Pyrylium salts in polyene natural product synthesis: organometallic additions to 4-methylpyrylium tetrafluoroborate

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1995 Pyrylium salts in polyene natural product synthesis: organometallic additions to 4-methylpyrylium tetrafluoroborate Richard J. K. Taylor,*," Karl Hemming" and Edna Faria De Medeirod a Department of Chemistry, University of York, York YO1 5DD, UK School of Chemical Sciences, University of East Anglia, Norwich NR4 7TJ, UK The synthetic utility of organometallic additions to pyrylium salts as a procedure for the stereocontrolled preparation of 22,4E-dienals, and the use of these compounds in polyene natural product synthesis, is summarised. The extension of this methodology to 4-methylpyrylium tetrafluoroborate to give a new route to 3-methy1-22,4E-dienalsvia a six-carbon organometallic homologation procedure is then described. Finally, the utilisation of this methodology to provide a concise synthetic approach to 132-retinal, retinal and a range of retinal analogues is then elaborated.Overview and introduction The biological importance of polyene-based natural products ' such as antibiotics, insect pheromones, leukotrienes and related compounds has stimulated the search for versatile, stereocon- trolled routes to these types of compounds.2 We have or their precursors, that can be further elaborated to higher polyenes via Wittig-type processes if required. Thus, a 'double acetylene carbocupration' modification of the Normant reaction has been developed to prepare a range of 2,Z-dienoic acids,4 and E,E-dienals have been obtained by organometallic addition to silylated glutaconaldehyde derivatives followed by hydrolysis of the adducts.' As shown in Scheme 1, we were also interested in the preparation of Z,E-dienals by a related organometallic homologation procedure.We were intrigued by the idea that the required cationic pentadienal synthon 1 could be provided, in a stereoselective manner, by the pyrylium cation 2. Thus, as shown in Scheme 2, organometallic addition at C-2 of the pyrylium cation to give the 2H-pyrans 3 followed by electrocyclic ring should give the required Z,E-dienals 4. The nucleophilic additions of substituted pyrylium salts had been described in the literature6V7 and some examples using organometallic nucleophiles had been rep~rted.~However, although unsubstituted pyrylium salts are known, lo there had been no reports of their nucleophilic additions prior to our study.Indeed, it had been stated that unsubstituted pyrylium cations 'do not give clean reactions, even with the most common nucleophiles . . .' Contrary to this statement, we found that i, excess HCZCH I I RM, -78':@ -78-0 '5 +2 3 4 X-the organometallic addition-ring opening process occurred smoothly giving reasonable to high yields of the required dienals 4, with excellent Z,E-stereoselectivity, when organo- lithium reagents were employed.' The only by-product observed in this reaction was the 4-substituted pyran resulting from organometallic addition to C-4 of the pyrylium salt: this adduct was normally present in low amounts but became more significant when softer organometallic reagents were em-ployed." The value of this new route to 22,4E-dienals was subsequently demonstrated by its use as the cornerstone in the synthesis of a range of polyunsaturated natural products as shown in Scheme 3.' '-16 These syntheses illustrate the synthetic potential of 22,4E-dienals: they can be employed, with retention of stereochemistry, to prepare trienes using Wittig homologation (32,SE-undecatriene l1 and lignarenone A' 3), dienoates via oxidation (umbraculumin A l4 and umbraculumin C 14), and trienols by use of a vinyl organometallic followed by organometallic 1,Zaddition (leukotriene B,I5).In addition, by isomerisation, all-E natural products can be prepared (lignarenone B l3 and navenone B 16), and the latter example illustrates that tetraenes are also available using this me thodology .2, 2-Dienoicacids etc. from +2 Scheme 1 Stereoselective organometallic homologation routes to functionalised dienes 2386 J. CHEM. SOC. PERKIN TRANS, 1 1995 (-)-Umbracuturnin A'4 Scheme 3 lH+ LRbsol; C bsol; HO 8 Scheme 4 Scheme 5 Reagents and conditions: i, 200 "C, 24 h"; ii, aq. HCI 'O; iii, HCl(g), -78 "C1*; iv, PhNMe, 140 "C1*; v, Ph,CBF,, MeCN (6 1-78) The synthesis and reactions of Cmethylpyrylium tetrafluoro- borate In an extension of this work (Scheme 4),17 we envisaged using the 4-methylpyrylium salt 5 to provide a six-carbon homologation procedure leading, via the pyran 6,to the methyl substituted dienals 7 with potential in isoprenoid natural product synthesis.A major attraction of this approach is that it would be expected to produce initially 2,E-dienals 7, which should be easily isomerised to their all-trans isomers 8, thereby making both systems readily accessible in a stereocontrolled manner. In addition, the presence of the 4-methyl substituent would be expected to hinder C-4 attack on the pyrylium salt. We therefore investigated the viability of this synthetic Table 1 Yields of compounds 7 and 8 (see Scheme 4) -C(a) Bu 55 (b) 2-Thienyl 49(63d) 81 (c) Cyclohexenyl -(90d) --' (4 Ph 57 (68d) 86 (e) PhCX 54 68 " THF as solvent at -70 "C unless otherwise stated. Yield from 7; isomerisation using conc.HCI-EtOH-CHCl,. Dienal 7 decomposed under these reaction conditions. Diethyl ether as solvent at -70 "C. Table 2 Selected NMR data for the aldehydes 7 and 8 H NMR:a,,, (J/Hz) NMR: Z, E-7 E, E-8 Z,E-7 E,E-8 (a) Bu 10.17 (8.2) -21.39 - (b) 2-Thienyl(c) Cyclohexenyl 10.21 (7.9) 10.25 10.12 (7.9) 20.84 12.83 -20.90 - (4 Ph (e) PhC=C 10.26 (7.6)*," 10.18 (7.9) 10.10 (8.15)22b 20.93 13.03 10.14 (8) 20.12 - sequence. 4-Methylpyrylium tetrafluoroborate 5 was obtained from crotonaldehyde and ethyl vinyl ether by modification of the procedure employed by Degani and Vincenzi 18-20 for the preparation of the corresponding perchlorate salt (Scheme 5). This sequence can be carried out on a large scale and allows access to multi-gram quantities of 5 and its precursor, 4-methyl- 4H-pyran.In contrast to the unsubstituted pyrylium salt 2, the 4-methyl substituted salt 5 darkened and appeared to decompose on storage and was therefore prepared immediately before use. We were aware that, on treatment with organometallic reagents, the pyrylium salt 5 might undergo deprotonation at the 4-Me group to give the corresponding anhydro base 21 but in the event this process was not detected. Thus, addition of the organolithium reagent to the freshly prepared pyrylium salt in tetrahydrofuran (THF) or diethyl ether at -70 "C under nitrogen, followed by quenching with aqueous ammonium chloride, gave a range of the dienals 7 in reasonable, unoptimised yields (Table 1). It should also be noted that 4H-pyrans, which result from C-4 addition and which are observed with the unsubstituted pyrylium cation 2, J.CHEM. SOC. PERKIN TRANS. 1 1995 were present in negligible amounts according to an NMR analysis of the crude reaction product. The E,Z-stereochemistries of compounds 7 were confirmed by highfield lsquo;H NMR spectroscopy (J4,5in the range 15.5-1 5.9 Hz) and NOE studies (irradiation of 2-H caused enhancement of the 3-Me signal but had no effect on 4-H; in the E,E-isomers irradiation of 2-H caused enhancement of 4-H but had no effect on the 3-Me signal). Isomerisation of the E,Z-dienals 7 into their E,E-isomers 8 proceeded smoothly in acid with three of the aldehydes examined (Table 1). As shown in Table 2, the formyl proton is deshielded in the E,Z-dienals as compared to their E,E-isomers but the difference is not so marked as in the non- methylated analogues (where the E,Z-formyl proton is usually 0.5 ppm to lower field).However, as is also shown in Table 2, the 3C resonance of the 3-methyl substituent is extremely diagnostic: in the E,Z-isomers the methyl resonates in the 20-22 pprn range whereas in the E,E-isomers, 12-13 ppm is the norm. This observation is supported by published data22 and by examples described later in this paper. The dienals 7 readily isomerise and/or decompose on storage at room temperature. The aromatic examples, 7b and 7d, were stable indefinitely when stored at -20 OC, whereas at this temperature 7c and 7e showed significant signs of isomeris- ation/decomposition after 1 week, and the butyl adduct 7a deteriorated in hours, even when stored at low temperature. It is therefore advisable to carry out further modifications as soon as possible.For example, the aldehydes can be reduced (see later) or oxidised to the more stable carboxylic acid (e.g.7d to 9) with retention of configuration. 7d 9 The use of pyrylium salts for the synthesis of retinoids and retinal The approach shown in Scheme 4 seemed ideally suited to the synthesisof retinoids 23 which are of interest in studies of visual processes,24 as devices,25 and as anti-cancer agents,26 in both 13E- and I3Z-f0rms.~~ 29 In addition, retinoic acid analogues, which are of use in cell growth studies,30 and retinol (vitamin A) analogues 31 would be readily available by such a route.The successful implementation of this strategy is illustrated in Schemes 6 and 7.rdquo; The viability of the process was first tested using pyrylium tetrafluoroborate 2 producing 13-demethyl-l3Z-retinal 12 27 as is shown in Scheme 6. p-Ionone was first converted into the alkyne 10 and then into vinylalane lla using the methodology Additiondevised by Negishirsquo;s gro~p.~~,~~ of lla to the pyrylium salt 2 gave the retinal analogue 12 in 3 1 yield (along with 1lc in 62 yield). The use of the corresponding alanate 11b raised the yield of 12 to 43. In both cases, 4 equiv. of the organometallic reagent were required to obtain satisfactory yields (with 1 equiv. no reaction was observed, with 2 equiv.yields of 5-10 were obtained). The pyrylium salt 2 was also converted into the novel dehydro-demethyl-retinoid 14 in 56 yield by reaction with the acetylide 13, prepared by deprotonation of 10. With this success in hand, we turned our attention to the use of the 4-methylpyrylium salt 5 as is shown in Scheme 7. Thus, treatment of 5 with the previously described alanate llb gave 13Z-retinal 1528in 48 yield. This route enables a range of retinal analogues to be prepared extremely easily as both organometallic reagent and pyrylium salt can be varied. Thus, the use of the alkynyllithium reagent 13 with the 4-methylpyrylium salt 5 gave the known29 retinoid 16 in 57 p-ionone 10Iii t 21Hollb M =AMBuLi--lla M=AMe, -1 iii llc M=H 12 14 Scheme 6 Reagents and conditions: i, see ref.32; ii, Me,Al, Zr(Cl)JCl2, (CH,CI),, 0 ldquo;C to room temp.33 (then replace solvent by THF); iii, BuLi, THF, -78 to 0 ldquo;C; iv, pyrylium tetrafluoroborate 2, THF, -78 ldquo;C (3143, see text); v, THF, -78 ldquo;C (56) yield and treatment of the 4-cyclohexylpyrylium tetrafluoro- borate 1734with the same organometallic reagent gave the novel retinal analogue 18 in 52 yield. In agreement with the generalisations drawn from the data in Table 2, the 13C NMR spectra of the Z-unsaturated aldehydes 15 and 16 show the methyl substituents resonating at 6 20.12 and 19.63 ppm, respectively. These lsquo;initial adductsrsquo; can be further modified. Thus, 15 was efficiently i~omerised,~ thereby completing a new synthesis of retinal 19.In addition, 16 was reduced with DibalH to give the novel retinol analogue 20 in 81 yield. Highfield NMR and NOE studies confirmed that the 2Z,4E-~tereochemistry had been retained. To summarise, the preparation and organometallic additions of 4-methylpyrylium tetrafluoroborate 5 have been described and shown to provide a new, stereoselective route for the preparation of 3-methyl-2Z,4E-dienals via a six-carbon homologation procedure. Examples have been provided to demonstrate that corresponding 3-methyl-2Z,4E-dienols and dienoic acids are also available by this route, as are the corresponding E,E-isomers. This new methodology has been utilised to prepare a number of known and novel retinal analogues, and we feel that these examples illustrate the potential of this new route to retinoids and related isoprenoids.Experimental lsquo;H NMR spectra (SH)were recorded using JEOL PMX 60, JEOL EX 270 and JEOL GSX 400 NMR spectrometers referencing to TMS as internal standard or to the deuteriochloroform lock and were assigned using homonuclear decoupling experiments or COSY-45 at 270 or 400 MHz and DIFNOE experiments at 270 MHz where necessary. I3CNMR spectra (8,) were recorded using JEOL EX 90, JEOL EX 270 or 2388 J. CHEM. SOC. PERKIN TRANS. 1 1995 19 16 18 Scheme 7 Reagents: i, Ilb (4 equiv.), THF, -78 "C,48; ii, 13, THF, -78 "C, 58; iii, 13, THF, -78 "C, 52; iv, I,, Et,O, PhH, room temp., 48 h, 91;v, DibalH, -78 to 0 "C,81 JEOL GSX 400 NMR spectrometers at 22.5, 67.5 or 100 MHz, respectively, referencing to the deuteriochloroform lock and were assigned using DEPT or heteronuclear correlation experiments.Samples were run as solutions in CDCl, unless otherwise stated. J Values are in Hz. IR spectra were recorded on a Perkin-Elmer FTIR 172OX spectrometer or an AT1 Mattson Genesis Series FTIR and were run as neat liquid or deposited solid films. Mass spectra were recorded on a Kratos MS25 (low resolution EI only) or a Fisons Instruments VG Analytical Autospec Spectrometer system (low and high resolution EI and CI spectra). Light petroleum refers to the fraction of boiling range 4MO "C and was redistilled before use. THF and diethyl ether were dried over sodium-benzophenone ketyl and distilled immediately before use; triethylamine, acetonitrile, dichloromethane and dichloro-ethane were dried by boiling over calcium hydride and distilled immediately before use.Ethyl acetate refers to HPLC grade solvent and was used as purchased. Solutions of organolithium compounds were regularly titrated using diphenylacetic acid. 36 Other starting materials were used as purchased or prepared according to established literature procedures using references given in the text. Low temperature reactions were carried out in a Cryocool C80 immersion bath. Analytical TLC was performed on Merck 5554 aluminium- backed silica gel plates and were visualised using UV, KMn0,- acetone solutions or acidic ethanolic vanillin solutions.Column chromatography was carried out under flash conditions 37 unless otherwise stated using silica gel (Phase Separations Ltd Sorbsil C60 40/60H or ICN Biomedicals GmbH silica 32-63, 60A) and the specified eluent. Preparative centrifugal chromato- graphy was carried out on Chromatotron Model 7924T using silica gel (Merck 7749) plates. Melting points were recorded on a Kofler hot-stage melting point apparatus or an Electrothermal IA9100 digital melting point apparatus and are uncorrected. Boiling points refer to oven temperatures (Kugelrohr) or distillation temperatures. Microanalyses were performed by Mr A. W. Saunders at The University of East Anglia. 4Methylpyrylium tetrafluorobor a te 5 (a) l8 HCl gas was passed for 50 min through a stirred solution of freshly distilled P-methylglutaric dialdehyde 19,20 (53.2 g, 0.466 mol) in CH,Cl, (300 em3) the internal temperature of which was kept at ca. -40 "C.The reaction mixture was stirred at -78 "C for 8 h, warmed to room temperature over 4 h and stirred at this temperature for a further 4 h. The resulting aqueous phase was removed and the organic phase was stirred for 1 h in the presence of Na,SO,. The mixture was filtered and the filtrate was evaporated under reduced pressure at room temperature, the residual CH,Cl, being removed using high vacuum (2 mmHg) for 4 h to give the crude 2,6-dichloro-4- methyltetrahydropyran (70.76 g) as a pale tan oil. (b) * The m,a'-dichlorotetrahydropyran (70.76 g) was placed in a flask containing N,N-diethylaniline (330 cm3) and equipped with a Vigreux column and a distillation apparatus. The mixture was then heated for 1 h in an oil bath pre-heated to 140deg;C at atmospheric pressure; it was noted that when the internal temperature of the solution reached 110 "C, a strong evolution of gas took place and the solution darkened significantly.The pressure was now slowly reduced to 55 mmHg and the fraction distilling up to 90 "C was collected in a cooled (-78 "C) receiver flask. This fraction was redistilled at lower pressure (1.5 mmHg) using a cold-finger condenser and a cooled (-78 "C) receiver flask. The fraction distilling at 8- 13 "C/1.5 mmHg consisted of the first batch of pure 4-methyl- 4H-pyran (cu.15 g). The residue of the redistillation was recharged into the N,N-diethylaniline flask and reheated as before to afford a second batch of crude 4-methyl-4H-pyran, which was redistilled as above to give a second batch of pure 4-methyl-4H-pyran. The combined batches of 4-methyl-4H-pyran" (23.08 g, 51), obtained as a colourless liquid, decomposed rapidly when stored at RT and at a slower rate when kept at -20 "C. A 10 g batch stored at -20 "C for 1 month yielded 7.4 g of 4-methyl-4H-pyran on redistillation. (c) A suspension of trityl tetrafluoroborate Fluka (other brands gave lower yields) 19.62 g, 59.4 mmol in dry MeCN (100 cm3) was added over 30 min to a stirred solution of freshly prepared 4-methyl-4H-pyran (5.69 g, 59.2 mmol) in dry MeCN (10 cm3) held at -40 "C.The resulting mixture was stirred at 0 "C for 1 h, after which it was diluted with dry ether (250 cm3) to precipitate a white sand-like solid. The solid was filtered off under N,, washed with dry ether (2 x 50 cm3) and dried under high vacuum (0.5 mmHg) for 1 h to give 4-rnethylpyryEiurn tetrupuoroborute 5 (7.87 g, 73) as a pale tan solid, which rapidly darkened to give a dark brown solid, mp 11 1-1 14 "C (decomp.) (Found: C, 39.8; H, 3.7. C6H,BF,0 requires C, 39.6; H, 3.9); S,(60 MHz, CF,CO,D/TMS) 3.0 (3 H, s, Me), 8.3- 8.4 (2 H, m, 3-H and 5-H) and 9.3-9.4 (2 H, m, 2-H and 6-H); 6,(67.5 MHz, CF,CO,D)27.06, 131.19, 169.34and 182.87. The pyrylium salt 5 was usually prepared fresh from freshly distilled pyran and used immediately.J. CHEM. SOC. PERKIN TRANS. 1 1995 Organolithium additions to 4-methylpyrylium tetrafluoroborate 5 Typical procedure. The organolithium reagent (1.1 mol equiv.) in the specified solvent was added dropwise over 10 min to a suspension of freshly prepared 4-methylpyrylium tetrafluoroborate 5 (-0.2-0.5 g) in dry diethyl ether or dry THF (5-20 cm3) held at -70 "C under an atmosphere of dry nitrogen. The dark reaction mixture was stirred at -78 "C for 30 min to 24 h (longer times sometimes gave a small increase in yield) and then quenched with sat. aq. NH4C1 (10-20 cm3) and diluted with water (20 cm3). The resulting mixture was extracted with ether (5 x 25 cm3) and the combined extracts were washed with water (3 x 25 cm3) and brine (3 x 25 cm3), dried (Na,SO,), filtered and evaporated under reduced pressure.The crude product was purified either by flash silica column chromatography or by preparative centrifugal chromatography using the eluent specified to give the aldehyde 7. (22,4E)-3-Methylnona-2,4-dienal7a. This compound was prepared from butyllithium (1.52 mol dm-3 in hexane; 0.7 cm3, 1.06 mmol), 4-methylpyrylium tetrafluoroborate 5 (178 mg, 0.978 mmol) in dry THF (5.0 cm3) following the typical procedure above. 'H NMR (60 MHz) spectroscopic analysis of the crude product showed the presence of a single isomeric aldehyde (formyl proton at 6 10.17) together with neglible amount ( 5) of 4-butyl-4-methylpyran as indicated by a signal at 6 4.5.Purification by preparative centrifugal chromatography light petroleum-CH,Cl, (1 :l) gave the title compound 7a (82 mg, 55) as a pale yellow oil {Found (CI): M + H+, 153.1281. CloHI6O requires M + H', 153.1279); R, 0.19 light petroleum-CH,Cl, (1 :l); v,,,/cmP' 1668, 1634 and 963; 6,(400 MHz) 0.93 (3 H, t, J 7.3,9-H), 1.31- 1.49 (4 H, m, 8-H and 7-H), 2.07 (3 H, d, J 1.2, Me), 2.22-2.27 2 H, m (appt. q), 6-H, 5.81 (1 H, br d, J 8.2, 2-H), 6.21 (1 H, dt,J15.6andJ7.0,5-H),7.07(1H,d, J15.6,4-H)and10.17(1 H, d, J8.2, l-H);6,(22.4 MHz) 13.84,21.39,22.30,30.99,33.11, 125.44, 127.30, 140.87, 155.26 and 190.25; m/z (EI) 152 (M', 279, 151 (1) and 95 (100). A sample of the aldehyde stored at -20 "C showed major decomposition and isomerisation products (TLC analysis) after 1 day.(22,4E)-3-Methyl-5-(2-thienyl)penta-2,4-dienal7b. This com- pound was prepared from 2-thienyllithium prepared from BuLi (2.51 mol dm-3 in hexanes; 2.39 cm3, 6.0 mmol) and thiophene (510 mg, 6.05 mmol) in THF (10 cm3) stirred at -78 "C for 3 h and 4-methylpyrylium tetrafluoroborate 5 (1000 mg, 5.50 mmol) in diethyl ether (10 cm3) using the typical procedure given previously. Purification by flash column -chromatography light petroleum-EtOAc-triethyl-amine (90 : 10:0. l) gave the title compound 7b (61 7 mg, 63) as a yellow solid, mp 58.1-61.2 "C (Found: C, 67.2; H, 5.45; S, 17.9. C,,H,,OS requires C, 67.4; H, 5.65; S, 18.0); R, 0.18 light petroleum-EtOAc (9 :l); v,,,/cm~' 3088, 3075, 3065, 1653, 1601.945 and 710; 6,(400 MHz) 2.10 (3 H, d, J 1.2, Me), 5.86(1 H, brd, J7.9,2-H),6.98-7.02(1 H,m, 3'-Hthioph.),7.06 (1 H, d, J 15.6, 4-H$), 7.13-7.18 (1 H, m, 4'-H thioph.), 7.26 7.29(1 H,m,5'-Hthioph.),7.57(1H,d,J15.6,5-H$)and10.21 (1 H,d, J7.9, l-H);6,(22.4MHz)20.84, 122.64, 126.88, 127.95, 128.21, 128.73, 129.38, 141.43, 153.38 and 189.48; m/z (EI) 180 (8), 179 (12), 178 (M', 100) and 135 (62).($ These assignments may be interchanged.) (2Z,4E)-5-Cyclohex-l-enyl-3-methylpenta-2,4-dienal7c. This compound was prepared from cyclohex- 1 -enyllithium 38 (0.56 mol dm in diethyl ether; 7.08 cm3, 3.96 mmol) and 4- methylpyrylium tetrafluoroborate 5 (601 mg, 3.30 mmol) in diethyl ether (10 cm3) according to the typical procedure given above. Purification of the crude mixture by flash column chromatography light petroleum-EtOAc-triethylamine (80: lO:O.l) gave the title aldehyde 7c (526 mg, 90) as an 2389 orange-coloured oil {Found (EI): M+, 176.1200.C,,H160 requires M', 176.1201); R, 0.4 light petroleum-EtOAc (4: l); v,,,/cm-' 2933, 2884, 1665, 1605, 11 18 and 958; 6,(270 MHz) 1.62-1 34 (4 H, m, cyclohexyl methylenes), 2.15 (3 H, s, Me), 2.22-2.33 (4 H, m, cyclohexyl allylics), 5.87 (1 H, br d, J 7.9, 2-H), 6.09 (1 H, br s, 2'-H), 6.67 (1 H, d, J 15.6,4-Ht), 7.18 (1 H, d, J 15.6, 5-Ht), 10.25 (1 H, d, J 7.9, 1-H); DIFNOE experiments showed enhancement at Me on irradiation at 2-H; 6,(67.5 MHz) 20.90,21.93,24.06,26.15,119.21, 127.24, 135.51, 135.89, 140.36, 154.82 and 189.51; m/z (EI) 176 (M', 40), 161 (21), 147 (48), 105 (loo), 95 (58) and 79 (29). A sample of the aldehyde stored at -20 "C showed major decomposition products (TLC analysis) after 1 week.(7 These assignments may be interchanged.) (22,4E)-3-Methy1-5-phenylpenta-2,4dienal 7d. This com-pound was prepared from phenyllithium (1.8 mol dmP3 in hexane; 1.42 cm3, 2.56 mmol), 4-methylpyrylium tetrafluorobo- rate 5 (387 mg, 2.13 mmol) and diethyl ether (10 cm3) following the typical procedure above. 'H NMR (60 MHz) spectroscopic analysis of the crude reaction mixture showed the presence of a single isomeric aldehyde (formyl proton at 6 10.2) and complete absence of the 4-methyl-4-phenylpyran by-product. Purification by flash column chromatography light petroleum-EtOAc- triethylamine (100 :10:0.l) gave the title aldehyde 7d (249 mg, 68) as a gummy oil (Found (EI): M', 172.0892.C,,HI20 requires M', 172.0888); R, 0.22 light petroleum-EtOAc (9: l); vmax/cm-' 3057,3024, 1661, 1615, 1449, 1199, 11 18,957, 750 and 691; 6,(270 MHz) 2.16 (3 H, d, J 1.2, 3-Me), 5.92 (1 H, br d, J7.6, 2-H), 6.96 (1 H, d, J 15.9, 5-H), 7.29-7.50 (5 H, m, PhH),7.79(1 H,d, J15.9,4-H)and 10.26(1 H,d, J7.6, 1-H)(in agreement with published data); DIFNOE experiments showed enhancement at 3-Me and no enhancement at 4-H on irradiation at 2-H; 6,(67.5 MHz) 20.95, 123.03, 127.16, 128.43, 128.66, 129.03, 135.74, 136.56, 153.86 and 189.65; m/z (EI) 172 (M', loo), 171 (28), 157 (46), 143 (24), 129 (67) and 128 (64).(22,4E)-3-Methyl-7-phenylhepta-2,4dien4ynal 7e. This compound was prepared from lithium phenylacetylide prepared in turn from BuLi (1.6 mol dm-3 in hexanes; 1.4 cm3, 2.24 mmol) and phenylacetylene (222 mg, 2.17 mmol) in dry THF (2 cm3) at -78 "C for 2 h and 4-methylpyrylium tetrafluoroborate 5 (362 mg, 1.99 mmol) in dry THF (10 cm3) following the typical procedure given above. 'H NMR spectroscopic analysis of the crude material indicated the presence of a single isomeric aldehyde (formyl proton 6 10.18) and the absence of any 4-methyl-4-substituted pyran by-product. Purification by preparative centrifugal chromatogra- phy light petroleum-EtOAc (95 :5) gave the title aldehyde 7e (210 mg, 54) as a yellow solid, mp 46.248.5 "C; R, 0.14 light petroleum-EtOAc (95 :5); v,,,/cmP' 2190, 1653,1603,939,763 and 693; 6,(400 MHz) 2.06 (3 H, d, J 1.2,3-Me), 5.88 (1 H, br d, J7.9,2-H), 6.24(1 H, d, J 15.9,4-H), 7.32-7.34(3 H, m, PhH), 7.46-7.49(2H,m,PhH),7.66(1 H,d, J15.9,SH)and 10.18(1 H, d, J7.9, I-H);6,(22.4MHz)20.12, 88.13 and96.24, 116.36, 122.42, 128.73, 129.09, 130.20, 131.53, 135.24, 152.95 and 189.35; m/s (EI) 196 (M', 5973, 195 (34).181 (loo), 167 (62) and 152 (64). A sample of the aldehyde stored at -20 "C showed decomposition products (TLC analysis) after 1 week. Isomerisationof the 2,E-dienals 7 into the E, Edienals 8 General procedure. To a solution of the Z,E-dienal (50-200 mg) in chloroform (5-10 cm3) and ethanol (5-10 cm3) was added 2 or 3 drops of concentrated hydrochloric acid.The mixture was then stirred whilst the progress of the reaction was monitored by TLC. Upon completion of the reaction (usually 24 h) the mixture was concentrated under reduced pressure and the crude product was purified either by flash column chromatography or by preparative centrifugal chromatography using the eluent specified. (2E,4E)-3-Methyl-5-(2-thienyl)penta-2,4-dienal8b. This com- pound was prepared according to the general procedure from (22,4E)-3-methyl-5-(2-thienyl)penta-2,4-dienal7b (150 mg), the crude mixture being purified by preparative centrifugal chromatography light petroleum-EtOAc (9 :l) to give the title (E,E)-dienal 8b (121 mg, 81) as a yellow gummy solid (Found (EI): M+, 178.0458.CloHloOS requires M', 178.0452); RF 0.11 light petroleum-EtOAc (9 :l); v,,,/cm-' 3088, 3075 and 3065, 1653, 1601, 956 and 710; 6,(400 MHz) 2.33 (3 H, d, J0.9, Me), 6.03 (1 H, br d, J7.9, 2-H), 6.69 (1 H, d, J 15.9, 4-H?), 7.03 (1 H, dd, J 3.7 and 5.2, 4'-H thioph.), 7.15-7.17 (1 H, m, 3'-H thioph.), 7.19 (1 H, d, J 15.9, 5-Ht), 7.31 (1 H, d, J 5.2, 5'-H) and 10.12 (1 H, d, J 7.9, 1-H); dc(22.4 MHz) 12.83, 126.84, 127.89, 128.31, 128.60, 129.41, 130.55, 141.43, 153.57 and 190.75; m/z 178 (M+, loo), 163 (49), 149 (52) and 135 (74). (t These assignments may be interchanged.) (2E,4E)-3-Methyl-5-phenylpenta-2,4dienal8d. This com-pound was prepared according to the general procedure from (22,4E)-3-rnethyl-5-phenylpenta-2,4-dienal7d (100 mg), with the crude product purified by preparative centrifugal chromatography light petroleum-EtOAc (10 : l) to give the title compound 8d as an orange-coloured oil (86 mg, 8673, which was fully characterised and which displayed data consistent with those published.22b (2E,4E)-3-Methyl-7-phenylhepta-2,4-dien-6-ynaI 8e.This compound was prepared according to the general procedure from the (2,E)-aldehyde 7e (100 mg) which was purified by preparative centrifugal chromatography light petroleum-EtOAc (95 :5) to give the title compound 8e (68 mg, 68) as an orange-coloured oil; R, 0.10 light petroleum-EtOAc (95 :5); d,(400 MHz) 2.29 (3 H, s, 3-Me), 6.01 (1 H, d, J 8.0, 2-H), 6.36 (1 H, d, J 15.9, 5-H), 6.79 (1 H, d, J 15.9, 4-H), 7.34- 7.37 (3 H, m, PhH), 7.46-7.50 (2 H, m, PhH) and 10.14 (1 H, d, J8.0, 1-H).(22,4E)-3-Methy1-5-phenylpenta-2,4dienoicacid 9. To a solution of (22,4E)-3-methyl-5-phenylpenta-2,4-dienal7d(3 13 mg, 1.82 mmol) and 2-methylbut-2-ene (1 1 cm3) in tert-butyl alcohol (50 cm3) was added, with vigorous stirring at room temperature, a solution of sodium chlorite (2.3 g) 39 and potassium dihydrogen phosphate (2.3 g) in distilled water (20 cm'). The reaction was monitored by TLC for disappearance of the aldehyde. After 48 h the volatile components were removed on the rotary evaporator at room temperature and the residue extracted with diethyl ether (5 x 20 cm3). The combined extracts were dried (Na,SO,) and concentrated under reduced pressure and the residue purified by flash chromatography light petroleum-EtOAc-AcOH (400: 100: l) to give the title acid 9 (219 mg, 64) as a white solid, mp 128.9-131.4 "C (lit.,,' 125 "C) which was fully characterised and gave spectroscopic data in accord with the assigned structure.DIFNOE experiments showed enhancement at 3-Me on irradiation at 2- H and no enhancement at 4-H. (22,4E,6E,8E)-7-Methyl-9-(2',6',6'-trimethylcyclohex-1-en-yl)nona-2,4,6,8-tetraenal 12 (13-cis-13demethylretinal). (i) Via the alanate 1lb.33-To a solution of zirconocene dichloride (1.250 g, 4.28 mmol) in freshly distilled dichloroethane (20 cm3) at OOC, under an atmosphere of dry nitrogen, was added trimethylaluminium (2.0 mol dm-3 in hexanes; 4.28 cm3, 9.56 mmol) dropwise over 15 min.The resultant lemon-yellow solution was warmed to room temperature and treated with a solution of 1-(trans-but-1'-en-3'-ynyl)-2,6,6-trimethylcyclohex-1-ene 10 (700 mg, 4.30 mmol) in dichloroethane (5 cm3) added dropwise over 15 min. The resulting clear brown solution was stirred at room temperature for 24 h, after which the solvent was removed under reduced pressure and replaced with THF (10 cm3); the THF solution of the alane lla was then cooled to -78 "C and treated with butyllithium (2.50 mol dm in J. CHEM. SOC. PERKlN TRANS. 1 1995 hexanes; 1.72 cm3, 4.30 mmol). The resulting solution of the alanate llb was allowed to warm to 0 "C over 3 h after which it was recooled to -78 "C and added via a cannula to a stirred suspension of pyrylium tetrafluoroborate 2 (180 mg, 1.07 mmol) in THF (10 cm3) at -78 "C, over 10 min.The mixture was stirred for 40 h at this temperature and worked up as described in the typical procedure. The crude mixture showed the presence of a single retinal isomer in its 'H NMR spectrum (270 MHz). Purification by flash column chromatography light petroleum-EtOAc-triethylamine (100 :0 :0.1 to 160: 1O:O.l) (gradient elution) in a darkened room gave 1-(3'- me thy 1-trans- bu t- 1',3'-dienyl)-2,6,6-t rimet hylcyclo hex- 1-ene llc (515 mg, 62) as a yellow oil; RF 0.5 (light petroleum); dH(60 MHz) 1.0 (6 H, s, 2 x 6 Me), 1.1-2.1 (6 H, m, 3-H, 4-H, 5-H), 1.7 (3 H, s, 2-Me), 1.9 (3 H, br s, 3'-Me), 4.9 (2 H, br s, 4'-H), 6.1 (2 H, br s, 1'-H and 2'-H) in accord with published values.41 Next to be eluted was the title compound 12 (124 mg, 43) as an intense orange oil which was stored and handled in the dark; (Found (EI): M', 270.1981.Calc. for C1,H,,O, 270.1984); R, 0.40 light petroleum-EtOAc (8 :l); v,,,/cm-' 2943, 1672 and 1594; d,(270 MHz) 1.03 (6 H, s, 2 x 6'-Me), 1.45-1 SO (2 H, m, 4'-H), 1S3-1.59 (2 H, m, 5'-H), 1.77 (3 H, s, 2'-Me), 1.97- 2.02 (2 H, m, 3'-H), 2.03 (3 H, s, 7-Me), 5.81 (1 H, dd, J 7.9, 11.2, 2-H), 6.09 (1 H, d, J 15.9, 8-H), 6.20 (I H, d, J 11.9, 6-H), 6.35 (1 H, d, J 15.9,9-H), 6.94 (1 H, dd, J 14.1, 11.9, 5-H), 7.04 (1 H, dd, J 11.8, 11.2, 3-H), 7.20 (1 H, dd, J 14.1, 11.8,4-H) and 10.19 (1 H, d, J 7.9, 1-H); dc(67.5 MHz) 12.81, 19.43, 22.11, 29.77, 33.24, 34.53, 39.70, 124.89, 126.13, 128.76, 130.35, 130.59, 136.59, 137.82, 138.80, 142.54, 147.38 and 190.07; m/z (EI) 270 (40), 253 (12), 225 (77), 171 (60), 105 (57), 91 (75) and 41 (100).All spectroscopic data were in accord with those reported in the literature. (ii) Via the alane lla.33-Procedure (i) was followed exactly to obtain a THF solution of alane lla which was then added via a cannula to a stirred suspension of pyrylium tetrafluoroborate 2 (1 80 mg, 1.07 mmol) in THF (5 cm3). The mixture was stirred at -78 "C for 36 h after which work-up and purification as above gave llc41 (460 mg, 60) and the title compound 12 (91 mg, 31). (22,4E,8E)-9-(2',6',6'-Trimethylcyclohex-l-enyl)nona-2,4,8-trien-6-ynal 14.This compound was prepared from the organolithium reagent 13 from 1-(trans-but-1'-en-3'-ynyl)-2,6,6-trimethylcyclohex-1-ene lo3, (560 mg, 3.21 mmol) and BuLi (2.61 mol dm-3 in hexanes; 1.23 cm3, 3.21 mmol) in dry THF (5 cm3), -78 to 0deg;C over 2 h and pyrylium tetrafluoroborate (500 mg, 2.98 mmol) in THF (5 cm3) according to the typical procedure given previously. Work-up according to the typical procedure and purification by flash .~ chromatography light petroleum-EtOAc-triethylamine (550:25:0.5) gave the title compound 14 (462 mg, 56) as an orange-coloured syrup {Found (EI): M', 254.1667. C1,H,,O requires M', 254.1671 ); RF 0.29 light petroleum- EtOAc (1 6 : l); v,,,/cm-' 2956, 2930, 2864, 2 171, 1737, 168 1, 1607, 1457, 1373, 1157, 1144, 1133,1109, 1009 and 955; d,(270 MHz) 1.05 (6 H, s, 6'-Me), 1.441.47 (2 H, m, 5'-H), 1.58-1.61 (2 H, m, 4'-H), 1.75 (3 H, s, 2'-Me), 2.02-2.05 (2 H, m, 3'-H), 5.67 (1 H, dd, J 16.45,2.44,8-H), 5.88 (1 H, dd, J 10.99,7.65,2-H),6.16(1 H,dd, J14.95,2.44,5-H),6.72(1 H,d, J16.48,9-H), 6.95(1 H,t,J11.75,3-H),7.51(1H,dd,J15.11,12.36,4-H)and 10.18 (I H, d, J 7.81, 1-H); dc(67.5 MHz) 19.28, 21.96, 29.09, 33.62, 34.36, 39.91, 89.11,98.64, 111.50, 122.21, 128.01, 133.53, 133.60, 137.30, 143.50, 146.00 and 190.15; m/z (EI) 254 (M', 5779, 239 (23), 21 1 (loo), 185 (20), 171 (20), 157 (38), 141 (28), 129 (28), 115 (28), 91 (26) and 41 (25).(22,4E,6E,8E)-3,7-Dimethyl-9-(2',6' ,6' -trimethylcyclohex-1- enyl)nona-2,4,6,8-tetraenal 15 (13-cis-retina1, 13-cis-vitamin A aldehyde).A solution of the alanate llb33 (4.30 mmol) in THF (25 cm3), prepared as in experiment (i) for compound 12, was J. CHEM. SOC. PERKIN TRANS. I 1995 added uiu a cannula to a stirred suspension of rlmethylpyrylium tetrafluoroborate 5 (195 mg, 1.07 mmol) in THF (10 cm3)at -78 "C over 10 min. The mixture was stirred for 40 h at this temperature and worked up as described above in the typical procedure. The crude mixture showed a single retinal isomer in the 'H NMR spectrum (270 MHz). Purification by flash column chromatography light petroleum-EtOAc-triethyl-amine (300 :10:0.1 to 200 :10:0.1) (gradient elution) in a darkened room gave 1-(3'-methyl-trans-but-l',3'-dienyl)-2,6,6-trimethylcyclohex-1-ene llc (487 mg, 59) as a yellow Next to be eluted was the title compound 15 (146 mg, 48) as an intense orange-coloured oil which was stored and handled in the dark; RF0.25 light petroleum-EtOAc (16: l); v,,,/cm-' 2927, 1660, 1581, 1452, 1379, 11 15 and 968; 6,(270 MHz) 0.97 (6 H, s, 2 x 6'-Me), 1.32-1.43 (2 H, m, 4'-H), 1.461.62 (2 H, m, 5'-H), 1.64 (3 H, s, 7-Me), 1.90-2.00 (5 H, br s, 3'-H and 2'-Me), 2.14 (3 H, d, J 1.2, 3-Me), 5.76 (1 H, br d, J 7.91, 2-H), 6.03-6.35 (3 H, m, 6-H, 8-H, 9-H), 6.98 (1 H, dd, J 11.2, 15.2, 5-H), 7.25 (1 H, d, J 14.8, 4-H) and 10.21 (1 H, d, J 7.91, 1-H); dc(67.5 MHz) 13.10, 19.16, 20.12, 21.75, 28.95, 33.11, 34.25, 39.57, 126.25, 127.66, 129.36, 129.67, 130.49, 133.42, 137.02, 137.57, 141.47, 154.66 and 189.88; m/z (EI) 284 (M+, loo), 269 (18), 187 (19), 173 (61), 147 (40), 133 (48), I19 (70), 105 (65), 95 (71), 77 (42), 69 (56), 55 (54) and 41 (84).All spectroscopic data were in accord with those reported in the literature.28 (22,4E,8E)-3-Methyl-9-(2',6',6'-trimethylcyclohex-l -enyl)-nona-2,4,8-triend-ynal 16. Butyllithium (2.61 mol dm-3 in hexane; 2.2 cm3, 5.74 mmol) was added dropwise to a solution of 1-(trans-but-1'-en-3'-ynyl)-2,6,6-trimethylcyclohex-1 -ene (1000 mg, 5.74 mmol) in dry THF (10.0 cm3) under an atmosphere of dry nitrogen at -78 "C and the resulting solution was stirredand allowed to warm to 0 "C over 2 h where- upon it was stirred for a further 2 h. Addition of this solution of compound 13 to 4-methylpyrylium tetrafluoroborate 5 (1000 mg, 5.50 mmol) in THF (10.0 cm3) following the typical procedure with purification by flash silica column chromato- graphy light petroleum-EtOAc-triethylamine (200: 10: O.l) gave the title compound 16 (907 mg, 58) as a yellow oil (Found (EI): M', 268.1826.Calc. for C19H240; M', 268.1827); R, 0.25 light petroleum-EtOAc (16: l); v,,,/cm-' 2928, 2174, 1668, 1593, 1445, 1378, 1203, 1114, 953 and 732; 6,(270 MHz) 1.04 (6 H, s, gem CH,), 1.43-1.47 (2 H, m, CH,), 1.56-1.62(2H,m,CH2), 1.75(3H,s,2'-Me),2.01-2.06(2H,m, 3'-H), 2.08 (3 H, d, J 1.32, 3-Me), 5.66 (1 H, dd, J 16.31, 2.47, 8-H), 5.87 (1 H, br d, J7.9, 2-H), 6.21 (1 H, dd, J 15.51, 2.31, 5-H), 6.70 (1 H, d, J 16.16,9-H), 7.59 (1 H, d, J 15.51,4-H) and 10.19 (1 H, d, J 7.9, 1-H); DIFNOE experiments showed enhancement of 3-Me on irradiation of 2-H and no enhance- ment of 4-H; 6,(67.5 MHz) 18.91, 20.33, 21.55, 28.68, 33.19,33.95, 39.50, 88.81,96.89, 111.25, 116.93, 128.84, 132.85, 134.38, 136.91, 142.71, 152.40 and 189.52; m/z (EI) 268 (M+, 14), 253 (15), 241 (7), 225 (79), 199 (33), 171 (72), 128 (48), 115 (60), 105 (40), 91 (66), 77 (54) and 41 (100).The spectroscopic data were in full agreement with published data.29 (2Z,4E,8E)-3-Cyclohexyl-9-(2',6',6'-trimethylcyclohex-l-enyl)nona-2,4,8-trien-6-ynal 18. This compound was prepared from the organolithium reagent 13 prepared from I -(trans-but-1'-en-3'-ynyl)-2,6,6-trimethylcyclohex-l-ene (320 mg, 1.82mmol) and BuLi (2.84 mol dm-3 in hexanes; 0.65 cm3, 1.85 mmol) in dry THF (5 cm3), -78 to 0 "C over 2 h and 4- cyclohexylpyrylium tetrafluoroborate 34 (41 2 mg, 1.65 mmol) in THF (5 cm3) according to the typical procedure.Purification of the crude material by silica column chromatography light petroleum-EtOAc-triethylamine (200 :10:0.l) gave the alkyne starting material 10 (82 mg) and the title compound 18 (235 mg, 52) as an orange-coloured oil {Found (EI): M', 336.2453. Camp;32O requires M', 336.2453); RF 0.41 light petroleum- 2391 EtOAc (16: l); ~,,,,~/cm-~ 2925, 2854, 2174, 1664, 1626, 1588, 1450,1199,1174,1133,1115 and 953; 6,(270 MHz) 1.12 (6 H, s, 2 x Me), 1.25-1.45 (4 H, m, cyclohexyl), 1.52-1.56 (2 H, m, 5'- H), 1.66-1.71 (2 H, m, 4'-H), 1.83 (3 H, s, Me), 1.85-1.91 (6 H, m, cyclohexyl), 2.12 (2 H, t, J 5.94, 3'-H), 2.45 (1 H, t, J 11.21, (3-cyclohexyl) 1-H), 5.73 (1 H, d, J7.92, 2-H), 6.26 (1 H, dd, J 2.31,15.83,8-H),6.77(1 H,d, J16.5,4-H),7.34(1 H,d, J15.84, 9-H) and 10.18 (1 H, d, J 7.25, 1-H); DIFNOE experiments showed enhancement at the 3-cyclohexyl 1-H proton and enhancement in the other 3-cyclohexyl ring protons and no enhancement at 4-H on irradiation at 2-H; 6,(67.5 MHz) 18.96, 21.60, 25.95, 26.45, 28.74, 32.46, 33.23, 34.02, 39.53, 41.69, 88.63, 95.71, 111.30, 116.41, 126.18, 132.78, 134.27, 136.98, 142.64, 163.12 and 191.10; m/z (EI) 336 (M', 15), 308 (52), 293 (loo), 239 (26), 21 1 (25), 145 (24), 131 (21), 105 (20), 91 (26) and 41 (27).(2E,4E,6E,8E)-3,7-Dimethyl-9~2',6',6'-tr~ethylcyclohex-l-enyl)nona-2,4,6,8-tetaenall9 (vitamin A aldehyde, retinal). Toa stirred solution of 13-cis-retinal 15 (1 20 mg) in diethyl ether (5 cm3) at room temperature was added dropwise a solution of iodine (5 mg) in benzene (5 cm3). The mixture was stirred at room temperature for 48 h,35 after which the solvent was removed under reduced pressure and the residue purified by preparative centrifugal chromatography light petroleum- EtOAc (20: l) to yield the title aldehyde 19 as an orange- coloured oil (109 mg, 91); R, 0.21 light petroleum-EtOAc (16: l); v,,,/cm-' 2956, 1660, 1579, 1447, 1381, 1361, 1162, 1131, 1121 and 970; 6,(270 MHz) 1.12 (6 H, s, 2 x 6'-Me), 1.54-1.58 (2 H, m, 4'-H), 1.67-1.76 (2 H, s, 5'-H), 1.81 (3 H, s, 5'-Me), 2.12 (5 H, br s, 4'-H and 7-Me), 2.26 (3 H, d, J 1.2, 3- Me), 6.06 (1 H, br d, J 8.25,2-H), 6.22-6.33 (2 H, m, 6-H and 8-H), 6.41-6.49 (2 H, m, 4-H and 9-H), 7.23 (1 H, dd, J 15.18, 11.55, 5-H) and 10.10 (1 H, d, J 8.24); 6,(67.5 MHz) 13.01, 13.12, 19.18, 21.76, 28.69, 33.14, 34.27, 39.59, 129.00, 129.38, 129.72, 130.53, 132.54, 134.50, 137.07, 137.61, 141.29, 154.84 and 191.12.The spectroscopic data were in full accord with published data.28 (2Z,4E,8E)-3-Methyl-9-(2',6',6'-himethylcyclohex-l-enyl)-nona-2,4,8-trien-6-yn-l-ol 20. To a solution of the aldehyde 16 (252 mg, 0.94 mmol) in dry diethyl ether (10 cm3), stirred at -78 "C under an atmosphere of dry nitrogen, was added DibalH (1 .O mol dm-' in hexanes; 0.94 ~m-~, 0.94 mmol) and the mixture was stirred at this temperature for 14 h; it was then allowed to warm to 0 "C over 2 h and held at this temperature for a further 1 h.The mixture was then quenched by the addition to it of saturated aqueous sodium hydrogen carbonate (10 cm3), after which it was extracted with ethyl acetate (5 x 10 cm3). The combined extracts were dried (NaSO,) and concentrated under reduced pressure and the residue was purified by flash column chromatography light petroleum- EtOAc-triethylamine (450 :100:5) to give the title alcohol20as a pale yellow-range oil (205 mg, 81) (Found (EI): EM', 270.198 05. C19H260requires M', 270.1984); R, 0.23 light petroleum-EtOAc (4: l); vmax/cm-' 3342, 2928, 21 76, 1626, 1456, 1379, 1361, 1294, 1022 and 953; 6,(270 MHz) 1.11 (6 H, s, 2 x 6'-Me), 1.51-1.55 (2 H, m, 4'-H), 1.66-1.71 (2 H, m, 5'-H), 1.82 (3 H, s, 2'-Me), 1.95 (3 H, d, J 0.99, 3-Me), 2.04 (1 H, br s, OH), 2.08-2.13 (2 H, m, 3'-H), 4.40 (2 H, d, J 6.93, 1-H), 5.67-5.74 (2 H, dd overlapped with t, J 16.17, 2.31, 7.16, 2-H and 8-H), 5.93 (1 H, dd, J 2.31, 15.83, 5-H), 6.68 (1 H, d, J 16.16, 9-H) and 7.05 (1 H, d, J 15.84, 4-H); DIFNOE experiments showed clear enhancement at 3-Me on irradiation of 2-H with no enhancement at 4-H; 6,(67.5 MHz) 18.99, 19.63, 21.57, 28.72, 33.14, 33.98, 39.52, 58.24, 89.31 and 92.49, 109.96, 111.84, 130.39, 131.90, 134.41, 136.55, 137.04 and 141.06; mjz (EI) 270 (M', loo), 255 (21), 237 (27), 183 (33), 165 (32), 155 (29), 141 (33), 128 (52), 115 (47), 105 (34), 109 (66), 77 (36), 55 (30) and 39 (62).Acknowledgements We thank the SERC for the award of a postdoctoral research assistantship (K. H.) and to CNPq, Brazil for a scholarship (E. F. D. M.). Financial support for the earlier stages of this programme from the SERC, Fisons Pharmaceuticals, the University of East Anglia and the British Council is also acknowledged. Richard Taylor would also like to record his gratitude to Dr Mark Furber for initiating this area of research and Drs John Herbert, Yuri Belosludtsev, Ben Borer, Edna Faria De Medeiros and Karl Hemming (see references) for continuing the programme with such dedication and enthusiasm. References (a) Polyunsaturated antibiotics: S.Omura and H. Tanaka in Macrolide Antibiotics: Chemistry, Biology and Practice, ed. S. OmurB, Academic Press, New York, 1984; for a recent reference see S. D. Rychnovsky, G. Griesgraber and R. Schlagel, J. Am. Chem. SOC.,1995, 117, 197; (b) Pheromones: K. Mori, Total Synth. Nat. Prod., 1992, 9, 1 and references therein; (c) Polyunsaturated arachidonic acid metabolites: J. Rokach, Y. Guindon, R. N. Young, J. Adams and J. G. 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