Synthesis of larreantin, a cytotoxic naphthoquinonoid sesquilignan fromLarrea tridentata

摘要

J. CHEM. so(.. PERKIN TRANS. I 1991 Synthesis of La r reant in, a Cytotoxic Nap ht hoquinonoid SesquiI igna n f rorn Larrea tridentata l Mark F. Comber and Melvyn V. Sargent * Department of Chemistry, The University of Western Australia, Nedlands, Western Australia, 6009 Larreantin 8-(4- hydroxy-3- methoxyphenyl) -6-(4- hydroxy-3- met hoxybenzyl) -2-methoxy-7- methyl- naphthalene-I ,4-dione 1, a biogenetically unique cytotoxic naphthoquinonoid sesquilignan has been synthesized by a convergent route. The key intermediate was 4,5-dihydro-2- (5,7-diisopropoxy-I -methoxy-2-naphthyl) -4,4-dimethyloxazole 14 which was elaborated by treatment with 4-isopropoxy- 3-methoxyphenylmagnesium bromide 26 and the product of this reaction was lithiated and allowed to react with 4-isoproproxy-3-methoxybenzaldehyde 28.Subsequent steps then gave larreantin 1. The creosote bush, Larrea tridentata (DC) Coville (Zygophyl- laceae) is native to the south-west of the United States of America and northern Mexico.’ In continuation of their studies of this plant, Cordell and his co-workers have recently examined a methanol extract of its roots in the search for cytotoxic constituent^.^ Fractionation of this extract by chromatography yielded the naphthoquinone larreantin 1. This compound, the structure of which was deduced entirely by spectroscopic methods, was shown to have an ED,, value of 0.38 pg ~m--~, a value which represents cytotoxicity by more than an order of magnitude. Larreantin 1 is an unprecedented type of 1,4-naphthoquinone and its nearest structural relatives are OH 0Me R Me0 2;R=H 3; R = OMe OH OMe OMe OMe OMe 4 5 R 4OMeOH OMe OMe lassumunaquinone 1 2 and lassumunaquinone 2 3 which co- occur in Zingiber cassumunar R~xb.~ The lignans and neolignans are groups of natural products which arise from radical coupling of two oxygenated cinnamyl sub-units. Compounds derived from the coupling of three such phenylpropanoid sub-units have been termed ‘sesquilignans’ of which larreatin 1 appears to represent an unusual e~ample.~ The furanoid lignans malabaricanol 4 and 3’,3”-dimethoxyl- arreatricin 5 have recently been isolated from Larrrrr tridentatu and bear substitution patterns similar to larreantin 1.These lignans probably arise from the radical coupling of two units of isoeugenol 6 and further transformations. If coniferyl alcohol 7and isoeugenol 6 were to couple in a similar manner to that required for the biosynthesis of compounds 4 and 5 then a possible precursor 9 to larreantin 1 might be produced.Some evidence for this type of transformation comes from the recent work of Umezawa et al.’ Further transformations of intermediate 9 could give the diene 10. A Diels-Alder reaction, or its biochemical equivalent, of this diene with 2-methoxy- 1,4-?H ?Hb““ b“”‘0 OH OH 11 12 u OR 6;R=Me 9 OR 7;R = CH20H OH 13 8; R = COZH 10 Scheme 1 benzoquinone, derived from three successive side-chain de- carboxylations of ferulic acid,8 would then give larreantin 1.We now report the confirmation of the structure of larreantin 1 by a convergent synthesis. Although the synthesis of larreantin 1 by a Diels-Alder reaction is attractive we chose to adopt an approach based on dihydrooxazole chemistry. The immediate precursor to larreantin 1 (see Scheme 1) was perceived to be the 2-hydroxy- 1,4-naphthoquinone 11 which should undergo easy methylation since it contains a vinylogous carboxylic acid function. Such a naphthoquinone would be available by aerial oxidation of the 1,3-dihydroxynaphthalene 12 which would arise by deprotection of the precursor 13 in which the protective group R must be capable of removal in the presence of methoxy groups. For this purpose we chose the isopropyl group." The key intermediate which would allow the synthesis of the naphthalene 13 would then be the naphthyldihydrooxazole 14.Displacement of the methoxy group in the position ortho to the dihydrooxazole by the appropriate aryl Grignard reagent would introduce the aryl substituent. Advantage could then be taken of the directive power of the dihydrooxazole moiety in lithiation at the other ortho-position and subsequent reaction with an appropriate electrophile would introduce the benzyl group.' We thus sought a synthesis of the dihydrooxazole 14 (Scheme 2). Ozonolysis of the known propenylbenzene 15 gave the aldehyde 16 l3 which was caused to react with 2-tert-butoxycarbonyl-1-methoxycarbonylethylidene(triphenyl)phos-phorane l4 thereby supplying the itaconic ester 17.This com- pound on brief treatment with aqueous trifluoroacetic acid gave the acid 18 which underwent ring closure to the nZ' . 15 WMe I. OMe opt 27 26 OPr'WMe CHO 28 Pr '0 J. CHEM. SOC. PERKIN TRANS. I 1991 naphthoate 19 on boiling with acetic anhydride containing potassium acetate. Reduction of this intermediate with di-isobutyl aluminium hydride then furnished the diol 20 which was selectively converted into the isopropyl ether 21. Manganese dioxide oxidation now yielded the aldehyde 22 which on Baeyer-Villiger oxidation with tn-chloroperoxy-benzoic acid, hydrolysis of the intermediate formate, and subsequent isopropylation afforded the naphthalene 23. This was caused to react with copper(1) cyanide and hydrolysis of the resultant nitrile 24 gave the naphthoic acid 25 which converted into the required dihydrooxazole 14 by the standard method.' The dihydrooxazole was now allowed to react with the Grignard reagent 26 which yielded the biaryl 27 (8SoO),Treat-ment of a solution of this biaryl in tetrahydrofuran (I'HF) in the presence of 1 mol equiv. of N,N,N'N'-tetramethylethylene-diamine (TMEDA) at -78 'C with 1 mol equiv. of sec-butyl- lithium during 1 h gave an orange solution which was then treated with the benzaldehyde 28. The crude product of this reaction was boiled with aqueous hydrochloric acid in dioxane which brought about hydrolysis, presumably anchimerically assisted, of the hindered dihydrooxazole to give, after chromatography, the phthalide 29 (58",).Reduction of the phthalide with lithium aluminium hydride gave the diol 30. On catalytic hydrogenation under acidic conditions this diol 30 yielded the 1,3-dihydronaphtho2,3-cfuran 31 but when the reaction was repeated in the presence of trifluoroacetic anhydride and an excess of triethylamine the desired deoxy- genated product 32 resulted. Deprotection of this compound h I-OMe OMe OAc OR 19 20;R = HC21; R = CHMe2 1 ?Me OMe OHCWB' 6Pri 22 123; R = Br 24; R = CN b25; R = C02H 30 / 0P+ 30 OPri Scheme 2 J. CHEM. SOC. PERKIN TRANS. I 1991 by treatment with the boron trichloride followed by aerial oxidation of the anion of the resultant tetrol 12 gave the quinone 11 which on selective methylation provided synthetic larreantin 1.The spectral properties of this material were entirely in agreement with those recorded for the natural product3 so that structure 1 is correct. Experimental General directions have been given before.16 J Values are given in Hz. Light petroleum is the fraction with b.p. 55-65 "C. 3-Bromo-2-methoxybenzaldehyde 16.-A solution of (E)-3- bromo-2-methoxy-1-prop-1-enylbenzene15 (38.5 g) l2 in di- chloromethane (600 cm3) and methanol (6 cm3) was cooled to -78 "C and a stream of ozone was passed through the solution until a blue colour persisted. The excess ozone was removed by passage of nitrogen and then dimethyl sulphide (40 cm3) was added and the solution was stirred and allowed to warm to room temperature over 12 h.The solvents were removed by evaporation under reduced pressure and the residue was filtered through a column of neutral alumina with 2.5 ethyl acetate- light petroleum as eluent. The aldehyde 16 (34.0 g, 93) l3 crystallized from pentane as rods, m.p. 31-32 "C (Found: (1, 44.55; H, 3.4; Br, 37.25; M+, 214/216. C,H,BrO, requires C, 44.7; H, 3.25; Br, 37.15; M, 214/216); 6,(80 MHz) 4.00 (3 H, s, OMe), 7.19 (1 H, ddd, J5,4, J5,67.6, J5,,,,O.8,5-H), 7.81 (2 H, d, J4.s,J6,5,7.6,4- and 6-H) and 10.37 (1 H, br s, CHO). 4-tert-Butj-1 1-Methyl (E)-2-(3-Bromo-2-methoxybenzyli-dene)butanedioate 17.-A solution of the aldehyde 16 (17.0 g) and 2-tert-butoxycarbonyl-l-methoxycarbonylethylidene(tri-pheny1)phosphorane (44.2 g) l4 in anhydrous benzene (780 cm3) was stirred and heated under reflux for 20 h.The solvent was removed by evaporation under reduced pressure and the residue was purified by chromatography over silica gel with 1-5 ethyl acetate-light petroleum as eluent to afford the ester 17 (26.6 g, 91) as an oil, b.p. 120 "C at 0.005 mmHg (Found: C, 53.4; H, 5.8; Br, 20.6; M', 384/386. C17H,,Br0, requires C, 53.0; H, 5.5; Br, 20.75; M, 384/386); 6,(80 MHz) 1.45 (9 H, s, Bu'), 3.38 (2 H, s, CH,), 3.77 and 3.84 (each 3 H, s, OMe), 7.00 (1 H, dd, J5.4, J5,6 7.7, 5-H), 7.24 (1 H, dd, J6.5 7.7, J6,4 1.5, 6-H), 7.60 (1 H, dd, J4,57.7, J4,61.5, 4-H) and 7.90 (1 H, s, vinyl-H). (E)-4-( 3- Bromo-2-methoxyphenyl)-3-methoxycarbonylbut-3-enoic Acid 18.-The ester 17 (14.3 g) was dissolved in 90 aqueous trifluoroacetic acid (140 cm3) and the solution was stirred for 15 min.The solvent was removed by evaporation under reduced pressure and finally by azeotroping with benzene. The crude product was purified by dissolution in aqueous sodium hydrogen carbonate in the usual manner. The acid 18 (1 1.6 g, 95) crystallized from dichloromethane-light petroleum as hygroscopic prisms, m.p. 887 "C (Found: C, 47.3; H, 3.95; Br, 24.2; M+, 3281330. C13H13Br05 requires C, 47.45; H, 4.0; Br, 24.3; M, 3281330). Methj3l 4- A ceto.uy-7-bromo-8-metho.xynuphthulene-2-carbox-?,late 19.-The acid 18 (24.0 g) and anhydrous potassium acetate (7.0 g) were heated under reflux in acetic anhydride (450 cm3) for 5 min.The solution was poured into warm water (2 dm3) and the precipitated solid was filtered off, dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate. The crude product crystallized from methanol as needles (21.8 g, 84'1,) of the ester 19, m.p. 11 1-1 12 "C(Found: C, 5 1.35; H, 3.6; Br, 22.45O:;; M +,3521354. C 5H ,BrO, requires C. 51.0: H, 3.7; Br, 22.6:/;; M, 3521354); 6,(80 MHz) 2.47 (3 H, s, COMe), 3.99 and 4.06 (each 3 H, s, OMe), 7.54 and 7.72 (2 H, AB, J5,6 9.0, 6- and 5-H), 7.87 (1 H, d, J3,, 1.5, 3-H) and 8.77 (1 H, br s, I-H). 6- Bromo-3-( hydro.xymeth~~l)-5-methox~-1-naphthol 20.-A solution of diisobutylaluminium hydride (2 mol dm-3) in hexane (52.5 cm3) was added dropwise with stirring at -10 "C to a stirred solution of the ester 19 (7.4 g) in anhydrous tetrahydrofuran (THF) (250 cm3).The solution was stirred for 10 min and excess water was added dropwise followed by acidification with dilute hydrochloric acid. The crude product was isolated by extraction with ethyl acetate and then purified by filtration through a short column of silica gel with 800,: ethyl acetate-light petroleum as eluent. The diol 20 (5.6 g, 94) crystallized from ether-light petroleum as pale yellow needles, m.p. 165-167 "C (Found: C, 50.9; H, 3.7; Br, 28.3; M+, 282/284. Cl,Hl1BrO3 requires C, 50.9; H, 3.9; Br, 28.2; M, 282/284); 6,80 MHz; (CD,),SO 3.30 (2 H, br s, 2 x D,O exchangeable OH), 3.90 (3 H, s, OMe), 4.61 (2 H, s, CH,OH), 6.92 (1 H, d, J2,31.2, 2-H) 7.45 (1 H, br s, 4-H) and 7.51 and 7.80 (2 H, AB, J,,, 8.9, 7- and 8-H).(7-Bromo-4-isopropoxy-8-rnethoxy-2-naphth~I)methanol 21.-The diol 20 (10.0 g), 2-bromopropane (4.8 g) and anhydrous potassium carbonate (4.9 g) were stirred under nitrogen in DMF (120 cm3) for 4 d. Work-up gave a crude product which was purified by flash chromatography over silica with 20 ethyl acetate-light petroleum as eluent. The alcohol 21 (9.4 g, 82) crystallized from dichloromethane-light petroleum as pale yellow needles, m.p. 87-88 -C (Found: C, 55.5; H, 5.45; Br, 24.85; M+, 324/326. C15H1,Br03 requires C, 55.4; H, 5.25; Br, 24.55; M, 324/326); 6,(80 MHz) 1.44 (6 H, d, Me,), 3.98 (3 H, s, OMe), 4.76 (1 H, septet, CH), 4.82 (2 H, s, CH,OH), 6.89 (1 H, d, J3,i 1.2, 3-H), 7.49 and 7.88 (2 H, AB, J5,68.2,6- and 5-H) and 7.54 (1 H, br s, 1-H).7-Bromo-4-isopropo,~y-8-methoxynaphthalene-2-carbalde-hyde 22.-A solution of the alcohol 21 (9.4 g) in di-chloromethane (1 50 cm3) was stirred with activated manganese dioxide (70 g) for 12 h under argon. Work-up gave the aldehyde 22 (8.4 g, 90"/,) which crystallized from dichloromethane-light petroleum as yellow needles, m.p. 98-99 'C (Found: C, 55.6; H, 4.6; Br, 24.85; M', 3221324. C1,HlsBr03 requires C, 55.75; H, 4.7; Br, 24.7; M, 3221324); 6,(80 MHz) 1.46 (6 H, d, Me,), 4.06 (3 H, s, OMe), 4.86 (1 H, septet, CH), 7.24 (1 H, br s, 3-H), 7.70 and 7.97 (2 H, AB, J5,69.0, 5-and 6-H), 8.16 (1 H, br s, 1-H) and 10.10 (1 H, s, CHO); vmax(KBr)/cm-' 1690 and 1580; i,,,(MeOH)/nm 227, 258, 298 and 368 (log E 4.52, 4.51, 3.86 and 3.78 respectively).2-Bromo-5,7-diisopropo.xy-1 -rnetho,xynaphthalene 23.-A solution of the aldehyde 22 (7.15 g) in dichloromethane (200 cm3) was stirred and heated under reflux under nitrogen with m-chloroperoxybenzoic acid (80,9.5 g) for 72 h. The solution was cooled and filtered and the solvent was removed from the filtrate and replaced by ether. The solution was washed in turn with water, aqueous sodium hydrogen carbonate and finally with saturated brine. The crude product was dissolved in methanol (50 cm3) and methanolic sodium methoxide (0.6 mol dm-? 40 cm3) was added and the solution was stirred for 5 min and acidified by the addition of a slight excess of dilute hydrochloric acid.Most of the methanol was removed under reduced pressure and the crude product was isolated by extraction with ether, and next dissolved in DMF (50 cm3) and stirred with anhydrous potassium carbonate (4.0 g) and 2- bromopropane (4.0 g) under dry nitrogen at 50 C for 72 h. Work-up gave a crude product which was purified by flash chromatography over silica with 1-2x ethyl acetate-light petroleum as eluent. The naphthalene 23 (2.0 g, 26) crystallized from light petroleum as prisms, m.p. 52-53 "C (Found: C, 58.0; H, 6.2; Br, 22.55; M +,3521354. C, .,H2 ,Br03 requires C, 57.8; H, 6.0; Br, 22.604; hf, 352/354); 6,(80 MHz) 1.41 and 1.42 (each 6 H, d, Me,), 3.95 (3 H, s, OMe), 4.68 (2 H, m, 2 x CH), 6.49 and 6.96 (2 H, AB, J6,* 2.2, 6- and 8-H) and 7.35 and 7.79 (2 H, AB, J3,49.0, 3-and 4-H).57- Diisopropoxy- 1-methoxynaphthalene-2-carbonitrile24.-The bromo compound 23 (2.0 g) and copper(1) cyanide (840 mg) were stirred and heated under reflux in anhydrous DMF (40 cm3) under dry nitrogen for 12 h. The cooled solution was diluted with aqueous ethylenediamine and extracted with ether. The extract was washed with more aqueous ethylenediamine, water, and finally with saturated brine. The crude product was purified by radial chromatography with 5 ethyl acetate-light petroleum as eluent. The nitrile 24 (1.6 g, 95) crystallized from dichloromethane-light petroleum as pink prisms, m.p. 85-86 "C (Found: N, 4.4; M+, 299.C,,H,,N03 requires N, 4.7; M, 299); 6,(80 MHz) 1.42 and 1.44 (each 6 H, d, Me,), 4.21 (3 H, s, OMe), 4.75 (2 H, m, 2 x CH), 6.60 and 7.03 (each 1 H, d, J 2.1, 6- and 8-H), and 7.28 and 7.91 (2 H, AB, J3,4 8.7, 3- and 4-H); v,,,/cm-' 2222, 1595 and 1410; i,,,(MeOH)/nm 254, 282, 290 and 365 (log E 4.73, 3.72, 3.72 and 3.55 respectively). 5,7-Diisopropoxy-1-methoxynaphthalene-2-carho.uylic Acid 25.-A solution of the nitrile 24 (1.6 g) in methanol (30 cm3) and aqueous sodium hydroxide (10; 10 cm3) was heated under reflux for 96 h. Most of the methanol was removed and the cooled solution was acidified by the addition of hydro-chloric acid. The crude product was isolated by extraction with ether and next crystallized from dichloromethane -light petroleum whereupon it formed needles of the acid 25 (1.45 g, S5), m.p.136-137°C (Found: C, 67.6; H, 6.85; M+, 318. C,,H,,05 requires C, 67.9; H, 6.95; M, 318); v,,,/cm-' 3480, 1700 and 1675; A,,,/nm 214, 244, 288 and 344 (log E 4.40,4.57, 3.83 and 3.46 respectively). 43- Dihydro-2-( 5,7-diisopropoxy- 1-methoxy-2-naphthyl)-4,4-dimethyloxazole 14.-Oxalyl chloride (270 mm3) was added to a solution of the acid 25 (500 mg) in dry dichloromethane (20 cm3) and the solution was stirred under argon for 2.5 h. The solvents were removed under reduced pressure and the residue was dissolved in dry dichloromethane (5 cm3) and the solution was added dropwise to a stirred solution of 2-amino-2-methylpropan-1-01 (300 mg) in dry dichloromethane (5 cm3) at 5 "C.After 2 h, the precipitate was filtered off and washed with a little dichloromethane. The filtrate was stirred at 0 ' C with thionyl chloride (260 mm3) and the solution was allowed to warm to room temperature and stirred for 2 h. The solution was next cooled to 0°C and treated with water, and the crude product was isolated by extraction with dichloromethane and then purified by radial chromatography with 1540 ethyl acetate-light petroleum as eluent. The dihydrooxnzole 14 (470 mg, 81) crystallized from light petroleum as prisms, m.p. 67-68 "C (Found: C, 71.45; H, 7.8; N, 3.7; M+, 371. C,,H2,N04 requires C, 71.15; H, 7.85; N, 3.7576; M, 371); 6,(80 MHz) 1.41 and 1.43 (each 6 H, d, CHMe,), 1.43 (6 H, s, Me,), 3.74 (2 H, s,CH2), 3.95 (3 H, s, OMe),4.74 (2 H, m, 2 x CH), 6.55 and 7.10 (each 1 H, d, J6,8 2.1, 6- and 8-H) and 7.60 and 7.89 (2 H, AB, J3.4 8.8, 3-and 4-H); vmax/crn-'1650, 1412 and 1112; i,,,(MeOH)/nm 215.250 and 349 (log t; 4.50, 4.80 and 3.60 respectively). 5-Bromo-2-isopro)po-u~~beti=~ild~~ii!~de.-Asolution of 5-bromo- 2-hydroxybenzaldehyde (1 7.9 g) and 2-bromopropane (13.0 g) in anhydrous DMF (200 cm3) was stirred at 50'C under nitrogen with anhydrous potassium carbonate (1 3.4 g) J. CHEM. soc. PERKIN TRANS. I 1991 for 12 h. Work-up gave the uldehjde (20.6 g, 95",,) as an oil, b.p. 130 'C at 0.1 mmHg (Found: C. 49.55; H, 4.6; Br, 33.1",,; M'. 2421244. CloH, ,BrO, requires C, 49.4: H, 4.55; Br, 32.85",,; M, 242i244); 6,(80 MHz) 1.40 (6 H, d, Me,), 4.65 (1 H, septet, CH), 6.89 (1 H, d, J3,4 9.0, 3-H), 7.59 (1 H, dd, J4,39.0, J4.6 2.6, 4-H), 7.90 (1 H, d, J6,42.6, 6-H) and 10.39 (1 H, s.CHO); vmax(film),'cm-l2980, 1680 and 1590. 5-Bromo-2-i.~opropo.~~~Jz~~n~)l.Asolution of the foregoing aldehyde (21.0 g) and nz-chloroperoxybenzoic acid (800/, 30 g) in carbon tetrachloride (300 cm3) was stirred for 5 h at room temperature. The solution was cooled in ice and the precipitate was filtered off. The filtrate was washed in turn with aqueous sodium hydrogen carbonate, water and finally with saturated brine. The crude product was dissolved in methanol (200 cm3) and stirred with aqueous potassium hydroxide (102);50 cm3). After 1 min the solution was acidified with dilute hydrochloric acid, and work-up gave the phenol as an oil (15.8 g, 79".;',),b.p.90 'C at 0.01 mmHg (Found: C, 46.8; H, 4.85; Br, 33.9"i,; M', 230/232. C,H, ,BrO, requires C, 46.8; H, 4.8; Br, 34.567,);M, 230/232); 6,(80 MHz) 1.35 (6 H, d, Me,), 4.53 (1 H, septet, CH), 5.73 (1 H, br, OH), 6.70 (1 H, d, J3.4 8.4, 3-H) 6.94 (1 H, dd, J4,38.4, J4,62.1,4-H) and 7.01 (1 H, d, J6.42.1, 6-H). l-Bromo-4-isopropo.u~~-3-t~zetJzo.u~~ben~ene.~Methylationof the foregoing phenol (15.5 g) with dimethyl sulphate and potassium carbonate in boiling acetone gave the hronzobenmw (16.0 g, 97) as an oil, b.p. 105 'C at 0.05 mmHg (Found: C, 49.0; H, 5.45; Br, 32.4; M', 244/246. C,,H,,BrO, requires C,49.0; H, 5.35; Br, 32.6; M, 2441246). 43- Dihq?dro-2- 1-(4-isopropo.u~~-3-metJio.uyph~nyl)-5,7-diiso-prc)po.u!i-2-naphthyl-4,4-dirnethq~I~).ua~~le27.-A solution of 4-isopropoxy-3-methoxyphenylmagnesium bromide 26 from magnesium (60 mg) and the bromoarene (600 mg) in anhydrous THF (3 cm3) was introduced by cannula to a stirred solution of the oxazoline 14 (450 mg) in anhydrous THF (10 cm3) at room temperature under argon. After 30 min an excess of saturated aqueous ammonium chloride was added and the crude product was isolated by extraction with ethyl acetate and next purified by radial chromatography with 20-30y" ethyl acetate-light petroleum was eluent.The dihjdroosuzole 27 (540 mg, 88) crystallized from dichloromethane-light petroleum as prisms, m.p. 117-1 18 'C (Found: C, 73.35; H, 8.05; N, 2.75",,; M', 505.C3,H3,NOS requires C, 73.65; H, 7.75; N, 2.75'>,,;M, 505); 6,(300 MHz) 1.21 and 1.22 (each 3 H, s, Me), 1.26 and 1.27 (each 3 H, d, Me,), 1.41 and 1.43 (each 3 H, d, Me,), 1.46 (6 H, d, Me,), 3.74 (2 H,s, CH,), 3.82 (3 H, s, OMe),4.38,4.62 and 4.71 (each 1 H, septet, CH), 6.52 and 6.58 (2 H, AB, .I6,* 2.1, 6-and 8-H), 6.85-6.90 (2 H, m, 2'-and 6'-H), 6.98 (1 H, d, J, ,6 8.1, 5-H), 7.52 (1 H, d,J3.48.6, 3-H) and 8.18 (1 H, d, J4.3 8.6,4-H); ,,,,(MeOH)/nm 245,292 and 346 (log E 4.48,3.79 and 3.42 respectively). ( )-3,9-Bis(4-iso~propo.~~~-3-nietl~o.~~~Jienq~l)-5,7-ciii~opr.o-po.u!~nup/itlioC2,3-c furun- 1(3H)-one 29.-A solution of the oxazoline 27 (512 mg) in anhydrous THF (10 cm-') was stirred and cooled to -78 C under argon and anhydrous N.N,N',N'-tetramethylethylenediamine (1 60 mm3) was added cia syringe; this was followed by the addition cia syringe of sivbutyllithium (0.42 mol dm-3) in pentane (2.46 cm3).The solution was stirred at -78 C for 1 h and then the aldehyde 28 (215 mg) " in anhydrous THF (5 cm3) was added viu a cannula and the solution was allowed to warm to room temperature over 1 h when water was added dropwise and most of the THF was removed under reduced pressure. The residue was heated under reflux for 0.25 h with dioxane (25 cm3) and concentrated hydrochloric acid (25 cm3). The cooled solution was diluted J CHEM. so(‘.PERKIN TRANS. 1 1991 with water and the crude product was isolated by extraction with ethyl acetate and next purified by radial chromatography with 15”/,ethyl acetate-light petroleum as eluent.Thefuranone 29 (370 mg, 59) crystallized from dichloromethane-light petroleum as yellow needles, m.p. 162-1 63 “C(Found: C, 72.75; H, 7.25); Mi, 628. C3,H,,08 requires C, 72.6; H, 7.05”; M, 628); 6,(300 MHz) 1.2G1.30 (6 H, m, Me,), 1.37-1.50 (18 H, m, 3 x Me,), 3.81 and 3.82 (each 1.5 H, s, OMe), 3.85 and 3.86 (each 1.5 H, s, OMe), 4.40 and 4.56 (each 1 H, septet, Me,), 4.69 (2 H, m, 2 x CHMe,), 6.43 (1 H, br s, 3-H), 6.59 and 6.69 (each I H, d, J 2.0, 6- and 8-H respectively), 6.83-7.07 (6 H, m, ArH) and 8.09 (1 H, br s, 4-H); v,,,(KBr)/cm-’ 1770 and 1615; jLmax’nm225, 264 and 385 (log E 4.64, 4.73 and 3.64 respectively) extract was shaken .ith ethanolic potassium hydroxide (5”,,; 10 cm3) for 2 min whereupon it turned a deep red colour: it was then acidified and worked up.A solution of the crude product in anhydrous DMF (10 cm3) was stirred with anhydrous potassium hydrogen carbonate (25 mg) and iodo- methane (0.5 cm3) at room temperature for 12 h after which it was worked up. The crude product was purified by radial chromatography using 70 ethyl acetate-light petroleum as eluent to afford synthetic farreantin 1 (9.8 mg, 13’,,) as yellow needles (from methanol), m.p. 189-191 -C (lit..? 204-206 ‘C) (Found: C, 67.75; H, 5.47;. C27H2407~H20 requires C, 67.75; H, 5.5); 6,(300 MHz) 2.02 (3 H, s, Me), 3.800, (3 H, s, 2-OMe), 3.827 (3 H, s, 3’-OMe), 3.848 (3 H, s.3”-OMe), 4.06 (2 H, s, CH,), 5.54 and 5.64 (each 1 H, s, 4‘ and 4”-OH), 6.08 (1 H, S, 3-H), 6.48 (1 H, d, J2j.6, 1.9,2’-H), 6.52 (1 H, dd, J69.5, 7.8, ( k)-diisopropo ~ynaphtho2,3-cfiran 31.-A solution of the furan- one 29 (175 mg) in anhydrous ether (15 cm3) was added dropwise to a stirred solution of lithium aluminium hydride (60 mg) in anhydrous ether (10 cm3) at 0 “C.The solution was stirred at room temperature for 2 h and then worked up by the addition of saturated aqueous sodium sulphate to give the diol 30 (175 mg, 99) as a gum. A solution of the diol30 (50 mg) in ethyl acetate (10 cm3) containing concentrated hydrochloric acid (1 drop) was stirred under an atmosphere of hydrogen with palladized charcoal (lo, 20 mg) for 18 h.Work-up gave the ,furan 31 (45 mg, 100) which crystallized from ether-light petroleum as prisms, m.p. 138-139 “C (Found: C, 74.15; H, 7.6; M’, 614. C3,H4,0-, requires C, 74.25; H, 7.55; M, 614); 6,(300 MHz) 1.28 and 1.29 (each 3 H, d, Me,), 1.361.48 (18 H, m, 3 x Me,), 3.836 (3 H, s, OMe), 3.844 and 3.848 (each 1.5 H, s, OMe), 4.42 and 4.54 (each 1 H, septet, CH), 4.64 (2 H, m, 2 x CH), 5.06 and 5.18 (1 H, AB, J 12.5, 1-CH,), 5.11 (1 H, br s, 1-CH,), 6.25 (1 H, br s, 3-H), 6.55 (1 H, d, J6,* 2.1, 6-H), 6.62 (1 H, m, 8-H), 6.86-7.03 (6 H, m, ArH) and 7.83 and 7.85 (each 0.5 H, s, 4-H); v,,,/cm-’ 1612 and i505; ,,ax( Me0H)inm 220,249,283 and 307 (log E 4.62,4.76,4.02 and 3.90 respectively). J68.2, 1.9, 6’-H), 6.62 (1 H, dd, J6,,.5,,8.0,J6.,.?,,1.9,6”-H), 6.67 (1I ,3-Dih~~dro-3,9-bis(4-isopropo.~y-3-metho.~~phen~f)-5,7-H, d, J2,),6,,1.9,2”-H), 6.85 (1 H, d, J,,,,z,,,8.0, 5“-H).6.97 (1 H. d, J5,,6j7.8, 5’-H) and 7.98 (1 H, s, 5-H); 6,(75.5 MHz) 17.25 (7- Me), 40.35 (7”-CH,), 55.90 (2-OMe), 55.94 (3’-OMe),56.28 (3”- OMe), 108.06 (C-3), 110.40 (C-2’), 11 1.23 (C-2”). 114.50 (C-57, 114.58 (C-5”), 120.42 (C-6’), 121.52 (C-6”), 127.1 1 (C-8), 127.25 (C-5), 130.31 (C-1”), 130.72 (C-4a), 132.19 (C-l’), 143.54 (C-7), 143.66 (C-8), 144.26 (C-4”), 144.59 (C-4’), 146.25 (C-6), 146.65 (1:-3”), 146.79 (C-3’),160.62 (C-2), 179.91 (C-1) and 185.23 (C- 4); v,,,(KBr)/cm-’ 3400, 1685, 1645, 161 8. 1508, 1340, 1284,. 1255, 1236, 1210 and 1082; mj: 460 (M+, loo”,,).445 (1 l), 443 (1 l), 429 (21), 305 (7), 304 (8) and 137 (52).References 1 Preliminary communication: M. F. Comber and M. V. Sargent, J. Chem. Soin., Cheni. Conimun., 1991. 190. 2 H. Z. Xue, Z. Z. Lu, C. Konno, D. D. Soejarto, G. A. Cordcll, H. H. S. Fong and W. Hodgeson, Phj.toc-hrn7.,1988, 27. 23. 3 Z. Luo, D. Meksuriyen, C. A. J. Erdelmeier, H. H. S. Fong and G. A. Cordell, J. Org. Cheni., 1988, 53,2183. 4 T. Amatayakul, J. R. Cannon, P. Dampawan, T. Dechatiwongse. R. G. F. Giles, C. Huntrakul, K. Kusamran, M. Mokhasamit, C. L. Raston, V. Reutrakul and A. H. White. AUSI.J. Chc,tii.,19’79, 32, 71; H. Dinter, R. Hansel and A. Pulter, Z. Ncirirr/br.vc~li..Swt. IT,1980, o.uyhenzj~1)-5.7-diisopropoxy-2-methyfnaphthafene32.-A sol-ution of the diol 30 (210 mg), triethylamine (8 drops) and trifluoroacetic anhydride (0.5 cm3) in anhydrous THF was stirred under an atmosphere of hydrogen with palladized charcoal (lo”., 50 mg) for 18 h.Work-up gave a crude product which was purified by radial chromatography with lo:/, ethyl acetate-light petroleum as eluent to give the naphthalene 32 (160 mg, XO”,,) as a gum (Found: C, 76.0; H, 8.3. C38H4806 requires C. 75.95; H, 8.050,’,); 6,(300 MHz) 1.21 (6 H, d, Me,), 1.33-1.45 (18 H, m, 3 x Me,), 2.06 (3 H, s, Me), 3.79 and 3.80 (each 3 H, s. OMe), 4.12 (2 H, s, CH,), 4.32, 4.47, 4.61 and 4.66 (each 1 H, septet CNMe,), 6.24 and 6.43 (each 1 H, d, J 2.1, 6- and 8-H), 6.64-7.01 (6 H, m, ArH’) and 7.97 (1 H, s, 4-H); vmax(fiIm)/cm’ 1110; m/z 600 (M+, 473, 432 (9) and 137 (100).35,254.1-(4-/.~c~propos~-3-met~~o~u~phen~l)-3-(4-isopropo.~~-3-meth-5 D. A. Whiting, Nut. Prod. Rc>ports,1985, 2, 191. 6 C. Konno, Z. Z. Lu, H. Z. Xue, C. A. J. Erdelmeier. D. Meksuriyen. C. T. Che, G. A. Cordell. D. D. Soejarto. D. P. Walter and H. S. Fong, J. Nut. Prod..,1990, 53,396. 7 T. Umezawa, L. B. Darvin. E. Yamamoto. D. G. I. Kingston and N. G. Lewis. J. Chm7. Soc.,Chtwi. C’onitnun., 1990. 1305. 8 U. Weiss and J. M. Edwards, Thtj Bio.~jwthr~sof ili.ot71utic Conipounrl.~,John Wiley and Sons, New York. 1980. p. 304. 9 G. Soliman and A. Latif, J. Chtwi. Soc., 1944. 55. 10 T. Sala and M. V. Sargent, J. Cheni.Sot,.,Pcrliiri Truti,!.I, 1979, 2593. 11 A. I. Meyers and W. B. Avila, J. Org. Cheni.. 1981. 46. 3881. 12 H. Pudleiner and H. Laatsch, S~~t7rhr.si.s.1989, 386. 13 P. A. Aristoff, A. W. Harrison and A. M. Huber. 7c~ri.ulic~clri)nLctr., 1984,3955. 14 M. A. Rizzacasa and M. V. Sargent, Aust. J. Ch~ni..1987, 40, 1737; A. F. Cameron, F. D. Duncanson, A. A. Freer. V. W. Armstrong and R. Ramage, J. Chcm. Soc., Pcrkiii Trut7.v.2, 1975, 1030. 15 A. I. Meyers, R. Gabel and E. D. Mihelich, J. Org. (’hcni.. 1978, 43, 1372. 16 M. A. Rizzacasa and M. V. Sargent, J. Cheni. Soc.. f’(JrkitiTrms. I,8-(4-H~~rlro.~~~~-3-r.iz~~t~z~~.~j~p~i~nj~l)-6-(4-h~~dro.~j~-3-~net~z~~.~~~-1,4-dione (Larrruntin) 1991,841.htw~~~~l)-2-ni~~tl~o.~~~~-7-met~~~~lnup/~t~ialene-17 L. C. Raiford and L. K. Tanzer, J. Org. Ch~wi..1941. 6. 722. 1. -A solution of the foregoing naphthalene 32 (100 mg) in 18 R. Dickinson, I. M. Heilbron and F. Irving, J. Chwi. .S’oc.. 1937, 1888. anhydrous dichloromethane (5.0 cm3) was stirred at -10 ‘C and treated with boron trichloride (592 mg) in dichloromethane (770 mm3). The solution was next stirred at 0 -‘Cfor 8 h and then treated with water and extracted with ethyl acetate. The