An approach to the synthesis of fujenoic acid

摘要

206 J.C.S. Perkin IAn Approach to the Synthesis of Fujenoic AcidBy Tadahiro Kato,' Takeshi Suzuki, Noboru Ototani, Hideo Maeda, Kenichi Yarnada, and (the late)Yoshio Kitahara, Department of Chemistry, Faculty of Science, Tohoku University, Sendai 980, JapanIn experiments directed towards the total synthesis of fujenoic acid (1). the 2-(2-furyl)-6-oxobicyclo3.2.1octane-1 -carboxylate (3b) was prepared as a key intermediate. The furyl group was designed to be transformed into ringA of fujenoic acid. In investigations of the transformation route, model compounds (the stereoisomeric dimethyl1 -methyl-7-oxabicyclo2.2.1 heptane-2.3-dicarboxylates (4). (5). and (1 2)) were examined, and it was foundthat diester (1 2) could be effectively converted into dimethyl 1.3-dimethyl-6-oxocyclohex-3-ene-l.2-dicarboxylate(18), which corresponds to ring A of fujenoic acid.The key intermediate (3b) was obtained by a Dieckmanncondensation of dimethyl 6-(2-furyl) -1 -methoxycarbonylmethylcyclohexane-l,3-dicarboxylate (23).FROM extracts of culture filtrates of Gibberella fujikzcroi,Cross and his co-workers isolated fujenoic acid and fujenaland characterized these two metabolites as the tricarbo-cyclic diterpenes (1) and (2), possessing a B-secokaur-ane skeleton. Structures (1) and (2) can each be regardedeasily without formation of any methylated product.We therefore attempted to obtain the oxo-ester (8) fromthe acetate (6) , the latter being obtainable quantitativelyby treatment of the adduct (4) with acetic toluene-p-sulphonic anh~dride.~Several attempts to hydrolyse the acetate group of (6)0 were, however, unsuccessful.For example, treatment eCH2 0-p with various kinds of base resulted in elimination ofdOzRMe 'PoCO 2Me0 i r o(1) X = CO2H( 2 ) X = CHO( 3 ) a; R = Hb; R = M eas composed of two parts, i.e. ring A and rings c and D.We have prepared the furyl compound (3) as a keyintermediate in an attempt to synthesise these diter-penoids, be derived We from hoped the furyl that group a functionalized by Diels-Alder ring A reaction might q M 'J-J a' C02MeCOzH COzMe CO ,Me AcO ''*with a suitably substituted dienophile.Model Ex+eriments for Ring A Construction.-We have C02Mepreviously reported a preliminary model experiment 0for the construction of ring A of fujenoic acid, using the ( 7 ) (81 (917-oxabicyclo2.2.lheptane derivatives (4) and 45), andhave demonstrated that the ether linkage is easily cleavedby boron trifluoride-ether in acetic anhydride, giving thecorresponding acetates (6) and (7) in 40 and 70 yields,respectively.The model compound (4) was obtainablefrom methylfuran by a Diels-Alder reaction with maleicanhydride, followed by hydrogenation and esterification.group at C-4 (kaurane numbering) we have performeddirect methylation at C-4 of structure (4) with methyliodide were unsuccessful under basic conditions LiNPr*, .acetic acid to give a mixture of amp;esters (9) and (10). Onor LiN(Pri)C,H,,: epimerization at C-4 took place the other hand, the lactone (11) was formed quantita-(a) B.E. Cross, R. H. B. Galt, J. R. Hanson, P. J. Curtis, * Y. Kitahara, T. Kato, N. Ototani, A. Inoue, and H. Izumi,J. F. Grove, and A. Morrison, J. Chem. SOC., 1963, 2937. (b) J . Clzem. SOC. (C), 1968, 2508.B. E. Cross, R. H. B. Galt, and J. R. Hanson, ibid., p. 6052. Y. Mazur and M. H. Karger, J. Org. Chem., 1971, 86, 540.@ 0"' / C02MeC02MeIn order to find conditions for introducing a methyl 0COzMefurther model experiments. Our first attempts at (10) (11 1977 207tively from (6) under acidic conditions. Since lactoniz-ation was apparently favoured by the cisrelationshipof the C-5 methoxycarbonyl group with the acetategroup, the isomeric diester acetate (14) was thenprepared and submitted t o hydrolysis in the hopeof avoiding lactonization.The Diels-Alder adduct(11) R = AC(15) R = H(16) (17) (18)(13), obtained quantitatively by the reaction ofmethylfuran with dimet h yl acet ylenedicarboxylate,and the long-range W-type coupling (1.5 Hz) betweenthe C 4 proton and one of the C-2 protons indicate theassigned stereo-structure (12).Treatment of (12) with acetic toluene-9-sulphonicanhydride afforded the dimethyl cyclohexenedicarboxyl-ate (14) in quantitative yield. As expected in this case,the acetyl group of (14) was easily removed by methanolichydrochloric acid to give the alcohol (15), in 90 yield.Oxidation of (15) with chromic oxide-pyridine complexand chromatography on silica afforded a mixture of enols(16) and (17), in 60 and 30 yield, respectively.Thelatter could be converted into the former in Myo yield byBirch reduction with lithium in liquid ammonia. Thephenolic diester (17) was also obtained quantitativelywhen the adduct (13) was treated with sulphuric acid indichloromethane.The appearance of a one-proton signal at 6 12.42 in thelH n.m.r. spectrum of (16) revealed that it existed pre-dominantly in the enol form. Introduction of a methylgroup at C-4 was achieved with methyl iodide in thepresence of potassium t-butoxide in t-butyl alcohol,giving compound (18) in 70 yield.This model experiment implies that the furyl group ofil .b c ~ o ~ L C 0 2 M e M eO2 C f p C02Melsquo;C0,Me(20)I V-0( 2 1 ) ( 2 2 ) ( 2 5 ) (26)+ I VL0C02 Me(23) (24) (27) (3blf = 2 - f u r y lv i , v i iSCHEME Reagents: i, AcOMe-Na; ii, methyl itaconate, 160 ldquo;C; iii, H,, Pd-C; iv, ButOK; v, Lil-C,H,N; vi, KOH; vii, CH,N,was catalytically reduced to give the endo,cis- the intermediate (3) might be convertible into ring A ofdiester (12).The stereochemistry of (12) was confirmed fujenoic acid although the stereochemistry at C-4 withby its 1H n.m.r. spectrum, in which the C-4 and C-3 respect to the C-5 methoxycarbonyl group remainsproton signals appeared at 6 3.23 (ddd, J4,5 12, J2,4 1.5, undefined at this stage.J3,4 6 Hz) and 4.50 (t, J3,4 = J2,3 = 6 Hz), respectively. Synthesis of the Key Intermediate (3).-By applicationThe 6 Hz coupling between the C-4 and C-3 protons of a method analogous to that developed by Bake208 J.C.S.Perkin Iand G ~ u d i e , ~ the intermediate (3) was synthesized asshown in the Scheme. Condensation of 3-(2-furyl)-acrylaldehyde with methyl acetate gave methyl 4-fur-furylidenecrotonate (19),5 which was subjected to aDiels-Alder reaction with dimethyl itaconate to affordthe adduct (20). The n.m.r. spectrum indicates that theadduct is a stereoisomeric mixture with respect to thefuryl and neighbouring methoxycarbonyl groups. Themixture was catalytically reduced and separated bysilica gel column chromatography to obtain twostereoisomeric triesters, (21) and (23), in 31 and 32yield, respectively. The relative stereochemistry of thetriesters was determined as follows. Treatment of thetriester (23) with potassium t-butoxide in refluxingxylene resulted in a mixture of the bicyclic oxo-ester (27),the epimerized triester (24), and unchanged (23), whichwere isolated in 11, 19, and 8 yield, respectively.Theepimerized triester (24) was formed selectively from thebicyclic oxo-ester (27) by fission of the five-memberedring with potassium hydroxide followed by esterificationwith diazomethane. These results show that the triester(23) has a trans-relationship between the C-1 CH,CO,Meand C-3 C0,Me groups.Similarly, the triester (21) was converted by potassiumt-butoxide into a mixture of the bicyclic oxo-ester (25),unchanged (21), and the epimerized triester (22), whichwere isolated in 18, 11, and 5 yields, respectively.The half-height widths of the C-3 proton signals in then.m.r.spectra of the four isomeric triesters indicated thatthese protons in the triesters (21) (Wi 18 Hz) and (24)(Wi 16 Hz) are axial, whereas those in the isomers (22)(W, 10 Hz) and (23) (W, 6 Hz) have the equatorialconfiguration. If we assume that the cyclohexane ringis in the chair conformation, and the furyl group isattached equatorially, the stereochemistry of theseisomers is as depicted in the Scheme.The Dieckmann condensation products (25) and (27),obtainable in 56 and 52 yield by an improved methodwere treated with lithium iodide in hot pyridine to givethe correspollding demethoxycarbonylated products (26)and (3b) in good yields. The lH n.m.r spectra of (26)and (3b) in the presence of a shift reagent supported theassigned stereostructure.6(28)Although the sequential reactions shown in the Schemeare not stereoselective, the key intermediate (3b) couldbe thus synthesized in relatively few steps.By applic-ation of Diels-Alder reactions to the furan ring of (3b)* A. J. Baker and A. C. Goudie, Chem. Comm., 1971, 180.T. Shono, K. Mishina, and Y. Yahama, Kogyo KugukuZusshi, 1964, 57, 769.and subsequent reactions, a demethylfujenoic acidderivative (28) has been synthesized.'EXPERIMENTALM.p.s were measured with a Thomas-Hoover capillaryapparatus. 1.r. spectra were recorded with a Hitachi 215grating spectrophotometer, n.m.r. spectra with a VarianT-60 or HA-100 instrument with deuteriochloroform orcarbon tetrachloride as solvent and tetramethylsilane asinternal standard, and mass spectra with a Hitachi RMU-6Dspectrometer.Dimethyl 1 -Methyl- 7-oxabicycZo r2.2.13 heptans-2-endo,3-endo-dicarboxylate ( 12) .-A mixture of 2-methylfuran (8.2 g)and dimethyl acetylenedicarboxylate ( 14.2 g) was heated at110 "C for 5 h in a sealed tube.The resulting adduct (13)(22.2 g ) was, without purification, dissolved in methanol(200 ml) containing 5 palladium-carbon (1 g) and wasshaken under hydrogen (uptake 3.6 1). Filtration, evapor-ation, and distillation of the residual oil gave the oily endo,-cis-diester (12) (14.6 g ) , b.p. 102-106 "C a t 1 mmHg,6 (CCl,) 1.46 (Me x l), 1.63 (Me x 2), 2.77 (dd, J 12 and2 Hz, 2-H), 3.23 (ddd, J 12, 6, and 1.5 Hz, 3-H), and 4.50(t, J 6 Hz, 4-H) (Found: C, 57.4; H, 7.3.C,,H,,O,requires C, 57.9; H, 7.1).Cleavage of the 7-0xabicyclo2.2. llheptane Derivatives (4)and (12).-To a stirred mixture of the exo,cis-diester (4)(5.0 g) and acetonitrile (20 ml) was added acetic toluene-p-sulphonic anhydride (5.0 g ) and stirring was continuedovernight a t room temperature. The mixture was dilutedwith ether and the ethereal solution washed with aqueoussodium hydrogen carbonate and then water, and evaporated.The residue was passed through a short silica gel column toobtain the oily dimethyl c-6-acetoxy-3-methyZcycZohex-3-ene-r-l,c-2-dicarboxyZate (6) (5.8 g), m/e 270 (M'), 6 (CDCI,) 1.88(3 H, dd, J 3.7 and 2.0 Hz), 1.95, 3.68, and 3.73 (each 3 H, s),2.94 (1 H, dd, J 6 and 2 Hz), 3.50br (1 H, d, J 6.0 Hz), and5.50 (2 H, m) (Found: C, 57.3; H, 6.8.Cl,Hl8O6 requiresC, 57.8; H, 6.7).Similarly, the oily t-6-acetoxy-r- 1 ,~-2-dicarboxyZate (14)(1.60 g ) was obtained from the eizdo,cis-diester (12) (1.24 g);m/e 270 (M'), 6 (CCl,) 1.72 (Me x l), 3.68 (Me x 2), 1.93(OAc), 2.87 (dd, J 11 and 6 Hz, 1-H), 3.36 (d, J 6 Hz, 2-H),and 5.40 (m, 4- and 5-H).A ttempted Hydrolysis of the Acetate (6) .-(A ) A mixture ofthe acetate (6) (42 mg), dioxan (0.5 ml), water (0.5 ml), andsodium hydrogen carbonate (50 mg) was stirred at roomtemperature overnight. Extraction with ether afforded thediester (9) as the sole product. Reaction of the acetate (6)with sodium acetate in methanol at 60 "C also gave (9) as thesole product. Dimethyl 6-methyEcyclol~exa-2,5-dime- 1,2-di-carboxylate (9) was an oil, m/e 210 (M'), vmax.(film) 1 732 and1714 cm-l, 6 (CCl,) 1.79 (3 H, dd, J 2 and 3 Hz), 3.60 and3.68 (each 3 H, s), 5.50 (m, 5-H), and 7.05 (t, J 4 Hz, 3-H).( B ) To a solution in methanol (10 ml) of the acetate (6)(1 17 mg) was added one drop of 1 2~-hydrochloric acid, andthe mixture was stirred a t room temperature for 5 days.Extraction with ether and work-up gave 2-methoxycarbonyl-6-methylcyclohex-5-ene- 1,3-carbolactone (1 1) as the soleproduct, m.p. 79-80", Y,,,. (KBr) 1 7 7 3 and 1 748 cm-l, 6(CCl,) 1.85 (3 H, dd, J 2 and 3.9 Hz), 3.65 (3 H, s), 3.05 (d,T. Suzuki, Ph.D. Thesis, Tohoku University, 1975.T. Kato, T. Suzuki, N. Ototani, and Y . Kitahara, Ckem.Letters, 1976, 8871977J 5Hz, 1-H), 3.41 (t, J 5 Hz, 2-H), 4.86 (m, 3-H), and 5.32(m, 5-H) (Found: C, 60.2; H, 6.9.C1,Hi,O, requires C,60.6; H, 7.1).Hydrolysis of the Acetate (14).-One drop of 12~-hydro-chloric acid was added to a solution in methanol (10 ml) ofthe acetate (14) (300 mg). The mixture was kept for 3 daysa t room temperature, then poured into water and extractedwith ether. The extract was washed with water, dried(MgSO,), and evaporated to give oily alcohol (15) (235 mg),m/e 228 (M+), vmax. (film) 3 600 and 1 736 cm-1, 6 (CC1,) 1.73,3.60, and 3.67 (each 3 H), 2.57 (dd, J 10 and 6 Hz, 1-H),3.45 (d, J 6 Hz, 2-H), 4.32 (m, 6-H), and 5.43 (m, 4-H)(Found: C, 57.4; H, 7.3. CllHl,O, requires C, 57.9; H,7.1).The enol ester (16).-(A) By oxidatiopt of the alcohol (15).To a mixture of the alcohol (15) (100 mg) and dichloro-methane (10 ml) was added chromic oxide-pyridine complex(800 mg).The mixture was stirred a t room temperatureovernight, then passed through a short silica column toremove solids. The eluate was washed with aqueoushydrochloric acid and then water, dried (MgSO,), and evap-orated. The residual oil was passed through a silica columnto give an oil (72 mg). The lH n.m.r. spectrum revealedthat this was a 3 : 1 mixture of esters (16) and (17).Toasolutionof lithium (45 mg) in liquid ammonia (10 ml) was added thephenol ester (17) (224 mg) in dry tetrahydrofuran (2 ml) atsolid carbon dioxide temperature. After 15 min, methanol(2 ml) was added and the solid C02-propan-2-01 bath wasremoved to allow the mixture to warm to room temperature.The mixture was diluted with water and neutral materialwas removed by shaking with ether.The aqueous layer was,after being acidified with hydrochloric acid, extracted withether. The solution was washed with water, dried (MgSO,),and evaporated to give a crude mixture, which was passedthrough a silica column to give dimethyl 3-lzydroxy-6-methyl-cyclohexa- 2,5-diene- 1,2-dicarboxylate ( 16) (9 1 mg) as an oil,m/e 226 (amp;I+), vmax. (film) 3 400, 1 737, 1 662, and 1 625 cm-l,6 (CCl,) 1.81, 3.73, and 3.80 (each 3 H), 3.99br (1 H, s, 1-H),5.60 (1 H, m, 5-H), and 12.42 (1 H, s, OH) (Found: C, 58.7;H, 6.0. CllHl,O, requires C, 58.4; H, 6.2).The Phenol Ester (17) from the Adduct (13).-To a stirredmixture of dichloromethane (200 ml) and the crude adduct(13), obtained by the reaction of 2-methylfuran (5.6 g) anddimethyl acetylenedicarboxylate (9.7 g), was added 3 6 ~ -sulphuric acid (4 ml) with cooling in ice.After removal ofthe ice-bath, stirring was continued for 3 h and then themixture was poured into water. The organic layer waswashed with sodium hydroxide solution and the washingswere acidified and extracted with ether. From the etherealsolution was obtained the phenol ester (17) (13.2 g), m/e 224(amp;I+), vIIMX. (KBr) 3 100, 1 732, 1 678, 1 598, 1 225, 841, and800 crn-l, 6 (CDC1,) 2.23 (Me x I ) , 3.93 (Me x 2), 7.02 (1 H,d, J 9 Hz), 7.39 (1 H, d, J 9 Hz), and 10.87 (1 H, s ) .Methylation of the Enol Ester (16).-To a solution int-butyl alcohol (10 ml) of the enol ester (16) (219 mg) wereadded potassium t-butoxide (130 mg) and methyl iodide(0.2 ml).The mixture was stirred a t 35 "C overnight, thendilutedwith ether, and the ethereal solution was washed withaqueous sodium hydroxide and then water, dried (MgSO,),and evaporated to give the crude product (18) (205 mg).Dimethyl 2,6-dimethyl- 3-oxocyclolzex-5-ene- l12-dicarboxylate(18) had m.p. 99-100 "C (from benzene), m/e 240 (M+),vmx. (KBr) 1 736 and 1 718 cm-l, 6 (CDCl,) 1.50 (3 H, 2-Me),1.90 (3 H, dd, J 1.0 and 3.0 Hz, 6-Me), 3.70 and 3.77 (Me x(TJ) ByBirchreduction of the Phenolester( 17).2),3.02and3.06(each1H,t,J6Hz,4-H2),3.27(lH,s,1-H),and 5.69 (m, 5-H) (Found: C, 59.7; H, 6.6. C1,Hl,05requires C, 60.0; H, 6.7).Methyl 4-Furfwrylidenecrotonate ( 19) .-Small pieces ofsodium (total 17 g) were gradually added with stirring tomethyl acetate (400 ml) pre-cooled to - 10 t o - 15 "C.Intothis mixture was dropped 3-( 2-fury1)acrylaldehyde (80 g)dissolved in anhydrous methyl acetate (100 ml), during 2 h,with the temperature of the mixture kept at - 10 to - 15 "C.The mixture was then stirred for an additional 8 h at thesame temperature, kept in a refrigerator overnight, dilutedwith ether, neutralized with acetic acid, washed with water,dried (MgSO,) , evaporated, and distilled under reducedpressure to afford methyl 4-furfurylidenecrotonate (19) (43.4 g,37) as pale yellow crystals, b.p. 111 "C at 2 mmHg, m.p.67-68' (Found: C, 67.8; H, 5.8.Cl0Hl0O3 requires C,67.4; H, 5.7).Formation of the Dimethyl 6- (2-Furyl) - l-methoxycarbonyl-methylcyclohexane- 1,3-dicarboxylates (2 1) and (23) .-A mix-ture of methyl 4-furfurylidenecrotonate (19) (12.5 g) anddimethyl itaconate (1 1 g) was stirred a t 160 "C under nitro-gen for 24 h to give the Diels-Alder adduct (20) as a viscousoil. The adduct was, without purification, dissolved inmethanol (200 ml) containing 5 palladium-charcoal (3 g)and shaken under hydrogen until 1.2 mol. equiv. of hydrogenhad been absorbed. Filtration and evaporation left a paleyellow oil. This oil (13.3 g) was passed through a silicacolumn in benzene-di-isopropyl ether (40 : 1). Elutionwith the same solvent afforded the oily triester (21) (4.1 g,31) (Found: C, 60.0; H, 6.2.C,,H,,O, requires C, 60.3;H, 6.6) and then the isomer (23) (4.3 g, 32) (Found:C, 60.1; H, 6.3).Dieckmann Colzdensations of the Triesters (2 1) and (23) .-A mixture of the triester (21) (1.44 g), anhydrous benzene(35 ml), and dried potassium t-butoxide (610 rng) wasrefluxedfor 2.5 h with stirring under nitrogen. After cooling, themixture was poured into aqueous 10 acetic acid and extrac-ted with ether. The extract was washed with water, dried(MgSO,) , and evaporated, and the resulting oily material wasdissolved in ether (10 ml) and kept at room temperature;dimethyl 2-( 2-ficryl)-6-oxobicyclo3.2. lloctane- 1,7-dicarboxyl-ate (25) was deposited as crystals (728 mg, 56), m.p. 127-128" (Found: C, 63.0; H, 5.9. C1,H1,O, requires C , 62.7;H, 5.9).A mixture of the isomeric triester (23) (1.314 g), anhydrousbenzene (30 ml), and dried potassium t-butoxide (620 mg)was refluxed for 1 h with stirring under nitrogen.Aftercooling, the mixture was diluted with ether and passedthrough a short silica gel column in order t o remove basicmaterials. Elution with ether afforded an oil (877 mg).Addition of a small amount of ether caused deposition of theisomeric 0x0-ester (27) as crystals (618 mg, 52), m.p. 121-122" (Found: C , 62.8; H, 5.7).Epimerization of the Triesters (21) und (23).-A mixture ofthe triester (21) (434 mg), anhydrous xylene (15 ml), anddried potassium t-butoxide ( 158 mg) was refluxed overnightunder nitrogen, cooled, poured into 0.5~-sodium hydroxide,and extracted with ether.The extract was washed withwater, dried (MgSO,), and evaporated, and the resultingoily mixture (210 mg) was passed through a silica (20 g)column. Elution with benzene-di-isopropyl ether (20 : 1)gave the triester (21) (52 mg), a mixture of (21) and the epi-merized triester (22) (64 mg) , and the epimerized triester (22)(22 mg) . From the aqueous alkaline solution was obtainedacidic material (192 mg) (after acidification with aq. HC210 J.C.S. Perkin Iand extraction with ether). Silica gel column chromato-graphy afforded the Dieckmann product (25) (72 mg).Efiimerization of the Triester (23).-The triester (23)(537 mg) was treated with potassium t-butoxide (195 mg)under the same conditions as in the case of (21), and theneutral oil was chromatographed t o give the epimerizedtriester (24) (1 17 mg), a mixture of (23) and (24) (22 mg), andthe triester (23) (45 mg). From the acidic fraction wasisolated the Dieckmann product (27) (68 mg).Demethoxycarbonylation of the Dieckmann Product (27) .-( A ) A mixture of the Dieckmann product (27) (5.0 g),anhydrous pyridine (100 ml), and lithium iodide (3 g) wasgently refluxed for 2 days under nitrogen. After cooling,the mixture was poured into ice- 12~-hydrochloric acid andextracted with dichloromethane. The extract was washed(aq. HC1, aq. NaOH, and then water), dried (MgSO,), andevaporated to leave methyl 2-( 2-furyZ)-6-oxobicycZo3.2.1-octane-1-carboxylate (3b) (3.94 g), m.p. 68-68.5" (Found:C, 68.0; H, 6.4. Cl4Hl6O4 requires C, 67.6; H, 6.5).(B) A mixture of (27) (600 mg), anhydrous collidine (30 ml),and lithium iodide (1.84 g) was warmed a t 140 "C for 4 h,then treated as in ( A ) to give the 0x0-acid (3a) (360 mg)(from the aq. NaOH solution), m.p. 185-186" (Found:C, 66.4; H, 6.1. Camp;1404 requires C, 66.7; H, 6.0).6/1201 Received, 21st June, 1976