A Short Formal Synthesis of (±)-Perhydrohistrionicotoxin

Abstract

The reaction of a silyl enol ether bearing a nitrogen atom with a hemiacetal vinylog in the presence of a catalytic amount of boron trifluoride etherate led to the corresponding ketoaldehyde. The cyclisation of the ketoaldehyde into azaspiroenone and nitrogen deprotection was performed in basic medium. The N-benzylation of this enone gave the known key intermediate of total synthesis of (±)-perhydrohistrionicotoxin.

Key words

perhydrohistrionicotoxin - azaspiranic alkaloids - silyl enol ether - hemiacetal vinylog - Michael-type addition

References and Notes

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• 10a

  The low yield of N-benzylation was previously reported for similar compounds.

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1

Current address: Laboratoire de Chimie Organique Fine et Hétérocyclique, IRCOF, INSA Rouen, CNRS UMR 6014, B.P. 08, 76131 Mont-Saint-Aignan Cedex, France.

7

Preparation of Silyl Enol Ethers 5: To a stirred solution of LDA or LiHMDS [22 mmol; prepared from i-Pr₂NH or hexamethyldisilazane and n-BuLi (22 mmol)] in THF (22 mL) at -78 °C was added aldehyde 8 (20 mmol) in THF (6 mL). After 30 min the reaction mixture was warmed to -15 °C and TBSCl (26 mmol) in THF (6 mL) was added. The mixture was allowed to react at r.t. and pentane (50 mL) was added. After filtration, the organic layers were evaporated in vacuo. The residue was purified by flash chromatography (PE-Et₂O, 90:10) to afford the silyl enol ethers 5 as a pale yellow oil as a single stereoisomer of an unknown configuration (49% in 5a and 63% in 5b). 5a: IR (film): 1680 cm^-1. ¹H NMR (200 MHz, C₆D₆): δ = 5.72 (s, 1 H), 3.41 (s, 3 H), 3.32 (m, 2 H), 1.14 (m, 6 H), 0.8 (s, 9 H), -0.1 (s, 6 H). ¹³C NMR (50 MHz, C₆D₆): δ = 154.43, 130.06, 119.80, 52.04, 45.83, 27.32, 26.29, 25.33, 25.12, 17.69, -5.80. 5b: IR (film): 1680 cm^-1. ¹H NMR (200 MHz, C₆D₆): δ = 5.80 (s, 1 H), 4.05 (q, J = 6.7 Hz, 2 H), 3.05 (m, 2 H), 1.65 (m, 2 H), 1.15 (m, 4 H), 0.95 (t, J = 6.7 Hz, 3 H), 0.80 (s, 9 H), -0.1 (s, 6 H). ¹³C NMR (50 MHz, C₆D₆): δ = 153.13, 132.46, 118.78, 60.35, 43.64, 26.57, 26.29, 25.72, 24.12, 17.69, 13.31, -5.80.

8

The crude product was a mixture of aldehyde 4 and ketals of 4 and 8 which after hydrolysis in acidic medium led to aldehydes 4 and 6 easily separated by flash chromatography. The modest yield of ketoaldehydes 4 may be explained by the steric hindrance of the reaction centre of the silyl enol ethers 5.^5b

9

Synthesis of Ketoaldehydes 4: To a solution of 5 (8 mmol) in nitromethane (5 mL) were added at 0 °C a hemiacetal vinylog 9 (5 mmol) in nitromethane (5 mL) and BF₃·Et₂O-Et₂O (4:1; 1.8 mmol, 300 µL). The mixture was kept at r.t. until disappearance of 5 (TLC, 4 h) and then hydrolysed at 0 °C with sat. NaHCO₃ (5 mL). The mixture was extracted with CH₂Cl₂, dried over MgSO₄, filtered and evaporated. The crude product was treated with aq 1.5 M HCl at r.t. for 30 min. and extracted with CH₂Cl₂, dried over MgSO₄, filtered and evaporated. Purification was performed by flash chromatography (PE-Et₂O, 90:10 → 70:30), providing ketoaldehydes 4 as a pale yellow oil (23% in 4a and 24% in 4b). 4a: IR (film): 1710, 1680 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 9.30 (s, 1 H), 4.03 (m, 2 H), 3.66 (s, 3 H), 2.62 (m, 2 H), 2.20 (m, 2 H), 2.23 (s, 3 H), 1.40 (m, 6 H). 4b: IR (film): 1710, 1680 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 9.30 (s, 1 H), 4.10 (q, J = 6.7 Hz, 2 H), 4.00 (m, 2 H), 2.62 (m, 2 H), 2.20 (m, 2 H), 2.12 (s, 3 H), 1.60 (m, 6 H), 1.25 (t, J = 6.7 Hz, 3 H). ¹³C NMR (50 MHz, CDCl₃): δ = 201.10, 194.40, 156.50, 64.50, 61.90, 40.30, 38.00, 30.40, 29.70, 24.00, 22.70, 18.40, 14.30. Anal. Calcd for C₁₃H₂₁NO₄: C, 60.81; H, 8.02; N, 5.35. Found: C, 61.16; H, 8.29; N, 5.49.

11

The spectroscopic data of azaspiroenone 3 were in agreement with the literature.⁴ⁱ