N-alkenyl nitrone dipolar cycloaddition routes to piperidines and indolizidines. Part 3. Approach to the gephyrotoxin ring system

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1992 N-Alkenyl Nitrone Dipolar Cycloaddition Routes to Piperidines and Indolizidines. Part 3.t Approach to the Gephyrotoxin Ring System Andrew B. Holmes," Andrew B.Hughes, Adrian L. Smith and Simon F. Williams University Chemical Laboratory, Lensfield Road, Cambridge CB2 I EW, UK Intramolecular dipolar cycloaddition studies on the N-alkenyl nitrones 16, 17, 36 and 45 are re- ported. The regio- and stereo-chemistry of the product bicyclic isoxazolidines (precursors to ring B of gephyrotoxin 1) are sensitive to the nature and geometry of the alkene dipolarophile. Previously we have reported the use of the intramolecular thermal dipolar cycloaddition of (Z)-N-alkenyl nitrones in the synthesis of all-cis-2,3,6-trisubstitutedpiperidines' (and related indolizidines isolated from the Dendrobatidae family of neo- tropical frogs) as well as epimerisation of the C-3 substituent from cis to trans.24 We considered that the methodology was amenable to more complex poison arrow alkaloids such as gephyrotoxin 1 which was one of the alkaloids isolated from skin extracts of the Colombian frog Dendrobates histrioni~us.~-' It shows mild muscarinic,* and other interesting neurophysio- logical a~tivity.~ The structure and absolute configuration follow from X-ray crystallographic and chemical analysis,' *vl ' although the rotation observed for 1 which had been syn- thesised by Kishi from L-glutamate was opposite to that reported for material assigned the absolute configuration 1.' Other syntheses of gephyrotoxin have been reported by '7' Hart 13,14 and Overman." Our planned synthesis of gephyrotoxin recognised the presence of the 2,3,6-trisubstituted piperidine ring B in which the substituent at the 6-position is trans to the remaining cis substituents at C-2 and C-3.This cis-relationship could be established by an intramolecular nitrone cycloaddition, while the trans-relationship could be established by an intermolecular cycloaddition of a suitable dipolarophile to a piperideine N-oxide derived from regioselective oxidation of a bicyclic isoxazolidine (Scheme 1). This strategy would establish four of the five stereocentres in gephyrotoxin and enhance the versatility of the nitrone cycloaddition strategy in alkaloid synthesis.Our analysis (Scheme 1) showed that the A-ring might be formed by intramolecular alkylation of the anion of the indol- izidinone sulfone 3 as employed by LeBel and Balasubramanian in their synthesis of pumiliotoxin C.l6 The indolizidinone could be elaborated according to Hart's formal synthesis of gephyro- toxin.' In the course of the preparation of compound 3 we have discovered some interesting chemistry which further delineates the mechanistic subtleties of nitrone cycloadditions. The trans- formation of the isoxazolidine 4 to the indolizidinone 3 and thence gephyrotoxin will be the subject of a future paper. The following discussion details our efforts to prepare the isoxazol- idine 4 from nitrones of general structure 5 (in which it was hoped to use the dipolarophile's double bond geometry to con- trol relative stereochemistry in ring B of 1).Such nitrones 5 are available from enoates 6 by standard transformations. Results and Discussion The preparation of the nitrone 5 is shown in Scheme 2. Alkylation of the butynol silyl ether 7 proceeded best by prolonged reflux in tetrahydrofuran (THF; 48 h, 56). How- t Part l, ref. 2; Part 2, ref. 3. HO 1 2 TsO f HPS02Ph 0 4 3 -0 5U -RO-COSEt 6 Scheme 1 ever, a shorter period of reflux, while resulting in a reduced yield of the dioxolane 9 (3773, did allow recovery of the starting material 7 (61), which could then be recycled to provide a higher total conversion. Hydrogenation of the acetylene 9 over Lindlar catalyst was quantitative.The resulting (Z)-alkenyl dioxolane 10( >95 2-isomer as determined by 'H NMR)was hydrolysed to give the crude aldehyde 11 which was stirred immediately with hydroxylamine to afford the oxime 12 as a 1 :1 mixture of geometrical isomers in 61 yield from the dioxolane 10. The y-sulfonyl aldehyde 13 was also prepared from the dioxolane 8 (Scheme 3) by alkylation with the lithium anion of methyl phenyl sulfone over a long reaction time at -78 "C. However, it proved to be unstable, decomposing with time to give acrolein. It was therefore stored as the dioxolane 14 and converted into the aldehyde immediately before use. The oxime 12 was reduced to the unstable 17*18 hydroxyl-amine 15 with sodium cyan~borohydride.~ After a rapid work- up at 0 "C,a solution of the y-sulfonyl aldehyde 13 was added.Stirring of the mixture at room temperature gave the nitrone 16 J. CHEM. SOC. PERKIN TRANS. 1 1992 7 9 N(H)OH i"(lOTBDPSOTBDPS OTBDPS 11 10 l5 12 ?--+NwTBDPSO-SO2Ph 16 Scheme 2 Reagents and conditions: i, BuLi, 8 THF, tetramethylethyl- enediamine (TMEDA), reflux; ii, Lindlar catalyst, H,, EtOAc; iii, 2 mol dm-, HCl, Et,O; iv, NH,OH-HCl, NaOAc; v, NaCNBH,, aqueous MeOH, pH 3,O "C; vi, 13,CH,Cl,, 0 "C to room temp., 12 h 8 14I ii t SO,Ph 13 Scheme 3 Reagents and conditions: i, MeSO,Ph, THF, BuLi, -78 "C, 6 h; ii, Et,O, 2 mol dm-, HCl (85). The nitrone 16 was chromatographed on silica before thermal cyclisation was attempted. However, when a solution of the purified nitrone 16 in toluene was heated at 90°C no cyclisation or double bond isomerisation had occurred, while prolonged reaction at higher temperature (110 "C) caused decomposition. It was felt that the large active volume associated with the tert-butyldiphenylsilyl protecting group may prevent the nitrone 16 from folding into a reactive conformation.A reduction of this steric demand should facilitate the cycloaddition. To this end the nitrone 17 was prepared (Scheme 4). The benzyl ether 18 l9 was converted into the aldehyde 21 by an analogous method to that used to prepare the aldehyde 11. The crude aldehyde afforded the unstable hydroxylamine by reduction of the oxime 22.Conversion into the nitrone 17 and prolonged heating in toluene gave the isoxazolidines 23 and 24 in 20 and 13 yield respectively. However, none of the regiosomeric isoxazolidine 25 was isolated. This result, while showing that a dipolar cycloaddition was possible with these intermediates, raised some interesting mechanistic questions. The assignment of the structure 23 follows by analogy with the results reported by LeBel.16 The relative stereochemistry of the adduct 24 follows from the absence of vicinal coupling between the 5-and 6-H (6, 4.28, t, J 6) which is analogous to results obtained with the corresponding methyl analogues prepared in the synthesis of carpamic acid. It is appropriate at this point to discuss the factors affecting the nitrone cycloaddition in the light of the above result.Huisgen 2o has collated a considerable amount of chemical 0-18 191 ii t BnO- 0R iii- . 21 R=O 20 N(22 R=NOH v, vi ft SOZPh n-17 BnOFf SOpPh 24 Scheme 4 Reagents and conditions: i, BuLi, THF, 0 "C, 1.5 h, 8, reflux; ii, Lindlar catalyst, H,, EtOAc; iii, THF, H20, AcOH, 50 "C, 60 h; iv, NaOAc, NH,OH*HCl; v, NaCNBH,, aqueous MeOH, pH 3,O "C, vi, 13,CH,Cl,, 0 "C to room temp., 2 h; vii, toluene, reflux BnOfif LS02Ph 25 evidence in support of the concertedness of dipolar cyclo- additions in general. Nitrones and other dipoles are well known to provide excellent levels of stereoselectivity and predictable regiochemistry.2' It is generally accepted that nitrone cyclo- additions are concerted though asynchronous, the C-C bond being formed in advance of the C-0 bond.21" In nitrone cycloadditions where electronic control predominates, FMO theory allows the prediction of reaction regio~hemistry.~~ Intramolecular nitrone cycloadditions are not subject solely to electronic control. Other factors such as the length of the tether between the nitrone and the dipolarophile 'I3" and steric con- siderations can play an important role in the regiochemistry of cycloaddition.'I3 There are, however, some examples of nitrone cycloadditions in which the electronic and stereochemical factors controlling the reaction are in opposition and mixtures are obtained.Oppolzer's work 'I3" with intramolecular N-alkenylnitrone cycloadditions has demonstrated the reversal of regiochemistry achieved by placement of substituents with increasing steric bulk and differing electronic demand at specific points around the nitrone and the double bond.N-Alkenyl nitrone cycloadditions are well precedented to occur suprafacially on the double bond of the dipolarophile.21b Yet it is noted that the adduct 24 is formally the product of dipolar cycloaddition to the (E)-double bond isomer of the nitrone 17. It is notable that the nitrone 17 represents, to the best of our knowledge, only the second example of the use of a J. CHEM. SOC. PERKIN TRANS. 1 1992 (Z)-disubstituted dipolarophile in an intramolecular nitrone cycloaddition. The other example is the (Z)-hex-4-enyl side chain used in LeBel and Balasubramanian's synthesis of pumiliotoxin C.Evidently the difference between that ex- ample, in which the dipolarophile bears a (2)-methyl sub- stituent, and 17 is the increased A,,,-strain22 which is intro- duced by the presence of a bulkier substituent in the transition state for the cyclisation of the nitrone 17 to the adduct 23. The second product 24 is formally the product of double bond isomerisation. As such, it may represent evidence of a stepwise mechanism for a nitrone cy~loaddition.~~ It is also feasible that isomerisation may occur before or after concerted cy~loaddition.~' That neither of the pathways giving the isoxazolidines 23 and 24 is particularly favourable is shown by their low chemical yields (20 and 13 respectively) after prolonged reaction.It was, therefore, apparent that a (2)-substituent of even lower steric demand than the benzyloxymethyl group was required in order to facilitate the cycloaddition. The (Z)-dienyl nitrone 36 was, therefore, selected as the next target. The diene 32was prepared from prop-2-ynyl alcohol (Scheme 5). Alkylation of the THP ether 26 with the bromodioxolane 8 gave a moderate yield (52) of the disubstituted acetylene 27. Following Lindlar hydrogenation to give the (Z)-alkene 28 (98), the THP ether could be selectively removed by trans- ketalisation with toluene-p-sulfonic acid and dry methanol in 74 yield. Oxidation of the allylic alcohol 29 with activated manganese dioxide gave the unstable aldehyde 30 as a mixture of (Z)/(E)-enals.The enals 30 were methylenated by a Wittig reaction to give the dienes 31 and 32 in 95 yield in a ratio of 1:9 ('H NMR) respectively. The loss of (2)-double bond integrity and the instability of the enal 30 necessitated an alternative route to the (2)-diene 32 that avoided the alde- hyde. Thus, the (2)-alkenyl silyl ether 10 was desilylated (88) (Scheme 6) with tetrabutylammonium fluoride (TBAF) and the resulting alcohol 33 was converted into the tosylate 34 (79). Treatment of the tosylate 34 with potassium tert-butoxide in dry dimethyl sulfoxide caused elimination to afford the dienes 32 and 31 in 90 yield as a 97:3 (Z)/(E)-mixture as shown by 'H NMR and GC analysis.Careful hydrolysis of the THP group of the (Z)-diene 32 gave the aldehyde which was not isolated but was converted as usual via the corresponding oxime 35(80;mixture of geometric isomers) into the required nitrone 36 in 82 yield from the oxime. The cycloaddition of the nitrone 36 could be effected in refluxing benzene, toluene or xylene. In each of these solvents 26 R = tetrahydropyranyl 27 31 30 iii 28 R = tetrahydropyranyl 29 R=H Scheme 5 Reagents and conditions: i, BuLi, TMEDA, THF, 8,O "C to reflux, 48 h; ii, Lindlar, H,, EtOAc; iii, TsOH, MeOH; iv, MnO,, CH,Cl,, room temp., 1 h; v, CH,=PPh,, THF, -78 "C, 1 h iv, v 10 R=TBDPS ,!'33 R=OH "(34 R=OTs 32 /35 J S02Ph N+-A thpPh S02Ph 38 37 Scheme 6 Reagents and condirions: i, Bu,N+F-, THF, 0 "C,30 min; ii, pyridine, TsCl, 20 "C, 16 h; iii, KOBu', DMSO, 20 "C, 2 h; iv, 2 mol dm-, HCl, Et,O, 20°C, 36 h; v, NaHCO,, NaOAc, NH,OH*HCl, H,O, EtOH, 20 "C, 14 h; vi, NaCNBH,, 6 mol dm-, HCI, H,O, MeOH; vii, benzene, reflux, 24 h; viii toluene, reflux, 24 h; ix, xylene, reflux two C-6 epimeric isoxazolidines 37 and 38 were isolated in similar total chemical yields although in different ratios.In refluxing benzene the ratio was 7:l in favour of the isox- azolidine 38. This ratio was reduced to 3: 1 in toluene and approached equality (1.8:1) in xylene. In one experiment the 7:l mixture of isoxazolidines produced from a reaction in refluxing benzene was reheated to reflux in xylene.On re-isolation the ratio of products had changed to that observed for the reaction of the nitrone 36 in xylene (1.8: 1). The ratio of compounds 37 and 38 obtained by equilibration in xylene is presumably a true thermodynamic ratio. The adduct 38 is formally the product of suprafacial cycloaddition to the (E)-isomer of the nitrone 36.It is sterically less congested than the isomer 37.The fact that 37 and 38 are interconvertible in refluxing xylene suggests that they are related by a pathway involving the intermediate 39 (Scheme 7). The intermediate 39 is a stabilised ally1 radical which may form readily under thermolytic conditions. However, an alternative heterolytic cleavage cannot be ruled out. It is also tempting to suggest that the production of the adduct 39 is consistent with initial C-C bond formation from the nitrone 36 which may be viewed as a diradical species as proposed by Kahn, Hehre and P~ple.~~ It would follow from this argument that the partitioning of the 38 39 37 Scheme 7 first formed intermediate 39 is kinetically controlled in benzene and toluene and only reflects thermodynamic control when sufficient activation energy is provided in refluxing xylene.Of course, it is impossible to exclude an alternative explanation in which kinetic concerted formation of 37 from the nitrone 36 is followed by equilibration between adducts 38 and 37 via the intermediate 39. The least likely explanation for the formation of adduct 38 is uia the isomerised (E)-isomer of the diene 36.Given the difficulty of introducing the required stereocentre in the gephyrotoxin precursor 4 from a (2)-alkene and the relatively facile cycloaddition possibilities with (E)-alkenes, it was recognised that the configuration of C-6 of the isoxazol- idines (e.g. 37) might be inverted to that required by, for example, a Mitsunobu reaction.27 Furthermore, the E-double bond could be substituted with a functional group serving as a latent enyne sidechain. The nitrone 45 (Scheme 8) was selected for this purpose. The required unsaturated oxime 44 was obtained from the ester 43 which was synthesised by the Johnson modification of the Claisen rearrangement.28 The allylic alcohol 42 was prepared by cerium(1rr) chloride 29 mediated addition of vinylmagnesium bromide to the aldehyde 41.This suppressed enolisation of aldehyde 41. Claisen rearrangement of the alcohol 42 gave the (E)-heptenoate 43 (89). Reduction of the ester 43 to the corresponding aldehyde with diisobutylaluminium hydride (DIBAL) and condensation with hydroxylamine hydrochloride afforded the oxime 44. However, for convenience, a brief work- up of the DIBAL reduction and immediate condensation of the crude aldehyde with hydroxylamine hydrochloride was at least as efficient. The oxime 44 was converted, via the usual sequence, into the nitrone 45 in 91 yield. This could be cyclised in refluxing benzene to give the required isoxazolidine 46 as the sole product (54). However, a better yield (76) could be obtained by performing the cycloaddition in refluxing toluene.Under these conditions a second compound, the regioisomeric isoxazolidine 47 was also isolated (14). The two isoxazolidines were not inter~onvertible.~' Evidently the homoallylic benzyloxy sub- stituent in the nitrone 45 does not encourage this equilibrium. The isoxazolidine 46 has the correct configuration at C-6 for Mitsunobu inversion 26 later in the synthesis. In summary then, we have succeeded in preparing the isox- azolidine 46 in 46 yield over six steps from the benzyl ether 40. In the course of the study a remarkable sensitivity to substitution at the furthest allylic centre from the nitrone function was found in a variety of intramolecular N-alkenyl nitrone dipolar cycloadditions.In particular, one product 24, was isolated which may represent experimental evidence for a stepwise mechanism in a nitrone cycloaddition. Further studies toward the synthesis of gephyrotoxin 1 using the methodology introduced in this paper will be reported later. Experimental NMR spectra were recorded using Varian EM390A, Bruker WM250 and WM400 instruments. Low and high resolution electron impact mass spectra were determined on AEI MS902 and MS30 instruments respectively. Chemical ionisation mass spectra were recorded by Dr. J. Ballantine and co-workers at the SERC Mass Spectrometry Service, Swansea. IR spectra were re- corded on a Perkin-Elmer 13 10 spectrophotometer, calibrated relative to polystyrene.J Values are recorded in Hz. Microanalyses were performed by Mr. D. Flory and staff at the Department of Chemistry, Cambridge. Melting points were determined on a Biichi 510 apparatus. Flash chromatography was carried out on Merck Kieselgel 60 (23WOO mesh). Thin layer chromatography was carried out on Merck Kieselgel J. CHEM. SOC. PERKIN TRANS. 1 1992 i BnO-OH -BnO-yo -BnoTOH 40 41 42 I iii t BnO CO2Et 44 43 S02Ph viii 46 + 45 SO2PhBnO 47 Scheme 8 Reagents and conditions: i, Swern; ii, CeCl,, vinyl MgBr, THF, -78 "C to -65 "C, 6 h; iii, MeC(OEt),, EtC0,H (cat.), 125 "C; iv, DIBAL, THF, -100 "C, 3 h; v, EtOH, NH,OH-HCl, NaOAc, 30 min; vi, NaCNBH,, EtOH, pH 3, -10 "C; vii, 13, CH,CI,, Na,SO,, 1 h; viii, toluene, reflux, 15 h 60 GF254 plates, coated to a thickness of 0.25 mm. Gas chromatography (GC) was carried out using a Carlo Erba 4130 instrument, S.G.E.BP5 (5 phenylmethylsiloxane as sta-tionary phase) 25 m column, diameter 0.33 mm, carrier gas flow rate 2.0 cm3 min-'1. THF refers to tetrahydrofuran distilled from potassium in a recycling still. Dimethyl sulfoxide (DMSO) was dried by distillation from calcium hydride, and stored over 4 A molecular sieves. Ether refers to diethyl ether. Triethylamine and N,N,N',N'-tetramethylenediamine(TMEDA) were dried by distillation from calcium hydride, and stored over calcium hydride or potassium hydroxide. 1-(tert-ButyldiphenyZssilyloxy)but-3-yne7.-A solution of but-3-yn-1-01 (2.00 g, 28.6 mmol) in dry dichloromethane (40 cm3) was treated with imidazole (4.28 g, 62.9 mmol) and tert-butyldiphenylsilyl chloride (8.16 cm3, 31.5 mmol) at 0 "C.The solution was stirred at 20 "C for 2 h, poured into saturated aqueous sodium hydrogen carbonate (100 cm3) and extracted with dichloromethane (3 x 100 cm3). The combined organic extracts were dried (Na,SO,), evaporated under reduced pressure and the residue was purified by flash chromatography on silica eluting with 10 ethyl acetate-hexane to give the pure silyl ether 7 as a colourless liquid (8.80 g, 100) (Found: C, 77.6; H, 7.7. C,,H,,SiO requires C, 77.9; H, 7.8); v,,,(CCl,)/cm-' 3300s (CCH) and 2120m (Cg); 6,(250 MHz; CDCl,) 7.78- 7.73 (4 H, m, ArH), 7.48-7.40 (6 H, m, ArH), 3.85 (2 H, t, J 7.1, CH,O), 2.51 (2 H, dt, J7.1 and 2.6, CH,C=C), 1.99 (1 H, t, J2.6, CSH) and 1.13 (9 H, s, Bu'); dc(10O MHz; CDCl,) 135.5,133.5, 129.7, 127.7, 81.4, 69.3, 62.3, 26.8, 22.6 and 19.2; m/z (EI) 308 (M', 573, 269 (44), 251 (loo), 221 (76), 211 (17) and 105 (37) (Found: M +,308.1622.C20H2,Si0 requires M, 308.1597). 2-6-(tert-Butyldiphenylssil~l~xy)~ex-3-ynyl-1,3-dioxolane 9.-(a) A solution of the acetylene 7 (8.00 g, 26.0 mmol) in dry J. CHEM. SOC. PERKIN TRANS. 1 1992 THF (50 cm3) was treated with TMEDA (3.92 cm', 26.0 mmol) and butyllithitim (1.60 mol dm-, solution in hexane; 16.25 cm3, 26.0 mmol) at 0 "C and the mixture was stirred for 1 h. 2-(2- Bromoethyl)-1,3-dioxolane8 (3.66 cm3, 3 1.2 mmol) was added and the solution was heated at reflux for 22 h.The solution was poured into saturated aqueous sodium hydrogen carbonate (500 cm3) and extracted with dichloromethane (3 x 200 cm3). The combined organic extracts were dried (Na,SO,), evaporated under reduced pressure and the residue was puri- fied by flash chromatography on silica eluting with 20 ethyl acetate-hexane to afford the starting material 7 (4.86 g, 61). Further elution gave the acetylene 9 (3.97 g, 37); v,,,(CCl,)/cm-' 3020w (CH) and 3000~ (CH); 6,(250 MHz; CDCl,) 7.71-7.68 (4 H, m, ArH), 7.44-7.35 (6 H, m, ArH), 4.96 (1 H, t, J4.7, OCHO), 3.97-3.80 (4 H, m, OCH2CH,0), 3.75 (2 H, t, J 7.1, CH,OSi), 2.47-2.39 (2 H, m, CH,C=C), 2.32-2.24 (2 H, m, CH,C=C), 1.87-1.79 (2 H, dt, J7.5 and 4.8, CH,) and 1.07 (9 H, s, Bu'); 6,(100 MHz; CDC1,) 135.5, 133.7, 129.6, 127.6, 103.2,80.1,77.3,64.8,62.8,33.1,26.7,22.9and 19.1; m/z (EI) 407 (M+ -H, 30), 351 (49,307 (loo), 277 (28), 229 (42), 199 (100) and 183 (45) Found: (M+ -H), 407.2019.C25H31Si03 requires M, 407.20421. (b) To a stirred solution of 4-(tert-butyldiphenylsilyloxy)but-1-yne 7 (6.0 g, 19.48 mmol) in dry THF (120 cm3) at -5 "C was added butyllithium (1.6 mol dm-, solution in hexane; 12.17 cm3, 19.47 mmol). The resulting solution was stirred for 1.5 h and then allowed to warm to room temperature. TMEDA (2.27 g, 19.53mmol) was added and the solution was stirred for 10 min. 2-(2-Bromoethyl)-1,3-dioxolane8 (3.8 g, 21 mmol) was added and the solution was heated at reflux for 48 h.Saturated aqueous sodium hydrogen carbonate was added and the mix- ture extracted with ether (3 x 150 cm3). The combined organic phases were dried (MgSO,), filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 10 --+ 40 ether- hexane to give the acetylene 9 as a colourless oil (4.48 g, 56) identical with material prepared above. 2-6-( tert-Butyldiphenylsilyloxy)-(Z)-hex-3-enylJ-1,3-dioxol-ane 10.-A solution of the acetylene 9 (3.63 g, 8.90 mmol) in ethyl acetate (100 cm3) was treated with Lindlar catalyst (500 mg, Kataly Sator type C) and stirred under a hydrogen atmos- phere (1 atm) for 3 h. The solution was filtered, the filtrate evaporated under reduced pressure, and the residue was purified by flash chromatography on silica eluting with 20 ethyl acetate-hexane to give the pure alkene 10 as a colourless liquid (3.64 g, 100); ~,,,(CCl,)/cm-~ 3080s (CH), 3060m (CH) and 700s (2-CHSH); 6,(250 MHz; CDCl,) 7.72-7.64 (4 H, m, ArH), 7.45-7.33 (6 H, m, ArH), 5.46-5.40 (2 H, m, CHSH), 4.83 (1 H, t, J4.8, OCHO), 3.97-3.79 (4 H, m, OCH2CH20), 3.65 (2 H, t, J6.9, CH,OSi), 2.37-2.29 (2 H, m, CH,C==C), 1.71-1.64 (2 H, m, CH2) and 1.04 (9 H, s, Bu'); (lo0 MHz; CDCl,) 135.5, 133.9, 130.4, 129.5, 127.6, 126.5, 104.1,64.8,63.7,33.7,30.7,26.8, 22.0 and 19.2; m/z (EI) 410 (M+, 279, 409 (20), 353 (15), 309 (30), 243 (40),225 (22), 199 (92), 183 (25), 165 (38), 139 (28), 135 (22), 111 (loo), 93 (40), 73 (30) and 67 (40) (Found: M+, 410.2252.C,,H,,SiO, requires M, 410.227). 7-( tert- Butyldiphenylsilyloxy)-(Z)-hept-4-enalOxime 12.-A solution of the dioxolane 10 (70 mg, 0.171 mmol) and con- centrated hydrochloric acid (0.3 cm3, 2.5 mol) in wet acetone (20 cm3) was stirred for 30 min. Saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ether (3 x 30 cm3). The combined organic phases were dried (MgSO,) and filtered and the filtrate was evaporated under reduced pressure. Sodium acetate (28 mg, 0.342 mmol) was added to a stirred solution of the crude aldehyde in methanol (1 5 cm3) at room temperature, followed by hydrox- 1093 ylamine hydrochloride (24 mg, 0.345 mmol). The mixture was stirred for 12 h and then evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (25 cm3) was added to the residue and the aqueous phase was extracted with dichloromethane (3 x 20 cm3).The combined organic phases were dried (MgSO,) and filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 10 -33 ether- hexane to give the oxime 12 as a colourless oil (1 : 1 mixture of geometrical isomers) (39.7 mg, 61) (Found: C, 72.1; H, 8.3; N, 3.5. C23H31N02Si requires C, 72.4; H, 8.2; N, 3.7); vmax-(CHCl,)/cm-' 3580m (OH) 3300br s (OH), 2920s (CH) and 2840s (CH); 6,(250 MHz; CDCl,) 7.68-7.64 and 7.42-7.34 (10.5 H, 2 x m, ArH and CHNOH), 6.75-6.65 (0.5 H, m, CHNOH), 5.44-5.42 (2 H, m, CHSH), 3.65 and 3.64 (2 H, t, J 6.9, CH,OSi), 2.30-2.17 (6 H, m, CH,CH=CHCH,CH,) and 1.03 (9 H, s, Bu'); m/z (El) 324 (M+ + Bu', 573,308 (1 l), 307 (13), 306 (54), 246 (3 l), 222 (12), 200 (21), 299 (loo), 197 (13), 183 (14), 18 1 (17), 139 (15), 135 (10) and 81 (9) (Found: M+ -Bur, 324.1407.C19H2,N02Si requires M, 324.1420). 2-(3-Phenylsulfonylpropyl)-1,3-dioxolane 14.-A solution of methyl (phenyl) sulfone (11.70 g, 75 mmol) in dry THF (100 cm3) was cooled to 0 "C under a dry nitrogen atmosphere and treated with butyllithium (1.60 mol dm-, solution in hexane; 45 cm3, 72 mmol). The resulting white suspension was stirred for 15 min at 0 "C, and then cooled to -78 "C. 2-(2-Bromoethyl)-l,3- dioxolane 8 (4.40 cm3, 37.5 mmol) was added dropwise, and the solution was maintained at -78 "C for 6 h; it was then allowed to warm to room temperature slowly over 15 h.The reaction mixture was quenched with saturated aqueous ammonium chloride and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na,SO,) and evaporated under reduced pressure; the residue was purified by flash chromatography on silica eluting with 25 ---+ 50 ethyl acetate-hexane to give the pure 1,3- dioxolane 14 as a colourless liquid (7.83 g, 81) (Found: C, 56.3; H, 6.5; S, 12.2. C12Hl,S0, requires C, 56.2; H, 6.3; S, 12.5); v,,,(neat)/cm-' 3060m (CH), 1300s (SO,) and 1140s (SO,); 6,(250 MHz; CDC1,) 7.97-7.86 (2 H, m, Ph), 7.69-7.52 (3 H, m, Ph), 4.81 (1 H, t, J 4.1, OCHO), 3.94-3.72 (4 H, m, OCH,- CH,O), 3.17 (2 H, t, J 7.7, CH,SO,) and 1.99-1.61 (4 H, m, CH,CHZ); m/z (EI) 255 (M' -H, 473,222 (3), 181 (3), 179(5), 81 (6), 77 (7), 73 (100) and 67 (7).4-Phenylsulfonylbutanall3.-A solution of the 1,3-dioxolane 14 (5.44 g, 21.2 mmol) in ether (50 cm3) was treated with 2 mol dm-, hydrochloric acid (50 cm3) and stirred at 20 "C for 1 h. The solution was neutralised with solid sodium hydrogen carbonate, diluted with sufficient water to dissolve the salts, and then extracted with dichloromethane (1 x 200 cm3, 3 x 100 cm3). The combined organic extracts were dried (Na,SO,), evaporated under reduced pressure, and the resulting residue was subjected to the above conditions twice more to completely hydrolyse the acetal 14.The combined organic extracts were dried (Na,SO,), evaporated under reduced pressure, and the residue was purified by flash chromatography on silica eluting with 50 ethyl acetate-hexane to give the pure aldehyde 13 as a colourless liquid (4.19 g, 93) (Found: C, 56.3; H, 5.7; S, 15.2. Cl,H12S0, requires C, 56.6; H, 5.7; S, 15.1); v,,,(neat)/cm-' 3060m (CH), 2730s (CHO), 1300s (SO,) and 1140s (SO,); SH(250 MHz; CDCl,) 9.72 (1 H, s, CHO), 7.92-7.84 (2 H, m, Ph), 7.70-7.52 (3 H, m, Ph), 3.14 (2 H, t, J 7.6, CH,SO,), 2.67 (2 H, t, J 7.2, CH,CHO) and 2.02 (2 H, m, CH,); m/z (EI) 184 (1273, 182 (5), 142 (ll), 94 (ll), 91 (34), 78 (72), 77 (loo), 73 (16), 71 (83) and 64 (21).(2)-1-(tert-Butyldiphenylsilyloxy)-7-N-(4-phenylsu~onyl-butylidene)amino-(Z)-hept-3-ene N-Oxide 16.-A solution of sodium cyanoborohydride (60 mg, 0.955 mmol) in methanol (4 cm3) was added dropwise to a stirred solution of the oxime 12 (240 mg, 0.63 mmol) in methanol (20 cm3) containing Methyl Orange indicator (3 mg) at 0°C. Concurrently, a solution of hydrochloric acid in aqueous methanol (6 mol dm-,) was added dropwise so as to maintain pH 3. After 30 min, the solution was basified with 6 mol dm-, potassium hydroxide and the aqueous phase was extracted at 0 "C with dichloromethane (3 x 30 cm3). The combined organic phases were dried (MgSO,) and filtered. To the filtrate at 0°C was added anhydrous Na,SO, (2.0 g) followed by a solution of 4-phenylsulfonylbutanal 13 (267 mg, 1.26 mmol) in dry dichloromethane (2 cm3).After 12 h the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromato- graphy on silica eluting with ethyl acetate to give the nitrone 16 as a colourless oil (310 mg, 85); v,,,(neat)/cm-' 3060m (=CH), 3000m (CH), 2920s (CH), 2840s (CH), 1590m (nitrone), 1440s (nitrone), 1300s (SO,), 1150s (SO,) and 700s (Z-CH=CH); 6,(250 MHz; CDCI,) 7.91-7.34 (15 H, m, ArH), 6.60 (1 H, t, J 6.0, N=CH), 5.44-5.29 (2 H, m, CHSH), 3.74-3.62 (4 H, m, CH,OSi and CH2N+), 3.15-3.07 (2 H, m, CH,SO,), 2.55-1.89 (10 H, m, methylene envelope) and 1.03 (9 H, s, Bu'); m/z (EI) 520 (M+ -Bu', 5), 504 (12), 378 (8), 310 (8), 255 (12), 225 (14), 200 (21), 199 (loo), 197 (12), 183 (20) and 181 (14) Found: (M+ -Bu'), 520.2004.C29H3,N04SSi requires M, 520.19781. Attempted Thermal Cyclisution of the Nitrone 16.-A solution of the nitrone 16 (270 mg, 0.47 mmol) in toluene (250 cm3) was heated under an argon atmosphere at 90 "C for 12 h. Thin layer chromatographic analysis (TLC) indicated no reaction. The temperature was raised to 110 "C and the reaction was stirred for a further 12 h. TLC indicated decomposition of the nitrone 16and the reaction was abandoned. 5-Benzyioxypen~-3-ynyl- 1,3-dioxoIune W-To a stirred solution of 3-benzyloxyprop-1-yne 18 (14.9 g, 102.1 mmol) in dry THF (300 cm3) was added butyllithium (1.60 mol dm-, in hexane; 64 cm3, 102.4 mmol) at 0 "C.The solution was stirred for 1.5 h and then allowed to warm to room temperature. TMEDA (11.85 g, 102 mmol) was added and the solution was stirred for 10 min. 2-(2-Bromoethyl)- 1,3-dioxolane 8 (18.44 g, 102.2 mmol) was added and the solution was heated at reflux for 48 h. Water (100 cm3) was added, the organic phase was separated and the aqueous phase extracted with ether (3 x 100 cm3). The combined organic layers were dried (MgS0,) and filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 10 -25 ether-hexane to give the dioxoiune 19 as a colourless liquid (17.26 g, 69); v,,,(neat)/cm-' 3060w (CH), 3020m (CH), 2920s (CH) and 2860s (CH); 6,(250 MHz; CDCl,) 7.35-7.26 (5 H, m, ArH), 4.97 (1 H, t, J4.7, OCHO), 4.57 (2 H, S, CH,Ph), 4.14 (2 H, t, J 2.2, CCCHZO), 3.99-3.82 (4 H, 2 x m, OCH,CH,O), 2.41-2.34 (2 H, m, CCCH,) and 1.93- 1.85(2 H, m, CH,CHO,); 6,( 100 MHz; CDCl,) 137.52, 128.27, 127.95, 127.65, 103.03,85.98,76.03,71.25,64.84,57.55,32.75and 13.55;m/z (EI) 158 (M+ -C4H802, 4), 155 (7), 105 (12), 92 (15), 9 1 (46), 86 (1 3), 84 (19), 77 (1 3), 73 (loo), 70 (8) and 65 (1 1) Found: (M+ -C4H802), 158.0738.C1,HloO requires M, 158.07321. 5-Benzy loxy- (Z)-pen t-3 -en yl- 1,3 -dioxolane 20.-A solution of the dioxolane 19 (15.00 g, 60.98 mmol) in dry ethyl acetate (250 cm3) was stirred with Lindlar catalyst (Kataly Sator type C, 1.5 g) at room temperature under a hydrogen atmosphere (1 atm) for 3 h.The suspension was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 10 ---25 ether-- J. CHEM. SOC. PERKIN TRANS. i 1992 hexane to give the dioxolune 20 as a colourless liquid (13.8 g, 91) (Found: C, 72.5; H, 8.0. C,,H,OO, requires C, 72.6; H, 8.1); v,,,(neat)/cm-' 3060w (CH), 3020m (CH), 2940s (CH), 2850s (CH) and 700m (2-CHSH); 6,(250 MHz; CDCl,) 7.35- 7.25 (5 H, m, ArH), 5.74-5.59 (2 H, m, CH=CH),4.85 (1 H, t, J 4.7, OCHO), 4.50 (2 H, s, CH,Ph), 4.10-4.08 (2 H, m, OCH,CH=CH), 4.00-3.80 (4 H, m, OCH,CH,O), 2.23-2.15 (2 H, m, CHSHCH,) and 1.79-1.70 (2 H, m, CH,CHO,); m/z (EI) 160 (M+ -C4H,02, 673,157 (18), 99 (14), 92 (12), 91 (74), 80 (16) and 73 (100) Found: (M+ -C4H802), 160.0294. C,,H,,O requires M, 160.02881.6-Benzyloxy-(Z)-hex-4-enulOxime 22.-A solution of the dioxolane 20 (5.00 g, 20.2 mmol) in THF-water-acetic acid (1:1:3; 25 cm3) was stirred at 50 "C for 60 h, diluted with toluene (100 cm3), and then evaporated to dryness under reduced pressure. The residue was diluted with saturated aqueous sodium hydrogen carbonate and the aqueous phase was extracted with dichloromethane (3 x 50 cm3). The combined organic layers were dried (MgSO,), filtered and evaporated under reduced pressure. The residual crude aldehyde 21 was taken up in methanol (100 cm3) and treated with sodium acetate (3.2 g, 39 mmol). This mixture was then treated with hydroxylamine hydrochloride (2.73 g, 39.3 mmol) and stirred for 12 h at room temperature, after which the solution was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (100 cm3) was added and the aqueous phase was extracted with dichloromethane (3 x 100 cm3).The combined organic extracts were dried (MgSO,), filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 25 ether-hexane to give the oxime 22 (1 :1 mixture of geometrical isomers) as a colourless liquid (3.29 g, 74); v,,,(neat)/cm-' 3300br s (OH), 3080m (CH), 302Om (CH), 2900s (CH), 2860s (CH) and 700s (2-CH=CH); 6,(250 MHz; CDCl,) 7.45-7.24 (5.5 H, m, ArH and CHNOH), 6.70 (0.5 H, t, J 5.4, CHNOH), 5.74-5.53 (2 H, m, CH=CH), 4.5 1 and 4.50 (2 H, 2 x s, CH,Ph), 4.094.05 (2 H, m, OCH,CH=CH) and 2.53-2.16 (4 H, m, CH2- CH,CHNOH); 6,(100 MHz; CDCl,) 151.53, 151.06, 138.12, 131.73, 131.38, 128.34, 127.60, 127.54, 127.47,72.16,65.49,29.31, 24.76, 24.62 and 24.01; m/z (EI) 202 (M' -OH, 2), 112 (23), 107 (23), 107 (12), 92 (17), 91 (loo), 79 (10) and 65 (11) Found: (M' -OH), 202.1236.C,,H,,NO requires M, 202.12321. (2)-1-Benzyloxy-7-(4-phenyisulfonyibutylideneumino)-(Z)-hept-2-ene N-Oxide 17.-A solution of the oxime 22 (300 mg, 1.37 mmol) in methanol (25 cm3) containing Methyl Orange indicator (3 mg) at 0 "C was treated dropwise with a solution of sodium cyanoborohydride (129 mg, 2.05 mmol) in methanol (4 cm3). The reaction mixture was also treated dropwise with a solution of hydrochloric acid in aqueous methanol (6 mol drn-,) so as to maintain pH 3 during the course of the reaction.After 30 min, the solution was basified with 6 rnol dm-, aqueous potassium hydroxide and extracted at 0 "C with dichloro- methane (3 x 50 cm3). The combined organic phases were dried (MgSO,) and filtered. To the filtrate, maintained at 0 "C, a solution of 4-phenylsulfonylbutanal 13(435 mg, 2.05 mmol) in dry dichloromethane (4 cm3) and anhydrous sodium sulfate (3.0 g) were added. After being stirred for 2 h the reaction mixture was evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 0 --+ 6 methanol-dichloromethane to give the nitrone 17 as a colourless oil (370 mg, 65); v,,,(CHCl,)/cm-' 2930s (CH), 2840s (CH), 1590m (nitrone), 1450 m (nitrone), 1300s (SO,) and 1140s (SO,); 6,(250 MHz; CDCl,) 7.91-7.86 (2 H, m, SO,Ph), 7.69-7.53 (3 €4, m, PhSO,), 7.34-7.25 (5 H, m, PhCH,), 6.64 (1 H, t, J 6.0, CH=N+), 5.67-5.56 (2 H, m, CH=CH), 4.50 (2 H, s, PhCH,), 4.074.01 (2 H, m, OCH,CHSH), 3.72-3.67 (2 H, m, J.CHEM. SOC. PERKIN TRANS. 1 1992 CH,N+), 3.16-3.04 (2 H, m, CH,SO,), 2.57-2.48 and 2.13-1.90 (8 H, m, methylene envelope); m/z (EI) 324 (M+ -C7H7, 1 l), 1 59 ( 11), 1 30 ( lo), 1 27 ( lo), 122 (lo), 1 1 5 ( 1 3), 1 1 2 ( 12), 1 10( 1 1 ), 108 (13), 107 (16), 105 (ll), 97 (12), 96 (13), 92 (13), 91 (loo), 82 (12), 81 (13), 79 (22), 78 (22), 77 (38), 75 (13), 70 (12), 65 (13), 57 (18) and 55 (15) Found: (M+ -C,H,), 324.1279.C16H22- N04S requires M, 324.12691. (5R*,6R* ,8R *)-6- Benzyloxymethyl-8-3-(phenylsulfonyl)-propyll-7-oxa- 1-azabicyclo3.2. lloctane 23 and (5R*,6S*,8R*)- 6-Benzyloxymethyl-8- 3-( phenylsulfonyI)propyl -7-oxa- 1 -aza- bicyclo3.2.loctane 24.-A solution of the nitrone 17 (300 mg, 0.72 mmol) in toluene (50 cm3) was heated at reflux for 5 days, cooled and then evaporated to dryness under reduced pressure. The residue was purified by flash chromatography on silica eluting with 66-100 ethyl acetate-hexane to give the isox- azolidine 24 as a colourless oil (40 mg, 13); vma,(CHCl,)/cm-' 2920s (CH), 2860s (CH), 144Om, 1290s and 1130s (SO,); SH(400 MHz; CDC1,) 7.90-7.53 (5 H, m, PhSO,), 7.34-7.24 (5 H, m, PhCH2), 4.55 and 4.46 (2 H, s x d, JAB 12.1, PhCH,), 4.28 (1 H, t, J6.2, HCO), 3.46 (1 H, dd, J9.8 and 6.6, OCHHCH), 3.38 (1 H, dd, J9.8 and 5.8, OCHHCH), 3.31 (1 H, dd, J 14.2 and 6.5,2- He,), 3.15 (lH, ddd, J 15.8, 10.3 and 5.5, CHHSO,), 2.99 (1 H, ddd, J 15.8, 10.2 and 5.5, CHHSO,), 2.78-2.70 (2 H, m, 2-Ha, and 8-H), 2.33 (1 H, br s, 5-H) and 1.94-1.24 (8 H, m, methylene envelope); Sc(lOO MHz; CDC1,) 139.19, 137.93, 133.58, 129.21, 128.33, 127.95, 127.73, 127.69, 127.64, 83.44, 73.19, 72.38, 56.86, 55.91, 44.71, 31.39, 30.40, 21.00 and 18.62; m/z (EI) 415 (M+, 2), 324 (21), 274 (14), 232 (12), 126 (13), 124 (12), 98 (ll), 97 (13), 96 (12), 91 (loo), 82 (13), 81 ll), 80 (ll), 79 (12), 78 (13), 77 (23) and 65 (12) (Found: M', 415.1779.C,,H,,NO,S requires M, 415.1817). Further elution afforded the more polar isoxazolidine 23 as a colourless oil (60 mg, 20); vmax(CHCl3)/cm-' 2920s (CH), 2860s (CH), 144Om, 1290s and 1130s (SO,); 6,(250 MHz; CDC1,) 7.92-7.86 (2 H, m, SO,Ph), 7.68-7.51 (3 H, m, PhSO,), 7.34-7.23 (5 H, m, PhCH,), 4.63 and 4.52 (2 H, 2 x d, JAB 12.0, PhCH,), 4.25-4.17 (1 H, m, 6-H), 3.91-3.75 (2 H, m, OCH,CH), 3.51-2.70 (5 H, m, 2-Ha,, 2-He,, 7-H and CH,S02), 2.23-2.21 (1 H, m, 5-H) and 1.961.33 (8 H, m, methylene envelope); m/z (EI) 415 (M+,273, 324 (26), 274 (17), 232 (15), 126 (13), 124 (ll), 98 (ll), 97 (13), 96 (15), 92 (ll), 91 (loo), 82 (12), 81 (ll), 80 (lo), 79 (ll), 78 (11) and 77 (19) (Found: M+, 415.1795. C,,H,,NO,S requires M, 415.1818).2-Prop-2-ynyloxytetrahydro-2H-pyran26.-Prop-2-ynyl al-cohol (10.0 g, 178 mmol) and dihydropyran (15.0 g, 178 mmol) were dissolved in dry dichloromethane (200 cm3), cooled to 0 "C and treated with a catalytic amount of toluene-p-sulfonic acid. After 2 h, the solution was washed with saturated aqueous sodium hydrogen carbonate (200 cm3) and the aqueous washing was extracted with dichloromethane (2 x 100 cm3). The combined organic layers were dried (Na,SO,), filtered and evaporated under reduced pressure to give a yellow oil which was distilled under reduced pressure to give the THP-ether 26 as a colourless liquid (21.27 g, 85) (b.p. 82-86 "C; 30 mmHg); ~,,,~,(CCl,)/cm-' 3300s (CgH); aH(400 MHz; CDCl,) 4.77 (I H, t, J 3.3, OCHO), 4.2 1 (2 H, ddd, J 26.1,15.8 and 2.4, CS-CH,), 3.79(1 H,dt,J9.3and3.1,OCHH),3.51-3.46(1H,m,OCHH), 2.37 (1 H, t, J 2.3, CgH) and 1.83-1.45 (6 H, m, methylene envelope); 6,(100 MHz; CDCl,) 96.7, 79.7,76.7, 73.9,61.9,53.9, 30.1, 25.2 and 18.9; m/z (EI) 139 (M+ -H, 17), 101 (lo), 85 (100) and 56 (55) Found: (M+ -H), 139.0758.C,H 0,requires M, 139-0759. 2-(5-Tetrahydro-2H-pyranyloxypent-3-ynyl)-1,3-dioxolane 27.-A solution of the THP ether 26 (6.00 g, 42.9 mmol) in dry THF (100 cm3) at 0 "C under an argon atmosphere was treated with TMEDA (6.41 cm3) and butyllithium (1.6 mol dm-3 solution in hexane; 26.8 cm3, 42.9 mmol). The solution was stirred at 0 "C for 15 min after which 2-(2-bromoethyl)-l,3- dioxolane (6.0 an3,51.5 mmol) was added, and the solution was heated at reflux for 48 h.The resulting black solution was poured into saturated aqueous sodium hydrogen carbonate (100 cm3) and the mixture extracted with ether (3 x 100 cm3). The combined organic layers were dried (MgSO,), decolourised (charcoal), filtered and evaporated under reduced pressure to give a pale yellow oil. The residue was purified by flash chromatography on silica eluting with 9 --, 20 ethyl acetate-hexane to give the pure alkylated producr 27 as a colourless liquid (5.36 g, 52); vma,(CCl,)/cm-' 3940s (CH); dH(400 MHz; CDC13) 4.91 1 H, t, J4.6, OCHO (THP), 4.75 (1 H, t, J 3.4, OCHO), 4.18 (2 H, ddt, J 36.4, 15.2 and 2.1, CH,OTHP), 3.94-3.76 5 H, m, OCH,CH,O and OCHH (THP), 3.50-3.45 1 H, m, OCHH (THP), 2.35-2.29 (2 H, tt, J 7.6 and 2.1, CH,C=C) and 1.88-1.45 (8 H, m, methylene envelope); dC(100 MHz; CDCl,) 103.1,96.6,85.4,76.0,64.9,61.9, 54.5, 32.8, 30.2, 25.3, 19.0 and 13.6; m/z (El) 155 (879, 139 (32), 85 (30), 73 (loo), 67 (20) and 55 (15) Found (CI, NH,): M + NH,, 258.1712.C3,H2,N04 requires M, 258.17191. 2-(5-Tetr ahydro-2H-pyran y loxy- (Z)-pen t-3 -en y 1)-1,3-dioxol-ane =.-A solution of the acetylene 27 (4.17 g, 17.38 mmol) in ethyl acetate (50 cm3) was treated with Lindlar catalyst (50 mg, Kataly Sator type C) and stirred under an atmosphere of hydrogen (1 atm) for 3.5 h. After that time 1 equiv. of hydrogen had been taken up and GC analysis indicated that the reaction was complete. The solution was filtered, evaporated under re- duced pressure and the residue was purified by flash chromato- graphy on silica eluting with 20 ethyl acetate-hexane to give the pure allylic ether 28 as a colourless liquid (4.10 g, 98) (Found: C, 64.2; H, 9.3.ClJH2204 requires C, 64.4; H, 9.2); vma,(CCl,)/cm-' 1655~(CS); 6H(400 MHZ; CDCl,) 5.60-5.52 (2 H, m, CHSH), 4.82 l H, t, J4.7, OCHO (THP), 4.59 (1 H, t, J, 3.6, OCHO), 4.264.21 and 4.07-4.03 (2 H, 2 x m, MCH,O), 3.96-3.78 5 H, m, OCH,CH,O and OCHH (THP), 3.50-3.44 l H, m, OCHH (THP), 2.21-2.16 (2 H, 2 x my CH,CS) and 1.82-1.46 (1 H, my methylene envelope); Sc(100 MHz; CDCI3) 132.2, 126.5, 103.9, 97.9, 64.8, 62.6, 62.1, 33.6, 30.6, 25.4, 22.1 and 19.4; m/z (EI) 242 (M', l), 198 (l), 173 (2), 157 (lo), 141 (20), 99 (29), 85 (45), 74 (100) and 55 (27) (Found: M+, 242.1495.C13H2204 requires M, 242.1518). 2-5-Hydroxy-(Z)-pent-3-enyl-1,3-dioxolane 29.-The allyl-ic ether 28 (2.0 g, 8.26 mmol) in dry methanol (50 cm3) was treated with toluene-p-sulfonic acid (ca. 10 mg) and stirred for 16 h under an argon atmosphere. The solution was poured into saturated aqueous sodium hydrogen carbonate (100 cm3) and extracted with dichloromethane (3 x 50 cm3). The combined organic layers were dried (Na,SO,), filtered and evaporated under reduced pressure. Purification of the residue by flash chromatography on silica eluting with 50 ethyl acetate-hexane gave the pure allylic alcohol 29 as a colourless liquid (964 mg, 74); vma,(CCl,)/cm-' 3620m (OH), 3500br m (OH) and 1655w (M);SH(250 MHz; CDCl,) 5.73-5.50 (2 H, m, CHSH), 4.87 (1 H, t, J 4.9, OCHO), 4.17 (2 H, d, J 6.5, OCH,W), 3.99-3.81 (4 H, m, OCH2CH20), 2.28-2.11 (2 H, m, CH,C==C), 1.84-1.69 (2 H, m, CH,) and 1.66 (1 H, br s, OH); 6,(100 MHz; CDCl,) 313.3, 129.3, 103.8, 64.8, 57.9, 33.3 and 21.9; m/z(EI) 158 (M+,l),157 (2), 141 (3), 129 (6), 99 (23), 86 (10) and 73 (100) (Found: M +,158.0928.C,H 1403requires M, 158.0943). 2- 4-Formyl-(Z)-but- 3-enyll- 1,3-dioxolane 30.-A solution of the allylic alcohol 29 (200 mg, 1.27 mmol) in dry dichloro- methane (10 cm3) was treated with activated manganese(1v) 1096 oxide (Aldrich Co., ca. 3 g) and stirred at 25 "C for 1 h. The sol-ution was filtered, evaporated under reduced pressure, and the residue was purified by flash chromatography on silica eluting with 33 ethyl acetate-hexane to give the unstable aldehyde 30 (99 mg, 50) (as a mixture of the Z/E-enals in the ratio 9: 1 as determined by 'H NMR of the dienes from Wittig olefination); v,,,(CCl,)/cm-' 1685s (C=O) and 1640w (C=C-C--O); E-isomer 6,(250 MHz; CDCI,) 9.49 (1 H, d, J7.9, CHO), 6.88 (1 H, dt, J 15.6 and 6.7, CHCCO), 6.12 (1 H, ddt, J 15.6, 7.9 and 1.5, CSHCO), 4.91 (1 H, t, J 4.4, OCHO), 4.01-3.79 (4 H, m, OCH,CH,O), 2.52-2.38 (2 H, m, CH,C=C) and 1.90-1.83 (2 H, m, CH,); 2-isomer 6,(250 MHz; CDCl,) 10.09 (1 H, d, J 8.0, CHO), 6.64 (1 H, dt, J 11.2 and 8.2, CHSCO), 5.94 (1 H, ddt, J 11.2, 8.1 and 1.6, CSHCO), 4.91 (1 H, t, J 4.4, OCHO), 4.01- 3.79 (4 H, m, OCH,CH,O), 2.79-2.68 (2 H, m, CH2M) and 1.90-1.83 (2 H, m, CH,).2-(3Z)-Hexa-3,5-dienyl-1,3-dioxolane32.--(a) A suspen-sion of methyl(tripheny1)phosphonium bromide (502 mg, 1.40 mmol) in dry THF (6 cm3) was treated with butyllithium (1.6 mol dm-' solution in hexane, 0.8 cm3, 1.31 mmol) under argon at 25 "C. The yellow ylide solution was stirred for 1 h prior to use. The aldehyde 30 (99 mg, 0.64 mmol) in dry THF (10 cm3) was cooled to -78 "C under an argon atmosphere and treated dropwise with the ylide solution until a permanent yellow colour developed. The solution was stirred for 1 h at -78 "C, allowed to warm to 25 "C and the poured into saturated aqueous sodium hydrogen carbonate (25 cm3). The mixture was extracted with dichloromethane (3 x 25 cm3).The combined organic extracts were dried (Na,SO,), filtered and evaporated under reduced pressure and the residue purified by flash chromatography on silica eluting with 20 --+ 50 ethyl acetate-hexane to give the diene 32 as a colourless liquid (94 mg, 95). Ratio of Z/E-isomers 9: 1 as determined by 'H NMR. (b) A solution of the tosylate 34 (1.05 g, 3.23 mmol) in dry DMSO (1 5 cm3) was treated with potassium tert-butoxide (726 mg, 6.46 mmol) and stirred at 20 "C for 2 h. The solution was diluted with saturated aqueous ammonium chloride (200 cm3) and extracted with ethyl acetate (3 x 100 cm3). The combined organic layers were dried (Na,SO,), filtered and evaporated under reduced pressure to afford a mixture of the dienes 31 and 32 as a colourless liquid (450 mg, 90) ('H NMR and GC analysis indicated a Z/Eratio of 97: 3); v,,,(CCl,)/cm-' 3090m (C=CH) and 1640w (C=C); 6,(250 MHz; CDCl,) 6.65 (1 H, ddt J 16.8, 10.2 and 1.1, CH,=CH-C==C), 6.01 (1 H, t, J 11.4, CH,= CCH=C),5.46(1 H,dt, J10.0and7.7,CH2CH=C),5.l8(lH,dd, J 6.9 and 2.0, CHH=CC=C), 5.09 (1 H, d, J 10.2, CHHSW), 4.86 (1 H, t, J4.7, OCHO), 3.99-3.81 (4 H, m, OCH,CH,O), 2.37-2.20 (2 H, m, CH2C==C) and 1.79-1.63 (2 H, m, CH,); 6,(100 MHz; CDCl,) 132.0, 131.4, 129.6, 117.1, 103.9,64.8, 33.6 and22.2;m/z(EI) 154(M+,4) 153(19), 125(18), 112(20), 107 (20), 99 (81), 73 (loo), 67 (18) and 55 (10) (Found: M+, 154.0994.C9H1402 requires M, 154.0994). 2-(2E)-Hexa-2,5-dienyl-1,3-dioxolane31; 6,(250 MHz; CDCl,) 6.30 (1 H, dt, J 16.8 and 10.2, CH,=CHC=C), 6.12-6.00 (1 H, m, CH,=CCH=C), 5.71 (1 H, dt, J 14.6 and 6.8, CH,CH=C), 5.08 (1 H, d, J 15.1, CHH=CHCC=C), 4.96 (1 H, dd, J 9.6 and 1.0, CHH=CHC=C), 4.86 (1 H, t, J 4.7, OCHO), 3.99-3.81 (4 H, m, OCH2CH20), 2.37-2.20 (2 H, m, CH,C==C) and 1.79-1.63 (2 H, m, CH,).2-6-Hydroxy-(Z)-hex-3-enyl-l,3-dioxolane33.-A solution of the silyl ether 10 (3.26 g, 7.95 mmol) in dry THF (40 cm3) at 0 "C was treated with tetrabutyl ammonium fluoride (1.0 mol dm-, solution in THF; 8.35 cm', 8.35 mmol) and stirred for 30 min. The solution was poured into saturated aqueous sodium hydrogen carbonate (200 cm3) and extracted with dichloro- methane (3 x 100 cm3). The combined organic extracts were J.CHEM. SOC. PERKIN TRANS. 1 1992 dried (Na,SO,), filtered and evaporated under reduced pressure, and the residue was purified by flash chromatography on silica eluting with 20 50 ethyl acetate-hexane to give the pure alcohol 33 as a colourless liquid (1.2 g, 88); v,,,(CCl,)/cm-' 3640m (OH) and 3600m (OH); 6,(250 MHz; CDCl,) 5.57-5.46 (1 H, m, WH), 5.42-5.31 (1 H, m, CSH), 4.83 (1 H, t, J 4.8, OCHO), 3.963.77 (4 H, m, OCH,CH,O), 3.59 (2 H, q, J6.0, CH,O), 2.34-2.26 (2 H, m, CH,C=C), 2.22- 2.13 (2 H, m, CH,C=C), 2.02 (1 H, t, J 5.8, OH) and 1.73-1.64 (2 H, m, CH2); 6,(100 MHz; CDCI,) 131.7, 126.0, 104.0,64.8,62.1, 33.5,30.7 and 21.9; m/z (EI) 172 (M', 373, 171 (6), 141 (33), 129 (12), 113 (20), 110 (30), 99 (23) and 73 (100) (Found: M+, 172.1098.C9Hi603 requires M, 172.1099). 2-6-(p-Tolylsulfonyloxy)-(Z)-hex-3-eny(l-1,3-dioxolane 34. -A solution of the alcohol 33 (706 mg, 4.10 mmol) in dry pyridine (10 cm3) was treated with toluene-p-sulfonyl chloride (1.17 g, 6.15 mmol) and stirred at 20 "C for 16 h. The solution was poured into saturated aqueous sodium hydrogen carbonate (100 cm3) and extracted with dichloromethane (3 x 100 cm3). The combined organic extracts were dried (Na,SO,), filtered, evaporated under reduced pressure, and the residue was purified by flash chromatography on silica eluting with 20 ethyl acetate-hexane to give the pure tosylate 34 as a colourless liquid (1.05 g, 79) (Found: C, 59.1; H, 6.8. C16H,,S05 requires C, 58.9; H, 6.8); v,,,(CCl,)/cm-' 1360s (OTs), 1170s (OTs) and 675s (CH=CH); 6,(250 MHz; CDCl,) 7.75 and 7.31 (4 H, AA'BB', J8.2, OTs), 5.52-5.42 (1 H, m, WH), 5.28-5.17 (1 H, m, C=CH), 4.79 (1 H, t, J 4.7, OCHO), 3.98 (2 H, t, J 6.8, CH,OTs), 4.02-3.77 (4 H, m, OCH,CH,O), 2.42 (3 H, s, ArCH,), 2.42-2.33 (2 H, m, CH,CS), 2.13-2.04 (2 H, m, CH,C==C) and 1.67-1.60 (2 H, m, CH,); 6,(100 MHz; CDCl,) 144.7, 133.1, 132.5, 129.8, 127.8, 123.5, 103.8, 69.7, 64.8, 33.3, 26.9, 21.9 and 21.6; m/z (EI) 326 (M', 17), 171 (15) and 73 (100) (Found: M+, 326.1178.C16H22S05 requires M, 326.1 188). (4Z)-Hepta-4,6-dienal Oxime 35.-A solution of the 1,3-dioxolane 32 (450 mg, 2.92 mmol) in ether/2 mol dm-, hydrochloric acid (40 cm3 of a 1 : 1 mixture) was stirred at 20 "C for 36 h.The solution was neutralised with solid sodium hydrogen carbonate. Hydroxylamine hydrochloride (609 mg, 8.76 mmol) and sodium acetate trihydrate (1.19 g, 8.76 mmol) in water (5 cm3) were combined, and sufficient ethanol was added to give a homogeneous solution. The solution was stirred for 14 h at 20°C and then poured into saturated aqueous sodium hydrogen carbonate (500 cm3) and extracted with dichloro- methane (3 x 200 cm3). The combined organic extracts were dried (Na,SO,), filtered, evaporated under reduced pressure and the residue purified by flash chromatography on silica eluting with 20 ethyl acetate-hexane to give recovered 1,3- dioxolane 32 (89 mg, 20). Further elution gave the pure oxime 35 as a colourless liquid (292 mg, 80) (1: 1 mixture of geometrical isomers); v,,,(CCl,)/cm-' 3600s (OH), 3500-3100br s (OH) and 910s (vinyl CH); 6,(250 MHz; CDC1,) 9.7- 9.3 and 9.3-8.9 (1 H, 2 x br s, OH), 7.42 and 6.72 (1 H, 2 x t, J 5.7 and 5.1, CH=N), 6.69-6.51 (1 H, m, CH,=CHC==C), 6.09-5.99 (1 H, m, CH,=CCH=C), 5.46-5.36 (1 H, m, CH,CH=C), 5.24 5.10 (2 H, m, CH,=CC==C) and 2.52-2.24 (4 H, m, CH,CH,); 6,(100 MHz; CDCI,) 151.7 151.3, 131.8, 130.5, 130.4, 130.0, 1 17.9,29.5,24.9,24.8 and 24.1; m/z(EI) 125 (M +,lo), 108 (12), 80 (32) and 67 (100) (Found: M', 125.0834.C,H,,NO requires M, 125.0840). (Z)-N-(4-Phenylsulfonylbutylidene)-(4Z)-hepta-4,6-dienyl-amine N-Oxide .-A solution of the oxime 35 (243 mg, 1.94 mmol) in methanol (10 cm3) under an argon atmosphere was treated with Methyl Orange indicator (5 drops), cooled to J.CHEM. SOC. PERKIN TRANS.1 1992 -10"C, and treated with sodium cyanoborohydride (200mg, 3.2 mmol). A solution of 6 mol dm-, hydrochloric acid in water/methanol was added dropwise to maintain a pink colour until the reduction was complete by TLC (ca.30 min). The reaction mixture was poured into ice-brine (100 cm3), made strongly alkaline (20 NaOH) and extracted with dichloro- methane (3 x 50 cm3). The organic extracts were added directly to a solution of 4-phenylsulfonylbutanall3 (500 mg, 2.36mmol) in dichloromethane (20 cm3) containing anhydrous MgSO,. The solution was stirred under argon for 2 h and filtered with the aid of Celite. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography on silica eluting with 10 methanol-ethyl acetate to give the pure nitrone 36 as a viscous colourless oil (513 mg, 82); v,,,(CCl,)/cm-' 3080m (CH), 1640w (diene), 1600m (diene), 1440s (nitrone), 1140s (SO,) and 690s (2-CHSH); 6,(250 MHz; CDCl,) 7.88-7.84 (2 H, m, SO,Ph), 7.66-7.50(3 H, m, SO,Ph), 6.62 (1 H, t, J 6.0, CH=N), 6.58-6.46 (1 H, m, CH,CCH=C), 6.01(1 H, t, J 10.9,CHZCCHS), 5.39-5.26(1 H, dry xylene (20 cm3) was heated at reflux under an argon atmosphere with a Dean-Stark distillation head for 24 h.The solvent was removed under reduced pressure and 'H NMR of the residue indicated the adducts were present in the ratio 1 :1.8. 3-BenzyloxypropanaZ41.-A solution of oxalyl chloride (3.01 cm3, 34.4mmol) in dry dichloromethane (100 cm') was cooled to -78 "C under a nitrogen atmosphere, and a solution of dry dimethyl sulfoxide (5.39g, 68.9mmol) in dry dichloromethane (50 cm') was added dropwise. The solution was stirred at -78 "C for 15 min, after which the alcohol 40,' (4.76g, 28.7 mmol) in dry dichloromethane (50 cm3) was added dropwise. Stirring was continued at -78 "C for a further 15 min, after which additional dry triethylamine (24 cm3, 172 mmol) was added.After a further 10 min at -78 "C, the solution was allowed to warm to 20 "C and stirred at that temperature for a further 30min. The solution was poured into saturated aqueous sodium hydrogen carbonate (200 cm3) and the aqueous layer was extracted with dichloromethane (3 x 100 cm3).The combined organic extracts were dried (Na,SO,), filtered,m,CH2CH=C),5.16(1H,dd,J16.8and1.3,CHH=CC==C),5.07 (1 H, d, J 10.2, CHHSCS), 3.69 (2 H, t, J6.8,CH,N), 3.14-3.07(2H, m, CH2S02), 2.56-2.48 (2 H, m, CH,C=N), 2.23-2.14 (2 H, m, CH2C==C) and 2.m1.87 (2 H, m, CH,); 6,(100 MHz; CDCl,) 138.9, 136.7, 133.8, 131.6, 130.7, 130.2, 129.4, 128.0, 118.0,64.3,55.7, 26.7, 25.1, 24.2 and 19.0; m/z (EI) 321 (M', 1273, 224 (30), 138 (loo), 122 (28), 96 (60),79 (92), 67 (40)and 55 (47) (Found: M+, 321.1393.C17H2,NS03 requires M, 321.1398). (5R*,6S*,8R*)-8-(3-Phenylsulfonylpropyl)-6-uinyl-7-oxa-1-azabicyclo3.2.loctane 37. (5R*,6R*,8R*)-8-3-Phendvlsulfon-ylpropyl-6-vinyl-7-oxa-1-azabicyclo3.2.1 octane 38.--(a) A solution of the nitrone 36 (93.5mg, 0.29mmol) in dry benzene (20 cm3) was heated at reflux under an argon atmosphere for 24 h using a Dean-Stark distillation head.The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica eluting with 50 ethyl acetate- hexane to afford an inseparable mixture of the cycloadducts37 and 38 (60.4mg, 65) as a colourless gum (in the ratio 1 :7 by 'H NMR); v,,,(CCl,)/crn-' 3040w (CH), 1430s,1310s (SO,), 1140s(SO,), 1070s(C-0), 910s(vinyl CH) and 675s(Aryl CH); 6,(250 MHz; CDCl,; 37/38 1 :3) 7.87-7.83 (2 H + 0.6 H, m, SO,Ph, 37 + 38), 7.64-7.48(1 H + 3 H, m, S02Ph, 37 + 38), 6.18-6.03 (0.33 H, m, CHSH,, 37), 5.86-5.72 (1 H, m, CH=CH,, 38), 5.33(0.33 H, d, J 17.1,CHHSH, 37), 5.25(0.33 H, d, J 10.3,CHHSH, 37), 5.14(1 H, d, J 17.1,CHH=C, 38), 4.99(1 H, d, J 10.3,CHHX, 38), 4.50(1 H, d, J5.9,CH-O,38), 4.39 (0.33 H, t, J 5.6, CH-0, 37), 3.31-2.95(1 H + 3 H, m, CH2S0, and CHN, 37 + 38),2.89-2.82(0.33 H, m, CHHN, 37), 2.78-2.70 (2 H + 0.33 H, m, CH,N 38 + CHHN 37), 2.33 (1 H, br s, bridgehead H, 38), 2.16(0.33 H, br s, bridgehead H, 37) and 2.W1.24(8 H + 2.66H, m, methylene envelope, 38 + 37); -(lo0MHz; CDCl,; 37/38 1:3) 139.1, 138.9, 133.6, 132.4, 129.3, 128.0, 119.2, 115.8, 84.7, 82.7, 72.3, 72.1, 56.8, 56.5,56.0, 53.5,47.2,45.0,31.1,30.4,30.1,25.9, 20.7, 20.3, 18.8 and 18.0; m/z (EI) 321 (M+, 2073, 224 (30), 180 (ll), 138 (loo), 96 (58), 79 (81), 67 (28) and 55 (40)(Found: M+, 321.1392.CI7H2,NSO3 requires M, 321.1399). (b) A solution of the nitrone 36 (260 mg, 0.81mmol) in dry toluene (20cm') was subjected to the same procedure as above to give an inseparable mixture of the cycloadducts 37 and 38 as a colourless gum (161 mg, 62) (ratio 1 :3 by 'H NMR). (c) A solution of the nitrone 36 (61.2mg, 0.81mmol) in dry xylene (20cm3) was subjected to the same procedure as above to give an inseparable mixture of the cycloadducts 37 and 38 (33.2 mg, 54)as a colourless gum (ratio 1 :1.8by 'H NMR). (d) Equilibration of the cycloadducts37 and 38. A solution of the adducts 37 and 38 (50 mg, 0.16mmol) (in the ratio 1 :7) in evaporated under reduced pressure, and the residue was purified by flash chromatography on silica eluting with 25 ethyl acetate-hexane to give the pure aldehyde 41 as a colourless liquid (3.99g, 85); v,,,(CCl,)/cm-' 3080w (CH), 306Ow (CH), 3030m,272Om (CHO) and 1725s (GO);6,(250 MHz; CDCl,) 9.77(1 H, t, J 1.9, CHO), 7.39-7.25 (5 H, m, Ph), 4.52 (2 H, s, OCH,Ph), 3.80 (2 H, t, J6.0,CH20) and 2.67 (2 H, dt, J6.0and 1.9,CH2CO); Sc(100 MHz; CDCl,) 201.2(CO), 137.9, 128.5, 127.8,127.7,73.2,63.9and 43.9;m/z(EI) 164(M +,8), 120 (28), 107 (loo), 91 (SO), 79 (22) and 65 (12) (Found: M+, 164.0833.C10H1202requires M, 164.0837). l-Benzyloxypent-4-en-3-ol4X--Cerium(111) chloride hepta- hydrate (38.8g, 104 mmol) was heated to 140"C and stirred for 2 h under reduced pressure to give the anhydrous compound as a white powder. The flask was allowed to cool, dry nitrogen was admitted, and dry THF (550cm3) was added.The suspension was stirred for 1 h at 20 "C, cooled to -78 "C, and vinyl- magnesium bromide (1.0mol dm-, solution in THF; 97 cm', 97.5mmol) was added. Stirring was continued for a further 1 h, and the aldehyde 41 (10.66g, 65 mmol) in dry THF (270cm3) was added dropwise. After a further 4h at -78 "C, the reaction was allowed to warm to -65 "C for 2 h. The reaction mixture was quenched by the addition of water, allowed to warm to room temperature, poured into dilute acetic acid solution and extracted with dichloromethane (3 x 300 cm3). The combined organic extracts were washed sequentially with brine (1 x 150 cm3), saturated aqueous sodium hydrogen carbonate (1 x 150 cm3) and brine (1 x 150 cm'), dried (Na,SO,), filtered, and the filtrate was evaporated under reduced pressure.The residue was purified by flash chromatography on silica eluting with 20 ethyl acetate-hexane to give the allylic alcohol42as a colourless oil (11.31 g, 91); v,,,(CCl,)/cm-' 3620m (OH), 3520s (OH), 3080m (=CH), 3060m (=CH) and 3020s (CH); 6H(400 MHz; CDCl,) 7.42-7.29(5 H, m,Ph), 5.96-5.88 (1 H, m,CHCH,), 5.32 (1 H, dt, J 15.7 and 1.5,CHHS), 5.12(1 H, dt, J 10.5 and 1.5, CHH=C), 5.12(1 H, dt, J 10.5 and 1.5,CHHS), 4.56 (2 H, s, OCH,Ph), 4.404.36(1 H, m, CH-0), 3.78-3.65 (2 H, m, CH,-0), 3.10-2.95(1 H, br s, OH) and 1.96-1.82 (2 H, m, CH,); dc(100 MHz; CDCl,) 140.6, 138.0, 128.5, 127.7, 127.7, 114.4, 73.3, 71.7,66.2 and 36.4; m/z (EI) 192 (M+, lo), 174 (23), 120 (12), 107 (43), 91 (loo), 79 (17) and 68 (56) (Found: M+, 192.1159.C12H1602requires M, 192.1150).Ethyl 7-benzyloxy-(E)-hept-4-enoate43.-A solution of the allylic alcohol 42(3.14g, 16.4mmol) in triethyl orthoacetate (20 cm', 115 mmol) was treated with propionic acid (20drops) and heated under an argon atmosphere to 125 "C, with removal of ethanol by distillation, for 2 h. The solution was cooled and concentrated under reduced pressure, and the residue was purified by flash chromatography on silica eluting with 5 ethyl acetate-hexane to give the pure ester 43 as a colourless liquid (3.82 g, 89); v,,,(CCl,)/cm-' 1730s (C--O);6,(250 MHz; CDCl,) 7.34-7.30(5 H, m, Ph), 5.50-5.47 (2 H, m, CHSH), J.CHEM. SOC. PERKIN TRANS. I 1992 dried (Na,SO,) and filtered into a solution of freshly prepared and purified aldehyde 13(3.37g, 15.9mmol) in dichloromethane (140cm3) containing anhydrous Na,SO,. The solution was stirred under an argon atmosphere for 1 h at room temperature. Filtration of the reaction mixture and evaporation of the filtrate under reduced pressure gave an oil which was purified by flash 4.50(2H,s,OCH,Ph),4.11(2H,q,J7.1,CO,CH2),3.46(2H,t,chromatography on silica eluting with 10 methanokthylJ 6.8, CH,O), 2.35-2.30 (6 H, m, methylene envelope) and 1.23 (3 H, t, J 7.1, CH,); 6,(100 MHz; CDCl,) 173.1, 138.5, 130.2, 128.3, 127.7, 127.6, 127.5, 72.8, 70.0, 60.2, 34.2, 33.0,28.0and 14.2; m/z (EI) 262 (M', lo), 216 (20), 188 (20), 175 (28), 141 (68), 113 (29), 99 (47) and 91 (100) (Found: M +,262.1568.C,,H,,O, requires M, 262.1569). 7-Benzyloxy-(E)-hept-4-enalOxime 44.-A solution of the ester 43 (4.07g, 15.55 mmol) in dry THF (100 cm3) was cooled to -100°C under a nitrogen atmosphere, and diisobutyl- aluminium hydride (1.5 mol dm-, solution in toluene; 31 cm3, 46.5mmol) was added dropwise. Stirring was continued for 3 h after which the reaction was quenched at -100°C by the dropwise addition of saturated aqueous ammonium chloride (20 cm3). The solution was allowed to warm to 20 "C and saturated aqueous Rochelle's salt (50 cm3) was added. Stirring was continued for 1 h, by which time the aluminium salts had dissolved. The solution was diluted with saturated brine (100 cm3) and extracted with ethyl acetate (4 x 100 cm3).The combined organic layers were dried (Na,SO,), filtered, and evaporated under reduced pressure to give crude heptenal as a colourless oil (3.39g, 100); v,,,(CC1,)/cm-' 3080m (=CH), 3060m (=CH), 3030s (CH), 2800s, 2710s (CHO) and 1725s (GO); 6,(250 MHz; CDC1,) 9.75(1 H, t, J 1.6, CHO),7.39-7.25 (5 H, m, Ph), 5.52-5.45 (2 H, m, CHSH), 4.51 (2 H, s, OCH,Ph), 3.48 (2 H, t, J 6.8, CH,O), 2.37-2.28 (4 H, m, 2 x CH2) and 2.15-2.07 (2 H, m, CH,CO); 6,(100 MHz; CDCl,) 202.3, 138.5, 129.9, 128.4, 128.0, 127.6, 72.9, 69.9, 33.9, 33.0and 26.6; m/z (EI) 218(M', l8), 173 (48), 107 (58), 97 (38) and 91 (100)(Found: M', 218.1295.CI4Hl8O2 requires M, 218.1307). The crude aldehyde was dissolved in ethanol (50 cm3), and a solution of hydroxylamine hydrochloride (3.04g, 46.5 mmol) and sodium acetate trihydrate (5.95 g, 46.5mmol) in water (50 cm3) was added.The resulting solution was stirred at 20 "C for 30 min. The ethanol was removed under reduced pressure, and the aqueous solution was extracted with dichloromethane (3 x 50 cm3). The combined organic extracts were dried (Na2S0,), filtered and evaporated under reduced pressure and the residue was purified by flash chromatography on silica eluting with 33 ethyl acetate-hexane to give the pure oxime44 as a colourless liquid (1:1 mixture of geometrical isomers) (3.50 g, 97); v,,,(CCl,)/cm-' 3600s (OH), 3500-3100br s (OH), 3080w (=CH), 3060m (SH) and 3030s (CH); 6,(250 MHz; CDCl,) 7.41and 6.72(1 H, 2 x t, J 5.3,CH=N), 7.35-7.25(5 H, m, Ph), 5.52-5.49 (2 H, m, CHSH), 4.51 (2 H, s, OCH2Ph), 3.48 (2 H, t, J 6.8, OCH,) and 2.49-2.16 (6 H, m, methylene envelope) (Found: M+, 233.1429.Cl4HI9NO2 requires M,233.1415). (Z)-1 -Benzyloxy-7-(4-phenylsulfonylbutylideneamino)-(Z)-hept-3-eneN-Oxide45.-A solution of the oxime 44(3.46g, 14.8 mmol) in ethanol (80 cm3) was cooled to -10°C under a nitrogen atmosphere and treated with Methyl Orange indicator (10 drops) and sodium cyanoborohydride (1.89g, 30 mmol). Aqueous HCl (6mol drn-,) was added to maintain a light pink colouration until the reduction was complete as judged by TLC (ca.30 min). The reaction mixture was treated with an excess of dilute aqueous sodium hydroxide and then filtered with the aid of Celite.The filtrate was extracted with cold dichloromethane and the cold combined organic extracts were washed with brine, acetate to afford the nitrone 45 as a colourless oil (5.78g, 91); v,,,(CCl,)/cm-' 3060m (SH), 3030m (CH), 1440s (nitrone) and 1145s (SO,); 6,(250 MHz; CDCl,) 7.91-7.84 (2 H, m, SO,Ph), 7.67-7.49 (3 H, m, S02Ph), 7.36-7.23 (5 H, m, OCH2Ph), 6.60 (1 H, t, J 5.9,CH=N), 5.49-5.37 (2 H, m, CHXH), 4.48 (2 H, S, OCH,Ph), 3.67 (2 H, t, J6.7,CHZN), 3.47 (2H, t, J 6.6, CH20),3.15-3.06 (2 H, m, CH,SO,), 2.55-2.47 (2 H, m, CH2C=N), 2.33-2.23 (2 H, m, CH,C=C) and 2.06-1.85 (6 H, m, methylene envelope); 6,(100 MHz; CDC1,) 138.9, 138.3, 136.5, 133.8, 131.8, 130.1,129.3, 128.4, 128.3, 127.9, 127.6, 72.8, 69.9,64.4,55.6,32.9,29.1,26.5,24.9and 18.9; m/z (EI) 429 (M+, 12), 412 (18), 338 (25), 246 (18) and 91 (100)(Found: M+, 429.1976.C24H3 NSO, requires M, 429.1974).(5R*,6S*,8R*)-6-2-Benzyloxyethyl-8-(3-phenylsulfonylpro-pyl)-7-oxa-1-azabicyclo3.2. lloctaine 46 and (5S*,6R*,7S*)-6- (2-Benzyloxyethyl)-7-(3-phenylsulfonylpropyl)-8-oxa-1-azabi-cyclo3.2. lloctane47.-(a) A solution of the nitrone 45 (108mg, 0.252mmol) in dry benzene (20 cm3) was refluxed under an argon atmosphere for 48h using a Dean-Stark distillation head. The solution was evaporated under reduced pressure and the residue was purified by flash chromatography on silica eluting with 50-66 ethyl acetate-hexane to give, as the sole product, the adduct 46 as a pale yellow oil (58.7 mg, 54); v,,,-(CCl,)/cm-' 3060m (CH), 303Om (CH), 1440s and 11 50s (SO,); 6,(250 MHz; CDCl,) 7.89-7.85 (2 H, m, SO,Ph), 7.65-7.49(3 H, m, S02Ph), 7.31-7.24(5 H, m, CH2Ph), 4.47and 4.44(2 H, 2 x d,J~~12.0,OCH~Ph),4.17(1H,t,J7.0,CH-O),3.50(2H, t, J6.4,CH,OBn), 3.31-3.04(3 H, m, CH,S02 and CHN), 2.79-2.68(2 H, m, CH2N), 2.27(1 H, br s, 5-H), 1.91-1.75 (6 H, m, methylene envelope), 1.73-1.54 (2 H, m, CH2) and 1.44-1.36 (2 H, m, CH,); dc(10O MHz; CDCl,) 139.0,138.2,133.5, 129.2, 128.2, 127.9, 127.5, 127.5, 81.8, 73.0, 72.2, 67.5, 56.8, 55.9, 46.5, 35.9, 31.5,30.3,21.2 and 18.6; m/z (EI) 429 (M+,30), 412 (20), 338 (52), 288 (18),246 (33, 140(38)and 91 (100) (Found: M+, 429.1977.C24H31NS04requires M,429.1973).(b) A solution of the nitrone 45 (7.39g, 17.2mmol) in dry toluene (500cm3) was refluxed under an argon atmosphere for 15 h using a Dean-Stark distillation head. The solution was concentrated under reduced pressure and the residue purified by flash chromatography on silica eluting with 50 ethyl acetate- hexane to give pure adduct 46 as a pale yellow oil (5.6g, 76). Further elution with ethyl acetate gave the more polar title compound47 as a pale yellow oil (1.00 g, 14); v,,,(CCl,)/cm-' 3060w (CH), 3030w (CH), 1440m and 1150s (SO,); 6,(250 MHz; CDCl,) 7.92-7.86 (2 H, m, SO,Ph), 7.68-7.51(3 H, m, SO,Ph), 7.38-7.23 (5 H, m, CH,Ph), 4.50 and 4.45 (2 H, 2 x d, JAB 11.9, OCHZPh), 4.36(1 H, t, J 5.8, CH-0), 3.55 (2 H,t, J6.8,CH20CH,Ph),3.17(2H,brt,J7.1,CH2S02),3.10(1 H, br s, CHN), 3.05-2.96(1 H