Development of a synthesis of lankacidins: an investigation into 17-membered ring formation

摘要

J. CHEM. SOC. PERKIN TRANS. I 1995 Development of a synthesis of lankacidins: an investigation into 17-membered ring formation Ernest0 G. Mata and Eric J. Thomas * The Department of Chemistry, The University of Manchester, Oxford Road, Manchester A413 9PL, UK Studies are reported concerning the synthesis of macrocyclic analogues of the lankacidins. The long-chain trienylphosphonate 33 has been synthesized as a mixture of epimers at C(7), by a convergent route which involved alkylation of ethyl 2-methyl-3-oxobutanoate 10 by the lo-(tert-butyldimethylsilyloxy)-3,9-dimethyldeca-2,4,8-trienylchloride 11 to give 27 followed by an aldol addition to the aldehyde 12. Stereoselective reduction then gave the 1,3-syn-diol35 which was protected as its acetonide 36.However, it did not prove possible to hydrolyse the 1,3-dioxolane ring in 36 to reveal the keto phosphonate grouping and leave the acetonide component intact.To avoid this problem, acrolein was added to the alkylated keto ester 27 to give the aldol product 40 as a mixture of diastereoisomers. Stereoselective reduction gave the 1,3-syn-diols 41 and 42, in a ratio of 75:25, which were separated and taken through to the &lactones 47 and 48. The lactone 47 corresponds to the C(14)-C(12) fragment of the lankacidins, and the diol 41 is an advanced intermediate for a synthesis of a 17-membered macrocyclic analogue of the lankacidins. The diols 41 and 42 were protected as their acetonides 43 and 44 and these were taken through to the 16-formyl-2-oxophosphonates 7 and 57.Cyclisations into the cycloheptadeca-2,4,8,lO-tetraenones8 and 58were carried out using potassium carbonate in the presence of 18-crown-6 in toluene at 100 “C. Alternative conditions for the cyclisations were less successful as were attempts to cyclise the halogeno sulfones 62 and 63 although the 17-acetoxy sulfone 64 was cyclised using tetrakis(tripheny1phosphine)palladiumfo) and 1,3-bis(triphenylphosphino)propane, but only in a modest yield (18%). Deprotection and reduction of the cyclised products have been briefly investigated. The lankacidins, exemplified by lankacidin C 1, are an interesting group of natural products which exhibit both antibacterial and antitumour activity. An approach to the Ao Bo U *Me m synthesis of the lankacidins based on ring-opening of 3-(3‘- hydroxya1kyl)azetidinones to provide the 3-[1’-(acy1amino)- alkyll-&lactone component has been developed independently in both our and Kende’s laboratories,24 and Kende has recently reported the first total synthesis of a lankacidin using HO#HO 14 10 OH this strategy.’ During the course of our work we found that life reduction of the 3-( 1’-oxoalky1)azetidinone 2 using sodium borohydride in ethanol is accompanied by azetidinone cleavage to give the 6-lactone 3.3 This has the stereochemistry and 1 2].-.functionality required for incorporation into a synthesis of a lankacidin, and was taken through to the aldehyde 4 in order to investigate procedures for the introduction of the C(10 jC(14) dienyl fragment. However, the aldehyde 4 was found to be unstable under basic conditions, showing a tendency to undergo opening of the &lactone leading to the formation of ap-unsaturated aldehyde^.^ It would appear prudent to avoid having intermediates which contain both the &-lactone and a carbonyl substituent at C(14) (lankacidin numbering)? at least before formation of the macrocycle.If, for example, a keto phosphonate-aldehyde condensation is to be used to introduce the C(l0)-C(14) diene, it would seem necessary to carry out this reaction at the azetidinone stage, before the rearrange- ment to the 6-lactone. This option was shown to be viable by preparation of the 3-(6‘-dimethoxyphosphinoy1-.5‘-oxo-0 04 4 .r/ 3 Met-” OR 0 hexy1)acetidinone 5 which was condensed efficiently with 2-methylbut-2-enal (tiglic aldehyde) to give the dienyl ketone 6.The next stage in our work was to devise a procedure for the 0-Me IP(OX0Me)L Me 5 6 formation of the 17-membered macrocyclic ring of the R = SM%Bd lankacidins. As keto phosphonate-aldehyde reactions have been used to prepare macrocyclic compounds6 it was decided to investigate an intramolecular keto phosphonate reaction, preparation of the macrocyclic ring of the lankacidins. We now analogous to that which had been used to prepare 6, for the report on the synthesis of the 17-(dimethoxyphosphinoyl)- 786 J. CHEM. SOC. PERKIN TRANS. 1 1995 CHO h;le ~e 9 8 heptadecatrienal 7, and its cyclisation to the 17-membered carbocycle 8, a macrocyclic precursor of the lankacidin analogue 9.A convergent synthesis of the heptatrienal 7 was envisaged based on the alkylation of ethyl 2-methyl-3- oxobutanoate 10 using (2E,4E,8E)- 10-(tert-butyldimethyl- silyloxy)-3,9-dimethyldeca-2,4,8-trienylchloride 11 followed by an aldol condensation with 4-(dimethoxyphosphin-oyl)-3,3-(ethylenedioxy)butanal 12 to give the heptadecatriene 13, a possible precursor of the aldehyde 7. Results and discussion (2E,4E,8E)- lo-( tert-Butyldimethylsilyloxy)-3,9-dimethyldeca-2,4,8-trien-l-o126 was prepared as outlined in Schemes 1 and 2. Alkylation of tert-butyl acetate using 3-methylbut-2-enyl bromide gave ethyl 5-methylhex-4-enoate 14 which was oxidised stereoselectively using selenium dioxide in ethanol to give the aldehyde 15.7This was reduced to the alcohol 16 using sodium borohydride (75% overall yield), and after protection of the hydroxyl group as its tert-butyldimethylsilyl ether, the ester 17 was reduced using lithium aluminium hydride and the alcohol 18 so obtained oxidised using Collin's reagent to give the aldehyde 19.This was found to decompose substantially on attempted silica gel chromatography, but could be used in the next step without purification. Free-radical bromination of ethyl 3-methylbut-2-enoate 20 gave a mixture of the (2)-and (E)-4-bromobutenoates 21 and 22 which were separated by flash chromatography. Conversion 12 10 0 Me 13 Me Br4Me Me Me 14 16 R=H 15 17 R = SiMqBd 19 Scheme 1 Reugents: i, LiCH,CO,Bu', tetrahydrofuran, DMPU (97%); ii, selenium dioxide, ethanol; iii, sodium borohydride, ethanol (75% from 14); iv, tert-butyldimethylsilyl chloride, triethylamine, 4-(dimethy1amino)pyridine (90%);v, lithium aluminium hydride (97%); vi, chromium trioxide, pyridine, dichloromethane (87%) of the (E)-isomer 22 into the diethyl phosphonate 23 was carried out with no isomerisation of the double-bond via an Arbusov reaction using triethyl phosphite (87%).The Wadsworth Emmons Horner condensation of the phosphonate 23 with the aldehyde 19 was investigated under a variety of conditions. Initial reactions using lithium diisopropylamide as the base in tetrahydrofuran-l,3-dimethyl-3,4,5,6-tetra-hydropyrimidin-2( 1 H)-one (DMPU) were non-stereoselec- tive and gave the (E)-and (Z)-alkenes 24 and 25 in an approximately 50 :50 ratio, the lack of stereoselectivity being attributed to isomerisation of the lithiated phosphonate.Subsequently it was found that by carrying out the deprotonation of the phosphonate at -90 OC, with addition of the aldehyde within 1 min, the E:2ratio could be improved to 93 :7 with a combined yield of 84%. Reduction of the E-isomer 24 using lithium aluminium hydride-aluminium chloride then gave the allylic alcohol 26 in a 95% yield. The geometry of the 4,5-double-bond in the trienol 26 was apparent from the coupling constant of 15 Hz between 4-H and 5-H in its 'H NMR spectrum. The geometry of the 2,3-double-bond was confirmed by NOE studies later in the synthesis. CI Me Me 11 Me OSiM%Bu' J.CHEM. SOC. PERKIN TRANS. 1 1995 20 w2cJBr Me + mC&Br 21 50 : 50 22 Me Me ii OSiBu' iv I 26 Scheme 2 Reagents: i, N-bromosuccinimide, carbon tetrachloride; ii, triethyl phosphite, 165-170 "C (87%); iii, lithium diisopropylamide, -90 "C, 1 min, then add 19 (24,78%; 25,673; iv, lithium aluminium hydride, aluminium chloride (97%) The conversion of the alcohol 26 into the corresponding allylic bromide or chloride was found to be complicated by the instability of the product. The best procedure in our hands was found to involve the use of butyllithium, toluene-p-sulfonyl chloride and lithium chloride as reported for dienyl alcohols by Stork which gave the chloride 11 which was used immediately without purification.12 The long-chain keto ester 27 was then prepared by alkylation of ethyl 2-methyl-3-oxobutanoate using the crude allylic chloride 11in an acceptable overall yield (57%).BuLi CI &J0SMQEiUl'' toluenep -dfonylc chloride,LiCI 11 0 I CO2Et t Mew&OSiM%B 12 u' I CO2Et 27 The stereochemistry assigned to the trienyl keto ester 27 was confirmed by NOE studies. Irradiation of the 6-Me peak at 6 1.72 resulted in enhancement of the multiplets at 6 2.62 and 5.58 assigned to 4-H, and 8-H, respectively, but no enhancement of the peaks due to 5-or 7-H. Irradiation of the 12-Me peak at 6 I .59 caused an increase in the multiplet at 6 2.1 assigned to 10-H,, but not for the multiplet at 6 5.39 due to 11-H. The dimethyl phosphonate 12 was prepared as outlined in Scheme 3.Dilithiation of the ketophosphonate 28 and addition to formaldehyde was inefficient in our hands giving only a 7% Me 2I i PtO' n--A . WMek I kO)(OMe)2 P(O)(OMe)2 29 28 30 ii I YH YBnt IlCHOI 12 32 31 Scheme 3 Reagents: i, sodium hydride, butyllithium, benzyl chloromethyl ether (62%); ii, ethylene glycol, toluene-p-sulfonic acid (cat.), benzene, heat under reflux (78%); iii, hydrogen, 10% palladium- on-charcoal (95%); iv, tetrapropylammonium perruthenate, N-methyl- morpholine N-oxide (70%) yield of the hydroxy ketone 29. However, alkylation using benzyl chloromethyl ether gave an acceptable, 62%, yield of 4-benzyloxy-1 -(dimethoxyphosphinoyl) butan-2-one 30 which, after protection of the ketone as its 1,3-dioxolane using ethylene glycol, was hydrogenolysed to give the alcohol 32.Oxidation of the alcohol using tetrapropylammonium perruthenate l4 gave the aldehyde 12 (70%). The aldol reaction between the keto ester 27 and the aldehyde 12 gave a 60% yield of the adduct 33 together with a minor side- product identified as the oxaphosphorinane 34 (see Scheme 4). Although the aldol product 33 comprised a mixture of two diastereoisomers, no attempt was made at this stage to separate them or to control the stereoselectivity of the aldol process. However, a stereoselective procedure was chosen to reduce the ketone carbonyl group in order to avoid increasing the number of diastereoisomers present. Reduction using sodium boro- hydride and dimethylmethoxyborane, a procedure which is known to reduce 3-hydroxy ketones stereoselectively to give syn-1,3-diols,' gave the diol35 as a mixture of epimers at the quaternary centre, and these were protected as the acetonide 36.However, all attempts to hydrolyse the 1,3-dioxolane ring selectively without hydrolysis of the acetonide were unsuccess- ful. For example the use of aqueous acidic tetrahydrofuran l6 cleaved the acetonide selectively and gave the starting diol 35 together with some trio1 corresponding to cleavage of the tert-butyldimethylsilyl ether. Similar results were obtained using pyridinium toluene-p-sulfonate in acetone-water, and oxalic acid in acetone" gave rise to the formation of complex mixtures of products.Preliminary studies were carried out into the use of a 1,3- dithiolane as a ketone protecting group which it was hoped would be removed selectively in the presence of the acetonide. However, the aldol reaction between the dithiolane-protected formyl ketone 37 and the keto ester 27 was very inefficient, giving the aldol product 38 as only a minor component of a mixture with the I ,2-oxaphosphorinane 39. Since preliminary attempts to methanolyse this to give more of the dimethoxyphos- phonate 38 were unsuccessful, this approach was discontinued in favour of an alternative sequence in which this selective deprotection was avoided.The aldol reaction between the keto ester 27 and acrolein gave the adduct 40as an inseparable mixture of diastereoisomers (see Scheme 5). Reduction of this mixture using sodium borohydride and dimethylmethoxyborane l5 gave the syn-l,3- diols 41 and 42, ratio 70 : 30, respectively, which were separated 788 J. CHEM. SOC. PERKIN TRANS. 1 1995 27 + 12 0 Me Me 0 Me Me OSiMezBu' OSiM%Bu' '%(O)(OMeh 33 34 ii OH Me Me OSiM9Bu' )..oHb~ iii -P(O)(OMe)2 35 36 Scheme4 Reagents: i, lithium diisopropylamide (33,60%;34,873; ii, dimethylmethoxyborane, sodium borohydride (86%);iii, dimethoxypropane, '% acetyl chloride (80%) 0 Me Me OSiMQBu' /CHO 38 + b0C02Et 39 by flash chromatography. Protection of the separated diols using dimethoxypropane l8 gave the acetonides 43 and 44 the I3CNMR spectra of which confirmed the syn-l,3-relationship between the hydroxyl groups." To establish the identity of each diol, they were separately taken through to the 6-hydroxy lactones 45 and 46 which were oxidised to the keto lactones 47 and 48. These were studied by 'H NOE difference spectroscopy.Irradiation of the singlet due to 3-Me in the 'H NMR of the ketone prepared by oxidation of the major hydroxy lactone caused a 10% NOE enhancement of the multiplet assigned to 6-H, and vice uersa, whereas no such NOE enhancement was observed for the keto lactone prepared from the minor diol. Analogous, although less pronounced effects were observed during 'H NMR studies of the hydroxy lactones 45 and 46.The major diol was, therefore, identified as diastereoisomer 41, the derived hydroxy- and keto-lactones being identified as 45 and 47. The minor diol was correspondingly identified as the diastereoisomer 42, with the minor hydroxy- and keto-lactones being identified as 46 and 48. It is perhaps fortuitous that the stereochemistry of the major diol41 and the lactones 45 and 47 corresponds to that found in the lankacidins. Indeed the lactone 47 possesses the structure of the C(14)-C( 12) fragment of the lankacidins, missing only the 17-Me, the 3-acylamino-, and the 8-OH substituents. It was now necessary to develop the chemistry of the terminal double- bond of the acetonides 43 and 44 to prepare intermediates for macrocyclisation studies. The major acetonide 43, which has stereochemistry corresponding to the lankacidins, was converted into the 16- formyl keto phosphonate 7 as shown in Scheme 6.Regioselective hydroboration of the terminal double-bond using 9-borabicyclononane followed by oxidation gave the alcohol 49 which was oxidised using pyridinium chlorochro- mate 2o to the aldehyde 50. This was found to be rather unstable and, after rapid flash chromatography, was treated with lithiated dimethyl methylphosphonate to give a mixture of the epimeric hydroxy phosphonates 51. After selective removal of the tert-butyldimethylsilyloxy protecting group, oxidation of both of the hydroxyl substituents was carried out using tetrapropylammonium perruthenate to give the 16-formyl-2- 0x0 phosphonate 7.The minor acetonide 44,with stereo- chemistry corresponding to the unnatural configuration at C( 3) in the lankacidins, was similarly taken through to the epimeric 16-formylketophosphonate57 (Scheme 7). Cyclisation of the formyl keto phosphonate 7 was studied under a wide variety of conditions. Diazabicycloundecane and lithium chloride in acetonitrile at 40°C led to a complex mixture of products, lithium hexamethyldisilazide in tetrahydrofuran-DMPU returned unchanged starting material,22 and sodium hydride and 18-crown-6 in dimeth- oxyethane23 gave only low yields of the required macrocycle together with complex mixtures of other products which were not separated or identified.Finally, the use of potassium carbonate in toluene at 100 "C in the presence of 18-crown-6 was found to give the cycloheptadecatetraenone 8 in yields of 3540%. The epimeric phosphonate 57 was similarly cyclised to give the cycloheptadecatetraenone 58, the geometry of the 2,3- double-bond of these products being assigned as E on the basis J. CHEM. SOC. PERKIN TRANS. 1 1995 0 Me Me OP i27 -40 ii,iiiIMAopOR + C-Et II 41 R=H 42 R=H 43 RR=CMe, 44 RR=CM% 45 46 47 48 (P = SiMqBd ) Scheme 5 Reagents: i, lithium diisopropylamide, -78 "C, 30 min, then add acrolein (72%); ii, dimethylmethoxyborane, sodium borohydride (95%); iii, 2,2-dimethoxypropane, acetyl chloride (cat.) (90-98%); iv, sodium hydroxide acidified and heated under reflux in benzene (45, 92%;46, 85%); v, tetrapropylammonium perruthenate, N-methylmorpholine N-oxide (47,77%; 48.69%) of 16 Hz coupling between 2-H and 3-H in their 'H NMR spectra.Alternative macrocyclisation procedures were briefly investi- gated. The 17-bromo- and 17-iodo sulfones 62 and 63 were prepared as summarised in Scheme 8, but attempts to cyclise them under basic conditions, e.g. using potassium hexamethyldisilazide-18-crown-6 or lithium diisopropyl-a~nide,~~gave complex mixtures of products perhaps due to interference by the ethyl ester. The corresponding 17-acetoxy-3- 0x0 sulfone 64 was converted into its enol trimethylsilyl ether using O,N-bis(trimethylsilyl)acetonide,and this was cyclised to the cycloheptadecatrienone 65, albeit in rather a low yield, 18%, by addition to a mixture of tetrakis(tripheny1phosphine)-palladium(0) and 1,3-bi~(diphenylphosphino)propanein tetra- hydrofuran heated under reflux.Having prepared the macrocycles 8 and 58, aspects of their chemistry were briefly investigated. Reduction of the enone 8 using diisobutylaluminium hydride gave a mixture of epimeric alcohols in a ratio of 75:25 whereas sodium borohydride- cerium(Ir1) chloride 26 was more stereoselective and gave the same alcohols in a ratio of 87 :13. The configurations of these alcohols were not formally established, but simple modelling studies suggested that attack on the less hindered face of the enone 8 would give rise to the 14-p-isomer 66. Reduction of the epimeric ketone 58 similarly gave two alcohols identified as 69 and 70, the major diastereoisomer also being provisionally identified as the 14-fl-epimer 69.Attempts to hydrolyse the acetonide group in the alcohol 69 using acidic methanol gave mixtures of products in which the dienyl alcohol fragment appeared to have rearranged. Similarly attempts to deprotect thep-methoxybenzyloxy- or acetoxy-acetonides 68and 71using acidic methanol gave complex mixtures of products. However, a preliminary study of the hydrolysis of the benzoyloxyacetonide 72 indicated formation of the diol 73 as the major product although proper characterisation of these advanced intermedi- ates was not possible because of lack of material. The work described in this paper establishes the viability of assembling the 17-membered carbocyclic ring of the lankacidins using a keto phosphonate-aldehyde cyclisation. The yields of the cyclisation step are, however, only modest, perhaps due to base-induced elimination of the 3,5-isopropylidenedioxy group from the keto phosphonate.Present work is concerned with applying the strategy reported here, and in the preceding paper^,^.^ to complete a total synthesis of lankacidin C l.27 Experimental For general experimental details see the first full paper in this series. tert-Butyl5-methylhex-4-enoate 14 Butyllithium (1.6 mol dm-3 in hexane; 6.6 cm3, 10.57 mmol) was added to diisopropylamine (1.64 cm3, 11.7 mol) in tetrahydro- furan (THF; 14 cm3) at -78 "C.After 50 min, a solution of tert-butyl acetate (1.5 cm3, 11.13 mmol) in THF (4 cm3) was added dropwise over a period of 5 min to the reaction mixture. HO 49 h.1 &O)(OMe)z 51 R=SiM%Bd 52 R=H 0 ;(OXOMe), 7 Scheme 6 Reagents: i, 9-borabicyclononane, then sodium hydroxide and hydrogen peroxide (8 1%); ii, pyridinium chlorochromate, dichloromethane (73%); iii, LiCH,P(O)(OMe), (77%); iv, anhydrous terr-butylammonium fluoride, tetrahydrofuran (95%); v, N-methyl-morpholine N-oxide, tetrapropylammonium perruthenate (69%) After being maintained at -78 "C for 40 min, the reaction mixture was transferred in portions to a solution of 3-methylbut-2-enyl bromide (0.7 cm3, 6 mmol) in THF (1 1 cm3) and DMPU (2 cm3) at -78 "C.The mixture was stirred for a further 30 min, after which saturated aqueous ammonium chloride (20 cm3) was added to it and the whole allowed to warm to room temperature. The mixture was extracted with ether (3 x 140 cm3) and the extracts were washed with brine (3 x 90 cm3), dried (MgSO,), and concentrated under reduced pressure.Flash column chromatography of the residue on silica gel with light petroleum+ther (99: 1) as eluent, gave the title compound 14 as a colourless liquid (1.07 g, 97%); v,,,/cm-' 1733,1455,1368,1257,1118,1040,850 and 755; dH 1.40 [9 H, s, C(CH3),], 1.58 and 1.64 (each 3 H, s, CW,),2.19 (4 H, m, 2-H, and 3-H,) and 5.03 (1 H, m, 4-H); 6, 172.95, 132.69, 122.85, 80.05, 35.87, 28.20, 23.97, 25.77 and 17.78. tert-Butyl (E)-5-formylhex4-enoate 15 A mixture of tert-butyl 5-methylhex-4-enoate 14 (1.39 g, 7.6 mmol) and selenium dioxide (1.175 g, 10.6 mmol) in aqueous ethanol (100 cm3, 95% ethanol) was stirred under reflux for 16 h and then concentrated under reduced pressure.The residue was J. CHEM. SOC. PERKIN TRANS. 1 1995 Me 44- i HO 53 Me .1 0 54 iiiivI Me. Ho."'lP(OX0Me)z 55 R = SiMezBu' 56 R=H Me P(O)(OMe)2 57 Scheme 7 Reagents: i, 9-borabicyclononane, then sodium hydroxide and hydrogen peroxide (80%); ii, pyridinium chlorochromate, dichloromethane (77%); iii, LiCH,P(O)(OMe), (76%); iv, anhydrous tot-butylammonium fluoride, tetrahydrofuran (89%); v, N-methyl-morpholine N-oxide, tetrapropylammonium perruthenate (68%) dissolved in ethyl acetate-hexane (1:l; 100 cm3), and the solution washed with saturated aqueous sodium hydrogen- carbonate (20 cm3).The aqueous phase was back-extracted with additional ethyl acetate-hexane (2 x 10 cm3), and the combined organic extracts were washed with brine, dried (MgSO,) and concentrated under reduced pressure to give the crude aldehyde 15 which was used without further purification. A small sample was purified by flash column chromatography, light petroleum+ther (3:l) to give the title compound 15 (Found: M+ + H, 199.1335. C,,H,,O, requires M, 199.1334); vmax/crn-' 2712,1729,1688,1646,1458,1393, 1368, 1256, 1153, 1030, 848 and 754; 6, 1.39 [9 H, s, C(CH,),], 1.72 (3 H, s, CH,), 2.43-2.47 (4 H, m, 2-H, and 3-H,), 6.4 (1 H, t, J 6,4-H) and9.35(1 H, s,CHO);6, 196.89,173.97, 154.22, 141.92,82.81, 35.96,30.10,26.51 and 11.28; m/z (CI) 216 (M+ + NH,, 5573, 199 (M+ + H, 54%) and 160 (100).tert-Butyl (E)-6-hydroxy-5-methylhex-4-enoate16 Sodium borohydride (152 mg, 4 mmol) was added in small portions to the aldehyde 15 (1.45 g, 7.3 mmol) in ethanol (25 cm3) at 0 "C. Dilute aqueous hydrochloric acid was added to the reaction mixture which was then concentrated under J. CHEM. SOC. PERKIN TRANS. 1 1995 Me. Me Me 5a -OSiM+BdMe%% \ 0 I 0-toluene 100 OC 37% 60Me Me a iii,iVl 0 61 X=OH 62 X=Brtoluene loo *c 63 X=I 64 x=oAc MeMD&e W2Et /58 reduced pressure and diluted with ether. The organic and aqueous phases were separated, and the aqueous phase 0 0 extracted with ether (3 x 20 cm3).The combined organic Phqs h extracts were dried (MgSO,) and evaporated under reduced 65 pressure and flash column chromatography of the residue on Scheme 8 Reagents: i, LiCH,SO,Ph (90%); ii, oxalyl chloride,silica gel with light petroleum+ther (3 :2) as eluent, gave the dimethylsulfoxide(41%); iii, tetrabutylammonium fluoride, tetrahydro-title compound 16 (1.14 g, 75%) (Found: M+ -CH,, 185.1173. furan (80%); iv, acetic anhydride, 4-dimethylaminopyridine (cat.), C,,H,,03 requires M, 185.1178); v,,,/cm-' 3436, 1729, 1457, pyridine, dichloromethane (80%); v, 0,N-bis(trimethylsily1)acetamide 1393, 1368, 1257, 1148, 1011, 849 and 754; 6, 1.39 [9 H, s, then Pd(PPh,),, Ph,PCH,CH,CH,PPh2 (18%) C(CH,),], 1.63 (3 H, s, 5-CH3), 1.7 (1 H, s, OH), 2.25 (4 H, m, 2-H, and 3-H2), 3.94 (2 H, s, 6-H,) and 5.35 (1 H, m, 4-H); 6, 174.64, 137.94, 125.94, 82.29, 70.64, 37.42, 30.18, 25.42 and 15.78;m/z (CI) 218 (M+ + NH,, 4%).revt-Butyl (E)-6-(tevt-butyldimethylsilyloxy)-5-methyI-hex4-enoate 17 Triethylamine (0.975cm3, 7 mmol), 4-(dimethy1amino)pyridine (28.5 mg, 0.233 mmol) and tert-butyldimethylsilyl chloride (844 mg, 5.6 mmol) were added to a solution of alcohol 16 (933 mg, Me Me 4.665 mol) in dichloromethane (17 cm3) and the mixture was 66 X=OH,Y=H 69 X=OH.Y=Hstirred for 2 h. Water (2 cm3)was then added to the mixture and 67 X=H,Y=OH 70 X=H.Y=OH the aqueous and organic phases were separated. The aqueous 68 X=OPMB.Y=H 71 X=OAc.Y=H phase was extracted with dichloromethane (3 x 2 cm3) and the 72 X=OBz,Y=H combined organic extracts were dried (MgSO,) and concen-trated under reduced pressure.Flash column chromatography of the residue with light petroleum-ether (97: 3), gave the title compound 17 (1.49 g, 90%) as a colourless oil (Found: M+ + NH,, 332.2621. C,7H38N03Si requires M, 332.2621); v,,,/cm-l 1733,1473,1368,1255,1147, I1 11,1072,838 and 777; 6, -0.03 [6 H, s, Si(CH,),], 0.82 [9 H, s, SiC(CH,),], 1.35 [9 H, s, C(CH3),], 1.52 (3 H, s, 5-CH3), 2.19 (4 H, m, 2-H, and 3-Me H,), 3.91 (2 H, s, 6-H2) and 5.29 (1 H, m, 4-H); 6, 172.57, 73 135.46, 122.43, 79.94, 66.29, 35.39, 28.06, 25.92, 23.23, 18.35, 13.37 and -5.32; m/z (EI) 257 (M+ -C,H,, 2.273, 201 (60) and 183 (100).(E)-6-(terf-Butyldimethylsilyloxy)-5-methylhex4en-l-ol 18 A solution of the ester 17 (753 mg, 2.4 mmol) in THF (5 cm3) was added dropwise to a suspension of lithium aluminium hydride (91 mg, 2.4 mmol) in dry THF (4 cm3) at 0 "C. The mixture was stirred at 0 "C for 1 h and then quenched by the sequential dropwise addition of water (0.1 cm3), aqueous sodium hydroxide (1 5% w/v; 0.1 cm3), and water (0.3 cm3). The resulting white suspension was stirred at room temperature for a further 30 min and then filtered through Celite which was then washed with THF (5 x 8 cm3). The filtrate was dried (MgSO,) and concentrated under reduced pressure to yield the title compound 18 (568 mg, 97%) (Found: M+ + H, 245.1946. C,,H,,O,Si requires M, 245.1936); v,,,/cm-' 3349, 1473, 1463, 1390, 1362, 1255,1114,1072,939,839 and 775; SH0.08 [6 H, s, Si(CH,),], 0.91 [9 H, s, SiC(CH,),], 1.6 (1 H, br s, OH), 1.62 (3 H, s, 5-CH3), 1.65 (2 H, m, 2-H,), 2.12 (2 H, m, 3-H,), 3.66 (2 H, t, J7, 1-H,), 4.02 (2 H, s, 6-H2) and 5.5 (1 H, m, 4-H);SC 135.16, 123.84, 68.68, 62.86, 32.74, 26.19, 24.07, 18.68 and -4.99; m/z (CI) 245 (M+ + 1,879 and 227 (87).(E)-6-(~ev~-Butyldimethylsilyloxy)-5-methylhex~-enall9 Chromium trioxide (8.92 g, 89 mmol) was added to a solution of pyridine (14.32 cm3, 178 mmol) in dichloromethane (212 cm3) at 0 "C and the mixture was stirred at room temperature for 15 min. A solution of the alcohol 18 (3.34 g, 13.7 mmol) in dichloromethane (20 cm3) was then added rapidly to it.After being stirred for 15 min the mixture was diluted with ether, washed with aqueous sodium hydroxide (573, aqueous hydrochloric acid (579, water, and saturated aqueous sodium hydrogen carbonate, dried (MgS04) and concentrated under reduced pressure to yield the aldehyde 19(2.88 g, 87%) (Found: M+ -H, 241.1630. C,,H,,O,Si requires M, 241.1624); vmaX/cm-' 1728,1473,1463,1390,1362,1253,1114,1073,1007, 839 and 776; 6,O. 12 [6 H, s, Si(CH,),], 0.91 [9 H, s, SiC(CH,),], 1.62(3 H, s, 5-CH3), 2.34 (4 H, m, 2-H, and 3-H,), 3.99 (2 H, s, 6-H,), 5.38 (1 H, m, 4-H) and 9.77 (1 H, t, J 1, CHO); 6, 202.33, 136.12, 121.87, 68.33, 43.89, 26.14, 20.57, 18.63, 13.64 and -5.05;m/~(CI)260(M+ + NH4,9%), 243(M+ + 1,4.5), 185 (40) and Ill (100).Ethyl (E)4bromo-3-methylbut-2-enoate 22 N-Bromosuccinimide (7.5 g, 42.5 mmol) and a catalytic amount of azoisobutyronitrile (0.01 g) were added to a solution of ethyl 3-methylbut-Zenoate (5 g, 39 mmol) in carbon tetrachloride (64 cm3) and the mixture was heated under reflux for 3 h. It was then cooled and filtered, and the precipitate was washed with chloroform. The combined organic phases were washed with saturated aqueous sodium sulfite and brine, dried (MgSO,), and concentrated under reduced pressure to give the (E)-and (Z)-4-bromo-3-methylbut-2-enoates21 and 22which were separated by flash column chromatography, light petroleum-ether (98.5 :I .5), to give the title compound 22 as a pale yellow oil (Found: M+, 205.9939.C7H1 ,79Br02 requires M, 205.9942); v,,,/cm-' 1719, 1651, 1445, 1369, 1282, 1231, 1157, 1042, 891, 863 and 736; 6,1.22 (3 H, t, J 7, OCH,CH,), 2.21 (3 H, d, J1.1,3-CH3), 3.89 (2 H, ~,4-H2), 4.15(2 H, 9, J7, OCH,CH,) and 5.9 (1 H, s, 2-H); 6, 167.75, 154.26, 121.44, 62.09, 40.36, 19.23 and 16.31; m/z (EI) 208 (Mf, 45%), 206 (M', 48%), 180 (43), 178 (44), 163 (76) and 161 (77). Ethyl(E)-4-(diethoxyphosphinoyl)-3-methylbut-2-enoate 23 The bromo ester 22 (779 mg, 4.02 mmol) was added to freshly J. CHEM. SOC. PERKIN TRANS. I 1995 distilled triethyl phosphite (0.7 cm3, 4.07 mmol) and the mixture was sitrred and heated to 165-170 "C for 5 min. The resulting material was fractionally distilled to provide the titZe compound 23 (922 mg, 87%) as a colourless liquid, bp l8O0C/l mmHg (Found: M+, 264.1 135.C,,H,,O,P requires M, 264.1127); v,,,/cm-l 1718, 1647, 1445, 1392, 1353,1213, 1147, 1098, 1029, 965,854 and 780; 6,1.25 (9 H, overlapping t, 3 x CH,CH,O), 2.25 (3 H, dd, J3.5, 1.4,3-CH3), 2.62 (2 H, d, J23,4-H,), 4.08 (6 H, m, 3 x CH,CH,O) and 5.72 (1 H, m, 2-H); 6,167.56 (d, J 3.9, 151.74(d, J11.9), 121.74(d, J11.2),63.98(d,J7.3),61.42, 40.29 (d, J 135), 21.81 (d, J2.7), 18.25 (d, J6.4) and 16.23; m/z (EI) 264 (M', 37%), 219 (55), 218 (loo), 190 (95) and 162 (72). Ethyl (2E,4E,8E)-lO-(ferf-butyldimethylsilyloxy)-3,9dimethyl-deca-2,4,8-trienoate24 Butyllithium (1.6 mol dm-, in hexane; 24.8 cm3, 39.6 mmol) was added to a stirred solution of diisopropylamine (5.55 cm3, 39.6 mmol) in dry THF (120 cm3) at -78 "C.After 50 min DMPU (60 cm3) was added to the reaction mixture which was then cooled to -90 "C. The phosphonate 23 (10.45 g, 39.6 mmol) dissolved in the minimum amount of THF was added rapidly to the reaction mixture and followed, within I min, by a solution of the aldehyde 19 (5.25 g, 21.7 mmol) also in the minimum amount of THF. The reaction mixture was stirred at -90 "C for 2 h and allowed to warm slowly to -10 "C when saturated aqueous ammonium chloride (63 cm3) was added to it. The aqueous and organic phases were separated and the former was extracted with ether (3 x 25 cm3). The combined organic extracts were washed with brine (3 x 40 cm3), dried (MgS0,) and concentrated under reduced pressure.Flash chromatogra- phy of the residue with light petroleum-ether (93 :7), gave the title compound 24 (5.92 g, 78%) (Found: M+ + H, 353.2524. C,,H,,O,Si requires M, 353.2512); vmax/cm-l 1714, 1638, 1614, 1463, 1389, 1353, 1239, 1153, 1112, 1068, 1007, 966, 838 and 777; SH0.02 [6 H, S, Si(CH,),], 0.88 [9 H, S, SiC(CH,),], I .23 (3 H, t, J7, OCH,CH3), I .56 (3 H, s, 9-CH3), 2.18 (4 H, m, 6-H2 and 7-H,), 2.22 (3 H, s, 3-CH3), 3.98 (2 H, s, 10-H,), 4.12 (2 H, q, J 7, OCH,CH,), 5.35 (1 H, m, 8-H), 5.64 (1 H, s, 2-H), 6.09 (2 H, m, 4-H and 5-H);6, 167.2, 152.47, 136.72, 134.09, 123.15, 117.94, 68.44, 59.56, 33.03, 27.11, 25.99, 18.44, 14.40, 13.82, 13.53 and -5.23; m/z (CI) 370 (M' + NH,, 4.573, 353 (M+ + 1, 10.3), 295 (19.4) and 221 (100). The (22,4E,8E)-isomer 25 (0.4 g, 6%) was also isolated. (2E,4E,8E)-lO-(ter~-Butyldimethylilyloxy)-3,9-dimethyldeca-2,4,8-trien-l-0126 Aluminium trichloride (235 mg, 1.74 mmol) was added to a solution of lithium aluminium hydride (215 mg, 5.7 mmol) in ether (4 cm3) at 0 "C and the mixture stirred at this temperature for 1 h.A solution of the ester 24 (1 g, 2.84 mmol) in ether was then added dropwise to the mixture which was then stirred at 0 "C for 30 min. Aqueous sodium hydroxide (2 mol dm-3) was then added cautiously to the reaction mixture from which the resulting solid was filtered off and washed with ether. The combined organic fractions were washed with brine, dried (MgS0,) and concentrated under reduced pressure. Flash chromatography with light petroleum-ether (7 :3), gave the title compound 26(797 mg, 97%) as an oil (Found: M+ + NH,, 328.2680.C, 8H38N02Si requires M, 328.2672); v,,,/cm-l 3344, 1463,1389,1253,1071,1006,965,838 and 776; SH0.06 [6 H, S, Si(CH,),], 0.9 [9 H, s, SiC(CH,),], 1.5 (1 H, br s, OH), 1.59 (3 H, s, 3-CH3), 1.77 (3 H, s, 9-CH3), 2.15 (4 H, m, 6-H, and 7- H,), 4.0 (2 H, s, 10-H,), 4.26 (2 H, d, J7, 1-H,), 5.39 (1 H, m, 8- H), 5.55 (1 H, t, J7,2-H), 5.66 (1 H, dt, J 15,6.5,5-H) and 6.07 (1 H, d, J 15, 4-H); 6, 136.53, 134.91, 134.31, 130.05, 127.99, 123.78, 68.69, 59.49, 33.0, 27.73, 26.16, 18.64, 13.72, 12.8 and -5.01; m/z (CI) 328 (M+ + NH,, 4%) and 161 (100). J. CHEM. SOC. PERKIN TRANS. 1 1995 (5E,7E,11E)-13-(tert-ButyldimethyIsilyloxy)Aethoxycarbnyl-3,6,12-trimethyltrideca-5,7,1l-hien-2-one27 Butyllithium (1.6 mol dm-3 in hexane; 0.88 cm3, 1.41 mmol) was added dropwise to a stirred solution of the alcohol 26(430 mg, 1.39 mmol) in THF (2.8 cm3) at 0 "C followed by DMPU (1 cm3) and toluene-p-sulfonyl chloride (319 mg, 1.67 mmol) in THF (1.8 cm3).After 30 min, a solution of lithium chloride (176 mg, 4.14 mmol) in DMPU and N,N-dimethylfonnamide (3.2 cm3, 60 :40) was added dropwise to the mixture and the stirring continued at 0°C for a further 45 min. Saturated aqueous sodium hydrogen carbonate (6 an3)was added to the mixture and the aqueous and organic phases were separated. The organic phase was extracted with ether (2 x 4 cm3) and the combined extracts were washed with water (2 x 3 cm3) and brine (3 cm3), dried (MgSO,) and concentrated under reduced pressure at 0°C to give the chloride 11 which was used immediately.Ethyl 2-methyl-3-oxobutanoate 10 (0.268 cm3, 1.86 mmol) was added dropwise to a solution of sodium ethoxide (106 mg, 1.53 mmol) in ethanol (9 cm3) at 0 "C and this was followed by the chloride 11 in ethanol (5.6 cm3). After 2.5 h at room temperature the reaction mixture was concentrated under reduced pressure and the residue taken up in ether (10 cm3). The ethereal solution was washed with brine (2 cm3) and the aqueous phase then back-extracted with ether (3 x 1 cm3). The combined extracts were dried (MgSO,) and concentrated under reduced pressure and the residue was subjected to flash chromatography on silica gel with light petroleum-ether (92.5:7.5) to give the title compound 27 (360 mg, 59% from alcohol 26)as a colourless oil (Found: M+ + NH,, 454.3336.C2,H,8N04Si requires M, 454.3352); v,,x/cm-l 1717, 1463, 1360,1285, 1251,1185,1111,964,838 and 777; ~5~0.06 [6 H, S, Si(CH,),], 0.9 [9 H, s, SiC(CH,),], 1.25 (3 H, t, J7,OCH2CH,), 1.32(3H,s,3-CH3), 1.59(3H,s, 12-CH3), 1.72(3H,s,6-CH,), 2.05 (4 H, m, 9-H, and 10-H,), 2.1 (3 H, s, 1-H,), 2.62 and 2.7 4-Benzyloxy-1-dimethylphosphinoyl-2,2-(ethylenedioxy)butane 31 The keto phosphonate 30 (2.7 g, 9.46 mmol), ethylene glycol (3.81 cm3,37.8 mmol) and toluene-p-sulfonic acid (20 mg) were dissolved in benzene (1 50 cm3) and the solution heated at reflux using a Dean-Stark trap for 1.5 h.The reaction mixture was poured into ether (70 cm3), and the ether solution washed with saturated aqueous sodium carbonate (40 an3).The aqueous and organic phases were separated and the aqueous solution was extracted with ether (2 x 20 cm3). The combined organic extracts were washed with brine (2 x 20 cm3), dried (MgSO,) and concentrated under reduced pressure to give a residue which was chromatographed on silica gel with light petroleum- ethyl acetate-methanol (1 2 :4 :1) as eluent to yield the title compound 31(2.41 g, 78%) as a colourless oil (Found: M++ H, 331.1290. C,,H,,O,P requires M, 331.1310); ~,,/cm-~ 1455, 1370, 1251, 1034, 951, 848 and 738; 6, 2.18 (2 H, t, J 6.6, 3-H,), 2.32 (2 H, J 19, l-H,), 3.6 (2 H, t, J6.6,4-H2), 3.7 [6 H, d, J 11, P(OCH,),], 3.98 (4 H, m, OCH,CH,O), 4.49 (2 H, s, CH,Ph) and 7.3 (5 H, s, ArH); 6, 140.3, 130.29, 129.65, 129.49, 109.85 (d, J 2.7), 75.02, 67.91, 66.95, 54.36 (d, J 6.4), 40.26 and 36.89 (d, J 130 Hz); m/z (CI) 331 (M+ + 1,7979 and 211 (100).4-Dimethoxyphosphinoyl-3,3-(ethylenedioxy)butan-1-0132 A solution of the benzyl ether 31(2.56 g, 7.76 mmol) in methanol (35 cm3) was added to a suspension of palladium-on-charcoal (10% w/w; 195 mg) in methanol (40 cm3). The reaction mixture was stirred overnight at room temperature under an atmosphere of hydrogen and then filtered through Celite and concentrated under reduced pressure. Flash column chromatog- raphy of the residue with light petroleum-ethyl acetate-methanol (1 2 :4 :1), gave the title compound 32(1.77 g, 95%) as a colourless oil (Found: M+ + 1, 241.0840.C,H180,P requires M, 241.0841); v,,,/cm-' 3405, 1475, 1247, 1039, 961 and 865; (eachlH,dd,J7.5,15,4-H),4.0(2H,s,13-H2),4.18(2H,q,Jd,(CD,Cl2) 2.1 (2 H, t, J 6.5, 2-H2), 2.28 (2 H, d, J 20, 4-H,), 7,0CH2CH3), 5.18 (1 H, t, J7, 5-H), 5.39 (1 H, m, 11-H), 5.58 (1 H, dt, J 15.7, 8-H) and 6.03 (1 H, d, J 15, 7-H); 6, 205.0, 172.72, 136.96, 134.82, 134.72, 128.43, 123.89, 123.45, 68.69, 61.51,59.97,33.59,32.97,27.79,26.4,26.15, 19.15, 18.63, 14.26, 13.69, 12.89 and -5.02; m/z (CI) 454 (M' + NH,, 5%), 437 (M+ + 1,0.5) and 305 (9). QBenzyloxy-ldimethylphosphinoylbutan-2-one 30 A solution of dimethylphosphinoylpropanone (1.66 cm3, 12 mmol) in THF (4.5 cm3) was added slowly to a suspension of sodium hydride (612 mg, 26 mmol) in THF (30 cm3) at 0 "C.After 1 h, butyllithium (1.6 mol dm-3 in hexane; 7.88 cm3, 12.6 mmol) was added dropwise to the mixture which was then stirred for 1 h. After this the solution was cooled to -78 "C and benzyl chloromethyl ether (1.66 cm3, 12 mmol) in THF (6 cm3) was slowly added to it. The resulting mixture was stirred at 0 "C for 1 h and then poured into brine (30 cm3). The mixture was acidified with aqueous hydrochloric acid (1 mol dm-,) to pH -2 and the organic phase separated. The aqueous solution was extracted with ether (2 x 15 cm3) and the combined organic extracts were dried (MgSO,) and evaporated under reduced pressure. Flash column chromatography of the residue on silica gel with light petroleum-ethyl acetate-methanol (1 2 :4 :I), gave the title compound 30 (2.12 g, 62%) (Found: Mf + H, 287.1047.C,,H,,O,P requires M, 287.1048); v,,,/cm-' 1718, 1497,1455,1369,1256,1186,1029,822 and 742; 6,2.84 (2 H, t, J6.4, 3-H,), 3.10 (2 H, d, J23, l-H2), 3.68 (2 H, t, J6.4, 4-H2), 3.7 [6 H, d, J 11.6, P(OCH,),], 4.44 (2 H, s, CH,Ph), 7.26 (5 H, s, ArH); 6, 202.27 (d, J 6.4), 139.92, 130.36, 129.67, 75.21, 66.93, 55.1 (d, J 6.4), 46.15 and 43.72 (d, J 128); m/z (CI) 287 (M' + 1,9379 and 186 (100). 2.65 (1 H, br s, OH), 3.18 (2 H, t, J6.5, 1-H2), 3.18 [6 H, d, J 11, P(OCH,),] and 3.99 (4 H, m, OCH,CH,O); 8, 110.73, 66.81, 60.32, 54.69 (d, J 6.3), 42.18 and 36.34 (d, J 138); m/z (CI) 241 (M+ + 1, 100%).4-DimethylphosphinoyI-2,2-(ethylenedioxy)butanal 12 The alcohol 32 (100 mg, 0.42 mmol) was dissolved in dichloromethane (4 cm3) containing powdered 4 A molecular sieves (50 mg) and N-methylmorpholine N-oxide (74 mg, 0.63 mmol). Solid tetrapropylammonium perruthenate (8 mg, 0.02 1 mmol) was added to the mixture which was then stirred at room temperature for 2 h. Flash chromatography with light petroleum-ethyl acetate-methanol (12 :4 :0.8), gave the title compound 12 (70 mg, 70%) as a colourless oil; v,,,/cm-' 1724, 1465,1401,1246,1034,951, 797and734;dH2.34(2H,d, J20,4- HZ), 3.02 (2 H, d, J 2.5, 2-H,), 3.72 [6 H, d, J 11, P(OCH,),], 4.03 (4 H, m, OCH,CH,O) and 9.7 (1 H, t, J 2.5, CHO); 6, 201.52, 108.67,67.30,54.8 (d, J6.4), 53.28 and 36.88 (d, J 138); m/z (FAB) 255 (M' + 17,100%) and 195 (90).(9E,11E,15E)-17-(tert-Butyldimethylsilyloxy)-1 -dimethyl-phosphinoyl-7-ethoxycarbonyl-2,2(ethylen~oxy)~-hy~oxy-7,10,16-trimethylheptadeca-9,11,15-trien-6-one 33 Butyllithium (1.6 mol dmP3 in hexane; 0.168 cm3, 0.268 mmol) was added to a stirred solution of diisopropylamine (0.038 cm3, 0.268 mmol) in THF (1.5 cm3) at 0 "C followed, after 20 min at 0 "C, by the keto ester 27(106 mg, 0.244 mmol) in THF (1 cm3). After the solution had been stirred for 30 min and cooled to -78 "C, the aldehyde 12(58 mg, 0.244 mmol) in THF (1 cm3) was added to it. After the mixture had been stored for 1.5 h at -78 "C, saturated aqueous ammonium chloride (1 cm3) was added to it and the whole was allowed to attain room temperature. The organic and aqueous phases were separated and the latter was extracted with ether (4 x 1 cm3).The combined organic extracts were washed with brine (1 cm3), dried (MgSO,) and evaporated under reduced pressure. Chromatography of the residue with light petroleum-ethyl acetate-methanol (14 :8 :0.8) as eluent gave the oxaphos-phorinane 34 (12 mg, 8%); v,ax/cm-l 1715, 1463, 1389, 1279, 1252, 1088, 1035, 991, 963, 838 and 777; SH 0.05 [6 H, s, Si(CH,),], 0.9 [9 H, s, SiC(CH,),], 1.26 and 1.27 (each 1.5 H, t, J7, OCH,CH,), 1.31 and 1.33 (each 1.5 H, s, 7-CH3), 1.58 (3 H, s, 16-CH3), 1.71 (3 H, s, 10-CH,), 1.69-1.88 (2 H, m, 5-H,), 2.0- 2.4(6H,m), 2.5-2.8 (3 H,m, 3-Hand 8-H2), 3.0(1 H,ddd, J17, J.CHEM. SOC. PERKIN TRANS. 1 1995 extracted with dichloromethane (2 x 0.4 cm3). The combined organic extracts were washed with brine (0.4 cm3), dried (MgSO,) and concentrated under reduced pressure. Flash chromatography of the residue gave the title compound 36 (32 mg, 80%) as a colourless oil (Found: M+ + H, 717.4176. C,6H6601$iP requires M, 717.4163); v,,.Jcm-' 1724, 1463, 1381,1256,1201, 1107,1035,965,838 and 777; SH0.05 [6 H, s, Si(CH,),], 0.9 [9 H, s, SiC(CH,),], 1.1 (3 H, s, 7-CH3), 1.2 (3 H, m, OCH,CH,), 1.29 and 1.32 (each 1.5 H, s, CH,), 1.38 (3 H, s, CH,), 1.57 (3 H, s, 16-CH3), 1.67 (3 H, s, lo-CH,), 1.7- 1.9 (4 H, m), 2.1 (4 H, m, 13-H, and 14-H2), 2.3-2.5 (2 H, m, 8-H2), 2.35 and 2.45 (each 1 H, d, J 18, 1-H), 3.7 [6 H, d, J 11, 7,2.5,3-H'),3.8and3.81 (each 1.5H,d,Jl1,OCH3),3.924.10P(OCH,),], 4.0 (2 H, s, 17-H2), 3.9-4.2 (8 H, m, 4-H, 6-H, (4 H, m, OCH,CH,O), 4.0 (2 H, s, 17-H,), 4.19 (2 H, m, OCH,CH,), 4.79 (1 H, m, 4-H), 5.16 (1 H, m, 9-H), 5.39 (1 H, m, 15-H), 5.6 (1 H, dt, J 10,4.5, 12-H) and 6.02 and 6.03 (each 0.5 H, d, J 16, 11-H); m/z (FAB) 665 (M+ + 23, 0.4%) and 643 (M' + 1, 1%); followed by the title compound 33 (98 mg, 60%) (Found: M+ + H, 675.3713.C33H60010PSi requires M, 675.3693); vmax/crn-l 3393, 1713, 1462, 1251, 1035,963, 838 and 778; 6, 0.01 [6 H, S, Si(CH,),], 0.92 [9 H, S, SiC(CH,),], 1.1 (3 H, t, J 7, OCH,CH,), 1.12 and 1.13 (each 1.5 H, s, 7-CH3), 1.54(3 H, s, 16-CH3), 1.68 (3 H, s, 10-CH,), 2.0 (2 H, m, 5-H,), 2.08 (4 H, m, 13-H2 and 14-H2), 2.22-2.73 (6 H, m), 3.21 (1 H, br s, OH), 3.7 [6 H, d, J 11, P(OCH,),], 3.96 (2 H, s, 17-H,), 4.004.06 (4 H, m, OCH,CH,O), 4.14 (2 H, q, J7,OCH2CH,), 4.35 (1 H, m, 4-H), 5.18 (1 H, t, J8,9-H), 5.38 (1 H, m, 15-H), 5.55 (1 H, dt, J 16, 6, 12-H) and 5.98 (1 H, d, J 16, 11-H); m/z (FAB) 697 (M' + 23,273 and 675 (M+ + 1, 1.5).(4RS,6SR,9E,11E,15E)-17-(tert-ButyldimethyIsilyloxy)-1-dimethylphosphinoyl-7~thoxycarbonyl-2,2-ethylenedioxy-7,10,16-trimethylheptadeca-9,11,15-triene-4,6-diol35 Dimethylmethoxyborane THF (0.144 cm3, 0.144 mmol) was added to a solution of the hydroxy ketone 33 (87 mg, 0.129 mmol) in THF-methanol (5:1; 1.5 cm3) at -78 "C. After 15 min, sodium borohydride (6 mg, 0.15 mmol) was added to the mixture which was then stirred at -78 "C for 5 h.After this, acetic acid (0.14 cm3) was added to the reaction mixture at -78 "C and the whole poured into saturated aqueous sodium hydrogen carbonate (4 cm3) and extracted with ethyl acetate (3 x 4 cm3). The combined extracts were washed with brine, dried (MgS0,) and concentrated under reduced pressure. The residue was taken up in methanol (4 cm3) and the solvent removed under reduced pressure. This procedure was repeated 10 times. Flash chromatography with light petroleum+thyl acetate-methanol (14 :8 :l), of the residue gave the title compound 35 (75 mg, 86%) as an inseparable mixture of diastereoisomers (Found: M+ + H, 677.3844. C,,H,,O,oPSi requires M, 677.3850); vmax/cm-' 3413, 1724, 1463, 1251, 1187, 1035,964, 838 and 777; BH 0.05 [6 H, s, Si(CH,),], 0.9 [9 H, s, SiC(CH,),], 1.15 (3 H, s, 7-CH3), 1.23 (3 H, t, J7,OCH2CH,), 1.58 (3 H, s, 16-CH3), 1.7 (3 H, s, 10-CH,), 1.95-2.6 (6 H, m, 3-H,, 5-H,, 8-H2), 2.12 (4 H, m, 13-H,, 14-H2), 2.3 (2 H, d, J 18, l-H2), 3.72 [6 H, d, J 11, P(OCH,),], 4.0 (2 H, S, 17-H2), 4.1 (4 H,m, OCH,CH,O), 4.14.25 (4 H, m, OCH,CH,, 4-H and 6-H), 5.3(1 H,t, J8,9-H),5.4(1 H,m, 15-H),5.55(1 H,dt, J15,6,12-H) and 6.05 (1 H, d, J 15, 11-H); m/z (FAB) 699 (M++ 23,2.5%).(4RS,6SR,9E,11E,15E)-l7-(tert-Butyldimethylsilyloxy)-l-dimethylphosphinoyl-7~thoxycarbonyl-2,2-ethy~enedioxy~,6-isopropylidenedioxy-7,lO,l~trimethylheptadeca-9,11,19triene 2,2-Dimethoxypropane (0.07 cm3, 0.56 mmol) and acetyl chloride (0.2 mm3) were added to a solution of the diol 35 (38 mg, 0.056 mmol) in dichloromethane (1 cm3) at 0 "C and, after 25 min, followed by saturated aqueous sodium hydrogen car- bonate.The phases were separated and aqueous phase was OCH2CH3, OCH2CH20), 5.2 (1 H, t, J7.5,9-H), 5.35 (1 H, m, 15-H),5.55(1 H,dt, J15,6,12-H)and6.0(1 H,d, J15,11-H);rn/z (CI)734(M+ + NH4,5.7%),717(M+ + 1,3.4%)and 195(100). (8E,1OE,14E)-16-(ter t-Butyldimethylsilyloxy)-6-ethoxy-carbonyl-3-hydroxy-6,9,15-trimethylhexadeca-1,8,10,14-tetraen-5-one 40 Butyllithium (1.6 mol dm-, in hexane; 3.1 cm3, 4.96 mmol) was added to a solution of diisopropylamine (0.7 cm3, 4.96 mmol) in THF (1 3 cm3) at 0 "C. After 20 min at 0 "C, the keto ester 27 (1.19 g, 2.73 mmol) in THF (6 cm3) was added to the mix- ture which was then stirred for 30 min before being cooled to -78 "C.Acrolein (0.35 cm3, 5.24 mmol) was added to the mixture which was then stirred for 1.5 h at -78 *C before the addition of saturated aqueous ammonium chloride (10 cm3) and warming to room temperature. The organic and aqueous phases were separated and the latter was extracted with ether (4 x 10 cm3). The combined extracts were washed with brine (7 cm3), dried (MgSO,), and concentrated under reduced pressure. Flash chromatography of the residue with light petroleum*ther (80:20) gave the title compound 40 (1.01 g, 72%) (Found: M+ + Na, 515.3165. C,,H,,NaO,Si requires M, 515.3169); v,,,/crn-' 3527, 1713, 1463, 1378, 1252, 1110, 1068,964, 838 and 777; ~5~0.05[6 H, s, Si(CH,),], 0.9 [9 H, s, SiC(CH,),], 1.26 (3 H, t, J 7, OCH,CH,), 1.32 and 1.34 (each 1.5 H, S, 6-CH3), 1.61 (3 H, S, 15-CH,), 1.71 (3 H, S, 9-CH3), 2.1 (4 H, m, 12-H, and 13-H,), 2.64 (4 H, m, 4-H, and 7-H,), 3.0 (1 H, br s, OH), 4.02 (2 H, s, 16-H2), 4.17 (2 H, q, J 7, OCH,CH,), 4.55 (1 H, m, 3-H), 5.11 (1 H, d, J 10, 1-H), 5.16 (1 H, t, J7.5, 8-H), 5.28 (1 H, dd, J 17, 1.5, 1-H'), 5.39 (1 H, m, 14-H), 5.58 (1 H, dt, J 15.5, 6.5, 11-H), 5.82 (1 H, ddd, J 17, 10, 5.5, 2-H), 6.03 (1 H, d, J 15.5, 10-H); m/~(FAB) 515 (M+ + 23,0.1%) and 493 (M+ + 1,0.26).(3SR,5RS,6SR)-and (3SR,5RS,6RS)-(8E,lOE, 14E)-l6-(tert- Butyldimethylsilyloxy)-6-ethoxycarbonyl-6,9,15-himethylhexadeca-l,8,10,14-tetraene-3,5-diols41 and 42 Following the procedure outlined above for the synthesis of 35, the hydroxy ketone 40 (0.95 g, 1.9 mmol) was reduced using sodium borohydride and dimethylmethoxyborane to give the diols 41 and 42(0.9 g, 95%).Flash chromatography with light petroleum-ethyl acetate (85 :15), gave the (3SR,5RS,6SR)- isomer 41 (Found: M+ + Na, 517.3345. C2,H5,Na05Si requires M, 517.3325); v,,,/cm-' 3415, 1723, 1463, 1253, 1189, 964, 926, 838 and 777; BH 0.05 [6 H, s, Si(CH,),], 0.9 [9 H, S, SiC(CH,),], 1.15 (3 H, s, 6-CH3), 1.25 (3 H, t, J 7,OCH,CH,), 1.58 (3 H, s, 15-CH3), 1.6 (2 H, m, 4-H,), 1.72 (3 H, s, 9-CH3), 2.12(4H,m,12-H,and13-H2),2.4land2.58(each1 H,dd,J8, 14.5, 7-H), 2.9 (2 H, br s, 2 x OH), 4.02 (2 H, s, 16-H2),4.05 (1 H,m,5-H),4.14(2H,m,OCH2CH,),4.38(1H,m,3-H),5.1 (1 H,d, JlO,l-H),5.27(1 H,d, J17,l-H'), 5.32(1 H, t, J8,8-H), 5.4(1 H,m, 14-H),5.6(1 H,dt, J15,7, 11-H), 5.86(1 H,ddd, J 17, 10,6,2-H)and6.05(1 H,d, J15, lO-H);d, 176.8, 141, 136.5, 135.8,135.7, 128.8, 125.3, 124.3, 115.4,76.8,74,69.2,61.6,51.7, 38.8, 34.7, 33.6, 28.1, 26.2, 18.7, 17.8, 14.9, 14.1, 13.5 and J.CHEM. SOC. PERKIN TRANS. I 1995 -5.02; mjz (FAB) 517 (M+ + 23, 0.4%) and 495 (M' + 1, 0.2%); followed by the (3SR,SRS,6RS)-isomer 42 (Found: M+ + H, 495.3525. C,,H,,O,Si requires M, 495.3506); v,,,/cm-' 3430, 1723, 1252, 1191, 1110, 1071, 964, 925, 838 and 777; 6, 0.05 [6 H, s, Si(CH,),], 0.9 [9 H, s, SiC(CH,),], 1.18 (3 H, s, 6-CH3), 1.27 (3 H, t, J7, OCH,CH,), 1.54 (2 H, m, 4-H,), 1.6 (3 H, s, 15-CH,), 1.7 (3 H, s, 9-CH3), 2.1 (4 H, m, 12-H, and 13-H2), 2.42 and 2.48 (each 1 H, dd, J 7.5,15,7-H), 3.0 (2 H, br s, 2 x OH), 3.98 (1 H, m, 5-H), 4.02 (2 H, s, 16-H2), 4.18 (2 H, q, J7,OCH2CH,), 4.37 (1 H, m, 3-H), 5.12 (1 H, d, J 10, 1-H), 5.25 (1 H, m, 8-H), 5.3 (1 H, d, J 17, 1-H'), 5.4 (1 H, m, 14-H), 5.6 (1 H, dt, J 15, 7, 11-H), 5.85 (1 H, ddd, J 17, 10, 6, 2-H) and 6.05 (1 H, d, J 15, 10-H); 6, 177.16, 140.9, 136.80, 135.22, 128.76, 124.39, 124.29, 115.14, 76.41, 73.87, 69.02, 61.46, 51.48, 37.91, 35.24, 33.28, 28.11, 26.43, 18.7, 17.89, 14.68, 13.97, 13.15 and -4.7; m/z (CI) 495 (M' + 1, 30%), 364 (54), 363 (100) and 345 (42).(3SR,5RS,6SR,8E,1OE,14E)-16-(tert-Butyldirnethylsilyloxy)-6-ethoxycarbonyl-3,5-isopropylidenedioxy-6,9,15-trimethyl-hexadeca-l,8,10,14tetraene 43 Following the procedure outlined above for the synthesis of the acetonide 36,the diol41 (576 mg, 1.17 mmol) gave, after flash chromatography with light petroleum-ether (90 :10) as eluent, the title compound 43 (612 mg, 98%) as an oil (Found: M+ -C4H9, 477.3026.C,,H,,O,Si requires M, 477.3036);.v,,,/cm-' 1724, 1463, 1388, 1256, 1201, 1094,990,964,923,838 and 776; SH0.08 [6 H, s, Si(CH,),], 0.91 [9 H, s, SiC(CH,),], 1.12 (3 H, s, 6-CH3), 1.23 (3 H, t, J7,OCH2CH,), 1.39 (2 H, m, 4-H,), 1.4 and 1.44 (each 3 H, s, CH,), 1.59 (3 H, s, 15-CH3), 1.7 (3 H, s, 9-CH,), 2.12 (4 H, m, 12-H, and 13-H2), 2.39 and 2.52 (each 1 H, dd, J7.5, 14.5,7-H),4.0(2H,s, 16-H2),4.1 (1 H,m,5-H),4.12 (2 H, q, J7,0CH2CH,), 4.35 (1 H, m, 3-H), 5.11 (1 H, d, J 10, 795 mmol) in THF (2 cm3) at 0 "C.After being stirred for 5 min at room temperature, the mixture was cooled at 0 "C and aqueous tartaric acid (12% w/v, 3.6 cm3) was added to it. The organic and aqueous phases were separated and the latter was extracted with ethyl acetate (4 x 2 cm3). The combined extracts were washed with brine (2 x 2 cm3), dried (MgSO,), and concentrated under reduced pressure to give the dihydroxy acid. This was dissolved in benzene (10 cm3) and the solution heated under reflux using a Dean-Stark trap for 16 h. Concentration under reduced pressure gave a residue which was flash chromatographed with light petroleum+ther (1 :1) as eluent to give the title compound45(100 mg, 92%) (Found: M + + H, 449.3028.C,,H,,O,Si requires M, 449.3087); v,,,/cm 3450, 1708, 1463, 1377, 1253, 1188, 1069, 1008, 964, 929, 838 and 777;BH 0.05 [6 H, s, Si(CH,),], 0.9 [9 H, s, SiC(CH,),], 1.3 (3 H, S, 3-CH3), 1.6 (3 H, S, 9'-CH3), 1.72 (3 H, S, 3'-CH3), 2.06 (2 H, m, 5-H,), 2.10 (1 H, br s, OH), 2.14 (4 H, m, 6'-H2 and 7'-H,), 2.48 (2 H, d, J7.5, 1'-H,), 4.0 (3 H, m, 10'-H, and 4-H), 5.13(1H,q,J6.5,6-H),5.23(1H,d,JlO,2"-H),5.35(1H,d,J 17,2"-H'), 5.35(1 H,m,2'-H), 5.4(1 H,m,8'-H), 5.61 (1 H,dt, J 16,6, 5'-H), 5.88 (1 H, ddd, J 17, 10, 5, I"-H), 6.05 (1 H, d, J 16, 4'-H); m/z (FAB) 449 (M' + 1,679. (3RS,4RS,6SR)-3-[(2'E,4'E,8'E)-lO'-(tevt-Butyldimethyl-silyloxy)-3',9'dimethyldeca-2',4',8'-trienyl] -4-hydroxy-3-methyl-6-vinyltetrahydropyran-2-one46 Following the above procedure, the dihydroxy ester 42 (48 mg, 0.097 mmol) gave the title compound 46 (37 mg, 85%) as an oil (Found: M' + NH,, 466.3356.C,,H,,NO,Si requires M, 466.3352); v,,,/cm~' 3437, 1709, 1462, 1369, 1253, 1187, 1068, 1007, 965, 929, 838 and 777; 6, 0.05 [6 H, S, Si(CH,),], 0.9 [9 H, s, SiC(CH,),], 1.28 (3 H, s, 3-CH3), 1.6 (3 H, s, 9'-CH,), 1.79 (3 H, s, 3'-CH,), 2.01 (2 H, m, 5-H,), 2.15 (4 H, m, 6'-H2 l-H),5.25(1 H,d,J17,l-H'),5.28(1H,t,J8,8-H),5.4(1H,m,and 7'-H,), 2.2 (1 H, br s, OH), 2.68 (1 H, dd, J 16,9, 1'-H), 2.72 14-H), 5.56(1 H,dt, J15.5,7, 11-H), 5.8(1 H,ddd, J17, 10,6, 2-H) and 6.04 (1 H, d, J 15, 10-H); 6, 175.44, 139.15, 136.17, 135.56, 135.05, 128.06, 125.74, 124.39, 115.86, 99.32, 72.31, 70.75,69.05,60.88,50.6,35.34,33.29,32.08,30.58,28.18,26.44, 20.14, 18.5, 16.74, 14.74, 13.96, 13.13 and -4.76; m/z (FAB) 519 (M' -15,0.3%) and 477 (M' -57,2.5).(3SR,5RS,6RS,8E,1OE,14E)-16-(tert-ButyldimethyIsilyloxy)-6-ethoxycarbonyl-3,5-isopropylidenedioxy-6,9,15-trimethylhexadeca-1,8,10,14-tetraene44 Following the procedure outlined above for the synthesis of the acetonide 36, the diol 42 gave the title compound 44 (Found: M' -C,H,, 477.3023. C27H,,Si05 requires M, 477.3036); v,,,/cm-' 1724, 1463, 1380, 1258, 1202, 1109, 1072, 990, 964, 924, 838 and 776; SH 0.07 [6 H, s, Si(CH,),], 0.9 [9 H, s, SiC(CH,),], 1.13 (3 H, s, 6-CH3), 1.23 (3 H, t, J 7, OCH,CH,), 1.37 (3 H, s, CH,), 1.42 (2 H, m, 4-H,), 1.43 (3 H, S, CH,), 1.58 (3 H, S, 15-CH,), 1.69 (3 HYS, 9-CH3), 2.13 (4 H, m, 12-H, and 13-H,), 2.22 and 2.4 (each 1 H, dd, J 14, 7, 7-H), 4.0 (2 H, s, 16-H2), 4.1 (2 H, m, OCH,CH,), 4.15 (1 H, m, 5-H), 4.35 (1 H, m, 3-H), 5.12 (1 H, d, J 10, 1-H), 5.25 (I H, m, 8-H), 5.26 (1 H, d, J 17, 1-H'), 5.39 (1 H, m, 14-H), 5.57 (1 H, dt, J 15, 7, 11-H), 5.84 (1 H, ddd, J 17, 10, 6, 2-H) and 6.04 (I H, d, J 15, 10-H); 6, 175.55, 139.18, 136.46, 135.37, 135.18, 128.35, 124.94, 124.36, 116.0, 99.26, 73.78, 70.88, 69.05, 60.82, 50.9, 34.23, 33.28, 31.40, 30.50, 28.14, 26.44, 20.03, 18.5, 16.18, 14.79, 13.97, 13.13 and -4.76; mi-7 (FAB) 519 (M+ -15,273and 477 (M' -57,8).(3SR,4RS,6SR)-3-[(2'E,4'E,8'E)-lO'-(tert-Bu tyldimethyl-silyloxy)-3',9'-dimethyldeca-2',4',8'-trienyl J -4hydroxy-3-methyl-6-vinyltetrahydropyran-2-one45 Aqueous sodium hydroxide (0.5 mol dm-,; 0.572 cm3) was added to a solution of the dihydroxy ester 41 (120 mg, 0.243 (1 H, dd, J 16,7, l'-H'), 3.95 (1 H, m, 4-H), 4.0 (2 H, s, 10'-H,), 5.18(1 H,t, J8,6-H),5.21(1 H,d,J10.5,2"-H),5.35(1 H,d, J17, 2"-H'), 5.4-5.55 (2 H, m, 2'-H and 8'-H), 5.62 (1 H, dt, J 15, 6, 5'-H), 5.89(1 H,ddd, J17, 10.5, 6, 1"-H)and6.09(1 H,d, J15, 4'-H); m/z(CI) 466 (M' + NH,, 3379, 449 (7), 352 (15), 335 (49) and 319 (50).(3SR,6SR)-3-[(2'E,4'E,8'E)- 10'-tert-( Butyldimethylsil y loxy)-3',9'-dimethyldeca-2',4',8'-trienyl] -3-methyl-Gvinyltetrahydro-pyran-2,4-dione47 The hydroxy lactone 45(30 mg, 0.067 mmol) was oxidised using tetrapropylammonium perruthenate and N-methylmorpholine N-oxide following the procedure outlined above for the synthesis of 12,to give the title compound 47 (23 mg, 77%) (Found: M+ 4-NH,, 464.3186.C26H46N04Si requires M, 464.3196); vmaX/cm-'1756, 1723, 1456, 1376, 1254, 1116, 1086, 965,938, 838 and 777; 6,0.09 [6 H, s, Si(CH,),], 0.92 [9 H, s, SiC(CH,),], 1.51 (3 H, s, 3-CH3), 1.62 (3 H, s, 9'-CH,), 1.73 (3 H, s, 3'-CH,), 2.13 (4 H, m, 6'-H2 and 7'-H,), 2.54 (1 H, dd, J 16, 10, 5-H), 2.8 (3 H, m, 5-H' and 1'-H,), 4.05 (2 H, s, 10'-H2), 5.0 (1 H, m, 6-H), 5.18 (1 H, t, J 7, 2'-H), 5.38 (1 H, d, J 10, 2"-H), 5.4 (1 H, m, 8'-H), 5.45 (1 H, d, J 16, 2"-H'), 5.63 (I H, dt, J 15, 6, 5'-H), 5.92 (1 H, ddd, J 16, 10, 6, 1"-H) and 6.0 (1 H, d, J 15, 4'-H); mi=(CI) 464 (M' + NH,, 2073, 447 (2) and 315 (64).(3RS,6SR)-3-[(2'E,4'E,8'E)-lO'-(ter~-ButyIdimethy lsilyloxy)-3',9'-dimethyldeca-2',4',8'-trienyl J -3-methyl-6-vinyltetrahydro-pyran-2,4dione48 The hydroxy lactone 46 was oxidised using tetrapropylammo- nium perruthenate and N-methylmorpholine N-oxide as outlined above for the synthesis of 12,to give the title compound 48 (69%) (Found: M+ + NH,, 464.3188. C26H,,No4Si requires M, 464.3 196); vmax/cm-'1752, 1719, 1462, 1374, 1308, 1251, 1072, 964, 938, 838 and 776; 6, 0.1 [6 H, s, Si(CH,),], 0.95 [9 H, s, SiC(CH,),], 1.46 (3 H, s, 3-CH3), 1.62 (3 H, S, 9'-CH,), 1.72(3 H, s, 3'-CH,), 2.17 (4 H,m, 6'-H2 and 7'-H,), 2.65-2.9 (4 H, m, 5-H, and 1'-H,), 4.04 (2 H, s, 10'-H,), 5.05 (1 H,m,6-H), 5.26(1 H, t, J8,2'-H), 5.38(1 H,d, J11,2"-H), 5.41 (1 H, m, 8'-H), 5.43 (1 H, d, J 17,2"-H'), 5.7 (1 H, dt, J 16, 6, 5'-H), 5.92(1 H, ddd, J17, 11, 5.5, 1"-H), 6.06(1 H, d, J16, 4'-H); rn/z (CI) 464 (M+ + NH,, 873,389 (3) and 315 (28).(3RS,5RS,6SR,SE,lOE,14E)-and (3RS,5RS,6RS,SE,1OE,14E)-16-(tert-Butyldimethylsilyloxy)-6-ethoxycarbonyl-3,5-ispropylidenedioxy-6,9,15-trimethyl-hexadeca-8,10,14-trien-l-o149and 53 9-Borabicyclononane (0.5mol dmP3 in tetrahydrofuran; 0.73 cm3, 0.38 mmol) was added dropwise over a period of 50 min to a solution of the alkene 43 (135 mg, 0.253 mmol) in the minimum amount of tetrahydrofuran at 30 "C and the mixture heated under reflux for 3 h. Water (0.62 cm3) was added dropwise at room temperature to the mixture which was then stirred for 10 min.After being cooled to 0 "C, the mixture was treated with aqueous sodium hydroxide (3 mol dmP3; 0.65 cm3) and aqueous hydrogen peroxide (30%; 0.65 cm3), and then stirred at 50 "C for 1 h. After this, water (3.2 cm3) was added at room temperature to the mixture and the aqueous and organic phases were separated; the latter was then extracted with ether (3 x 5 cm3). The combined extracts were washed with brine (2 x 2 cm3), dried (MgSO,) and evaporated under reduced pressure. Flash column chromatography of the residue with light petroleum-ether (40:60) as eluent gave the (3RS,5RS,6SR,8E,1OE,14E)-diastereoisomerof the title corn-pound 49 (1 19 mg, 81%) as a colourless oil; v,,,/cm-' 3462, 1724, 1472, 1463, 1381, 1252, 1201, 1166, 1108, 964, 838 and 776; BH0.08 [6 H, S, Si(CH,),], 0.91 [9 H, S, SiC(CH,),], 1.13 (3 H, s, 6-CH3), 1.23 (3 H, t, J7,0CH,CH3), 1.3-1.45 (2 H, m, 4- H,), 1.36 and 1.43 (each 3 H, s, H,CCCH,), 1.59 (3 H, s, 15-CH,), 1.69 (3 H, s, 9-CH3), 1.69 (2 H, m, 2-H,), 2.12 (4 H, m, 12-H, and 13-H,), 2.39 and 2.49 (each 1 H, dd, J 14.5,7.5,7-H), 2.56 (1 H, br s, OH), 3.76 (2 H, m, 1-H,), 4.0 (2 H, s, 16-H2), 4.09 (2 H, m, 3-H and 5-H), 4.12 (2 H, q, J 7,OCH,CH,), 5.26 J.CHEM. SOC. PERKIN TRANS. 1 1995 of alcohol 49(1 10 mg, 0.2 mmol) in dichloromethane (2 cm3) at 0 "C. After 1 h, the reaction mixture was filtered through a pad of Celite which was then washed with dichloromethane. The filtrate was concentrated under reduced pressure and quickly chromatographed on silica with ether-light petroleum (85 :15) as eluent to give the (3SR,5RS,6SR,8E,lOE, 14E)-diastereo- isomer of the titlecompound50 (80 mg, 73%) as an oil; vmax/cm-l 1729, 1463, 1381, 1255, 1201, 1108, 964, 838 and 776; ~5~0.06 [6 H, s, Si(CH,),], 0.9 [9 H, s, SiC(CH,),], 1.1 (3 H, s, 6-CH3), 1.24(3H,t, J7,OCH,CH,), 1.33(3H,s,H,CCCH,), 1.4(2H, m, 4-H2), 1.44 (3 H, s, H,CCCH,), 1.6 (3 H, s, 15-CH3), 1.7 (3 H, s, 9-CH,), 2.12 (4 H, m, 12-H, and 13-H,), 2.3-2.7 (4 H, m, 2-H, and 7-H,), 4.0 (2 H, s, 16-H,), 4.1 (3 H, q, J7, OCH,CH, overlapping 5-H), 4.4 (1 H, m, 3-H), 5.26 (1 H, t, J 8,8-H), 5.4 (1 H, m, 14-H), 5.56 (1 H, dt, J 15,7, 11-H), 6.06 (1 H, d, J 15, 10-H) and 9.75 (1 H, t, J 1.5, CHO); 6c 201.41, 175.36, 136.28, 135.47, 135.18, 128.22, 125.57, 124.40, 99.55, 72.47, 69.07, 65.27, 60.98, 50.57, 50.31, 35.28, 33.30, 31.95, 30.43, 28.20, 26.45,20.06, 18.6, 16.81, 14.65, 13.97, 13.15 and -4.75.The (3SR,5RS,6RS,8E, 1OE,14E)-diastereoisomer of the title compound 54 was similarly prepared; vmaX/cm-' 1729, 1463, 1381, 1255,1202,1110,1069,964,838 and 777; 6,0.08 [6 H, s, Si(CH,),], 0.9 [9 H, s, SiC(CH,),], 1.1 (3 H, s, 6-CH3), 1.22 (3 H, t, J 7, OCH,CH,), 1.3 (3 H, s, H,CCCH,), 1.4 (2 H, m, 4-H,), 1.42(3H,s,H,CCCH,), 1.58(3H,s, 15-CH,), 1.68(3H, s, 9-CH3), 2.12 (4 H, m, 12-H, and 13-H,), 2.1-2.7 (4 H, m), 4.0 (2 H, s, 16-H2), 4.024.22 (3 H, m, OCH,CH, and 5-H), 4.4 (1 H, m, 3-H), 5.23 (1 H, t, J8, 8-H), 5.38 (1 H, m, 14-H), 5.55 (1 H,dt,J15,7, 11-H),6.04(1 H,d, J15, 10-H)and9.77(1 H, t, J 2, 1-H).(4SR,6RS,7SR,9E,llE,15Eand (4SR,6RS,7RS,9E,11E,15E)-17-(tert- Butyldimethylsily1oxy)- 1-dimethylphosphinoyl-7-ethoxycarbonyl-4, dioxy-7,10,16-trimethylheptadeca-9,11,15-trien-2-ol51and 55 Butyllithium (1.6 mol dm-, in hexane; 0.403 cm3, 0.65 mmol) was added to a solution of dimethyl methylphosphonate (0.068 cm3, 0.63 mmol) in tetrahydrofuran (2.5 cm3)at -78 "C. The mixture was stirred at -78 "C for 1 h after which a cooled H) and 6.05 (1 H, d, J 15, 10-H); 6, 175.48, 136.24, 135.49, 135.16, 128.17, 125.67, 124.41,99.37,72.58,70.08,69.07,61.49, 60.94, 50.6, 38.56, 35.30, 33.29, 31.98, 30.6,28.19, 26.41,20.19, 18.5, 16.75, 14.74, 13.97, 13.14 and -4.76; m/z(CI) 570 (M' + NH,, l%), 537 (M' -15,3) and 495 (M' -57, 100).The (3RS,5 RS,6RS,8E, 10E, 14E)-diastereoisomer of the title compound 53 was similarly prepared; vmaX/cm-' 3457, 1724, 1463, 1381, 1255,1202,1109,964,838 and 777; ~3~0.07 [6 H, s, Si(CH,),], 0.89 [9 H, s, SiC(CH,),], 1.1 (3 H, s, 6-CH3), 1.2 (3H,t, J7,OCH,CH3), 1.31 (3H,s,H,CCCH,), 1.33-1.43(2H, m, 4-H,), 1.4 (3 H, s, H,CCCH,), 1.57 (3 H, s, 15-CH3), 1.67 (3 H, s, 9-CH3), 1.67-1.77 (2 H, m, 2-H,), 2.06 (1 H, br s, OH), 11-(1 H,t,J7.5,8-H),5.39(1H,m,14-H),5.57(1H,dt,J15,7,(-78 "C) solution of aldehyde 50 (289 mg, 0.525 mmol) in tetrahydrofuran (2.5 cm3) was added to it. The resulting mixture was stirred at -78 "C for 1 h, after which it was treated with saturated aqueous ammonium chloride (2.5 cm3) and allowed to warm to room temperature.The organic and aqueous phases were separated and the latter was extracted with ether (3 x 3 cm3). The combined extracts were dried (MgSO,) and evaporated under reduced pressure, and chromatography of the residue with light petroleum4thyl acetate-methanol (14: 8 :0.8) as eluent gave the (4SR,6RS,7SR,9E, 11E,15E)-diastereoisomer of the title com-pound 51 (272 mg, 77%) as an inseparable mixture of epimers at C(2) (Found: M' -C,H,, 617.3283. C,,H,,O,PSi requires 2.1(4H,m,12-H,and13-H2),2.19and2.37(1H,dd,J14.5,7,M, 617.3275); v,,,/cm-' 3381, 1724, 1463, 1381, 1251, 1039, 7-H),3.76(2H,t,J5,1-H2),3.99(2H,s,16-H2),4.W.2(4H,m, OCH,CH,, 3-H and 5-H), 5.22 (1 H, t, J 7.5,8-H), 5.38 (1 H, m, 14-H), 5.55(1 H,dt, J15,7, 11-H)and6.02(1 H,d, J15, 10-H); 6, 175.5, 136.48, 135.34, 135.18, 128.39, 124.92, 124.35, 99.27, 73.97, 69.95, 69.04, 61.34, 60.85, 50.86, 38.73, 34.21, 33.28, 31.29, 30.52,28.14,26.44,20.08, 18.5, 16.28, 14.79, 13.97, 13.14 and -4.76; m/z (FAB) 537 (M' -15,0.4%) and 495 (M' -C,H,, 2.5). (3SR,5RS,6sR,sE,lOE,14~)-and (3SR,5RS,6RS,SE,1OE,14E)-16-(tert-ButyldimethyIsilyloxy)-6-ethoxycarbonyi-3,5-isopropylidenedioxy-6,9,15-trimethylhexa-deca-S,10,14-trienal50and 54 Pyridinium chlorochromate (104 mg, 0.49 mmol) and powdered 4 A molecular sieves (1 50 mg) were added to a stirred solution 964, 839 and 776; BH 0.02 [6 H, s, Si(CH,),], 0.9 [9 H, s, SiC(CH,),], 1.11 (3 H, s, 7-CH3), 1.22 (3 H, t, J7,OCH2CN,), 1.35 (2 H, m, 5-H,), 1.37 (3 H, s, H,CCCH,), 1.42 and 1.44 (each 1.5 H, s, H,CCCH,), 1.6 (3 H, s, 16-CH3), 1.69 (3 H, s, lo-CH,), 1.88-2.06 (4 H, m, 1-H, and 3-H,), 2.14 (4 H, m, 13-H, and 14-H2), 2.3-2.58 (2 H, m, 8-H2), 3.78 (6 H, d, J 10, OCH,), 4.0 (2 H, S, 17-H,), 4.1 (2 H, q, J7, OCHZCH,), 4.05-4.3 (3 H, m, 2-H, 4-H and 6-H), 5.25 (1 H, t, J 7,9-H), 5.4 (1 H, m, 15-H), 5.57 (1 H, dt, J 15, 7, 12-H) and 6.05 (1 H, d, J 15, 11-H); rn/z (FAB) 697 (M' + 23, lo%), 675 (Mf + 1,5) and 617 (M' -57, 20).The (4SR,6RS,7RS,9E, 11E,15E)-diastereoisomer of the title compound 55 was similarly prepared as a mixture of epimers at C(2); v,,,/cm-' 3392, 1724, 1463, 1381, 1255, 1035, 839 and 777; BH 0.08 [6 H, s, Si(CH,)J, 0.9 [9 H, s, Sic- J.CHEM. SOC. PERKIN TRANS. 1 1995 (CH),),], 1.15 (3 H, S, 7-CH3), 1.26 (3 H, t, J 7, OCHZCH,), 1.36 (3 H, s, H,CCCH3), 1.4 (2 H, m, 5-H,), 1.4 and 1.46 (each 1.5 H, s, H,CCCH,), 1.63 (3 H, s, 16-CH3), 1.72 (3 H, s, 10-CH,), 1.75-2.1 5 (4 H, m, 1-H2 and 3-H,), 2.1 3 (4 H, m, 13-H, and 14-H2), 2.23 and 2.43 (each 1 H, dd, J 14, 7.5, 8-H), 3.79 797 3-H),6.2(1H,d,J15,7-H)and9.3(1H,s, 1-H);dc199(d,J5), 194.43, 174.83, 152.74, 140.04, 136.91, 136.13, 127.35, 126.61, 99.58, 73.26,66.28,60.88, 52.89, 52.77, 50.91, 50.77,42.81 (d, J 131), 35.62, 32.13, 32.08, 30.6, 29.37, 19.97, 17.35, 14.75, 13.32 and 9.69; m/z (FAB) 579 (M' + 23, 1273, 557 (M' + 1,22), (6H,d, J 10,0CH3),4.03(2H,s,17-H2),4.05-4.30(4H,m,2-H,499 (50),481 (49,415 (39) and 305 (50). 4-H and OCH,CH,), 5.27 (1 H, t, J7,9-H), 5.43 (1 H, m, 1 5-H), 5.61 (1 H, dt, 15,6, 12-H) and 6.07 (1 H, d, J 15, 11-H).(4SR,6RS,7SR,9E,1 1E,15E)- and (4SR,6 RS,7RS,9 E,11E,15E)-1-Dimethylphosphinoyl-7-ethoxycarbonyl4,6-ispropylidenedioxy-7,10,16-trimethyl-heptadeca-9,11,15-triene-2,17diol52 and 56 Anhydrous tetrabutylammonium fluoride (1 mol dmP3 in tetrahydrofuran; 0.184 cm3, 0.184 mmol) was added dropwise to a solution of the phosphonate 51 (62 mg, 0.092 mmol) in tetrahydrofuran (1 cm3) and the mixture stirred at room temperature for 2 h. After concentration under reduced pressure, chromatography of the residue with light petroleum- ethyl acetate-methanol (6: 3 :1) as eluent, gave the (4SR,6RS,7SR,9E, 11E,15E)-diastereoisomer of the title com-pound 52 (49 mg, 95%) (Found: M+ + Na, 583.3012.C,,H,,NaO,P requires M, 583.3012); vmax/cm-' 3398, 1723, 1461, 1381, 1200, 1036 and 850; 6, 1.1 (3 H, S, 7-CH,), 1.25 (3 H, t, J7, OCH,CH,), 1.3-1.45 (2 H, m, 5-H,), 1.36 (3 H, s, H,CCCH,), 1.42 and 1.45 (each 1.5 H, s, H,CCCH3), 1.67 (3 H, s, 16-CH,), 1.7 (3 H, s, 10-CH,), 1.7-2.1 (4 H, m, 1-H, and 3-H,), 2.15 (4 H, m, 13-H, and 14-H,), 2.3-2.55 (2 H, m, 8-H2), The (4SR,6RS,7RS,2E,6E,8E)-diastereoisomerof the title compound 57 was similarly prepared (Found: M' + H, 557.2860. C28H4609P requires M, 557.2880); v,,/cm-' 171 9, 1686, 1644, 1463, 1382, 1262, 1202, 1109, 1034, 980, 874 and 810;&1.08(3H,~, 11-CH3), 1.18(3H,t,J7,OCH,CH,), 1.23 and 1.35 (each 3 H, s, H,CCCH,), 1.25-1.5 (2 H, m, 13-H2), 1.64 (3 H, s, 2-CH3), 1.69 (3 H, s, 8-CH3), 2.1-2.45 (6 H, m, 4-H,, 5-H, and 15-H,), 2.63 (1 H, dd, J 17, 5, 10-H), 2.79 (1 H, dd, J 17, 7, 10-H), 3.1 (2