution of lactam 5 (7.6 g, 59.0 mmol) in THF (80 mL) at -78  ˚C. The mixture was stirred at the same temperature for 1 h. A solution of bromodioxolane (8.85 g, 45.3 mmol) in DMSO (60 mL) was added slowly, and the reaction mixture was allowed to warm to r.t. After stirring at r.t. for 18 h, H₂O (250 mL) was added. The mixture was extracted with EtOAc (3 × 500 mL), and the combined organic layers were washed with H₂O and brine, then dried (MgSO₄). The solvent was removed under reduced pressure to give lactam (10.12 g, 92%) as a yellow oil, which was used without purification. ^¹H NMR (500 MHz, CDCl₃): δ = 4.98 (d, J = 6.3 Hz, 1 H), 4.87 (t, J = 4.2 Hz, 1 H), 3.98-3.92 (m, 2 H), 3.87-3.81 (m, 2 H), 3.58-3.51 (m, 1 H), 3.46 (q, J = 7 Hz, 2 H), 3.18-3.08 (m, 1 H), 2.57-2.48 (m, 1 H), 2.34-2.26 (m, 1 H), 2.18-2.08 (m, 1 H), 2.02-1.94 (m, 1 H), 1.76-1.61 (m, 4 H), 1.21 (t, J = 7 Hz, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 174.9, 103.8, 88.9, 64.9, 64.8, 61.3, 40.1, 31.1, 29.0, 24.8, 21.9, 15.2. IR (neat): ν_max = 2972, 2932, 2882, 1693, 1454, 1420, 1283, 1140, 1074 cm^-¹.

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20

Preparation of Allenol 3
Acetic acid (117 µL, 2.06 mmol) followed by indium (118 mg, 1.03 mmol) were added to a solution of aldehyde 4 (140 mg, 0.51 mmol) in THF (2 mL) and H₂O (0.25 mL) under nitrogen at -20 ˚C. After stirring at the same temperature for 24 h, the reaction mixture was diluted with CHCl₃ (100 mL). The mixture was stirred at r.t. for 10 min, and filtered through Celite, washing with CHCl₃. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel (10 g, 1.5% MeOH-CHCl₃) to give allenic alcohol 4 (81 mg, 82%) as a colourless solid; mp 98-100 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 5.11 (t, J = 1.7 Hz, 2 H), 4.35 (t, J = 7.7 Hz, 1 H), 4.18-4.08 (m, 1 H), 3.99-3.94 (m, 1 H), 2.78-2.72 (m, 1 H), 2.48-2.34 (m, 2 H), 2.31-2.23 (m, 1 H), 2.16-2.08 (m, 1 H), 1.98-1.86 (m, 1 H), 1.84-1.73 (m, 2 H), 1.68-1.53 (m, 2 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 203.7, 174.3, 110.6, 81.6, 67.8, 58.6, 41.7, 38.8, 30.7, 25.9, 24.7. IR: ν_max = 3377, 2933, 1954, 1651, 1416, 1364, 1320, 1264, 1202, 1155, 1064 cm^-¹. MS (EI): m/z = 194 (100) [M⁺ + 1], 187 (9). HRMS: m/z = calcd for C₁₁H₁₆NO₂ = 194.1181 [M⁺ + H]; found: 194.1181.

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