Synthesis of ubiquinones. Elongation of the heptaprenyl side-chain in ubiquinone-7

摘要

1978 1101 Synthesis of Ubiquinones. Elongation of the Heptaprenyl Side-chain in Ubiquinone-7 By Shinji Terao," Kaneyoshi Kato, Mitsuru Shiraishi, and Hiroshi Morimoto, Chemical Research Labora- tories, Central Research Division, Takeda Chemical Industries, Ltd., Osaka, 532, Japan Regio- and stereo-chemically selective transformation of the terminal trans-methyl group of the heptaprenyl side- chain in ubiquinone-7 (la; n = 6) and its O-benzylated quinol (lb) into the trans-chloromethyl group and the coupling of the resulting compound (1Ob) with prenyl, geranyl, and farnesyl p-tolyl sulphones (14a, b, c), with subsequent reductive elimination of p-tolylsulphonyl and benzyl groups and oxidation of the corresponding quinols, have resulted in a novel synthesis of ubiquinone-8, -9, and -10 (1 a; n = 7,8, and 9).'H and 13C n.m.r. spectra of ubiquinone-7 and its derivatives, and of several sulphones as reference compounds, are discussed. UBIQU $0~ESare a family of 2,3-dimethoxy-5-methyl- 6-polyprenyl-l,4-benzoquinoneswhich function in the electron transport and oxidative phosphorylation pro- cesses in mitochondria. Ubiquinones having an all-trans polyprenyl side-chain and containing from one to twelve isoprenoid units have been found in nature. Ubiquinone-10 is the most common member in animals.l* Classi~ally,~-~ubiquinone-8, -9, and -10 (la; n = 7, 8, and 9) have been synthesised by acid-catalysed con-densation of 2,3-dimethoxy-5-methylhydroquinonewith the corresponding polyprenyl alcohol or isopolyprenyl alcohol, followed by oxidation of the resulting ubiquinol to the quinone.Optimal yields for ubiquinones syn- thesised by this method rarely exceed 20. Recently lo the prenyl component has been activated as a nucleo- phile via the x-allylnickel complex and condensed with appeared possible based on the report by Johnson et a2.l1 in which a trans-trisubstituted olefinic bond was gener- ated stereospecifically by the SNi' reaction of thionyl chloride with an allylic alcohol. We further considered the modification of the terminal prenyl group of the side-chain of a ubiquinone possible by the same type of reaction employed by van Tamelen et aZ.12in the syn- thesis of 2,3-epoxysqualene. Ubiquinone-7 (la; n = 6) was chosen by us as the starting material because of its availability from the fermentation of Candida utiZis.The second type of component euro;or the coupling re- action which appeared attractive was a prenyl p-tolyl sulphone based on an analogous study by Grieco et Below we described the preparation of these two types of components and the coupling reactions in- volving them. Because of the known sensitivity of the a protected 6-bromo-2,3-dimethoxy-5-methylhydro-quinonoid moiety of ubiquinones to nucleophiles and to quinone with subsequent oxidation to the corresponding prenylated quinone. By this method ubiquinone-10 has been synthesised in 28y0 yield from decaprenyl bromide. These approaches remain fundamentally limited by the inherent instability of the allylic alcohol component under the acidic conditions employed and by the lack of complete retention of trans-stereo-chemistry at the A2 position.The present method over- comes these difficulties in synthesis and provides a novel and versatile synthesis of quinones with a polyprenyl side-chain. For this coupling reaction, one type of component that seemed possible was a ubiquinone derivative in which the terminal trans-methyl group 7 of the poly- prenyl side-chain had been converted into a chloro-methyl group. The synthesis of such compounds t Geometrical configurations of the two methyl groups of the terminal prenyl group in the side-chain of ubiquinones follow the IUPAC-IUB Tentative Rules for Nomenclature (J. Biol. Chem., 1972, 247, 2638).' Ciba Foundation Symposium on Quinones in Electron Transport ', ed. G. E. W. Wolstenholme and C. M. O'Connor, J. amp; E. Churchill, London, 1961. A. F. Wagner and K. Folkers, ' Vitamins and Coenzymes ', Interscience, New York, 1964, p. 435. ' Biochemistry of Quinones ', ed. R. A. Morton, Academic Press, New York, 1965. ' Vitamins and Hormones ', Vol. 24, ed. R. S. Harris, 1. G. Wool, and J. A. Loraine, Academic Press, New York, 1966, pp.427, 465, and 551. ' Methods in Enzymology ', ed. D. B. McCormick and L. D. Wright, Academic Press, New York and London, 1971, Vol. 18, Part C, p. 135. alkaline reaction conditions, we have carried out parallel series of reactions involving ubiquinone-7 (la; n = 6) and its corresponding O-benzylated hydro-quinone (1b).Bromohydrination of (la; n = 6) and (lb) with N-bromosuccinimide (NBS) in 20 aqueous 1,2-di-methoxyethane at -5 "C gave the terminal mono-bromohydrins (2a, b) in good yields. During this re- action a small amount of presumably more than one dibroniohydrin compound was obtained, but these were not further investigated. The lH n.m.r. spectra of (2a) and (2b) showed a new dimethylcarbinol group at 8 1.34 (singlet) and CHBr at 6 3.97 (quartet) with the dis- appearance of the terminal trans-methyl (8 1.68) of the starting materials. When monobromohydrins (2a, b) were treated with an equimolar amount of potassium H. Morimoto and I. Imada, ' Methodicum Chimicum ', ed. I;.Korte, Georg Thieme Verlag, Stuttgart, 1977, vol.11, part 2, p. 117.' C. H. Shunk, R. E. Ericlrson, E. L. Wong, and K. Folkers, J. Amer. Chem. SOC.,1959, 81, 5000.* R. Riiegg, U. Gloor, R. N. Goel, G. Ryser, 0. Wiss, and 0. Isler, Helv. Chtim. Acta, 1959, 42, 2616. R. Ruegg, U. Gloor, A. Langemann, M. Kofler, C. von Planta, G. Ryser, and 0. Isler, Helv. Chim. Ada, 1960, 43, 1745. lo K. Sato, S. Inoue, and R. Yamaguchi, J. Org. Chem., 1972,37, 1889. l1 W. S. Johnson, T.-t. Li, C. A. Harbert, W. R. Bartlett, T. R. Herrin, B. Staskun, and D. H. Rich, J. Amer. Chem. SOC.,1970, 92, 4461. l2 E. E. van Tamelen and T. J. Curphey, Tetrahedron Letters, 1962, 121. P. A. Grieco and Y. Masaki, J. Org. Chem., 1974, 89, 2136. carbonate in methanol, the terminal epoxides (3a, b) were obtained in good yields. The epoxide (3b) could also be prepared by treatment of (3a) with sodium borohydride in ethanol to give the hydroquinone epoxide, which was then benzylated with benzyl bromide in the presence of sodium hydride.The epoxides (3a, b) were treated in aqueous 1,2-dimethoxyethane in 0 Me0 Me0 0 0 002 Me0 Me0 a b R Br H2CTe Me OH ,CHO YC the presence of perchloric acid to give the glycols (4a, b) in good yields. When oxidised with metaperiodic acid, the glycol (4a) produced acetone and the aldehyde (5a). This confirms that the double bond of the terminal prenyl unit of (la; n = 6) was modified regiospecifically. Acetylation of the glycols (4a, b) with acetic anhydride and pyridine gave the monoacetates (6a, b) in good yields.The monoacetate (6a) was also prepared by treatment of (3a) with a hot mixture of acetic acid and sodium acetate. The two terminal methyl groups showed different chemical shifts at 6 1.26 and 1.30 in J.C.S. Perkin I (3a, b) and at 6 1.16 and 1.20 in (4a, b) while appearing as a single signal at 6 1.34 in (2a, b), at 6 1.20 in (6a), and at 6 1.17 in (6b). Dehydration of (6a) and (6b) in n-hexane with thionyl chloride and pyridine at 0 "C gave the ally1 acetates (7a, b), respectively, together with a small amount of the isomeric monoacetates (8a, b). OBz 00z BZo-pRR C R R OAc (lOa,b,c) HzCTCl ?Ac H2C Me Me OHI Ike Me OH Ae he The structures of (2a), (3a), (4a), (6a), and (7a) are also supported by the 13C n.m.r.spectra shown in the Table. The carbon assignments * were based on chemical shifts, multiplicities in the off-resonance spectra, comparison with polyisoprenoid compounds, ubiquinones, and theoretical considerations. It is believed that assign- ments for the quinone ring carbons (1-6), isoprenoid carbons (1'-4' and 24'-28'), and carbons of vinyl methyl groups are reasonably certain, although assign- * Chemical shifts of the carbons in ubiquinones and the related polyprenylated compounds will be published elsewhere. ments for carbons (5rsquo;-23rsquo;) in the heptaprenyl side- chains are somewhat doubtful. Hydrolysis of the allyl acetates (7a, b) with sodium hydroxide gave the desired allyl alcohols (9a, b) in good yields.The allyl alcohol (9b) could also be prepared by the direct isomerisation l4 of the epoxide (3b) with an excess of lithium di-isopropylamide in absolute tetra- hydrofuran. This reaction was also convenient for the preparation of the allylic alcohol (9b). By reaction with 1.5molar equivalents of thionyl chloride in n-hexane the allyl alcohols (9a, b) were converted into the desired trans-chloromethyl compounds (10a, b) via an SNirsquo; reaction; a small amount (5) of the secondary chloride (lla, b) arose from direct SNi substitution. CHCl (6 4.80). To clarify the relationship between the chloromethyl group and the vinyl proton (HA), (loa) and (lob) were converted into the corresponding formyl compounds (12a, b) by the silver-assisted dimethyl sulphoxide oxidation of Ganem et a1.l5 From the n.m.r.spectra of the formyl compounds (12a, b) ,the relation- ship bet-ween the vinyl proton (HLL,6 6.46) and the formyl group (6 9.37) can be assigned as cis, by com-parison with values in the literature.l69 l7 Therefore, it is clear that CH,Cl and HAin the chloromethyl com-pounds (10a, b) must be in a cis-relationship. Similar oxidation of (lla)led to the ap-unsaturated ketone (13a). Grieco et aZ.13 have succeeded in activating the methylene group adjacent to the hydroxy-group in 13C N.m.r. chemical shifts a of ubiquinone-7 and its derivatives Carbon No. 1 (la) n = 6 184.4 (2a) 184.0 (3a)184.0 (4a) 184.3 (6a) 184.3 (7a) 184.3 Carbon No.15rsquo; (la) n = 6 134.6 (2a) 134.4 (3a) 134.4 (44134.6 (6a) 134.6 (74 134.7 2 144.0 144.1 144.1 144.2 144.2 144.1 16rsquo; 39.7 39.5 39.4 39.6 39.6 39.6 3 144.2 144.2 144.2 144.3 144.4 144.2 17rsquo; 26.6 26.5 26.5 26.7 26.5 26.7 4 183.6 183.3 183.2 183.5 183.5 183.5 18rsquo; 124.0 124.2 124.1 124.1 124.1 124.2 5 141.5 141.3 141.3 141.5 141.5 141.5 19rsquo; 134.6 134.2 134.2 134.6 134.6 135.0 6 138.6 138.7 138.3 138.6 138.6 138.6 20lsquo; 39.7 39.5 39.4 39.6 39.6 39.6 2-OCH3 61.0 60.6 60.6 60.8 60.8 60.9 21lsquo; 26.4 26.3 26.3 26.7 26.5 26.7 3-OCH, 5-CH3 61.0 11.9 60.6 11.6 60.6 11.6 60.8 11.8 60.8 11.7 60.9 11.8 22rsquo; 23rsquo; 124.2 135.0 25.6 32.7 24.6 33.5 24.3 34.5 124.8 133.7 124.7 133.6 1lsquo; 25.2 25.1 25.1 25.2 25.2 25.2 24lsquo; 39.7 38.0 36.1 36.7 36.1 35.2 2rsquo; 118.7 118.7 118.7 118.8 118.9 118.8 3rsquo;-CH3 16.3 16.1 15.8 16.2 16.2 16.2 3rsquo; 137.4 137.0 137.0 137.3 137.3 137.3 7rsquo;-CH3 16.0 15.8 15.8 15.9 15.9 15.9 4lsquo; 5rsquo; 39.7 26.6 39.5 26.5 39.4 26.5 39.6 26.5 39.4 26.5 39.6 26.7 lllsquo;-CH, 15rsquo;-CH3 16.0 16.0 15.8 15.8 15.8 15.8 15.9 15.9 15.9 15.9 15.9 15.9 6rsquo; 123.6 123.6 123.6 123.7 123.7 123.7 19rsquo;-CH3 16.0 15.8 15.8 15.9 15.9 15.9 7rsquo; 134.6 134.7 134.7 134.9 134.7 134.6 23rsquo;-CH3 16.0 15.8 15.8 15.9 15.9 15.9 8lsquo; 39.7 39.5 39.4 39.6 39.6 39.6 25lsquo; 25.6 32.0 27.3 29.8 28.0 31.1 9rsquo; 26.6 26.5 26.5 26.5 26.5 26.7 26lsquo; 123.6 70.0 63.7 78.2 70.7 76.9 10rsquo; 124.0 124.0 123.9 124.0 124.1 124.1 27lsquo; 130.9 72.1 57.7 72.7 72.3 143.0 11rsquo; 134.6 134.4 134.4 134.6 134.6 134.7 28rsquo; 25.4 26.1 24.6 23.4 24.9 112.4 18rsquo; 13rsquo; 14rsquo; 39.7 26.6 124.0 39.5 26.5 124.0 39.4 26.5 124.0 39.6 26.7 124.1 39.6 26.5 124.1 39.6 26.7 124.1 CH,COO CH3CO0 27rsquo;-CH, 17.5 22.7 18.5 25.2 26.7 20.8 170.7 18.0 20.9 169.7 In parts per million downfield from SiMe,.*The numbering system of ubiquinone-7 and its derivatives follows the IUPAC-IUB nomenclature (see Biochim. Biophys. Ada, 1965, 107,5). The reaction of (9a) with thionyl chloride and pyridine in methylene chloride gave the secondary chloride (1la) in good yield. Compounds (10a) and (lob) were characterised and their chloromethyl groups were shown to have a trrzm-configuration, as described below.The lH n.1n.r. spectra of (10a) and (lob) showed characteristic methylene protons of the chloromethyl group at 6 3.99 (singlet) with disappearance of the terminal methylene protons (6 4.85 and 4.94) observed in the allyl alcohols (9a, b). The compounds (10a, b) can be clearly distin- guished from the secondary chloride (lla)by the com- parison of their lH n.m.r. spectra. The latter (lla) shows absorption characteristic of the terminal methylene protons (6 4.95 and 5.00) and the methine proton of l4 cf. J. F. Crandall and L.-Ho Chang, J. Org. Chem., 1967, 32, 435. farnesol by introducing a sulphonyl group and in using this intermediate in synthesising squalene in a highly stereosyecific manner.By this method the prenyl derivatives (14a, b, c and 15a, b) were prepared from the reaction of sodium toluene-fi-sulphinate with l-bromo- 3-methylbu t -2-ene ,geran yl chloride, trans,trans-f arnesyl bromide, neryl chloride, and cis,trans-farnesyl bromide, respectively. As expected the more mobile cis-isomer was readily separated from the trans-isomer by chro- matography on silica gel. In the lH n.m.r. spectra, the y-methyl to the sulphone group in the trans-isomers (14a, b, c) appears at a considerably higher field (6 ca. 1.37) compared with the other methyl groups, l5 B. Ganem and R. K. Boeckman, jun., Tetrahedron Letters, 1974, 917. l6 A. F. Thomas, Chem. Comm., 1968, 1657. l7 D.J. Faulkner, Synthesis, 1971, 175. 1104 J.C.S. Perkin I while the y-methyl in the cis-isomers (15a, b) appears this could be done by a combination of lH n.m.r. and at a much lower field (6 ca. 1.72). It was difficult to 13C n.m.r. spectroscopy for the specific decoupling of Ar 6 1.65 6 1.37 +Y6 1.73 6 1.55 ( 14a) (15a 1 61.72 6 1.55 6 l..SO (15 b) At 6 1.70 6 1.37 6 1.61 6 1.61 Me0 H Ar 6 1.21 -1.24. (16) a; m=O b;m=l c;m=2 620 6 1.68 6 1 .-61 61.54 At 61.24 6 1.61 (17 1 6 1.58 6 1.60 6 1.65 6 1.65 6 1.60 6 1.60 61.25 Ar (18) assign each chemical shift of the vinyl methyl groups each vinyl methyl group of (15a). Our results see in the cis-isomers (15a, b) by comparing their lH (15a)I are inconsistent with the data (6 1.50, 1.60, and n.m.r. with those of trans-isomers (14a, b, c).However, 1.65 for methyls at positions 3 and 7, and for 8-methyl, respectively) which were reported by Campbell et d.18 This characteristic difference of the y-methyls between cis-and trans-isomers is helpful for the judgement of cis-and trans-configuration in the products of the coupling reactions described below. When 1 mol equivalent of (lob) was added at -70 ldquo;C to each of orange coloured carbanionic solutions, pro- duced from the sulphonyl compounds (14a, b, c) with n-butyl-lit hium in absolute tetrahydrofuran-hexamethyl-phosphoramide at -20 ldquo;C, the orange colour faded as the reaction proceeded. After gradual warming of the reaction mixtures to 0 ldquo;C, the coupled compounds (16a, b, c) were obtained by purification on silica gel.In the lH n.m.r. spectra of (16a, b, c) the y-methyl group -( p)C=(y)C-CH, to the sulphonyl group appeared at a much higher field (6 ca. 1.24) as a split doublet. This characteristic methyl group indicates that it is cis to the bulky CHS0,Ph-CH, group. Some coupled com-pounds, (17), (19), and (18), were synthesised, as refer- ence compounds in order to compare their lH n.1n.r. spectra with those of (16a, b, c) by using the same coupl- ing reaction of the chloride (1Oc) which was prepared from geranyl benzyl ether according to the same transform- ation employed above, with (14b) and (15a), and of geranyl chloride with (14c), respectively. Our result in the coupling reaction is consistent with the finding of Grieco et a1.l3 that no isomerisation of the double bonds is observed during the synthesis of squalene.Reductive elimination of the sulphonyl and benzyl groups of the coupled compounds (16a, b, c) was con- veniently carried out at -30 ldquo;C with lithium in ethyl- amine. The resulting hydroquinones were oxidised with ferric chloride to give the crude quinones, which were purified by silica gel chromatography. The synthesised ubiquinone-8 (la; n = 7), ubiquinone-9 (la; n = S), and ubiquinone-10 (la; n = 9) were identified by lH n.m.r. and mass spectroscopy and by mixed melting points with authentic ~amp1es.l~ Clearly applicable to the synthesis of other quinone derivatives, this modification of the terminal trans-methyl group, followed by a coupling reaction with a reactive carbanion of an appropriate prenyl compound, could well provide a general synthesis of menaquinones, plastoquinones, and other natural products bearing a prenylated aromatic nucleus.The regio- and stereo- selectivity, as demonstrated here, makes this method ideal for such syntheses. EXPERIMENTAL M.p.s are uncorrected. lH and 13C n.m.r. spectra were recorded for CDCl, solutions with a Varian XL-100 spectro- meter using internal Me,Si (6 = 0) as a standard. 1.r. spectra were obtained on a Hitachi EPI-510 spectrometer. Mass spectra were determined on a JEOL JMS-OlSC spectrometer. U.V. spectra were recorded with a Hitachi EPS-3T spectrometer in ethanol.High-pressure liquid chromatographic analyses (h.p.1.c.) were performed on a Yanagimoto L- 1030 liquid chromatograph using a silica l8 R. V. M. Campbell, L. Crombie, D. A. R. Findley, R. W. King, G. Pattenden, and D. A. Whiting, J.C.S. Perkin I, 1975, 897. 1105 gel column. The latter were conducted by Mr. M. Hattori of our Chemical Laboratories. Liquid column chromato- graphy was carried out on Merck silica gel (less than 0.08 mm) for thin-layer chromatography under a pressure of 10-20 kg/cm2. Tetrahydrofuran (THF), hexamethyl- phosphoramide (HMPA), dimethyl sulphoxide (DMSO), and isopropyl ether (IPE) were dried by distillation from calcium hydride. In the 1H n.m.r. spectra of the compounds, derived from ubiquinone-7 (la; n = 6) and its hydroquinone dibenzyl ether (lb),the only signals described are for the protons at positions which were chemically changed, since the others appear at essentially the same positions as those in the spectraof (la; n = 6) and (lb).Ubiquinone-7 (la; n = 6).-Ubiquinone-7 20,21 was iso- lated from Candida utilis. It had m.p. 31-32 ldquo;C, 8 1.61 (18 H, broad s, six methyl groups), 1.68 (3 H, s, Me at position 28rsquo;), 1.74 (3 H, s, Me at position 3rsquo;), 2.02 (24 H, twelve methylene groups), 3.14 and 3.22 (2 H, AB d, CH, at position lrsquo;),3.97 and 3.99 (6 H, two s, OMe), ca. 5.10 (7 H, m, vinyl protons). Ubiquinol-7 Dibenzyl Ether (lb).-Ubiquinone-7 (la; n = 6) (1.32 g, 2 mmol) was reduced to the corresponding hydroquinone in ethanol with sodium borohydride (500 mg).The ethanolic solution was concentrated in vacuo to dryness. The residue was dissolved in dimethylformamide (DMF) (20 ml). To the solution was added benzyl bromide (513 mg, 6 mmol) and 50 sodium hydride (300 mg, dis- persed in oil, 6 mmol) under nitrogen at room temperature. This was stirred for 3 h. The crude product, obtained by addition of water and- extraction of the aqueous mixture with n-hexane, was chromatographed on silica gel (60 g) using n-hexane-IPE (3 : 1) for elution to give the benzyl ether (lb) (1.56 g); 6 1.60 (18 H, broad s, six vinyl methyls), 1.68 (6 H, s, two vinyl methyls at 3rsquo; and 28rsquo;), 2.01 (methyl- enes), 2.11 (3 H, s, arom-Me), 3.30 and 3.36 (2 H, AB d, CH, at 1rsquo;), 3.93 and 3.94 (6 H, two s, OMe), 4.96 (4 H, s, CH,Ph), ca.5.10 (7 H, m, vinyl protons), and 7.3-7.60 (10 H, m, arom-H) (Found: C, 82.9; H, 9.3. C,,H,,O, requires C, 82.81 ; H, 9.59). 6-(26rsquo;-Bromo-27rsquo;-hydroxy-3rsquo;,7rsquo;,1lrsquo;,15rsquo;, 19rsquo;,23rsquo;,27rsquo;-h@ta- methyloctacosa-2rsquo;, 6rsquo;, lolsquo;, 14rsquo;, 18rsquo;, 22rsquo;-hexenyl)-2, 3-dimethoxy- 5-methyl- 1,4-benzoquinone (2a) .-To a solution of ubi-quinone-7 (la; n = 6) (1.977 g, 3 mmol) in 20 aqueous 1,2-diniethoxyethane (100 ml), cooled to -5 ldquo;C and well stirred, was added NBS (590 mg, 3.6 mmol) portionwise over a period of 1 h. The reaction mixture was stirred for a further 2 h and then diluted with ethyl acetate. The organic layer was washed with water, dried (Na,SO,), and evaporated in vacuo to yield an orange oil (2.29 g) which was chromatographed on silica gel (100 g) using 2 : 1 n-hexane-IPE for elution to give the starting material (238 mg).Elution with IPE gave the bronzohydrin (2a) (1.542 g, 68) as an orange oil; vmxe (neat) 3 500 (OH), 1650 and 1614 (quinone and double bond), and 1265 cm-l; 6 1.34 (6 H, s, Me,COH) and 3.97 (1H, q, J = 6 and 13 Hz, =CHBr) (Found: C, 69.6; H, 8.9. C,,H,,BrO, requires C, 69.91; H, 8.93). Further elution with 9: 1 IPE-ethyl acetate gave the dibromohydrin (78 mg) which was not further investigated. l9 H. Morimoto, T. Shima, and I. Imada, Biochem. Z., 1965, 343, 329. 2O I. Imada, S. Wada, H. Shimazono, N. Miyata, and M. Miwa, Nippon Nogei-Kagaku Kaishi, 1963, 37, 580. 21 H. Morimoto, I. Imada, and G. Goto, Annalen, 1969,729,171.1106 6-(26rsquo;-Bromo-27rsquo;-hydroxy-3rsquo;,7rsquo;,1lrsquo;,15rsquo;, 19rsquo;,23rsquo;,27rsquo;-hepta- methyloctacosa-2rsquo;, 6rsquo;, lorsquo;, 14rsquo;, 18rsquo;, 22rsquo;-hexenyl) -2,3-dimethoxy- 5-methylhydroquinone 00lsquo;-Dibenzyl Ether (2b) .-Ubiquinol-7 dibenzyl ether (lb) (1.682 g, 2 mmol) in 20 aqueous 1,2-dimethoxyethane (100 ml) was bromohydrinated with NBS (427 mg, 2.4 mmol) as described above. The usual work-up gave a colourless oil which was chromatographed on silica gel (100 g) using 95 : 5 IPE-ethyl acetate for elution to yield the bromohydrin (2b) (1.21 g, 72); 6 1.34 (6 H, s, Me,C-OH), 3.97 (1 H, q, J = 6 and 13 Hz) (Found: C, 74.1; H, 8.5. C5,H8,Br0, requires C, 74.25; H, 8.70). Further elution with 9: 1 IPE-ethyl acetate gave the dibromohydrin (287 mg) which was not further investigated.6-(26rsquo;,27rsquo;-Epoxy-3rsquo;,7rsquo;, 1 lrsquo;,15rsquo;,19rsquo;,23rsquo;,27rsquo;-heptamethylocta-cosa-2rsquo;, 6rsquo;, lorsquo;, 14rsquo;, 18rsquo;, 22rsquo;-hexenyl) -2,3-dimethoxy-5-methyl-l14-benzoquinone (3a).-To a stirred solution of the bromo- hydrin (2a) (756 mg, 1 mmol) in methanol (10 ml) was added potassium carbonate (140 mg) at room temperature. After the reaction was completed, the mixture was concen- trated in vacuo. The residue was dissolved in n-hexane and the solution was washed with water and dried; the solvent was evaporated off to yield the epoxide (3a) (672 mg, 99.7). This was used without purification in the follow- ing reaction, vmax. (neat) 1650 and 1612 (quinone and double bond) and 1265 cm-l; m/e 81, 197, 235, 250, 678 (Mrsquo;), and 676 (M+ + 2); 6 1.26 and 1.30 (6 HI two s, =CMe,) and 2.68 (1 H, t, J = 6 Hz, XH-0) (Found: C, 78.5; H, 9.6.Camp;,@5 requires C, 78.29; H, 9.86). 6-(26rsquo;,27rsquo;-Epoxy-3rsquo;,7rsquo;, 1 lrsquo;,15rsquo;,19rsquo;,23rsquo;,27rsquo;-heptamethylocta-cosa-2rsquo;, 6rsquo;, 1 0rsquo;, 14rsquo;, 18rsquo;, 22rsquo;-hexenyl) -2,3-dimetlzoxy-5-methyl-hydroquinone (3b),-(a) Treatment of the bromohydrin (2b) (983 mg, 1 mmol) with potassium carbonate (140 mg) in methanol (10 ml) as described above gave the epoxide (3b) (896 mg, 99.3) as a colourless oil; 6 1.26 and 1.30 (6 H, two s, =CMe,) and 2.68 (1 H, t, J = 6 Hz, =CH-0) (Found: C, 81.3; H, 11.6. C5,H,,0, requires C, 81.26; H, 9.41). (b) Reduction of the epoxide (3a) (675 mg, 1 mmol) in 95 ethanol (10 ml) was performed with sodium boro- hydride (100 mg), and the resulting hydroquinone com- pound, after lsquo;removal of the ethanol, was dissolved in DMF (30 ml) and then benzylated with benzyl bromide (350 mg) in the presence of 50 sodium hydride (200 mg, dispersed in oil) at room temperature for 1 h.The reaction mixture was worked up as usual and then chromatographed on silica gel (30 g) using 3 : 2 n-hexane-IPE for elution to yield the epoxide (3b) (791 mg, 92.3). 6-(26rsquo;,27rsquo;-Dihydroxy-3rsquo;,7rsquo;, 1 llsquo;,15rsquo;, 19rsquo;, 23rsquo;, 27rsquo;-heptamethyl- octacosa-2lsquo;,6rsquo;, lolsquo;, 14rsquo;,18lsquo;,22lsquo;-hexenyl)-2,3-dimethoxy-5-methyl- 1,4-benzoquinone (4a) .-To a solution of the epoxide (3a) (1.348 g, 2 mmol) in aqueous 1,Qdimethoxyethane (50 ml) was added 70 perchloric acid (0.1 ml) at room temperature. The solution was then set overnight. The product was extracted with ethyl acetate and the organic layer was washed, dried, and evaporated.The residue was chromatographed on silica gel (100 g) using 96 : 4 n-hexane- ethyl acetate for elution to give the glycol (4a) (1.312 g, 94.7) as an orange oil; vnlax. (neat) 3 400 (OH), 1 650 and 1 612 (quinone and double bond), and 1 265 cm-l; 6 1.16 and 1.20 (6 H, two s, Me,COH) and 3.34 (1 H, q, J = 3 and 9 Hz, =CH-O) (Found: C, 76.0; H, 10.1. C44H6,06 requires C, 76.26; H, 9.89). 6-( 26rsquo;, 27rsquo;-Dihydroxy-3rsquo;, 7rsquo;, 1lrsquo;, 14rsquo;, 19rsquo;, 23rsquo;, 27rsquo;-octametlzyl- octacosa-2rsquo;, 6rsquo;, lorsquo;, 14rsquo;, 18rsquo;,22rsquo;-hexenyl)-2,3-dimethoxy-5-J.C.S. Perkin I methylhydroquinone OOrsquo;-Dibenzyl Ether (4b) .-Treatment of the epoxide (3b) (857 mg, 1 mmol) with 70 perchloric acid (0.1 ml) in 10 aqueous 1,2-dimethoxyethane (30 ml) as described above gave the glycol (4b) (865 mg, 98.8) as a colourless oil; 6 1.16 and 1.20 (6 H, two s, =CMe,) and 3.34 (1 HIq, J = 3 and 9 Hz, =CH-0) (Found: C, 79.4; H, 9.6.C5,H,B06 requires C, 79.59; H, 9.44). 6-( 25rsquo;-Formyl-3rsquo;, 7rsquo;, 1lrsquo;,15rsquo;, 19rsquo;, 23rsquo;-lzexamethylpentacosa-2rsquo;, 6rsquo;, lorsquo;, 14rsquo;,18lsquo;,22lsquo;-hexeny1)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (5a).-To a solution of the glycol (4a) (207 mg, 0.3 mmol) in 5 aqueous 1,2-dimethoxyethane (10 ml) was added a solution of sodium metaperiodate (77 mg, 0.36 mmol) and concentrated sulphuric acid (26 mg, 0.36 mmol) in a minimum amount of water. The mixture was stirred at room temperature until the reaction was completed. Water (25 ml) and n-hexane (30 ml) were added to the mixture and shaken.Then the organic layer was separated, washed, dried, and evaporated. The residue was chro-matographed on silica gel (10 g) using IPE for elution to yield the aldehyde (5a) (153 mg, 81.8); v,,,. (neat) 2 720 and 1720 (CHO), 1650 and 1610 (quinone and double bond), and 1270 cm-rsquo;; 6 2.40 (2 H, m, CH,CHO), 9.73 (1 H, t, J = 1.7 Hz, CHO) (Found: C, 77.6; H, 9.6. C4,H6,0, requires C, 77.80; H, 9.56). 6-(26rsquo;-Acetoxy-27rsquo;-hydroxy-3rsquo;,7rsquo;, 1 1 rsquo;,15rsquo;,19rsquo;,23rsquo;, 27rsquo;-hepta- methyloctacosa-2rsquo;, 6rsquo;, lorsquo;, 14rsquo;, 18rsquo;, 22rsquo;-lzexenyl) -2,3-dimethoxy- 5-meth-yl- 1,4-benzoquinone (6a).-(a) A mixture of the epoxide (3a) (674 mg, 1 mmol) and sodium acetate (400 mg) in acetic acid (4 ml) was warmed at 65 ldquo;C under nitrogen for 3 11, then cooled, and diluted with water (20 ml) and IIrsquo;E (40ml).The organic layer was separated, washed, dried, and evaporated. The residue was chromatographed on silica gel (50 g) using IPE for elution to give the mono- acetate (6a) (525 nig, 78) as an orange oil; vnBx. (neat) 3 450 (OH), 1735 (OAc), 1650 and 1612 (quinone and double bond), and 1 265 cm-l; 8 1.20 (6 H, s, =CMe,), 2.10 (3 H, s, OAc), 4.84 (1 H, q, J = 3 and 9 Hz, XHOAc) (Found: C, 75.2; H, 9.7. C46H,007 requires C, 75.16; H, 9.60). (b) To a solution of the glycol (4a) (693 mg, 1 mmol) in niethylene chloride (20 ml) was added pyridine (0.3 ml) and acetic anhydride (0.2 nil) at room temperature. The mixture was set aside overnight and then worked up as usual to give an orange oil.This material was chromato- graphed on silica gel (50 g) using IPE for elution to yield the monoacetate (699 mg, 95.2). 6-(26rsquo;-Acetoxy-27rsquo;-hydroxy-3rsquo;,7rsquo;,1lrsquo;,15rsquo;, 19rsquo;,23lsquo;,27rsquo;-hepta- methyloctacosa-2rsquo;,6rsquo;, lorsquo;, 14rsquo;, 18rsquo;, 22rsquo;-hexenyl)-2,3-dimethoxy-5-methylhydroquinone OOrsquo;-Dibenzyl Ether (Gb) .-Acetyl- ation of the glycol (4b) (438 mg, 0.5 mmol) in methylene chloride (5 mi) containing pyridine (0.1 ml) and acetic anhydride (0.1 ml) was carried out at room temperature overnight. The reaction mixture was diluted with IPE (30 ml) and worked up as usual to give an oil which was chromatographed on silica gel (20 g) using IPE for elution to yield the monoacetate (6b) (450 mg, 98.3) as a colourless oil; 6 1.17 (6 H, s, Me,COH), 2.07 (3 H, s, OAc), 4.84 (1 H, q, J = 3 and 9 Hz, =CHOAc) (Found: C, 78.4; H, 9.3.C,,H,,O, requires C, 78.56; 13, 9.23). 6-(26rsquo;-Acetoxy-27rsquo;-methylene-3rsquo;,7rsquo;,1 lrsquo;,15rsquo;, 19rsquo;,23rsquo;-hexa- methyloctacosa-2rsquo;,6lsquo;,lorsquo;,14lsquo;,18rsquo;,22rsquo;-hexenyl)-2,3-dimethoxy-5-methyl-l,4-benzoquinone(7a) .-To a solution of the mono- acetate (6a) (735 mg, 1 mmol) in n-hexane (20 ml), cooled to 0 ldquo;C, was added thionyl chloride (178 mg, 1.5 mmol) in n-hexane (5 ml). After the mixture had been stirred for 10 min, an n-hexane solution (5 ml) containing pyricline (0.25 ml) was added to the mixture. The reaction was further stirred for 20 min after which it was washed with water, dried, and concentrated. The residue was chro-matographed on silica gel (50 g) using 2 : 3 n-hexane-IPE to give the allyl acetate (7a) (687 mg, 95.8) as an oil; vmax (neat) 1735 (AcO), 1650 and 1613 (quinone and double bond), 1 265, and 1 235 cm-l; 6 1.74 (6 H, broad s, two vinyl methyl groups at 3rsquo; and 27rsquo; positions), 2.05 (3 H, s, OAc), and 4.89 and 4.95 (3 H, m, =CHOAc and =CH,) (Found: C, 76.9; H, 9.4.C4,H6,06 requires C, 77.05; H, 9.56). Further elution with IPE containing 3 ethyl acetate gave the isomeric acetate (8a) (21 mg) as an orange oil. When heated at 65 ldquo;C for 2 h in a mixture of sodium acetate (20mg) and acetic acid (0.5 ml), this material was converted into (6a). 6-(26rsquo;-Acetoxy-27rsquo;-methylene-3rsquo;,7rsquo;,1lrsquo;,15rsquo;, 19rsquo;,23rsquo;-hexa- methyloctacosa-2rsquo;, 6rsquo;, lorsquo;,14rsquo;. 18rsquo;, 22rsquo;-hexenyl) -2, 3-dimethoxy- 5-methylhydroquinone OOlsquo;-Dibenzyl Ether (7b).-Ile-hydration of the monoacetate (6b) (458 mg, 0.5 mmol) with thionyl chloride (120 mg, 1 mmol) and pyridine (0.2 ml) in n-hexane (10 ml) as described above gave the allyl acetate (7b) (437 mg, 97.3), after purification through a short column of silica gel; 6 1.74 (3 H, broad s, vinyl methyl at 27rsquo; position), 2.10 (3 H, s, OAc), and 4.89 and 4.95 (3 H, m, =CH-0 and C=CH,) (Found: C, 79.9; H, 9.1.C,,H,,O, requires C, 80.13; H, 9.19). Further elution with IPE containing 3 ethyl acetate gave the isomeric acetate (8b) (18 mg) as an oil. When heated at 65 ldquo;C for 2 h in a mixture of sodium acetate (20 mg) and acetic acid (0.5 ml), this material was con- verted into (6b). 6-(26rsquo;-Hydroxy-27rsquo;-methylene-3rsquo;,7lsquo;,1lrsquo;,15rsquo;, 19rsquo;,23lsquo;- hexamethyloctacosa-2rsquo;, 6rsquo;, lorsquo;,14rsquo;, 18rsquo;, 22rsquo;-hexenyl) -2,3-di- methoxy-5-methyl- 1,4-benzoquinone (9a).-A stirred solution of the allyl acetate (7a) (717 mg, 1 mmol) in 95 ethanol (20 ml) was treated with sodium borohydride (1 g) under nitrogen at room temperature until the orange colour had disappeared and then the mixture was treated with 10 aqueous sodium hydroxide (5 ml).After the hydrolysis was completed, 4 aqueous hydrochloric acid (25 ml) and IPE (40 ml) were added to the mixture. The usual work- up gave an oil which was dissolved in 10 aqueous 1,2-dimethoxyethane (20 ml) and oxidised with ferric chloride dihydrate (600 mg) with stirring at room temperature for 2 h. The reaction mixture was worked up as usual and the crude product was chromatographed on silica gel (30 g) using IPE for elution to yield the allyl alcohol (9a) (635 mg, 96.9) as an orange oil; vmax.(neat) 3 400 (OH), 1 650 and 1 612 (quinone and double bond), and 1 265 cm-l; 6 1.74 (6 H, broad s, two vinyl methyls at 3rsquo; and 27rsquo; positions), 4.03 (1 H, t, J = 6 Hz, =CHOH), and 4.85 and 4.94 (2 H, m, C=CH,) (Found: C, 78.3; H, 9.7. C44Hamp; requires C, 78.29; H, 9.86). 6-(26lsquo;-Hydroxy-27rsquo;-methylene-3lsquo;,7lsquo;,1 lrsquo;, 15rsquo;, 19rsquo;,23rsquo;- hexamethyloctacosa-2rsquo;, 6rsquo;, lorsquo;, 14rsquo;, 18rsquo;,22rsquo;-hexenyl-2,3-di- methoxy-5-methylhydroquinone OOrsquo;-Dibenzyl Ether (9b).-(a) The allyl acetate (7b) (450 mg, 0.5 mmol) in 10 aqueous 1,2-dimethoxyethane (10 ml) was hydrolysed with 1004 aqueous sodium hydroxide (0.4 ml) at room temperature for 6 h.The mixture was then concentrated in vacuo. The residue was dissolved in IPE (30 ml) and the solution was washed and dried. The solvent was evaporated to give the allyl alcohol (9b) (405 mg, 94.5) as a colourless oil, after purification through a short column of silica gel; 6 1.74 (3 H, broad s, vinyl methyl at 27rsquo; position), 4.03 (1 H, t, J = 6 Hz, =CHOH), and 4.85 and 4.94 (2 H, m, C=CH,) (Found: C, 81.2; H, 9.3. C,,H,,O, requires C, 81.26; H, 9.41). (b) A solution of the epoxide (3b)(875 mg, 1 mmol) in absolute THF (5 ml) was added to a THF solution (25 ml) containing lithium di-isopropylamide (500 mg). The mixture was set aside at 5 ldquo;C for 10 h and then neutralised with 2 aqueous hydrochloric acid (50 ml).The product was extracted with IPE and worked up as usual to yield an oil. This material was chromatographed on silica gel (30 g) using IPE for elution to give the allyl alcohol (9b) (756 mg, 86.4). 6-( 28rsquo;-CItloro-3rsquo;,7rsquo;, 1 lrsquo;,15rsquo;, 19rsquo;, 23rsquo;,27rsquo;-heptamethyZoctacosa-2lsquo;,6lsquo;, lorsquo;, 14rsquo;,18rsquo;,22rsquo;,26rsquo;-heptenyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (10a) .-A stirred mixture of the allyl alcohol (9a) (693mg, 1 mmol) and thionyl chloride ( 144 mg, 1.2 mmol) in n-hexane (10 ml) was set aside at room tem- perature. After the reaction was completed, the solution was washed with 3yo aqueous sodium hydrogencarbonate and water, dried, and evaporated. The residue was chromatographed on silica gel (50 g) using 1 : 1 n-hexane- IPE for elution to yield the chlorornethyl compound (loa) (587 mg, 84.7) as an orange oil; vmax.(neat) 1650 and 1 613 (quinone and double bond) and 1 265 cm-l; 6 1.74 (6 H, broad s, two vinyl methyls at 3rsquo; and 27rsquo; positions), 3.99 (2 H, s, CH,Cl), 5.52 (1 H, t, vinyl proton at 26rsquo; position) (Found: C, 76.0; H, 9.3. C,,H,,ClO, requires C, 76.21; H, 9.45). The h.p.1.c. analysis of the chloromethyl compound indicated the presence of the secondary chloride (lla) less than 5. 6-(28rsquo;-Chloro-3rsquo;,7rsquo;, 1lrsquo;,15rsquo;, 19rsquo;,23rsquo;,27rsquo;-he~tamethyloctacosa-2rsquo;, 6rsquo;, lorsquo;,14rsquo;, 18rsquo;, 22rsquo;, 26rsquo;-heptenyl) -2,S-dimethoxy-5-methyl-Ibydroquinone OOlsquo;-Dibenzyl Ether (lob) .-Chlorination of the allyl alcohol (429 mg, 0.05 mmol) with thionyl chloride (120 mg, 1 mmol) in n-hexane (10 ml) as described above yielded the chZoride (lob) (430 mg, 98.3); 6 1.72 (3 H, s, vinyl methyl at 27rsquo; position), 3.98 (2 H, s, CH,Cl) ,and 5.50 (1 H, t, vinyl proton at 26rsquo; position) (Found: C, 79.2; H, 8.9.C,,H,,ClO, requires C, 79.55; H, 9.09). The h.p.1.c. analysis of the chloromethyl compound indicated the presence of the secondary chloride (llb)less than 5. 6-(26rsquo;-Chloro-27rsquo;-methylene-3rsquo;,7rsquo;,1lrsquo;,15rsquo;, 19rsquo;,23rsquo;-hexa- methyloctacosa-2rsquo;,6rsquo;, lorsquo;,14lsquo;, 18rsquo;,22rsquo;-hexenyl)-2,3-dimethoxy-5-pl.zethyl-l,4-benzoquinone (1 la) .-To a stirred solution containing the allyl alcohol (9a) (135 mg, 0.2 mmol) and pyridine (1 ml) in methylene chloride (10 ml) at -20 ldquo;Cwas added slowly a methylene chloride solution (3ml) containing thionyl chloride (29 mg, 0.24 mmol).The temperature was raised to room temperature and stirred for 1 h. The mixture was diluted with 3 aqueous hydrochloric acid (25 ml) and methylene chloride (20 ml). The organic layer was separated, washed with water and aqueous sodium hydrogencarbonate, dried, and evaporated. The residue was chromatographed on silica gel (10 g) using IPE for elution to give the allyl chloride (lla) (127 mg, 91.6) as an orange oil; v,, (neat) 1 650 and 1 612 (quinone and double bond), 1 265, and 1 205 cm-l; 6 1.74 (6 H, s, two vinyl methyls at 3rsquo; and 27lsquo; positions), 4.80 (1 H, q, J = 6 and 14 Hz, =CHCl), and 4.95 and 5.00 (2 H, m, C=CH,) (Found: C, 76.1; H, 9.2. C,,H,,ClO, requires C, 76.21; H, 9.45). Oxidation of the Chloromethyl and the Secondary Chloro- compounds.-(a) 6-(27rsquo;-Formyl-3lsquo;,7lsquo;,1lrsquo;,15rsquo;, 19rsquo;,23rsquo;-hexa- methyloctacosa-2lsquo;, 6lsquo;,10rsquo;, 14lsquo;, 18rsquo;, 22lsquo;,26rsquo;-heptenyl) -2,3-dimeth- oxy-5-methyl-l,4-benzoquinone(12a).To a solution of the chloromethyl compound (loa) (166 mg, 0.239 mmol) in absolute Me,SO (5 ml) was added silver tetrafluoroborate (50 mg, ca. 90 with n-pentane) under nitrogen. The mixture was stirred at room temperature. A fine white precipitate developed as the reaction proceeded. After 2 h, triethylamine (0.6 ml) was added and the mixture was further stirred for 20 min. It turned black, water (10 ml) was added to the reaction mixture, and the product was extracted with IPE. The organic layer was separated, washed, dried, and evaporated.The residue was chro-matographed on silica gel (10 g) using 1: 2 n-hexane-IPE for elution to afford the formy2 compound (12a) (137 mg, 85.1) as an orange oil; A,,,. 227 (E 19 700, shoulder), 253 (E 9 100, trough), and 275 nm (c 14 800); vmax. (neat) 2 700, 1 690 and 1 660 (a,P-unsaturated aldehyde), and 1 650 and 1 610 cm-l (quinone and double bond) ; 6 1.74 (6 H, s, two vinyl methyls at 3rsquo; and 27rsquo; positions), 6.46 (1 H, t, J = 7 Hz, vinyl proton at 26lsquo; position), and 9.37 (1H, s, CHO) (Found: C, 78.3; H, 9.4. Camp;amp;, requires C, 78.53; H, 9.59). (b) 6-(27rsquo;-Formyl-3rsquo;,7rsquo;, 1 lrsquo;,15rsquo;,19lsquo;,23rsquo;-hexamethyloctacosa-2lsquo;,6lsquo;,lorsquo;, 14lsquo;, 18rsquo;,22rsquo;, 26rsquo;-heptenyl)-2,3-dimetlzoxy-5-methyl-hydroquinone OOrsquo;-Dibenzyl Ether (1 2b) .--Similar oxidation of the chloromethyl compound (lob) (220 mg, 0.25 mmol) with silver tetrafluoroborate (70 mg) in absolute Me,SO (5 ml) as described above gave the aldehyde (12b) (185 mg, 86.57;) as a colourless oil; 6 1.72 (3 H, s, vinyl methyl at 27rsquo; position), 6.44 (1 H, t, J = 7 Hz, vinyl proton at 26rsquo; position), and 9.37 (1 H, s, CHO) (Found: C, 81.2; H, 9.3.C5,H,,0, requires C, 81.45; euro;1, 9.19). (c) 6-(27rsquo;-Methylene-3lsquo;,7rsquo;,1lrsquo;,15rsquo;,19rsquo;,23rsquo;-kexanzethy1-26rsquo;-oxo-octacosa-2rsquo;,6rsquo;,lorsquo;, 14rsquo;,18rsquo;,22rsquo;-hexenyl) -2,3-dimethoxy-5- methyl- l,4-benzoquinone ( 13a). Similar oxidation of the secondary chloride (lla) (100 mg, 0.144 mmol) with silver tetrafluoroborate (30 mg) in absolute Me,SO (3 ml) as described above gave the ap-unsaturated ketone (13a) (58 mg, 65) as an orange oil; vmaX.(neat) 1 680, 1 660, 1 650, and 1 610 cm-l (a,P-unsaturated ketone, quinone and double bond); 6 1.87 (3 H, s, vinyl methyl at 27rsquo; position), 5.84 and 5.93 (2 H, m, C=CH,) (Found: C, 78.4; H, 9.4. C,,H,,O, requires C, 78.53; H, 9.59). Preparation of Prenyl Sulphone Derivatives.-(a) 3-Methyl-1-(p-tolylsulphonyl) but-2-ene ( 14a).-A stirred solu- tion of l-bromo-3-methylbut-2-ene(1.49 g, 10 mmol) in DMF (20 ml) was allowed to react with sodium toluene-p- sulphinate dihydrate (2.5 g, 11.6 mmol) at room tem-perature for 3 h. The usual work-up gave the sulphone (14a) (2.1 g, 96.4y0), n1.p. 71-72 ldquo;C, after recrystallisation from n-hexane; 6 1.37 (3 H), 1.73 (3 H), 2.46 (3 H), 3.77 (2 H), 5.20 (1 H), 7.34, and 7.76 (4 H) (Found: C, 64.1; H, 7.0.CI,H,,O,S requires C, 64.25; H, 7.19). (b) trans-3,rsquo;I-Dimethyl-1-(p-tolylsul~honyl)octa-2,B-diene (14b). Reaction of geranyl chloride (1.8 g, 10 mmol) with sodium toluene-p-sulphinate dihydrate (2.5 g, 1 1.6 mmol) in DMF (20 ml) as described above gave the trans-sulphone (14b) (2.82 g, 96.6) as needles, n1.p. 44 ldquo;C, after recrystal- lisation from n-hexane; 6 1.37 (3 H), 1.61 (3 H), 1.70 (3 H), 2.00 and 2.04 (4 H), 2.46 (3 H), 3.78 (2 H), 5.06 (1 H), 5.18 (1 H), 7.34, and 7.76 (4 H) (Found: C, 69.6; H, 8.4. C,,H,,O,S requires C, 69.82; H, 8.27). (c) cis-3,rsquo;I-Dimethyl-1-(p-tolylsul~honyl)octa-2,6-diene J.C.S. Perkin I (15a). Reaction of neryl chloride (1.8 g, 10 mmol) with sodium toluene-p-sulphinate dihydrate (2.5g, 11.6 mmol) in DMF (20 ml) as described above gave the cis-sulphone (Ma) (2.54 g, 87), m.p.15-16 ldquo;C, from n-hexane; 6 1.55 (3 H), 1.65 (3 H), 1.73 (3 H), 1.8-2.0 (4 H), 2.46 (3 H), 3.77 (2 H), 4.96 (1H), 5.20 (1H), 7.34, and 7.76 (4 H) (Found: C, 69.7; H, 8.1. C1,H,,O,S requires C, 69.82; H, 8.27). (d) cis,trans-3,7,1 l-Trimethyl-l-(p-tolylsulphony1)dodeca-2,6,1O-triene (15b) and trans,trans-3,7,1 l-trimethyl-l-(p- tolylsul~honyl)dodeca-~,6,10-triene(14c). Reaction of the bromide (2.85 g, 10 mmol), prepared by the reaction of neloridol with phosphorus tribromide, with sodium toluene-P-sulphinate in DMF (20ml) as described above gave a mixture of (14c) and ( 15b) which was chromatographed on silica gel (200 g).Elution with 2 : 1 n-hexane-IPE gave the cis,trans-compound (15b) (980 mg, 27) as an oil; 6 1.55 (3 H), 1.60 (3 H), 1.68 (3 H), 1.72 (2 H), 1.83 (4 H), 1.98 (4 H), 2.44 (3 H), 3.77 (2 H), 4.86-5.18 (2 H), 5.20 (1 H), 7.31, and 7.74 (4 H) (Found: C, 73.3; H, 8.7. C,,H,,O,S requires C, 73.28; H, 8.94). Further elution with the same solvent gave the trans,trans comfiound (14c) (2.43 g, 68y0)as an oil; 6 1.37 (3 H), 1.61 (6 H), 1.70 (3 H), 2.0-2.07 (8 H), 2.46 (3 H), 3.77 (2 H), 4.86-5.18 (2 H), 5.20 (1 H), 7.31 and 7.74 (4 H) (Found: C, 73.2; H, 8.7. C,,H,,O,S requires C, 73.28; H, 8.94). 6-(3rsquo;,7lsquo;, 1lrsquo;, 15rsquo;, 19rsquo;,23lsquo;,27lsquo;,31lsquo;-0ctamethyl-29rsquo;-p-tolylsul~h-onyldotriaconta-2rsquo;,6rsquo;, lorsquo;,14rsquo;,18rsquo;,22rsquo;,26rsquo;, 30rsquo;-octenyZ)-2, 3-di- methoxy-5-unethylhydroquinone 00rsquo;-Dibenzyl Ether (1 6a) .-To a stirred solution of the sulphone (14a) (134 mg, 0.6 mmol) in absolute THF-HMPA (4 ml, 3: 1) was added 10 (wlv) solution (0.39 ml) of n-butyl-lithium in n-hexane at -20 ldquo;C under nitrogen to generate an orange carbanion.After 10 min, the mixture was cooled to -70 ldquo;C. A solution of the chloromethyl compound (lob) (440 mg, 0.5mmol) in absolute THF (3 ml) was slowly added to the mixture with stirring for 1 h. The orange colour faded as the reaction proceeded. The product was isolated by allowing the mixture to warm to room temperature, adding acetic acid (0.5 ml) and water (50 ml), extracting with IPE, and evaporating the latter. The crude product was chromatographed on silica gel (30 g) using 3 : 1 n-hexane-IPE for elution to give the coupled compound (16a) (448 mg, 84.2) as a colourless oil; 6 1.21 (3 H, d, J = 1.2 Hz, vinyl methyl at 31rsquo; position), 1.52 (3 H, s, vinyl methyl at 27rsquo; position), 1.59 (15 H, broad s, five vinyl methyls), 1.66 (6 HI broad s, two vinyl methyls at 3rsquo; and 32rsquo; positions), 2.01 (methylene protons), 2.12 (3 H, s, methyl at 5position), 2.43 (3 H, s, arom-CH,), 3.31 and 3.37 (2 H, AB d, CH, at 1rsquo; position), 3.86 (1 H, sextet, J = 3 and 11 Hz, methine proton at 29rsquo; position), 3.95 (6 H, s, OCH,), 4.95 (4 H, s, CH,Ph), ca.5.10 (8 H, m, vinyl protons), 7.29 and 7.71 (4 H, AB q, arom-H), and 7.3-7.6 (10 HI m, arom-H) (Found: C, 79.2; H, 8.8. C,,H,,O,S requires C, 79.05; H, 8.91).6-(3rsquo;,7rsquo;, 1 lrsquo;,15rsquo;,19rsquo;,23rsquo;,27rsquo;,31rsquo;,35rsquo;-Nonamethyl-29rsquo;-p-tolyl-sulphonylhexatriaconta-2rsquo;, 6rsquo;, lorsquo;, 14rsquo;, 18rsquo;,22rsquo;, 26rsquo;,30lsquo;,34rsquo;-nonenyl)-2,3-dimethoxy-5-methylhydroquinoneOOlsquo;-Dibenzyl Ether (1 6b).-The lithium carbanion of the sulphone (14b) (175 mg, 0.6 mmol) was generated with 10 (w/v) n-butyl- lithium in n-hexane (0.4 ml) as described above. The carbanion was then coupled with the chloromethyl com-pound (lob) (440 mg, 0.5 mmol) according to the above procedure. The reaction mixture was worked up as usual to give an oil which was chromatographed on silica gel (30 g) using 3 : 1 n-hexane-IPE for elution to yield the coupled compound (16b) (452 mg, 79.8); 6 1.24 (3 H, d, J = 1.2 Hz, vinyl methyl at 31rsquo; position), 1.51 (3 HI s, vinyl methyl at 27rsquo; position), 1.59 and 1.60 (18 H, six vinyl methyls), 1.68 (6 H, s, two vinyl methyls at 3rsquo; and 36rsquo; positions), 2.01 (methylenes), 2.12 (3 H, s, methyl at 5 position), 2.42 (3 H, s, arom-CH,), 3.30 and 3.36 (2 H, AB d, CH, at 1rsquo; position), 3.84 (1 HI sextet, J = 3 and 11 Hz, =CH-SO,), 3.93 and 3.94 (6 H, two s, OCH,), 4.97 (4 H, s, CH,Ph), ca.5.10 (9 H, m, vinyl protons), 7.28 and 7.72 (4 H, AB q, arom-H), and 7.3-7.6 (10 H, arom-H) (Found: C, 79.5; H, 8.8. C,,H,,,O,S requires C, 79.60; H, 9.0874). 6-(3rsquo;,7rsquo;, 1 lrsquo;,15rsquo;,19rsquo;,23rsquo;,27rsquo;,31rsquo;,35rsquo;,39rsquo;-Decanzethyl-29rsquo;-p-tolylsulphonyltetraconta-2lsquo;,6lsquo;, lorsquo;, 14rsquo;, 18rsquo;, 22lsquo;, 26rsquo;, 30rsquo;, 34lsquo;, 38rsquo;- decenyl)-2,3-dirnethoxy-5-methylhydroquinone OOlsquo;-DibenzyZ Ether (1 6c) .-The lithium carbanion of the sulphone (1 4c) (216 mg, 0.6 mmol) was generated with 10 (w/v) n-butyl- lithium in n-hexane (0.4 ml) as described above.The carbanion was then coupled with the chloromethyl com- pound (lob) (440 mg, 0.5 mmol) according to the above procedure. The reaction mixture was worked up as usual to give an oil which was chromatographed on silica gel (30 g) 3 : 1 n-hexane-IPE for elution to yield the coupled compound (16c) (442 mg, 73.6); 6 1.24 (3 H, d, J = 1.2 Hz, vinyl methyl at 31rsquo; position), 1.51 (3HI s, vinyl methyl at 27rsquo; position), 1.60 (21 HI seven vinyl methyls), 1.68 (6 HI s, two vinyl methyls at 3rsquo; and 40rsquo; positions), 2.00 (methyl- enes), 2.12 (3 H, s, methyl at 5 position), 2.42 (3 HI s, arom-CH,), 3.30 and 3.36 (2 H, AB d, CH, at 1rsquo; position), 3.84 (1 H, sextet, J = 3 and 11 Hz, =CH-SO,), 3.93 and 3.94 (6 H, s, OCH,), ca.5.10 (10 HI vinyl protons), 7.28 and 7.72 (4 H, AB q, arom-H), and 7.3-7.6 (10HIarom-H) (Found: C, 80.3; H, 9.3. C,,HI,,O,S requires C, 80.09; HI 9.24). A ll-trans-l-benzyloxy-3,7,11,15-tetramethyl-9-(p-tolyZ-sulphonyl)hexadeca-2,6,10,14-tetraene(17).-(a) Preparation of trans,trans-l-benzyloxy-8-chloro-3,7-dimet~~ylocta-2,6-diene (1Oc). Geranyl benzyl ether (10 g, 41.0 mmol) in 20 aqueous 1,2-dimethoxyethane (150 ml) was bromohydrin- ated with NBS (7.67 g, 43.0 mmol) to give the bromohydrin (2c) (13.9 g) which was followed by treatment with 2~- aqueous sodiutn hydroxide solution (25 ml) to give the epoxide (3c) (10.1 g, 94.6).The epoxide (6 g, 23.1 mmol) in 1501; aqueous 1,2-dimethoxyethane ( 120 ml) was hydrolysed in the presence of perchloric acid (0.1 ml) at 5 ldquo;C overnight to give the glycol (4c) (6.4 g) which was acetylated in methylene chloride (60 ml) containing acetic anhydride (8.8 ml) and pyridine (7.1 ml) at room tem-perature overnight to give the monoacetate (Gc) (6.83 g, 92.4). Dehydration of the monoacetate (5.0 g) with thionyl chloride (1.87 g) and pyridine (2.5 g) in IPE (50 ml) at 0 ldquo;C gave the allyl acetate (7c) (3.93 g, 82.9); 6 1.66 (3 H), 1.73 (3 H), 2.04 (OAc), 4.06 (2 H), 4.52 (2 H), 4.97 (2 H), 5.20 (1 H), 5.45 (1 H), 7.36 (5 H). Hydrolysis of the allyl acetate (3.93 g), obtained above, with potassium hydroxide (1.29 g) in methanol (50 ml) gave the allyl alcohol (9c) (3.22 g, 95.376) as an oil.Chlorination of the allyl alcohol (2.45 g, 9.0 mmol) in IPE-n-hexane (1: 1, 100 ml) was effected at 0 ldquo;C with thionyl chloride (2.23 g) to give an oil. This material was purified by passage through a short column of silica gel to yield the chloro- compound (10c) (2.5g, 95.5) as an oil; 6 1.65 (3 H), 1.74 (3 H), 4.00 (2 H), 4.04 (2 H), 4.50 (2 H), 5.45 (1 H), 5.54 (1 H), and 7.34 (5 H). (b) Coufiling reaction of tlae sulphone (lab) with tlae chloro- 1109 compound (1Oc). The lithium carbanion of the sulphone (14b) (292 mg, 1 mmol) was generated with 10 (w/v) n-butyl-lithium (0.8 ml) in n-hexane as described above. The carbanion was then coupled with the chloro-compound (1Oc) (300 mg, 1.1 mmol) in THF (5 ml).The reaction mixture was worked up as usual to give an oil which was chromatographed on silica gel (30 g) using IPE for elution to yield the coupled compound (17) (473 mg, 88.1y0); 6 1.24 (3 H), 1.54 (3 H), 1.61 (6 H), 1.68 (3 H), 2.44 (3 H), 2.16 and 2.87 (2 H), 3.86 (1 H, =CHSO,), 4.01 (2 H), 4.49 (2 H), 4.89 (1H), 5.0-5.2 (2 H), 5.37 (1 H), 7.28 and 7.71 (4 H), and 7.33 (5 H) (Found: C, 76.0; HI 8.8. C,,H,,O,S requires C, 76.36; HI 8.67). All-trans-2,6,11,15,19-pentamethyl-9-(p-tolylsul~honyl)-eZcosa-2,6,10,14,18-pentaene(18).-The lithium carbanion of the sulphone (lac) (360 mg, 1 mmol) was generated with 10 (w/v) n-butyl-lithium in n-hexane (0.8 ml) as described above. The carbanion was then coupled with geranyl chloride (180 mg) in THF (5 ml).The reaction mixture was worked up as usual to give an oil which was chromato- graphed on silica gel (20 g) using IPE for elution to yield the coupled compound (18) (348 mg, 81.37;); 6 1.25 (3 H), 1.58 (3 H), 1.60 and 1.65 (15 H), 1.95 and 2.00 (CH,), 2.42(3H),3.74(1H,=CHS02),ca.5.10(5H),and7.30and 7.75 (4 H) (Found: C, 77.1; H, 9.6. C,2H,,0,S requires C, 77.37; HI 9.74). trans,trans,cis-l-BenzyZoxy-3,7,11,15-tetramethyl-9-(p-tolylsuZ~honyZ)hexadeca-2,6,10,14-tetraene(19).-The lithium carbanion of the sulphone (15a) (292 mg, 1 mmol) in THF (5 ml) was generated with 10 (w/v) n-butyl-lithium in n-hexane (0.4 nil) as described above. The carbanion was coupled with the chloride (1Oc) (300 mg, 1.1 mmol) in THF (5 nil).The reaction mixture was worked up as usual to give an oil which was chromatographed on silica gel (20 g) using IPE for elution to yield the coupled com-pound (19) (460 nig, 86.1); 6 1.54 (6 H), 1.62 (3 H), 1.66 (3 H), 1.67 (3 H), 2.0-2.4 (8 H), 2.43 (3 H), 2.16 and 2.81 (2 H), 3.87 (1H, =CHSO,), 4.01 (2 H), 4.49 (2 H), 4.8-5.3 (3 H), 5.40 (1 H), 7.29 and 7.74 (4 H), and 7.34 (5 H) (Found: C, 76.4; H, 8.5. C,4H,,0,S requires C, 76.36; HI 8.67yo). Formation of Ubiquinone-8, Ubiquinone-9, and Ubi-quinone-10.-(a) Ubiquinone-10 (la; n = 9). To asolution of the coupled compound (16c) (120 mg, 0.1 mmol) in ethylamine (5 ml) under nitrogen at -30 ldquo;C was added lithium (20 mg). The mixture was stirred and the temperature gradually raised to -20 ldquo;C.After the reaction mixture had turned blue, the reaction was further stirred for 10 min under the same conditions. Isoprene (1 ml) was added to the mixture to quench the excess of lithium and the ethylamine was evaporated. To the residue was added a tetrahydrofuran solution (30 ml) containing acetic acid (0.6 ml) and 10 aqueous ferric chloride solution (1 mi). The mixture was stirred for 2 h at room temperature and then the solvent was evaporated. The residue was dissolved in IPE (30 ml) and the organic layer was separated, washed with water, dried, and evapor- ated. The crude material was chromatographed on silica gel (30 g) using 3: 1 n-hexane-IPE for elution to afford ubiquinone-10 (62 mg, 720/,), m.p. 48-49 ldquo;C, as orange crystals. (b) Ubiquinone-9 (la; n = 8). Following the above procedure, the benzyl and p-tolylsulphonyl groups of the coupled compound (16b) (1 13 mg, 0.1 mmol) were eliminated and then oxidation of the resulting hydroquinone gave ubiquinone-9 (64 mg, 79), m.p. 43-44 "C, as orange crystals. (c) Ubiquinone-8 (la; n = 7). Following the above procedure, the benzyl and p-tolylsulphonyl groups of the coupled compound (16a) (106 mg, 0.1 mmol) were eliminated and then oxidation of the resulting hydroquinone gave ubiquinone-8 (54 mg, 74), m.p. 3amp;37 "C, as orange crystals. These ubiquinones were judged to be homogeneous by their t.1.c. and h.p.1.c. analyses on silica gel. The lH n.m.r. and mass spectra of the synthesised ubiquinone-8, ubi- J.C.S. Perkin I quinone-9, and ubiquinone-10 were identical with those of naturally occurring ubiquinone-8 (from Escherichia coZi),l9 ubiquinone-9 (from PeniciZZiurn chrysogenum),l9 and ubiquinone-10 (from ox heart muscle),1g respectively. The authors are grateful to Drs. E. Ohmura, M. Nishi- kawa, and I. Imada for their encouragement and many helpful discussions, and to Mr. E. Mizuta for his consider- able help with the lH and 13C n.m.r. measurements and their interpretation. 7/1059 Received, 20th June, 19771