An Ytterbium-Catalysed Intramolecular Aldehyde-Ene Reaction Approach to the Guaianolide and Pseudoguaianolide Diterpenoids: Synthesis of the Guaiane Skeleton

Abstract

A convergent approach to a functionalised guaiane ring system, the core of the guaianolide and pseudoguaianolide diterpenes, is described. The synthesis utilises an intramolecular aldehyde-ene reaction as the key step.

sesquiterpene lactone - guaianolide - pseudoguaianolide - perhydroazulene - intramolecular ene reaction

References and Notes

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<A NAME="RD23706ST-21">21</A>

(±)-(3a S ,7 R ,8 R ,8a R )-8-Hydroxy-7-isopropenyl-3-oxooctahydroazulene-5,5-dicarboxylic Acid Diethyl Ester(6) and (±)-(3a S ,7 S ,8 S ,8a R)- 8-Hydroxy-7-isopropenyl-3-oxooctahydroazulene-5,5-dicarboxylic Acid Diethyl Ester (7) .
BF₃·OEt₂ (0.86 mL, 7.0 mmol) was added to a stirred solution of 5 (490 mg, 1.4 mmol) in anhyd THF at -78 °C under a nitrogen atmosphere. After 1 h the solution was allowed to reach r.t. and stirred for further 22 h. The solution was diluted with EtOAc, washed with sat. aq NaHCO₃ and brine. The organic layer was dried over Na₂SO₄ and concentrated to dryness to give a colourless oil, which was purified by flash column chromatography on silica gel using 15-25% EtOAc-light PE as eluent to afford 6 (200 mg, 41%) and 7 (50 mg, 10%) as colorless oils. MS (EI): m/z calcd for C₁₉H₂₈O₆: 352.18859; found: 352.18226 [M⁺].
Compound 6: IR (neat): ν_max = 3542, 2978, 1730, 1645, 1245 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.17 (3 H, t, J = 7.1 Hz, CH ₃CH₂O), 1.18 (3 H, t, J = 7.1 Hz, CH ₃CH₂O), 1.76 (3 H, s, 11-H), 1.85-1.99 (4 H, m, 1-H_a, 1-H_b, 4-H_b, 8a-H), 2.06-2.17 (3 H, m, 1 of 6-H, 7-H, 1 of 2-H), 2.32-241 (2 H, m, 3a-H, 1 of 2-H), 2.43 (1 H, dd, J = 10.6, 15.0 Hz, 1 of 6-H), 2.61 (1 H, dd, J = 2.9, 15.2 Hz, 4-H_a), 3.82 (1 H, s, 8-H), 4.05-4.18 (4 H, m, 2 × CH₃CH ₂O), 4.76 (1 H, s, 10-Ha), 4.87 (1 H, s, 10-Hb). ¹³C NMR (100 MHz, CDCl₃): δ = 13.8, 13.9 (2 × CH₃CH₂), 22.7 (1-C), 23.3 (11-C), 29.5 (6-C), 32.6 (4-C), 37.3 (2-C), 44.9 (3a-C), 47.0 (7-C), 50.1 (8a-C), 55.2 (5-C), 61.3, 61.4 (2 × CH₃ CH₂), 67.8 (8-C), 111.7 (10-C), 148.7 (9-C), 172.3, 172.4 (2 × CO₂Et), 218.7 (3-C).
Compound 7: IR (neat): ν_max = 3533, 2979, 1737, 1731, 1646, 1255 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.22 (3 H, t, J = 7.1 Hz, CH ₃CH₂O), 1.23 (3 H, t, J = 7.1 Hz, CH ₃CH₂O), 1.49-1.60 (1 H, m, 1-Ha), 1.74 (1 H, dd, J ₁ = 5.8 Hz, J ₂ = 9.3 Hz, 8a-H), 1.76 (3 H, s, 11-H), 1.86 (1 H, dd, J ₁ = 10.0, J ₂ = 15.2 Hz, 6-Ha), 1.91 (1 H, dd, J ₁ = 10.6, J ₂ = 14.6 Hz, 1 of 4-H), 1.98 (1 H, dd, J ₁ = 10.9 Hz, J ₂ = 12.6 Hz, 3a-H), 2.13 (1 H, dd, J ₁ = J ₂ = 9.8 Hz, 7-H), 2.17 (1 H, dd, J ₁ = 9.1 Hz, J ₂ = 19.5 Hz, 2-Hb), 2.25 (1 H, d, J = 15.1 Hz, 6-Hb), 2.41 (1 H, dd, J ₁ = 8.8 Hz, J ₂ = 20.4 Hz, 2-Ha), 2.42-2.49 (1 H, m, 1-Hb), 2.71 (1 H, d, J = 14.2 Hz, 4-Hb), 3.35 (1 H, dd, J ₁ = J ₂ = 9.5 Hz, 8-H), 4.12-4.20 (4 H, m, 2 × CH₃CH ₂ O), 4.84 (1 H, s, 10-Ha), 4.95 (1 H, s, 10-Hb). ¹³C NMR (100 MHz, CDCl₃): δ = 13.9, 14.0 (2 × CH₃CH₂O), 19.2 (11-C), 26.3 (1-C), 31.6 (4-C), 34.3 (6-C), 36.7 (2-C), 47.8 (3a-C), 49.4 (7-C), 51.7 (8a-C), 54.9 (5-C), 61.6, 61.7 (2 × CH₃ CH₂O), 77.1 (8-C), 113.5 (10-C), 146.4 (9-C), 171.7, 172.7 (2 × CO₂Et), 217.3 (3-C).

<A NAME="RD23706ST-22">22</A>

Yb(OTf)₃ (900 mg, 0.0014 mol) was added to a stirring solution of 5 (80 mg, 0.23 mmol) in anhyd THF (10 mL), at 0 °C under an atmosphere of nitrogen. The mixture was stirred at r.t. for 5 d, diluted with CH₂Cl₂, extracted with sat. aq NaHCO₃, dried over anhyd MgSO₄, and concentrated to dryness to give a colourless crude oil (120 mg). This was purified by flash column chromatography using 10-35% EtOAc-light PE as eluent to give 6 (37 mg, 46%) and starting material 5 (14 mg, 18%).

<A NAME="RD23706ST-23">23</A>

NMR spectra were recorded using a Bruker Avance 400 MHz ultrashield spectrometer equipped with a shaped-pulse unit and employing a 5-mm auto-tune HX gradients probe.