Studies in terpenoids. Part 40. Synthesis of (plusmn;)-sydowic acid

摘要

34 J.C.S. Perkin IStudies in Terpenoids. Part 4 0 . l Synthesis of (+Sydowic AcidBy Putti R. Vijayasarathy, Ramachandra B. Mane, and G. S. Krishna Rao,' Department of Organic Chemistry,Indian Institute of Science, Bangalore 56001 2, India5-Methyl-2-(2,6,6-trimethyltetrahydropyran-2-yl)phenol (5a). a phenolic analogue of the naturally occurringcurcumen ether (1 ), has been synthesised via 5-(2-hydroxy-4-methyIphenyl) -5-oxopentanoic acid (3a). Oxid-ation with alkaline permanganate or treatment with N-bromosuccinimide of the acetate (5b) followed by hydrolysisgave (*)-sydowic acid 3-hydroxy-4-(2.6.6-trimethyltetrahydropyran-2-yl) benzoic acid (5c). a fungal metabolitei so I a ted from Aspergillus s ydo wi.A PHENOLIC tetrahydropyran sesquiterpenoid namedsydowic acid (5c) has been isolated recently fromH Hf p 3 0 2 Rbsol;( 3 ) a; R = Hb; R = MeR2 R2( 5 )a; R' =H,R*=Meb; R' =Ac, R2= Med ; R ' = A c , R 2 = CHBr2C; R' = H,R2 = CO2HA sfiergiZZas sydo~eri.~ The closely related non-phenolictetrahydropyran, curcumen ether (1) and the pyranonePart 39, T.K. John and G. S. Krishna Rao, Indian J.Chem., in the press.2 (a) T . Hamasaki. Y. Sato, Y. Hatsuda, M. Tanabe, andL. W. Cary, Tetrahedron Letters, 1975, 659; (b) T. Hamasaki, Y.Sato, and Y. Hatsuda, Agric. and Biol. Chem. (Japan), 1975, 39,2337; ( c ) K. Fukuyama, T. Tsukihara, Y. Katsube, T. Hamasaki,and Y. Hatsuda, Agric. and Biol. Chem. (Japan), 1976, 4-0, 1053.deodarone (2) of plant origin have been s~nthesised.~-~As part of a programme of synthesis of phenolic ses-quiterpenoids l y 7 and sesquiterpene acids ,* we undertookthe synthesis of sydowic acid.Acylation of m-cresol with glutaric anhydride furnishedthe phenolic 0x0-acid (3a), the methyl ester of which ontreatment with an excess of methylmagnesium iodideafforded the phenolic diol (4) as a crystalline solid.Ringclosure to the tetrahydropyran (5a) proceeded smoothlyon treatment with aqueous sulphuric acid at 0 "C. Theether (Sa) is of interest because of (i) its relationship withthe naturally occurring curcumen ether (1) and (ii) itsconformation.Conformationally, (6a) appears a satisfactory represen-tation of the ether (5a), with the aryl ring equatorial tothe tetrahydropyran ring, the ring oxygen and thearomatic hydroxy-group being involved in intramolecularhydrogen bonding 2~ v,, (CCL,) 3 300 cm-l (OH), nochange in maximum in solutions of different dilutions.Each of the three methyl groups on the tetrahydropyranring in compounds (5a-d) invariably gives rise to a wellseparated 1H n.m.r.singlet, as expected for the conform-ational model (6).The ether (5a) was acetylated ; oxidation of the acetate9 B. Tomita, Y. Hirose, and T. Nakatsuka, Mokuzai Gakkaishi,4 R. Shankaranarayanan, S. Krishnappa, S. C. Bisarya, and5 0. P. Vig, H. Kumar, J . P. Salota, and S. D. Sharma, Indian6 Y. Gopichand and K. K. Chakravarthi, Tetrahedron Letters,1969, 15, 47 (Chem. Abs., 1969, 71, 50250t).Sukh Dev, Tetrahedron Letters, 1973, 427.J . Chem., 1973, 11, 86.1974, 3851.-'I (a) J .Alexander and G. S. Krishna Rao, Tetrahedron, 1971,27, 645; (b) V. Viswanatha and G. S. Krishna Rao, TetrahedronLetters, 1974, 243; ( c ) R. B. Mane and G. S. Krishna Rao, IndianJ.,Chem., 1974,12, 938; (d) G. Usha Devi and G. S. Krishna Rao,zbzd., 1976, 14B, 162. * K. Subrahmania Ayyar and G. S. Krishna Rao, PerfumeryEssent. Oil Record, 1968, 58, 1141977 35(5b) with alkaline perrnanganate followed by hydrolysisof the crude acetoxy-acid furnished (amp;)-sydowic acid(54, m.p. 144" (lit.,2 151" for the optically active naturalproduct), identical in i.r. and n.m.r. spectra with thenatural product. Though several other attempts tooxidise the aromatic methyl group of the acetoxy-compound (5b) by cerium(1v) ammonium nitrate,1deg;chromic acid,ll, l2 or neutral permanganate 13 provedunrewarding, side-chain halogenation with a large excessof N-bromosuccinimide l1 followed by refluxing withethanolic potassium hydroxide afforded, in comparableyield and purity, crystalline (amp;)-sydowic acid (5c),formed presumably by aerial oxidation of the aldehyderesulting from the dibromomethyl compound (5d).EXPERIMENTAL1.r. spectra were recorded on a Perkin-Elmer Infracord127 or Zeiss UR-10 instrument, U.V.spectra with a UnicamSP 700 spectrometer and n.m.r. spectra with a VarianHA-100D or T-60 instrument. Light petroleum refers tothe fraction with b.p. 40-60 "C. Solvent extracts wereappropriately washed and dried (Na,SO,) before evaporation.5-( 2-Hydroxy-4-methyl~henyl)-5-oxo~entanoic A cid (3a) .-To a mixture of m-cresol(43.2 g), glutaric anhydride (45.6 g),and tetrachloroethane (188 ml), aluminium chloride (1 12 g)was added in portions with stirring during 1 h.The mix-ture was then gradually heated on an oil-bath to 130 "C,maintained a t this temperature for 2 h, cooled, and pouredinto ice (500 g) and concentrated hydrochloric acid (200 ml) .The organic layer was separated and the aqueous phase wasextracted with chloroform (200 ml) . The combined organicphase was washed with water (200 ml) and extracted withsaturated sodium carbonate solution (5 x 100 ml). Afterbeing washed with ether (200 ml), the sodium carbonatesolution was acidified with concentrated hydrochloric acid.The precipitated yellow solid was crystallised from benzeneto give the pure oxo-acid (3a) (25 g), m.p.135" (Found: C,64.8; H, 6.6. C12H1404 requires C, 64.85; H, 6.35).Refluxing the oxo-acid (3a) (18.5 g) with methanol (150 ml)and concentrated sulphuric acid (3.5 ml) on a water-bath for10 h and work-up in the usual manner gave the methyl ester(3b) (12 g), m.p. 50" (from hexane), vmx. (Nujol) 1 739 (esterG O ) and 1639 cm-l (hydrogen-bonded ketonic GO),6 (CCl,) 2.05 (m, 3-H,), 2.33 (5 H, merged s and m, ArMe and2-H,), 3.02 (2 H, t, 4-H,), 3.65 (3 H, s, C02Me), 6.67 (2 H, d,aryl H-3 and -5), 7.63 (1 H, d, J 8 Hz, aryl H-6), and 12.1(1 H, s, OH) (Found: C, 66.05; H, 7.0. C13H1@, requiresC, 66.1; H, 6.85).2- (2-Hydroxy-4-methylphenyl) -6-methylheptune-2,6-diol (4).-To a suspension of Grignard reagent prepared from methyliodide (23 ml) and magnesium (8.5 g) in dry ether (250 ml)was added with stirring a solution of the phenolic oxo-ester(3b) (11.7 g) in dry ether (100 ml) during 3 h.The mixturewas then refluxed for 2 h, left overnight, and decomposedwith cold saturated ammonium chloride solution (300 ml) .The ether layer was separated and the aqueous layer wasextracted with ether ( 150 ml) . Removal of the solvent fromthe combined organic phase gave the phenolic diol (4) (12 g)as a white solid, m.p. 140" (from ethanol), vmax. (Nujol) 3 636A. I. Vogel, 'A Text Book of Practical Organic Chemistry,'Longmans, London, 1971, 3rd edn., p. 520.lo T. L. Ho, Synthesis, 1973, 347.(free OH) and 3 390 cm-1 (hydrogen-bonded OH), 6 (CD3),-COl.l0(6H,s,CMe,*OH), 1.60(3H,sl2-Me),2.22(3H,s,ArMe), 3.08br (1 H, s, OH, exchanges with D,O), 6.58 (2 H,m, aryl H-3 and -5), 6.98 (1 H, d, J 8 Hz, aryl H-6), and9.70 (1 H, s, phenolic OH, exchanges with D,O) (Found:C, 71.4; H, 9.5.C15H2403 requires C, 71.4; H, 9.6).5-Methyl-2-( 2,6,6-trimethyltetrahydro~y~un-2-yZ)phenol(5a).-Sulphuric acid (70 ; 50 ml) was added dropwise to thephenolic diol (4) (10 g) dissolved in distilled ether (300 ml)a t 0 "C. The mixture was stirred a t room temperature for7 h. The ether layer was separated and the aqueous phasewas extracted with ether (100 ml) . The combined etherealextract was washed until neutral and dried. Removal ofthe solvent gave a viscous liquid (8 g) which was purified bypassing twice through a silica gel column.Elution withbenzene gave.the phenolic tetruhydropyrun (5a) (5.0 g), b.p.120" a t 3 mmHg, v,, (CCl,) 3 300 cm-l, 6 (CCl,) 0.93 (3 H, s,Me), 1.32 (3 H, s, Me), 1.43 (3 H, s, Me), 1.20-1.87 (6 H, m,CH,), 2.25 (3 H, s, 5-Me), 6.40-6.87 (3 HI m, ArH), and8.63 (1 HI s, phenolic OH, exchanges with D,O) (Found:C, 77.05; HI 9.65. C15H2202 requires C, 76.9; H, 9.45).The phenol (5a) (5.0 g) was heated with acetic anhydride(50 ml) and pyridine (50 ml) on a boiling water-bath for10 h. The mixture was poured into hydrochloric acid(5; 250 ml). The product was extracted with ether(5 x 100 ml). The usual work-up followed by columnchromatography (silica gel; benzene) gave the acetats (5b)(4.9 g), b.p.138" at 3 mmHg, vmx. (neat) 1 776 cm-l (phenolicacetate), 6 (cc1,)0.75(3 H,s,Me), 1.13 (3H, s, Me), 1.48 (3H,s, Me), 1.33-1.83 (6 HI m, CH,), 2.20 (3 H, s, 5-Me or OAc),2.27 (3 H, s, 5-Me or OAc), 6.73 (2 HI m, aryl H-3 and -5),and 7.20 (1 H, d, J 8 Hz, aryl H-6) (Found: C, 73.95; H,8.75. Cl,H2403 requires C, 73.9; H, 8.7).( f )-Sydowic Acid 3-Hydroxy-4-( 2,6,6-trimethyltetmhydro-pyran-2-yZ)benzoic Acid (5c) .-(u) A mixture of the foregoingacetate (5b) (250 mg), potassium permanganate (1 g),sodium carbonate (125 mg), and water (20 ml) was refluxedfor 3 h, cooled, acidified with dilute sulphuric acid, andheated on a water-bath for 10 min. The manganese saltswere decolourised with sodium hydrogen sulphite. Theproduct was extracted with ether (150 ml).Removal ofsolvent gave the crude acetoxy-acid (120 mg), which washydrolysed with ethanolic potassium hydroxide (20 ; 10ml) by heating on a water-bath for 6 h. The usual work-upafter acidification gave (f)-sydowic acid (5c) (50 mg), m.p.144' (from ethyl acetate-hexane).(b) A mixture of the acetate (5b) (276 mg), carbon tetra-chloride (60 ml) , N-bromosuccinimide (1.05 g) , and a cataly-tic amount of benzoyl peroxide was heated on a water-bathfor 2 h, then cooled and the separated succinimide wasfiltered off. Removal of the solvent left the dibromomethylcompound (5d) (400 mg), 6 (CCl,-CDCl,) 0.59 (3 H, s, Me),0.98 (3 HI s, Me), 1.30 (3 H, s, Me), 1.3-1.85 (6 HI m, CH,),2.08 (3 HI s, OAc), 6.5 (1 HI s, Br,CH), and 7.1-7.54 (3 H,m, aryl H-3, -5, and -6) (Found: C, 47.4; HI 4.75. C,,H,,-Br,O, requires C, 47.0; H, 5.05).The dibromomethylcompound (5d) was refluxed (6 h) with ethanolic potassiumhydroxide (10; 25 ml). The usual work-up afteracidification gave (-J-)-sydowic acid (5c) (80 mg) identicalwith the above, m.p. 144' (from ethyl acetate-hexane),l1 H. Gilman, C. G. Brannen, and R. K. Ingham, J . Amer.l2 C. Enzell and H. Erdtman, Tetrahedron, 1958, 4, 361.l3 A. W. Singer and S. M. McElvain, Org. Synth., Coll. Vol. 111,Chem. SOC., 1956, 78, 1689.1955, p. 740J.C.S. Perkin Ivmx. (CHCl,) 4 000-3 200br (OH and CO,H) and 1 685 cm-1( G O of C0,H) (the spectrum of a KBr pellet agreed with thespectrum of the natural product), Amx. (EtOH) 238 (4 BOO)and 290 nm (E 1 800), 6 (CDCl,) 0.97 (3 H, s, Me), 1.30 (3 H,s, Me), 1.50 (3 H, s, Me), 1.5-1.93 and 2.27-2.56 (6 H, m,CH,), 7.12 (1 H, d, J 9 Hz, aryl H-6), 7.56 (2 H, m, arylH-3 and -5), 9.33 (1 H, s, OH or CO,H), and 10.38br (1 H, s,OH or C0,H) (identical with an authentic spectrum of thenatural product) (Found: C, 67.8; H, 7.4. C,,H,,O,requires C, 68.15; H, 7.65).We thank the Council of Scientific and Industrial Re-search, New Delhi, for a Senior Research Fellowship(P. R. V.), and Professor Hamasaki for the i.r. and n.m.r.spectra of (-)-sydowic acid.6/807 Received, 26th April, 1976