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Synlett 2006(20): 3411-3414  
DOI: 10.1055/s-2006-956461
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Philip C. Bulman Page*, Giovanni Gambera, Colin M. Hayman, Mark Edgar
Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
Fax: +44(1509)223926; e-Mail: p.c.b.page@lboro.ac.uk;
Further Information

Publication History

Received 3 August 2006
Publication Date:
08 December 2006 (online)

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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.

Key words

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

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(±)-(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): νmax = 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-Ha, 1-Hb, 4-Hb, 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-Ha), 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): νmax = 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).

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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%).

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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.