Chand, Tek

Sharma, M L

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Indian Journal of ChemistryVoI.36B, July 1997, pp.553 - 556Synthesis of (+) curcuphenol and (+)-~-sesquiphellandreneM L Sharma" & Tek Chand tDepartment of Chemistry, Panjab University, Chandigarh 160014Received II June 1996: revised and accepted 3 February 1997Two naturally occurring compounds curcuphenol t and p-sesquiphellandrene 2 have been synthesised usinglithium tetrachlorocuperate catalysed coupling reaction.In continuation I of our work on the synthesis ofnatural products utilizing dilithium tetrachlorocuper-ate (LhCuCI4) catalysed coupling for the carbon-chain elongation, herein, we report the synthesis of(±)-curcuphenoll and (±)-j3-sesquiphellandrene 2.Wright et. al.2 reported the isolation of sesquiter-pene phenol, (+j-curcuphenol, from both deep andshallow water collection of the sponge Didiscusjlavis Van Soest (Fam. Latrunculizdae). Earlier Feni-cal and coworkers3 reported the isolation of (- j-cur-cuphenol from the metabolite of the gorgonian softcoral Pseudoptero gorgia rigida. The isolation 4,5of(-)-curcuphenol has also been reported from terres-trial plant Lasiamthaea podocephala. The isolationof j3-sesquiphellandrene was reported by Rodriguezet.al.6 from Aristolochia chilensis Miers roots. It wasthe first report of this compound from a naturalsource. The structures of both the compounds wereassigned on the basis of spectral data. Fenical andcoworkers have reported only the synthetic ap-proach to (±)-curcuphenol while no attempt has beenmade to synthesise j3-sesquiphellandrene. Herein, wereport a facile synthesis of the compounds 1 and 2through dilithium tetrachlorocuperate catalysed cou-pling. The reaction sesquences employed are shownin Scheme I and II.m-Cresol was brominated ortho- to hydroxy groupby protecting para-position with sulphonic acidgroup followed by deprotection leading to 2-bromo-5-methylphenoI3. Compound 3 was then methylatedwith dimethyl suphate in aqueous sodium hydroxidetpresent Addrress: ROO Mis Himachal Terpene products (p)Ltd. VPO Kala-AMB, Nahan -173030, Distt. Sirmour CHP),Indiaoy irradiating with microwave radiations to get bro-moanisole 4. Grignard reagent prepared from methylsubstituted bromoanisole. 4 was coupled with 6-bromo-2-methyl-2- heptene 12using dilithium tetra-chlorocuperate'' as catalyst at -10° to afford methylcurcuphenol 5, which upon subsequent demethyla-tion" with BBo in dichloromethane at _78° furnishedthe target molecule curcuphenol 1 (Scheme J).To acheive the target molecule 2, cyclohexanonewas converted 10 into cyclohex-2-enone ethyleneketal 6 which was subsequently brominated II atallylic position using NBS in anhydrous CCI4 toprocure 3-bromo-6,6-ethylenedioxycyclohexene 7.The Grignard reagent prepared from bromide 7 oncoupling with 6-bromo-2-methyl-2-hepteneI2 usingLi2CuCI4 as catalyst" at -10° in anhydrous THF fur-nished 8 which was subsequently deketalised to sub-stituted cyclohexenone 9. Wittig reaction 13of methyl~-~ --0OH 7'OH Y'OMeSr sr"3Scheme I554 INDIAN JCl-IEM.SEC B, JULY 1997(i) g-~----:>:. I -..:.....( ii-=--) ~~ 97 Br6un) ,. L(iV),. L8 9(V)~L2.Scheme IIdimethyl phosphonate with enone 9 using K2C03 asbase in retluxing aqueous media afforded the targetmolecule 2 (Scheme II).Experimental SectionBoiling points are uncorrected. IR spectra wererecorded on a Perkin-Elmer 1430 spectrophotometerVmax in em"); IHNMR spectra in COCb on a VarianEM-390 (90 MHz) spectrometer (chemical shifts in8, ppm and J values in Hz) using TMS as an internalstandard; mass spectra on a VG ANALYTICAL11-250-J 70-S spectrometer at 70 eV. Silica gel(Acme 100-200 mesh) was used for column chroma-tography. All solvents were dried prior to use em-ploying standard procedures. Unless statedotherwise, the organic extracts were dried over anhy-drous sodium sulphate.2-Bromo-5-methylphenol 5. A strirred mixtureofm-cresol (32.4g, O.3mole) and cone. sulphuric acid(84g, 45 .6mL) was heated on a boiling water-bath for2 hr. The reaction mixture was cooled to 10-15°C andthen 70g of sodium hydroxide in 175mL of water wasslowly added to obtain a solid which later dissolved.The solution was allowed to attain room temperatureand to this was added 53g (17mL) of bromine in 45min. While stirring constantly and maintaining thetemperature below 40°C. After the' addition of bro-mine was over, the reaction mixture was furtherstirred for I hr, and then distilled while passing astream of air. To the remaining thick residue wasadded 100mL of cone. sulphuric acid alowly whileshaking the reaction mixture. The reaction mixturewas then heated at 205-10° for 1 hr., cooled andextracted with ether, washed the ethereal layer withwater, and dried over anhyd. MgS04. Evaporation ofether followed by distillation under reduced pressureyielded pure 3 (37.6g, 67%) b.p. If?7-68°/20 mrn: IR(KBr) : 3350, 2870, 1645, 1070; IHNMR: 82.2 (s,3H, ArCH3, 6.1 (brs, 1H, OH, 020 exchangeable),6.73 (d, IH, aromatic, J = 4Hz), 7.03 (s, IH, aro-matic), 7.2 (d, IH, aromatic, J = 7Hz).2-Bromo-5-methylanisole 4. A mixture of 3(18.7g, O.lmole), sodium hydroxide (4.8g, 0.12mole) and dimethyl sulphate (13.5g, 0.11 mole) inIOOmLwater was subjected to microwave irradiationat a power level of 9 for I min. The contents of themixture were then cooled, extracted with ether,washed with water and dried. Evaporation of thesolvent yielded pure 4 (l9.8g, 98.7%); IR (KBr):2880, 1640, 1070; IHNMR; 82.26 (s, 3H, ArCH3),3.73 (s, 3H, OMe), 6.7 (d, IH, aromatic, J= 4 Hz),7.16 (s, IH, aromatic), 7.43 (d. IH, aromatic, J = 6Hz) Found: C, 47.8; H, 4.6. CsH9BrO requires C,47.76; H, 4.47%).Methyl curcuphenol 5. To an ice-cooled stirredsolution of Grignard reagent, prepared from the sub-stituted bromoanisole 4 (4.02g, 0.02 mole) and mag-nesium turnings (0.504g, 0.021 mole) in THF(70mL) under N2 atmosphere, was added dropwise asolution of 6-bromo-2-methyl-2-heptene (3.82g,0.02mole) in THF (50 mL) in about 20 min. Thesolution was cooled to -10° and then LhCuCI4 (4mL)was added. It was kept at -10° for another 6 hr, andthen stirred overnight at room temperature. The reac-tion mixture was decomposed with saturated solutionofNH4CI, extracted with ether, washed with water,brine and dried. Evaporation of the solvent followedby chromatographic purification over silica gel usinghexane - ether (9.5 : 0.5) as eluent afforded pure5 (3.68g, 79.4%); IR (KBr): 2920, 2865, 1640,1035; IHNMR: 81.03 (d, 3H, CH3, J= 6Hz), 1.3 (m,2H), 1.5, 1.6 (2s, 6H, -CH = C(CH3)2), 2.1 (m, 2H,SHARMA et al.: SYNTHESIS OF (±) CURCUPHENOL & (±)-P-SESQUIPHELLANDRENE 555-CH2.CH=C), 2.23 (s, 3H, ArcH3), 2.4 (m, IH, CH),3.9 (s, 3H, OMe), 5.36 (t, IH, olefinic, J=7Hz), 7.03(d, IH, aromatic, J=7Hz), 7.1 (s, IH, aromatic), 7.3(d, IH,aromatic,J=6Hz); 13CNMR: 16.1,20.2,21.6,25.6,26.1,31.8,37.4,60.5, 115.8, 121.6, 124.9,126.9,131.2,133,135.6,153.7; MS: 232 [Mt, 189,156, 137, 110, 105,95,91, 79, 77,69,67, 57, 55(Found: C, 82.8; H, 10.3. Cl6H240 requires C, 82.75;H,10.35%).Curcuphenoll. To a stirred solution of 5 (0.58g,2.5moles) in anhydrous CH2Ch (15mL) at _780 wasadded BBn (0.65g, 2.6mmoles). The reaction mix-ture was allowed to attam room temperature and thendecomposed with water (2mL), extracted the con-tents with ether and dried. Evaporation of the solventfurnished pure curcuphenol 1 (0.53g, 96.7%);IR(KBr) : 3340, 1635, 1070; IHNMR : 81.2 (d, 3H,J = 6.5Hz), 1.6 (m, 2H), 1.53, (s, 3H, CH3), 1.66 (s,3H, CH3), 1.96 (rn, 2H, CH2), 2.2 (s, 3H, CH3), 2.86(rn, IH, CH), 5.13 (t, IH, .J = 7Hz), 5.3 (brs, IH,OH, D20 exchangeable), 6.86 (s, IH, aromatic),7.03 (d, IH, aromatic,J= 7Hz), 7.13 (d, IH, aromatic,.J = 8Hz); MS: 218 [Mt, 149, 135, 121, 115, 109,107, 105,95,91,79,77,69,67,65,55; 13CNMR:16.7,20.2,21.6,25.7,26.1,31.9,37.2,115.8,122.1,123.7,126.9,130.8,131.5,137.6,151.5.Cyclohex-2-enone ethylene ketal 6. Cyclohex-anone was converted to cyclohex-2-enone ethyleneketal by standard procedure as reported in the litera-turelO.3-Bromo-6, 6-ethylenedioxycyclohexene 7 . Thecompound 6 (2.8g, 30 mmoles) and NBS (0.18g, 10mmoles) in anhydrous CCI4 (50 mL) containing cata-lytic amount of benzoyl peroxide were heated to 500slowly to avoid a vigorous reaction. After heating for2 hr when whole of the solid component startedfloating over organic layer, the reaction mixture wascooled and filtered. Evaporation of the solvent fol-lowed by distillation under diminished pressureyielded pure 7 (5.38g, 82%), b.p. 92- 93°C115 mm;IR (KBr) : 2920, 1620, 1050,480; IHNMR; 81.9 (m,4H, 2x CH2), 4.1 (s, 4H, -OCH2CH20.), 4.23 (m, IH,-CHBr), 6.86 (d, IH, -CH=CH-CHBr, J=9Hz), 7.13(m, IH, -CH=CH-CHBr); MS : 203 [M+], 123, 63,60 (Found: C, 47.3; H, 5.43; Br, 39.4. CSHIIBrOrequires C, 47.29; H, 5.4; Br, 39.4%).4-(1 ,5-Dimethyl-4-hexene) cyclohex-2-enoneethylene ketal 8. To a solution of the Grignardreagent prepared from Mg turnings (0.24g, 10 mmo-les) and the bromide 8 (2.19g, 10 mmoles) in THF(30 mL) in N2 atmosphere, was added dropwise asolution of 6- bromo-2-methyl-2-heptene (1.91 g, 10mmo les) in THF (20mL) in 10 min. After stirring for30 min, Li2CUCI4 (2mL) was added. The reactionmixture was stirred for 4 hr at -100 and then stirredfor 6hr at room temperature. It was decomposed withsaturated solution of NH4Cl, extracted with ether,washed with water, brine and dried. Evaporation ofthe solvent followed by chromatographic purifica-tion using hexane-ethyl acetate (9.5 :0.5) as eluentyielded pure 8 (1.48g, 59%); IR(KBr): 2990,1635,1240,1070,730; IHNMR: 81.03 (d,3H, methyl,J=6.3Hz). 1.36 (m, 2H, CH2), 1.5, 1.6 (2s, 6H,-CH=CCCH3)2), 1.9 (brs, 4H, cyclic 2xCH2), 2.3(m, 2H, allylic CH2), 2.6 (m, IH, allylic CH, 4.1 (s,4H, -OCH2CH20.), 5.3 (t, IH, olefinic, J= 7Hz), 6.2(s, IH, olefinic), 6.53 (dd, IH, olefinic, J= 9.3Hz);MS:250 [M+], 208, 167, 139, 190, 206, 69, 42(Found: C, 76.9; H, 10.3. CI6H2602 requires C, 76.8;H,IO.4%).4-(1,5-Dimethyl-4-hexene )cyclohex-2-enone 9.Compound 8 (2.5g, 10 mmoles) was stirred with 10%HCI (40mL) in acetone (80mL) for 2 hr. The progressof the reaction was monitored on TLC. The reac-tion mixture was then diluted with water (IOOmL),extracted with ether (50mL), washed with water,brine and dried. Evaporation of the solvent followedby chromatographic purification over silica gelusing hexane-ether (9.5 : 0.5) as eluent affordedpure 9 (1.63g, 79%); IR (KBr): 2970,1690,1635,1410,1070, 980,730; IHNMR: 81.06 (d, 3H, cu;J = 6Hz), 1.33 (rn, 2H, C~h), 1.5, 1.6 (2s, 6H,-CH = CCCH3)2), 1.9 (m, 2H, cyclic C112),2.16 (rn,2H, allylic CH2), 2.36 (t, 21-1,-ObCO-, J = 6.9Hz),2.6 (rn, IH, allylic CH), 5.3 (t, 11-1,olefinic,.J =7Hz),6.9 (brs, IH), 7.03 (rn, II I), MS : 206 [M+], 190, II I,164, 56, 42 (Found: C, 81.6; H, 10.7. C14H220requires C, 81.55; H, 10.68%).~sesquiphellandrene 1. A mixture of9 (2.47g,12 m moles), K2C03 (4.14g, 30 mmoles), methyldimethyl phosphonate (1.86g, IS mmoles), and water(30 mL) was refluxed for 4 hr. The reaction mixturewas then diluted with water, extracted with ether,washed the ethereal layer with brine and dried(MgS04). Evaporation of solvent followed by chro-matographic purification over neutral alumina withhexane-ether (9 : I) as eluent afforded pure 1 (1.91 g,78%); IR(KBr) : 2970, 1640, 1210, 730, 870;IHNMR: 81.03 (d, 3H, CH3, J= 6Hz), 1.39 (rn, 2H,CH2), 1.5, 1.6 (2s, 6H, -CH = CCCH3)2), 1.89 (brs,556 INDIAN J.CHEM.SEC B, JULY 19974H, cyclic 2xCH2), 2.3 (m, J = 7Hz), 5.7 (d, IH,olefinic CH2, J =7Hz), 5.93 (d, IH, olefinic CH2 J =6.6Hz), 6.l(brs, IH, olefinic), 6.33 (dd, IH, olefinic,J= 9, 3Hz); MS : 204 ~], 192, 156, 111,56,42.AcknowledgementThe authors are thankful to the CSIR, New Delhifor fmancial assistanceReferencesI (a) Sharma M L & Chand T, Indian J Chem, 35B, 1996,55.(b) Sharma M L, Verma S, Chand T, Indian J Chem, 34 B,1995, 1030.2 Wright A E, Pompani S A, McConnell 0 J, Kohmoto S &Mc Carthy P J, J Nat Prod, 50, 1987, 976.3 Fenical W & Mc Enroe F J, Tetrahedron, 34, 1978,1661.Bohlmann F & Lonitz M, Chem Ber, III, 1978,843.Ghisalberti E, Jefferies P & Stuart A, Aust J Chem, 32,1979,1627.Rodriguez A R & Urzua M.A., Bol Soc Chil Quim, 33,1988, 147.Mingos P, Michael D & Baghurst D R, cu« Soc Rev, 20,1991, I.Tamura M & Kochi J, JAm Chem Soc, 93,1971, 1483.McOmie J F W, Watts M L & West D E, Tetrahedron, 24,1968,2289.Garbiseh (Jr) E W, J Org Chem, 30,1965,2109.Sharma M L & Chand T, Indian J Chem, 35B, 1996, 55.Sharma M L, Arora R & Chand T, Indian J Chem, 33B,1994,874.Villeras & Ramband, Synthesis, 1983, 300.45678910111213

Synthesis of (±) curcuphenol and (±)-β-sesquiphellandrene

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Synthesis of (±) curcuphenol and (±)-β-sesquiphellandrene

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