J. Chem. Soc. Perkin Trans. 1 1997 3127 An eYcient total synthesis of (plusmn;)-laurene Mukund G. Kulkarni *,dagger; and Dhananjay S. Pendharkar Department of Chemistry University of Pune Pune 411 007 India A short and efficient total synthesis of (plusmn;)-laurene using a Wittig olefinationndash;Claisen rearrangementndash;Wacker oxidation protocol is described. Laurene 1 a sesquiterpene isolated from Laurentia glandulifera 1 is structurally related to the cuparane class of sesquiterpenes. Like other members of this class laurene has significant steric crowding around a compact cyclopentane ring. Several strategies 2 have been adopted for the synthesis of this sterically congested molecule. We report herein a short and efficient synthesis of (plusmn;)-laurene (Scheme 1) adopting the Wittig olefination methodology 3 developed in our laboratory.On treating a suspension of 4-methylacetophenone (1.0 equiv.) and but-2-enyloxymethylenetriphenylphosphonium chloride 3 (1.0 equiv.) in dry THF with potassium tert-butoxide (1.5 equiv.) the allyl vinyl ether 2 was obtained in 74 yield. This allyl vinyl ether 2 on heating in refluxing toluene for 18 h smoothly underwent Claisen rearrangement to yield the unsaturated aldehyde 3 in 95 yield. The 1H NMR spectrum of this aldehyde showed it to be a 3 2 mixture of diastereomers. Wacker oxidation 4 (10 mol PdCl2 10 mol CuCl2 oxygen atmosphere) of this diastereomeric mixture of the aldehyde 3 in H2O:DME (1 9) at ambient temperature furnished the keto aldehyde 4 as a mixture of diastereomers (1 1) in 82 yield. A Scheme 1 Reagents and conditions a CH3(H)C C(H)CH2OCH2P1- Ph3Cl2 ButO2K1 THF 0 8C; b toluene reflux 18 h; c PdCl2 (10 mol) CuCl2 (10 mol) O2 H2O:DME (1 9) room temp.2 h; d 5 aq. methanolic KOH room temp. 2 h; e 5 Pd/C ethyl acetate H2 (1 atm pressure) room temp. 8 h; f Zn CH2Br2 TiCl4 THF 0 8C 12 h O O O CHO a b 74 95 2 3 CHO O c 82 O 4 5 6 d e 90 97 f 80 + 7 1 dagger; E-Mail mgkul@chem.unipune.ernet.in (1 1) diastereomeric mixture of cyclopent-2-enone 5 was obtained in good yield (90) when the keto aldehyde 4 was treated with KOH (5 in aqueous methanol) at ambient temperature for 2 h. Hydrogenation of the cyclopent-2-enone 5 over 5 Pd/C at ambient temperature afforded the cyclopentanone 6 as a mixture of diastereomers (1 1) in 97 yield. On subjecting this cyclopentanone 6 to Lambardo methylenation conditions 5 (Zn TiCl4 CH2Br2 room temp.12 h) a 1 1 mixture of (plusmn;)-laurene 1 and (plusmn;)-epilaurene 7 was obtained in 80 yield. Experimental General All solvents were distilled before use. Dry THF was prepared by distillation over benzophenone and sodium under an argon atmosphere and toluene was distilled and stored over sodium wire. All the anhydrous reactions were carried out under an argon atmosphere. IR Spectra were recorded on a Perkin-Elmer model 1600 series FTIR instrument. 1H NMR Spectra ppm TMS internal standard; J values in Hz in CDCl3 were recorded on a JEOL FX90Q instrument and a Bruker AC-200 instrument. Elemental analysis was obtained on a HOSLI semiautomatic C H analyser. Silica gel (100ndash;200) mesh was used for column chromatography. 1-But-2-enyloxy-2-(4-methylphenyl)-2-methylethene 2 But-2-enyloxymethylenetriphenylphosphonium chloride (4.98 g 13 mmol) and 4-methylacetophenone (1.34 g 10 mmol) were suspended in dry THF (20 cm3).Potassium tert-butoxide (1.5 g 13 mmol) in tert-butyl alcohol (10 cm3) was added to it at 0 8C in a dropwise manner. The mixture was stirred at 0 8C for 1 h. Then the reaction mixture was diluted with water and extracted with diethyl ether (3 times; 50 cm3). The combined ether extracts were washed with water dried over anhyd. Na2SO4 and concentrated. The crude product on purification by column chromatography using hexane as eluent furnished pure 2 (E:Z 1:1) (1.49 g 74) as a colourless liquid (Found C 83.04; H 9.07; C14H18O requires C 83.12; H 8.97); nmax(film)/cm21 1638 1500 1435 1371 950 and 795; dH(90 MHz; CDCl3) 1.82 (3 H d J 5.1 C CCH3) 2.21 2.62 (3 H s E and Z C CCH3) 2.25 (3 H s ArCH3) 4.50 (2 H m OCH2CH ) 5.96 (2 H m CH CH) 6.45 6.68 (1 H s E and Z OCH C) 7.4 to 7.91 (4 H m ArH).2-(4-Methylphenyl)-2,3-dimethylpent-4-enal 3 Colourless oil 95 bp 162 8C/8 Torr (Found C 83.19; H 8.85. C14H18O requires C 83.12; H 8.97); nmax(film)/cm21 2710.1 1724.3 and 1636.9; dH(90 MHz; CDCl3) 0.76 (2 H d J 7.7 CHCH3) 1.00 (1 H d J 7.7 CHCH3) 1.34 (2 H s CCH3) 1.52 (1 H s CCH3) 2.53 (3 H s ArCH3) 3.08 (1 H m CHCH3) 5.10 (2 H m CH CH2) 5.29 to 5.95 (1 H m CH CH2) 7.23 (4 H s ArH) 9.63 (1 H s CHO). 2-(4-Methylphenyl)-2,3-dimethyl-4-oxovaleraldehyde 4 In a solution of unsaturated aldehyde 3 (0.8 g 4 mmol) in aqueous dimethoxyethane (10 cm3 1 9) was suspended PdCl2 (0.071 g 0.4 mmol) and CuCl2 (0.05 g 0.4 mmol).This mixture 3128 J. Chem. Soc. Perkin Trans. 1 1997 was stirred at room temp. under an oxygen atmosphere. On completion of reaction (TLC check 3 h) the mixture was diluted with water and extracted with diethyl ether (3 times; 25 cm3). The combined ether layer was washed with water and dried over anhyd. Na2SO4. The ether layer was concentrated and the crude product was purified by column chromatography using hexanendash; ethyl acetate (20 1) as eluent to obtain pure 4 (0.707 g 82) as a colourless oil bp 97ndash;99 8C/0.2 Torr (Found C 77.14; H 8.19. C14H18O2 requires C 77.03; H 8.31); nmax(film)/cm21 2748 1732 and 1725; dH(90 MHz; CDCl3) 0.95 1.14 (3 H d J 7.7 CHCH3) 1.59 1.64 (3 H s CCH3) 2.28 (3 H s COCH3) 2.35 (3 H s ArCH3) 3.34 (1 H m CHCH3) 7.25 (4 H s ArH) 9.57 (1 H s CHO ).4-(4-Methylphenyl)-4,5-dimethylcyclopent-2-enone 5 Colourless oil 90 (Found C 83.81; H 8.13. C14H16O requires C 83.96; H 8.05); nmax(film)/cm21 1715.6 1588.8 1513.6 and 1453.5; dH(90 MHz; CDCl3) 0.63 1.18 (3 H d J 7.2 CHCH3) 1.41 1.68 (3 H s CCH3) 2.32 (3 H s ArH) 2.45 (1 H m CHCH3) 6.52 (1 H t J 5.1 COCH CH) 7.38 (4 H m ArH) 7.8 8.0 (1 H d J 5.1 COCH CH). 3-(4-Methylphenyl)-2,3-dimethylcyclopentanone 6 Colourless oil 97 (Found C 83.25; H 8.91. C14H18O requires C 83.12; H 8.97); nmax(film)/cm21 1740.6 1515.0 and 1454.9; dH(90 MHz; CDCl3) 0.79 1.07 (3 H d J 6.9 CHCH3) 1.21 1.43 (3 H s CCH3) 1.28 (1 H m CH2) 1.71 (1 H m CH2) 2.08 (2 H m COCH2) 2.27 (3 H s ArCH3) 2.59 (1 H m COCHCH3) 7.24 (4 H m ArH). Laurene 1 and epilaurene 7 To a stirred suspension of Zn powder (5.6 g 85.6 mmol) in THF (16 cm3) a 1 M solution of titanium tetrachloride in dichloromethane (14 cm3) and dibromomethane (3.2 cm3 45 mmol) were added successively at 0 8C and the stirring was continued for 15 min at room temp.To this mixture was added a solution of ketone 6 (0.08 g 0.4 mmol) in THF (2 cm3) and the reaction mixture was stirred at ambient temperature for 12 h. It was then diluted with diethyl ether (10 cm3) and treated with 10 HCl (5 cm3). The mixture was extracted with diethyl ether and the extract was washed with NaHCO3 and brine. The ether layer was dried over anhyd. Na2SO4 and concentrated. The crude product was purified by column chromatography using pentane as eluent to give a mixture of 1 and 7 (1 1) (0.063 g 80) as a colourless oil bp 87ndash;89 8C/10 Torr (Found C 89.67; H 10.00.C15H20 requires C 89.94; H 10.06); nmax(film)/cm21 1654.1 1519.0 and 1447.8; dH(200 MHz; CDCl3) 0.73 1.02 (3 H d J 7.3 CHCH3) 1.1 1.61 (3 H s CCH3) 1.6 to 2.05 (2 H m CH2C) 2.39 (3 H s ArCH3) 2.5 to 2.91 (3 H m CHCH3 C CCH2) 5.0 (2 H br s C CH2) 7.35 (4 H m ArH). Acknowledgements One of the authors (D. S. P.) wishes to thank CSIR New Delhi for a research fellowship. References 1 T. Irie Y. Yasunari T. Suzuki N. Imai E. Kurosawa and T. Masamune Tetrahedron Lett. 1965 3619. 2 T. Irie T. Suzuki Y. Yasunari E. Kurosawa and T. Masamune Tetrahedron 1969 25 459; W. F. Bailey X. L. Jiang and C. E. McLeod J. Org. Chem. 1995 60 7791 and references cited therein. 3 M. G. Kulkarni D. S. Pendharkar and R. M. Rasne Tetrahedron Lett. 1997 38 1459. 4 M.G. Kulkarni and T. S. Mathew Synth. Commun. 1991 21 581. 5 K. Takai T. Kakiuchi Y. Kataoka and K. Utimoto J. Org. Chem. 1994 59 2668 and references cited therein. Paper 7/06510H Received 9th September 1997 Accepted 9th September 1997 J. Chem. Soc. Perkin Trans. 1 1997 3127 An eYcient total synthesis of (plusmn;)-laurene Mukund G. Kulkarni *,dagger; and Dhananjay S. Pendharkar Department of Chemistry University of Pune Pune 411 007 India A short and efficient total synthesis of (plusmn;)-laurene using a Wittig olefinationndash;Claisen rearrangementndash;Wacker oxidation protocol is described. Laurene 1 a sesquiterpene isolated from Laurentia glandulifera 1 is structurally related to the cuparane class of sesquiterpenes. Like other members of this class laurene has significant steric crowding around a compact cyclopentane ring.Several strategies 2 have been adopted for the synthesis of this sterically congested molecule. We report herein a short and efficient synthesis of (plusmn;)-laurene (Scheme 1) adopting the Wittig olefination methodology 3 developed in our laboratory. On treating a suspension of 4-methylacetophenone (1.0 equiv.) and but-2-enyloxymethylenetriphenylphosphonium chloride 3 (1.0 equiv.) in dry THF with potassium tert-butoxide (1.5 equiv.) the allyl vinyl ether 2 was obtained in 74 yield. This allyl vinyl ether 2 on heating in refluxing toluene for 18 h smoothly underwent Claisen rearrangement to yield the unsaturated aldehyde 3 in 95 yield. The 1H NMR spectrum of this aldehyde showed it to be a 3 2 mixture of diastereomers. Wacker oxidation 4 (10 mol PdCl2 10 mol CuCl2 oxygen atmosphere) of this diastereomeric mixture of the aldehyde 3 in H2O:DME (1 9) at ambient temperature furnished the keto aldehyde 4 as a mixture of diastereomers (1 1) in 82 yield.A Scheme 1 Reagents and conditions a CH3(H)C C(H)CH2OCH2P1- Ph3Cl2 ButO2K1 THF 0 8C; b toluene reflux 18 h; c PdCl2 (10 mol) CuCl2 (10 mol) O2 H2O:DME (1 9) room temp. 2 h; d 5 aq. methanolic KOH room temp. 2 h; e 5 Pd/C ethyl acetate H2 (1 atm pressure) room temp. 8 h; f Zn CH2Br2 TiCl4 THF 0 8C 12 h O O O CHO a b 74 95 2 3 CHO O c 82 O 4 5 6 d e 90 97 f 80 + 7 1 dagger; E-Mail mgkul@chem.unipune.ernet.in (1 1) diastereomeric mixture of cyclopent-2-enone 5 was obtained in good yield (90) when the keto aldehyde 4 was treated with KOH (5 in aqueous methanol) at ambient temperature for 2 h.Hydrogenation of the cyclopent-2-enone 5 over 5 Pd/C at ambient temperature afforded the cyclopentanone 6 as a mixture of diastereomers (1 1) in 97 yield. On subjecting this cyclopentanone 6 to Lambardo methylenation conditions 5 (Zn TiCl4 CH2Br2 room temp. 12 h) a 1 1 mixture of (plusmn;)-laurene 1 and (plusmn;)-epilaurene 7 was obtained in 80 yield. Experimental General All solvents were distilled before use. Dry THF was prepared by distillation over benzophenone and sodium under an argon atmosphere and toluene was distilled and stored over sodium wire. All the anhydrous reactions were carried out under an argon atmosphere. IR Spectra were recorded on a Perkin-Elmer model 1600 series FTIR instrument. 1H NMR Spectra ppm TMS internal standard; J values in Hz in CDCl3 were recorded on a JEOL FX90Q instrument and a Bruker AC-200 instrument.Elemental analysis was obtained on a HOSLI semiautomatic C H analyser. Silica gel (100ndash;200) mesh was used for column chromatography. 1-But-2-enyloxy-2-(4-methylphenyl)-2-methylethene 2 But-2-enyloxymethylenetriphenylphosphonium chloride (4.98 g 13 mmol) and 4-methylacetophenone (1.34 g 10 mmol) were suspended in dry THF (20 cm3). Potassium tert-butoxide (1.5 g 13 mmol) in tert-butyl alcohol (10 cm3) was added to it at 0 8C in a dropwise manner. The mixture was stirred at 0 8C for 1 h. Then the reaction mixture was diluted with water and extracted with diethyl ether (3 times; 50 cm3). The combined ether extracts were washed with water dried over anhyd. Na2SO4 and concentrated. The crude product on purification by column chromatography using hexane as eluent furnished pure 2 (E:Z 1:1) (1.49 g 74) as a colourless liquid (Found C 83.04; H 9.07; C14H18O requires C 83.12; H 8.97); nmax(film)/cm21 1638 1500 1435 1371 950 and 795; dH(90 MHz; CDCl3) 1.82 (3 H d J 5.1 C CCH3) 2.21 2.62 (3 H s E and Z C CCH3) 2.25 (3 H s ArCH3) 4.50 (2 H m OCH2CH ) 5.96 (2 H m CH CH) 6.45 6.68 (1 H s E and Z OCH C) 7.4 to 7.91 (4 H m ArH).2-(4-Methylphenyl)-2,3-dimethylpent-4-enal 3 Colourless oil 95 bp 162 8C/8 Torr (Found C 83.19; H 8.85. C14H18O requires C 83.12; H 8.97); nmax(film)/cm21 2710.1 1724.3 and 1636.9; dH(90 MHz; CDCl3) 0.76 (2 H d J 7.7 CHCH3) 1.00 (1 H d J 7.7 CHCH3) 1.34 (2 H s CCH3) 1.52 (1 H s CCH3) 2.53 (3 H s ArCH3) 3.08 (1 H m CHCH3) 5.10 (2 H m CH CH2) 5.29 to 5.95 (1 H m CH CH2) 7.23 (4 H s ArH) 9.63 (1 H s CHO).2-(4-Methylphenyl)-2,3-dimethyl-4-oxovaleraldehyde 4 In a solution of unsaturated aldehyde 3 (0.8 g 4 mmol) in aqueous dimethoxyethane (10 cm3 1 9) was suspended PdCl2 (0.071 g 0.4 mmol) and CuCl2 (0.05 g 0.4 mmol). This mixture 3128 J. Chem. Soc. Perkin Trans. 1 1997 was stirred at room temp. under an oxygen atmosphere. On completion of reaction (TLC check 3 h) the mixture was diluted with water and extracted with diethyl ether (3 times; 25 cm3). The combined ether layer was washed with water and dried over anhyd. Na2SO4. The ether layer was concentrated and the crude product was purified by column chromatography using hexanendash; ethyl acetate (20 1) as eluent to obtain pure 4 (0.707 g 82) as a colourless oil bp 97ndash;99 8C/0.2 Torr (Found C 77.14; H 8.19.C14H18O2 requires C 77.03; H 8.31); nmax(film)/cm21 2748 1732 and 1725; dH(90 MHz; CDCl3) 0.95 1.14 (3 H d J 7.7 CHCH3) 1.59 1.64 (3 H s CCH3) 2.28 (3 H s COCH3) 2.35 (3 H s ArCH3) 3.34 (1 H m CHCH3) 7.25 (4 H s ArH) 9.57 (1 H s CHO ). 4-(4-Methylphenyl)-4,5-dimethylcyclopent-2-enone 5 Colourless oil 90 (Found C 83.81; H 8.13. C14H16O requires C 83.96; H 8.05); nmax(film)/cm21 1715.6 1588.8 1513.6 and 1453.5; dH(90 MHz; CDCl3) 0.63 1.18 (3 H d J 7.2 CHCH3) 1.41 1.68 (3 H s CCH3) 2.32 (3 H s ArH) 2.45 (1 H m CHCH3) 6.52 (1 H t J 5.1 COCH CH) 7.38 (4 H m ArH) 7.8 8.0 (1 H d J 5.1 COCH CH). 3-(4-Methylphenyl)-2,3-dimethylcyclopentanone 6 Colourless oil 97 (Found C 83.25; H 8.91. C14H18O requires C 83.12; H 8.97); nmax(film)/cm21 1740.6 1515.0 and 1454.9; dH(90 MHz; CDCl3) 0.79 1.07 (3 H d J 6.9 CHCH3) 1.21 1.43 (3 H s CCH3) 1.28 (1 H m CH2) 1.71 (1 H m CH2) 2.08 (2 H m COCH2) 2.27 (3 H s ArCH3) 2.59 (1 H m COCHCH3) 7.24 (4 H m ArH).Laurene 1 and epilaurene 7 To a stirred suspension of Zn powder (5.6 g 85.6 mmol) in THF (16 cm3) a 1 M solution of titanium tetrachloride in dichloromethane (14 cm3) and dibromomethane (3.2 cm3 45 mmol) were added successively at 0 8C and the stirring was continued for 15 min at room temp. To this mixture was added a solution of ketone 6 (0.08 g 0.4 mmol) in THF (2 cm3) and the reaction mixture was stirred at ambient temperature for 12 h. It was then diluted with diethyl ether (10 cm3) and treated with 10 HCl (5 cm3). The mixture was extracted with diethyl ether and the extract was washed with NaHCO3 and brine.The ether layer was dried over anhyd. Na2SO4 and concentrated. The crude product was purified by column chromatography using pentane as eluent to give a mixture of 1 and 7 (1 1) (0.063 g 80) as a colourless oil bp 87ndash;89 8C/10 Torr (Found C 89.67; H 10.00. C15H20 requires C 89.94; H 10.06); nmax(film)/cm21 1654.1 1519.0 and 1447.8; dH(200 MHz; CDCl3) 0.73 1.02 (3 H d J 7.3 CHCH3) 1.1 1.61 (3 H s CCH3) 1.6 to 2.05 (2 H m CH2C) 2.39 (3 H s ArCH3) 2.5 to 2.91 (3 H m CHCH3 C CCH2) 5.0 (2 H br s C CH2) 7.35 (4 H m ArH). Acknowledgements One of the authors (D. S. P.) wishes to thank CSIR New Delhi for a research fellowship. References 1 T. Irie Y. Yasunari T. Suzuki N. Imai E. Kurosawa and T. Masamune Tetrahedron Lett. 1965 3619. 2 T. Irie T. Suzuki Y.Yasunari E. Kurosawa and T. Masamune Tetrahedron 1969 25 459; W. F. Bailey X. L. Jiang and C. E. McLeod J. Org. Chem. 1995 60 7791 and references cited therein. 3 M. G. Kulkarni D. S. Pendharkar and R. M. Rasne Tetrahedron Lett. 1997 38 1459. 4 M. G. Kulkarni and T. S. Mathew Synth. Commun. 1991 21 581. 5 K. Takai T. Kakiuchi Y. Kataoka and K. Utimoto J. Org. Chem. 1994 59 2668 and references cited therein. Paper 7/06510H Received 9th September 1997 Accepted 9th September 1997
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