Syntheses of the naturally occurring naphtho2,3-bpyran-5,10-quinones alpha;-caryopterone, dihydro-alpha;-caryopterone, andO-methyldihydro-alpha;-caryopterone

摘要

1632 J.C.S. Perkin ISyntheses of the Naturally Occurring Naphtho[2,3-b]pyran-5,lO-quinonesa-Caryopterone, Di hydro-a-caryopterone, and 0- Methyldihydro-a-caryop-teroneBy Robin G. F. Giles * and Gregory H. P. Roos, Department of Organic Chemistry, University of Cape Town,South AfricaThe title compounds have been prepared by appropriate al kylation of 3-hydroxy-5-methoxy-1.4-naphthoquinone.obtained from the adduct (6) derived by addition of 1 -methoxycyclohexa-l,3-diene (4) to 2-methoxy-1.4-benzo-quinone (5).SEVERAL prenyljuglones have recently been discovered innature. These include a-caryopterone (1) ,2 dihydro-a-caryopterone (2),3 and the O-methyl derivative of thelatter, 9-methoxy-a-lapachone (3) .3 We describe herethe synthesis of these three compounds from S-hydroxy-5-methoxynaphthoquinone (lo), conveniently synthe-sised by regiospecific addition of l-methoxycyclohexa-1,3-diene (4) to 2-methoxy-l,4-benzoquinone (5).( 1 1 ( 2 ) R = H( 3 ) R = MeA Diels-Alder reaction between the diene (4) * andthe quinone (5) gave the adduct (6) in 60% yield; noneof the alternative adduct (7) was detected.This regio-specificity is in accord with the expectation that thepowerfully electron-donating methoxy-substituentsshould play a dominant role in determining the favouredtransition state.l Structure (6) was assigned to theadduct since it could be converted into the known63,5-diacetoxy-l,4-naphthoquinone. This was accom-plished by enolisation of the adduct (6) with potassiumt-butoxide in tetrahydrofuran followed by oxidation ofthe resulting crude quinol to the quinone (8).This waspyrolysed with loss of ethylene to form the naphtho-quinone (9). The quinonoid methoxy-group of thiscompound was hydrolysed by treatment with aqueousbase; the aromatic methoxy-group was removed fromthe product (10) with boron tribromide and the deriveddihydroxy-compound (1 1) was acetylated with pyridinePreliminary communication, R. G. F. Giles and G. H. P.Roos, Tetrahedron Letters, 1975, 4159.T . Matsumoto, C. Mayer, and C. H. Eugster, Helv. Chim.Acta, 1969, 52, 808.and acetic anhydride. The m.p. (136") of the diacetateshowed it to be 3,5-diacetoxy-lJ4-naphthoquinone (12)(lit.,6 m.p. 137") rather than its 2,5-isomer (lit.,6 m.p.152").( 4 1 ( 5 )OMe0(71@OR* 0Two routes were0(6)U@OM@ 0(8)(9) R'= R 2 = Me(10) R' = Me, R2 =H(11) R'= R ~ = H(12) R' = R 2 = COMe(18) R' = Me, R2 = COMeestablished to the prenylatedquinones from 3-hydroxy-5-methoxy-1,4-naphtho-quinone (10) ; one afforded a-caryopterone and the otherthe dihydro-analogues (2) and (3).In the former case,the quinone (10) was subjected to a Hooker reaction withisovaleraldehyde in acetic acid. The product (13) wasoxidatively cyclised by stirring at room temperaturewith 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)in benzene, from which the naphthopyranquinone (14)Bull. (Japan), 1975, 23, 384.3 H. Inouye, T. Okuda, and T. Hayashi, Chern. and Pharm.* A. J. Birch and K. P. Dastur, J.C.S. Perkin I , 1973, 1650.J. A.D. Jeffreys, J . Chem. Soc., 1959, 2153.6 R. H. Thomson, J . Ovg. Chem., 1948, 13, 8701976 1633and the naphthofuranquinone (15) could be isolated inyields of 47 and 8%, respectively. In addition, a deeppurple product, thought to be the ortho-quinone (16)(28%), was obtained but not characterised because of itsready conversion into the quinone (14) on warming withethanol containing concentrated hydrochloric acid. Theformation of compounds (14) and (16) can be rationalisedin terms of cyclisation of the intermediate (17);' ringclosure of (13) followed by oxidation would afford theproduct (15). When treated with boron tribromide inmethylene chloride, the quinone (14) underwent de-methylation to yield a-caryopterone, identical with thenatural product.The route to the lapachones involved initial acetyl-ation of 3-hydroxy-5-methoxy-1,4-naphthoquinone (10).The derived acetate (18) was alkylated at the freequinonoid position with 4-methylpent-3-enoic acid inthe presence of silver nitrate and ammonium peroxo-clisulphate to afford the prenylated product (19), which,upon hydrolysis with aqueous sodium carbonate, gavethe methoxylapachol(20), isomeric with the product (13)of the Hooker reaction.Cyclisation of the quinone (20) with hydrochloric acidin acetic acid yielded a mixture of the a- and p-methoxy-lapachones, (3) and (21), respectively. These werereadily separable by column chromatography, and couldbe distinguished by their different colours and i.r.spectra.The former was identical with a sample ofnaturally occurring 9-methoxy-a-lapachone,3 and the00 I(17)physical properties of and spectral data for the lattercorresponded with those reported for O-methyldihydro-p-caryopterone, obtained by Eugster by reduction,treatment with concentrated sulphuric acid, and methyl-ation of naturally occurring a-caryopterone. This p-formK. H. Dudley and R. W. Chiang, J . Oyg. Chem., 1969, 34,130.(21) was readily isomerised to the a-lapachone (3) withconcentrated hydrochloric acid in ethanol. Interest-ingly, attempted demethylation of the methyl ether (3)with boron trichloride effected its reverse transformationinto the p-form (21). However, treatment of themethyl ether (3) with boron tribromide in methylenechloride at room temperature gave rise to dihydro-a-caryopterone (2), identical with the natural product .30 nU(19) R = COMe (21)( 2 0 ) R = H0(22)Under more vigorous conditions with an excess ofboron tribromide, a second product (22), in addition todihydro-a-caryopterone, was isolated in which thearomatic nucleus had undergone bromination.Theposition of bromination was indicated by its n.m.r.spectrum, which included two aromatic doublets atT 2.16 and 2.53 (J 8 Hz).We were unable to convert 9-methoxy-a-lapachone(3) into O-methyl-cc-caryopterone by heating underreflux in dioxan in the presence of DDQ, a procedurewhich has been successfuls for the conversion of a-lapachone to dehydro- a-lapachone. However, t reat -ment of the methoxylapachol (20) with DDQ at roomtemperature in benzene afforded a mixture of quinones(14) and (l6), which were separated.Crude (16) wasconverted into compound (14) wih ethanolic hydro-chloric acid as before. This oxidative cyclisation pre-sumably proceeds via the same intermediate (17) asthought to be implicated in the oxidation of the quinone(20) -EXPERIMENTALUnless otherwise stated i.r. spectra were measured forsolutions in carbon tetrachloride and n.m.r. spectra forsolutions in [2H]chloroform with tetramethylsilane asinternal reference. N.m.r. spectra were recorded at 100MHz with a Varian XL-100 spectrometer. Unless other-wise stated chromatography was carried out on dry columnswith Merclr Kieselgel 60 (70-230 mesh).Light petroleumrefers to the fraction of b.p. 60-80".1,4,4a, 8a-Tetrahydvo- 1,7-dimethoxy- 1,4-ethanona$hthalene-5,S-dione (6).-The diene (4) (6.4 g) (containing ca. 20% of8 A. R. Burnett and R. H. Thomson, J . Chewz. SOC. ( C ) , 196712611634 J.C.S. Perkin Ithe isomeric 1,4-diene,4 as deterniined by n.m.r. spectro-scopy) was heated under reflux in benzene (100 ml) con-taining the methoxy-l,4-benzoquinone ( 5 ) (3 g) for 1.5 h,at which stage all the quinone had been consumed, Thesolvent was evaporated off and the residue chromato-graphed over a short dry column of neutral alumina (Merck)with benzene as eluant, to give the product, m.p. 117-119"(from benzene-light petroleum) (3.2 g; 60% based onquinone) (Found: C, 67.7; H, 6.6.C14H1604 requires C,67.8; H, 6.4y0), v,,,. (Nujol) 1691, 1650, and 1612 cm-l,s, 6-H), 6.27 (3 H, s, OCH,), 6.55 (3 H, s, OCH,), 6.67 (1 H,d, J 8 Hz, 8a-H), 6.88 (1 H, m, 4-H), 6.96 (1 H, dd, J 8and 3 Hz, 4a-H), and 7.9-8.5 (4 H, m, CH,CH,).quinone (8).-The adduct (6) (1.0 g) in dry tetrahydrofuran(40 ml) was stirred with an excess of potassium t-butoxide(1.2 g) for 40 min. Water was added, followed by dilutehydrochloric acid until the solution was weakly acidic.The solution was extracted with ether; the extract wasdried (Na,SO,), and silver(1) oxide (3 g) was added. Themixture was stirred for 3.5 h, filtered, and evaporated toyield the orange quinone, m.p. 118-1 18.5" (from benzene-light petroleum) (1.0 g, 100%) (Found: C, 68.4; H, 5.9.C14H1,04 requires C, 68.3; H, 5.7%), v,,, (Nujol) 1671,1640, 1 611, and 1 579 cm-l, T 3.43 (1 H, dd, J 8 and 1 Hz,2-H), 3.67 (1 €3, dd, J 8 and 6 Hz, 3-H), 4.23 (1 H, s,quinone H ) , 5.7 (1 H, m, bridgehead H), 6.19 (3 H, s,OCH,), 6.38 (3 H, s, OCH,), and 8.0-8.8 (4 H, m, CH,CH,).2,8-Dirnethoxy- 1,Pnaphthoquinoute (9) .-The quinone (8)(0.31 g), was heated at 120 "C and 8 mmHg under whichconditions bubbling occurred as ethylene was eliminated.When bubbling ceased, sublimation at 140 "C (bath) and0.5 mmHg afforded the light yellow product (0.27 g, 98yo),m.p.202-202.5" (from methanol) (lit.,% 195") (Found: C,66.0; H, 4.6. Calc. for C1,H1004: C, 66.1; H, 4.6y0),Y,,,~. (Nujol) 1 674, 1 642, 1612, and 1 589 crn-l; z 2.2-2.5(2 H, m, 5- and 6-H), 2.75 (1 H, dd, J 2 and 7 Hz, 7-H),3.93 (1 H, s, quinonoid H), 6.00 (3 H, s, OCH,), and 6.12(3 H, s, OCH,).2-Hydroxy-8-unethoxy-l,4-na$hthoquinone ( 10) .-Thenaphthoquinone (9) (1.00 g) was stirred with aqueous 1%base (20 ml) until it had dissolved.The solution waswashed with ether and acidified with dilute hydrochloricacid. This was extracted with chloroform, and the extractwas dried and evaporated to give the known quinone,m.p. 209-211" (decomp.) [1it.,l1 211" (decomp.)] (0.86 g,92%), T 2.18-2.40 (2 H , m, 5- and 6-H), 2.73 (1 H, dd,J 2 and 7 Hz, 7-H), 3.72 (1 H, s, quinonoid H), and 5.95(3 H, s, OCH,).2,8-Diacetoxy- 1,4-naphthoquinone (12) .-The quinone (10)(0.17 g) in dry methylene chloride was treated at -78 "Cwith an excess of boron tribromide (1 g) in the same solvent.The solution was allowed to warm to room temperature andthen hydrolysed with water, extracted with ether, and re-extracted with aqueous potassium hydroxide.This aqueouslayer was finally acidified and extracted with ether, andthe extract was dried and evaporated. The crude di-hydroxyquinone so formed (0.15 g) was acetylated (pyridine-acetic anhydride) to yield the diacetate, which was purifiedover a short silica gel column (ethyl acetate-chloroform,4 : 1). This gave pale yellow crystals, m.p. 136" (lit.,6* G. R. Birchall and A. 13. Rees, Canad. J . CJtem., 1974, 52,7 3.83 (1 H, d, J 2 Hz, 2-H), 3.87 (1 H, S, 3-H), 4.12 (1 H,1,4-Dihydro- 1,7-diunethoxy- 1,4-ethanonaPhthalene-5,8-137") (0.09 g, 42%), 7 1.95 (1 H, d, J 8 Hz, 5-H), 2.25610.(1 H, t, J 8 Hz, 6-H), 2.63 (1 H, d, J 8 Hz, 7-H), 3.25 (1 H,s, quinonoid H), 7.56 (3 H, s, COCH,), and 7.62 (3 H, s,COCH,).3-Hydroxy-5-methoxy-2-( 3-methylbut- l-enyl) - 1,4-naPhtho-quinone (13).-The quinone (10) (0.40 g) in hot (80 "C)glacial acetic acid (10 ml) was treated with concentratedhydrochloric acid (1 ml), followed immediateIy by iso-valeraldehyde (1.25 ml).The dark solution was heatedunder gentle reflux for 1 h, then thrown into water (200 ml)and extracted with chloroform. The organic layer wasdried and evaporated and the residue chromatographed overa short silica gel column with methylene chloride as eluant.This yielded the orange product, which was sublimed at150 "C (bath) and 1.2 mmHg; m.p.179.5-180" (0.45 g,86%) (Found: C, 70.7; H, 6.0. Cl6Hl6O4 requires C, 70.6;H, 5.9y0), wmax. 3 320, 1 736, 1 658, 1618, and 1584 cni-l,T 2.14-2.44 (2 H, m, 6- and 7-H), 2.79 (1 H, dd, J 2 and8 Hz, 8-H), 3.02 (1 H, dd, J 7 and 16 Hz, 2'-H), 3.48 (1 H,d, J 16 Hz, 1'-H), 5.98 (3 H, s, OCH,), 7.47 (1 H, octet,J 7 Hz, 3'-H), and 8.89 (6 H, d, J 7 Hz, CH,).9-Methoxy-2,2-dinzethyZnaphtho [2,3-bJpyran-5,10-quinone(14) and 2-Isopropyl-8-rnethoxynaplztho[2,3-b] furan-4,9-quinone (15).-The quinone (13) (300 mg) in benzene (50 ml)was added to a solution of DDQ (300 m g ) in benzene (100ml). This was stirred at room temperature overnight.The precipitate (H,DDQ) was filtered off and washed withbenzene. The solution was evaporated and the residuechromatographed (eluant methylene chloride).A paleyellow band afforded the naphthofuranquinone (15), whichwas sublimed [150 "C (bath) and 2.2 mmHg]; m.p. 157-158.5" (25 mg, 8%) (Found: C, 71.1; H, 5.2. C16H1,04requires C, 71.1; H, 5.20/,), vnlau. 1 726 and 1 668 cm-l,T 2.10-2.56 (2 H, m, 6- and 7-H), 2.72 (1 H, dd, J 2and 8 Hz, 8-H), 3.49 (1 H, s, 3-H), 5.99 (3 H, s, OCH,),6.90 (1 H, septet, J 7 Hz, CHMe,), and 8.65 (6 H, d, J 7 Hz,CH,) . An orange-yellow band gave the naphthopyran-quinone (14), which was sublimed [150 "C (bath) and2 mmHg], m.p. 132-134" (140 mg, 47%) (Found: C, 71.1;H, 5.6. C16H1404 requires C, 71.1; H, 5.2%), vmE 1 727,1677, 1 650, and 1 636 cm-l, T 2.18-2.50 (2 H, m, 6- and7-H), 2.78 (1 H, dd, J 2 and 8 Hz, 7-H), 3.39 (1 H, d,OCH,), and 8.46 (6 H, s, CH,).Further fractions affordeda red crystalline material, assumed to be the ortho-quinone(16) (85 mg, 280/), which was converted into the quinone(14) with concentrated hydrochloric acid (1 ml) in ethanol(10 nil) on warming on a water-bath.a-Caryopterone (9-Hydroxy-2,2-dimethylnaphtho[2,3-b]-pyran-5,lO-quinone) ( 1) .-The quinone (14) (300 mg) inmethylene chloride (5 rnl) was treated a t -78 "C with anexcess of boron tribromide (500 mg) in inethylene chloride(10 ml). Work-up as described before afforded crudematerial which was chromatographed (methylene chloride).This gave a-caryopterone (160 mg, 55y0), which was re-crystallised from toluene-light petroleum. A sampleobtained by p.1.c.with 10% ethyl acetate-light petroleumhad m.p. and mixed m.p. 170-172" (decomp.), withdarkening a t 143" [lit.,l 143.5-145" (decomp.)] (Found:C, 70.2; H, 5.0. C1,H1,04 requires C, 70.3; H, 4.7%),identical (i.r. and n.m.r. spectra and t.1.c.) with the naturalmaterial.J 9 Hz, 3-H), 4.35 (1 H, d, J 9 Hz, 4-H), 6.01 (3 H, S,lo A. C . Baillie and R. H. Thomson, J . Chtenz. Soc. (C), 1966,l1 J. W. MacLeod and R. H. Thomson, J . Org. Chew., 1960,25,2184.361976 16353-A cetoxy- 5-methoxy-2- (3-methylbut-2-enyl) - 1,4-naPhtho-quinone (19) .-The quinone (10) (0.96 g) was acetylated withacetic anhydride ( 5 ml) containing concentrated sulphuricacid (0.2 ml) to give 2-acetoxy-~-methoxy-l,4-naphtho-quinone (0.65 g, 53%), T 2.2-2.5 (2 H, m, 5- and 6-H),2.6-2.8 ( 1 H, m, 7-H), 3.36 (1 H, s, quinonoid H), 6.01(1 H, s, OCH,), and 7.62 (3 H, s, COCH,).Because of itsready hydrolysis, the crude acetate was alkylated directlywith 4-methylpent-3-enoic acid (0.30 g) and silver nitrate(0.30 g) in acetonitrile (12 ml) and water (15 ml), to whichwas added a solution of ammonium peroxodisulphate(1.2 g) in water (10 ml) at 60-65 "C with vigorous stirringover 1 h. The mixture was neutralised with solid sodiumhydrogen carbonate and extracted with ether, and theorganic layer was dried and evaporated. The residue waseluted through a short silica gel column with methylenechloride to give the quinone (0.65 g, 75%). A sampleprepared by p.1.c. with methylene chloride had m.p. 103-104" (Found: C, 68.8; H, 5.9.C,,H,,O, requires C, 68.8;H, 5.7%), vmx. 1 785, 1 727, 1 675, and 1 650 cm-l, T 2.16-2.50 (2 H, m, 7- and 8-H), 2.66-2.83 (1 H, m, 6-H), 4.92(1 H, t, J 8 Hz, 2'-H), 6.02 (3 H, s, OCH,), 6.76 (2 H, d,J 8 Hz, CH,), 7.62 (3 H, s, COCH,), 8.25 (3 H, s, CH,),and 8.32 (3 H, s, CH,).3-Hydroxy-5-unethoxy-2- (3-methylbut-2-enyl) - 1,4-naphtho-quinone (20).-The acetate (19) (0.65 g) was heated undergentle reflux with hi-sodium carbonate (50 ml) until allmaterial was dissolved. The solution was cooled in ice,acidified with concentrated hydrochloric acid, and extractedwith methylene chloride. The organic layer was dried andevaporated and the residue chromatographed over a shortsilica gel column with methylene ehloride. A small quantityof starting material was eluted first, followed by the product(0.25 g, 55% based on starting material consumed).Thiswas sublimed [130 "C (bath) and 1.3 mmHgJ; m.p. 155.5-156.5" (Found: C, 70.8; H, 6.1. C16H1604 requires C,70.6; H, 5.9%), vmx. 3 360, 1 728, and 1 653 cm-1, T 2.1-2.5 (2 H, m, 7- and 8-H), 2.79 (1 HI dd, J 2 and 8 Hz,6-H), 4.79 ( 1 H, t, J 8 Hz, 2'-H), 5.98 (3 H, s, OCH,), 6.72(2 H, d, J 8 Hz, CH,), 8.21 (3 H, s, CH,), and 8.31 (3 H, s,O-Methyldihydro-a-caryopterone (3,4-Dihydro-9-methoxy-2,2-dimethylnaphtho[2,3-b]pyran-5,10-quinone) (3) and 3,4-Dihydro- 7-methoxy-2,2-dimethylnafihtho[ 1 , 2-b]pyran-5,6-quinone (21).-The quinone (20) (210 mg) in acetic acid(5 ml) and concentrated hydrochloric acid (0.75 ml) washeated on a water-bath for 75 min.The solution wascooled, water was gradually added, and the whole wasextracted with methylene chloride. The organic layer wasdried and evaporated, and the residue was chromatographed(methylene chloride) to give starting material (4 mg),followed by the quinone (3) (101 mg, 49%), which wassublimed [150-155 "C (bath) and 1.8 mmHg], m.p. andmixed m.p. 165-167" (lit.,, 168-169") (Found: C, 70.5;H, 6.0. C16H1604 requires C, 70.6; H, 5.9%), vmaX. (CHCI,)1 671, 1 640, 1 623, and 1 587 cm-l, T 2.22-2.54 (2 H, m,6- and 7-H), 2.82 (1 H, dd, J 2 and 8 Hz, 8-H), 6.04 (3 H,CHd.s, OCH,), 7.43 (2 H, t, J 7 Hz, 4-H,), 8.20 (2 H, t, J 7 Hz,3-H,), and 8.59 (6 H, s, CH,). The synthetic and naturalmaterials had the same RF value on t.1.c.A third bandafforded the ortho-quinone (21) (100 mg, 49'7"), m.p. 160-161" (lit.,, 162-163"). The i.r. and n.m.r. data areidentical with those recorded., The quinone (21) wasquantitatively converted into the quinone (3) by treatmentwith concentrated hydrochloric acid in hot ethanol.Dihydro-a-caryopterone (3,4-DiJzydro-9-Jtydroxy-2,2-dimethyZnuphtho[2,3-b]pyran-5,10-quinone) (2) .-(a) Thequinone (3) (30 mg) in dry niethylene chloride (10 ml) wastreated at -78 "C with boron tribromide (1.5 mol. equiv.)in the same solvent (10 ml). This was allowed to warm toroom temperature and was stirred overnight. Water wascautiously added, and the solution extracted with chloro-form. The contents of the organic layer were purified byp.1.c. (benzene), affording the product (2) (17 mg, BOY0),which was sublimed [loo-110 "C (bath) and 2.7 mmHg],m.p.119", mixed m.p. 119-120" (lit.,, 120-122" )(Found:C, 69.45; H, 5.6. C,,H,,O, requires C, 69.75; H, 5.45%).The synthetic and natural materials had the same RFvalues, and an n.m.r. spectrum consistent with thatreported.(b) In an initial experiment designed to afford the aboveproduct, the quinone (3) was treated with an excess (3 mol.equiv.) of boron tribromide at room temperature inmethylene chloride and the solution was heated underreflux for 20 min. Work-up and p.1.c. as above yielded, inaddition to (2), a preponderance of 8-bromo-3,4-dihydvo-9-hydroxy-2,2-dimethylnaphtho [ 2,3-b]pyran-5,1 O-quinone,which had the higher RF value. This was sublimed [145-150 OC (bath) and 4 mmHg], m.p. 180-181" (Found: C,54.0; H, 4.2. C,,H,,BrO, requires C, 53.45; H, 3.9y0),T -2.48 (1 H, S , OH), 2.16 (1 H, d, J 8 Hz, 6-H), 2.53( 1 H, d, J 8 Hz, 7-H), 7.38 (2 H, t, J 7 Hz, 4-H,), 8.18 (2 H,t, J 7 Hz, 3-H,), and 8.56 (6 H, s, CH,).9-Methoxy-2,2-dimethylnaphtlao [2,3-b]pyvan-5,1 O-quinone(14).-The quinone (20) (175 mg) and DDQ (215 mg) werestirred together in benzene (100 ml) at room temperaturefor 5 h. The precipitate (H,DDQ) was filtered off andwashed with benzene and the solution evaporated. Theresidue was chromatographed (methylene chloride) to affordstarting material (10 mg), followed by the quinone (14)(60 mg), identical with that obtained from compound (13).A final band gave rise to compound (16) which could beconverted into the quinone (14) as described earlier.Financial support from the Council of the University ofCape Town and the Council for Scientific and IndustrialResearch is gratefully acknowledged. We thank ProfessorC. F. Garbers, University of Stellenbosch, for a gift of4-methylpent-3-enoic acid, Professor C . H. Eugster,Zurich University, for a sample of natural a-caryopterone,Professor H. Inouye, Kyoto University, for samples ofnatural dihydro-a-caryopterone and its methyl ether, andMiss S. Jackson for technical assistance.[5/2493 Received, 221td Decewibev, 1975