2550 J.C.S. Perkin IProstaglandins. Part 4.l Synthesis of (+I 1 -Deoxyprostaglandinsfrom 2-(o-Hydroxyheptyl)cyclopent-2-enonesBy Trevor S. Burton, Michael P. L. Caton," Edward C. J. Coffee, Trevor Parker, Keith A. J. Stuttle, andG. Leonard Watkins, The Research Laboratories, May & Baker Ltd., Dagenham, Essex R M l O 7XSConjugate nitrile addition to 2-(7-hydroxyheptyl)cyclopent-2-enone ( I I I a ) and subsequent elaboration via thealdehydes [(VIa), (Xa)] affords a convenient direct route to ( * ) - l l -deoxyprostaglandins of the El and F, series.Syntheses of (&)-1 O-methyl- and (f) -a-nor-l1 -deoxyprostaglandins are also described.TERMINALLY substituted 2-alkylcyclopent-2-enones have We have developed a route to I I-deoxyprostaglandinsproved valuable intermediates for the synthesis of based upon nitrile addition to 2-(7-hydroxyheptyl) cyclo-prostaglandins (PGs), since they readily afford the pent-2-enone (IIIa) with subsequent elaboration via theprostanoic acid skeleton by conjugate addition reactions.aldehydes [(VIa), (Xa)] and Wittig coupling.1$2 We31. P. L. Caton, E. C. J. Coffee, and G. L. Watkins, Tetra- Part 3, M. P. L. Caton, E. C.. J. Coffee, and G. L. Watkins,Tetrahedron Lettevs, 1974, 583. hedron Letters, 1973, 7T31976 2551here describe full details of this work and its adaptationto the synthesis of ll-deoxyprostaglandins El, F,,, F1band certain derivatives and analogues.The value of this approach to 1 l-deoxyprostaglandinswas enhanced by our finding that the enone (IIIa) can beprepared by isomerisation of the corresponding hydroxy-alkylidenecyclopentanone (IIa) , which is readily avail-able from the reaction of cyclopentanone morpholineenamine and 7-hydroxyheptanal (Ia) .Hydroxy waschosen as the terminal substituent on the grounds thatthis group does not require protection during thenitrile-to-aldehyde stages, and because it can be oxidisedconveniently to the required carboxylic acid later in thereaction sequence.7-Hydroxyheptanal (Ia) can be made in high yield bycleavage of commercially available aleuritic acid(9,10,16-trihydroxypalmitic acid) with periodate, or, lesssatisfactorily, from 6-hydroxyhexanonitrile by treat-ment with di-isobutylaluminium hydride. The latterreaction was more easily performed on the tetrahydro-pyranyl (Thp) ether; this minimised the formation ofinsoluble intermediates. Both the hydroxy-aldehyde(Ia) and its Thp ether (Ib) afforded the enone (IIIa) inoverall yields of 50-60y0, it being unnecessary toisolate the intermediate exocyclic enone (IIa).Iso-merisation of the double bond [(IIa) + (IIIa)] couldbe effected in various acidic media, but choice of reagentand conditions such that the formation of resinous by-products was minimal, was critical. Satisfactory resultswere obtained by heating with concentrated hydro-chloric acid in butan-1-01 at 90 "C for 2.5 h.The enone (IIIa) was also prepared, as its acetoxy-derivative (IIIb), by bromination of the enol acetateof 2-(7-acetoxyheptyl)cyclopentanone and then dehydro-bromination with base.This procedure, however,involved several steps from commercially availablematerial, and was inferior to the hydroxy-aldehyderoute in overall yield.The reaction of the enone (IIIa) with acetone cyano-hydrin in the presence of base afforded the nitrile (IVa)as a mixture of cis- and tram-isomers. For the synthesisof (3)-ll-deoxy-PGE, the acetal (Va) of this mixturewas converted with di-isobutylaluminium hydride intothe aldehyde (VIa), which was shown by g.1.c. to beessentially a single component. We have assumed thatthe latter has the trans-configuration and that thisdisposition was maintained throughout subsequent stepsto the final products (VIII) The acetoxy-enone(IIIb) could be utilised for the synthesis of the acetal(Va) by converting it via the nitrile (IVb) into theacetoxy-acetal (Vb) and then removing the acetoxy-grOUP.The aldehyde (VIa) underwent some decompositionon distillation and was best carried forward in the crudeform.For the conversion (VIa) (VIb) we nowt Further evidence for these assignments will be presented in aforthcoming paper.111. Miyano, C. R. Dorn, and R. A. Miieller, J . Ovg. Chem.,1972, 37, 1810.prefer to use the sodio-derivative of dimethyl 2-0x0-heptylphosphonate rather than 2-oxoheptylidenetri-phenylphosphorane, as described in our preliminaryreport,l.2 since the latter gives rise to phosphorus-containing by-products which are difficult to eliminate.The resulting enone (VIb) was oxidised to the carboxylicacid (VII) with chromium trioxide and sulphuric acid indimethylformamide a t 0 "C.The synthesis was completed by reduction withborohydride and then acidic hydrolysis.When thereduction was carried out with sodium borohydride inaqueous sodium hydroxide, a substantial amount ofconjugate reduction took place giving rise to the dihydro-compounds (IXa and b) (as estimated from n.m.r. andmass spectra), but this could be largely avoided by usingpotassium borohydride in a citrate buffer at pH 8 as0 H C a [C H 2];C H ,-O R(I)a;r; =5,R=Hb : n =5,R=ThpC; n = A , R =Thp(rnla ; n = 6 . R=Hb ; n = 6 , R=Acc ; n = 5 , R = HCN(PIa ; R = Hb : R = B c8(II1a ; n = 5b ; n =.4a;n =6, R=Hb : n = 6 , R s A cc ; n = 5 . R=Ha ; R = C H O0described by Miyan~.~ Purification of the final productsand separation of (-+)-ll-deoxy-PGE, (VIIIa) from itsC-15 epimer (VIIIb) were effected by column chromato-graphy with ethyl acetate-toluene (1 : 4) as eluant.(-+)-ll-Deoxy-PGE, (VIIIa), the slower moving com-ponent, was recrystallised from ether-light petroleu2552 J.C.S.Perkin I(b.p. 40-60") (its m.p. agreed with literature values).The epimers (VIIIa and b) could also be separated byprepared, if required, by catalytic reduction of theolefins (VIIIa and b) over 5% palladium-charcoal. Wehave been unable to distinguish the C-15 epimers (IXaand b) from each other by chromatography; separationmust therefore be carried out before the hydrogenationstage if single epimers are required.1 l-Deoxyprostaglandins of the F, series were obtained,-,[cH2In.C02H d, [CH2]; C H3f ; R'= OH, R2= /OH - H --.H , n =6,.I [C H 2], . C H i 0 HCHO( X Ia;n=6b: n = 5by borohydride reduction of the E, compounds. Re-duction of (&)-l l-deoxy-PGE, (VIIIa) with potassiumborohydride gave a mixture of (-J-)-ll-deOxy-PGF1, *(VIIIc) and (j-)-ll-deoxy-PGFlp * (VIIId) ; similarly(-~-)-15-efii-l l-deoxy-PGE, (VIIIb) afforded the epimers(VIIIe) * and (VIIIf).* The F1, compounds (VIIIcand e) could be prepared stereospecifically by carryingout these reductions with lithium tri-s-butylborohydride(L-Selectride) .5An alternative route to the FIE compounds wasavailable from reduction by Selectride ' of the dioxo-acid (VIIIg), which afforded a mixture of the C-15epimers (VIIIc and e).Since the dioxo-acid (VIIIg)can be made directly from the nitrile (IVa) by reductionwith di-isobutylaluminium hydride, Wittig elaborationof the resulting aldehyde (Xa), and then oxidation, thisprocedure affords a simple seven-step overall route tothese F, compounds, which avoids the use of protectinggroups.(j-)-or-Nor-l l-deoxyprostaglandins [ e g . (VIIIh)] weresynthesised from the aldehyde (Ic), which was preparedby oxidation of the mono-Thp ether of hexane-l,6-diolwith pyridinium chlorochromate.preparative t .l.c. [ethyl acetate-cyclohexane-formic acid(40 : 40 : 1) ; this system was also useful for a n analyticalt.1.c. check on the purity of the final products, althoughAn- attempt to prepare 10-methyl analogues (XV) ofll-deoxyprostaglandins by first constructing the enone(XI) was complicated by the fact that the latter com-CNIXII) (XIIIIa; R'=EtO.CO.CO, R2=Thpb ; R'=Me, R2=Hit does not distinguish between the olefin (VIIIb) andthe dihydro-compounds (IXa and b) 3.pound, under the acidic reaction conditions, was partiallyisomerised to the enone (XII).However, the 10-methylThe dihydro-compounds (IXa and b,* M.p.s agreed with literature values.be 4 J. F. Bagli and T. Bogri, J . Org. Chem., 1972, 37, 2132.5 C. A. Brown, J . Amer. Chem. SOC., 1973, 95, 41001976 2553derivatives could be prepared unambiguously from theThp ether of the hydroxy-nitrile (IVa), which withdiethyl oxalate and sodium methoxide in benzeneafforded the oxo-ester (XIIIa).The latter on treatmentwith methyl iodide in acetone and then hydrolysis withperchloric acid in ethanol afforded the nitrile (XIIIb) asa mixture of diastereoisomers. Completion of thesynthesis via the aldehyde (XIV) then gave (&)-lo-methyl-1 l-deoxy-PGE, (XVa) and its C-15 epimer(XVb).EXPERIMENTAL7-Hydroxyheptanal (la) .-Aleuritic acid (753 g) wasadded with vigorous stirring to a solution of sodiumhydroxide (99 g) in water (3 1). The resulting turbidsolution was treated with chloroform (3 1) and then sodiumperiodate (634.5 g ) was added in portions a t 35-40 "Cduring 10 min. The mixture was stirred for another 15min with cooling to 20 "C, then filtered, and the filter cakewas washed with chloroform (300 ml).The aqueous layerwas extracted with chloroform (3 x 300 ml) and the com-bined chloroform washings and extracts were stirred for 1.25h with a mixture of saturated aqueous sodium hydrogencarbonate (1.2 1) and sodium carbonate (0.9 1). The chloro-form layer was evaporated in uacuo below 40 "C to give7-hydroxyheptanal as a viscous oil which slowly crystallised.A second crop was obtained by further extraction withchloroform (3 x 300 ml) of the carbonate washing; totalyield 271 g (89%); m.p. 65-67" (lit.,s 71') (Found: C,64.2; H, 10.6. Calc. for C,H1402: C, 64.6; H, 10.8%).7- (Tetralzydro~yran-2-yloxy) heptanal (Ib) .-Dihydro-pyran (2 1 g) was added dropwise with stirring to 6-hydroxy-hexanonitrile 7 (1 9.1 g) and concentrated hydrochloric acid(0.5 ml) a t 40 "C.The temperature was allowed t o rise t o65 "C, and maintained a t that level for 2 h, and then a t80 "C for a further 20 min. The cold mixture was extractedwith benzene and the organic layer washed successively withsaturated aqueous sodium hydrogen carbonate and brine,dried (Na,SO,), and distilled t o give the Thp ether (20.9 g,66O,/!o), b.p. 116-119" a t 0.1 mmHg, vmx. 1 040, 1 080,1 120, 1 140, and 2 230 cm-l.Di-isobutylaluminium hydride (19.35 g ) in dry benzene(50 ml) was added dropwise to a stirred solution of theThp ether (20.6 g) in dry ether (200 ml) a t 15-20 "C.Stirring was continued (at 15-20 "C) for 20 min and themixture was added to ice-cold 2~-sulphuric acid (300 ml)and stirred for 45 min.The mixture was then heated at30 "C for 0.5 h, saturated with sodium chloride, and ex-tracted with ether, and the extracts were washed withaqueous sodium hydrogen carbonate and brine, dried(Na,SO,), and distilled to give the aldehyde (Ib) (12.75 g,66%), b.p. 78-106" a t 0.1 mmHg, v,, 1040, 1080, 1 120,1140, 1710, and 2 700 cm-l (Found: C, 67.0; H, 10.2.C,,H,,O, requires C, 67.3; H, 10.3%).6- (Tetrahydropyran-2-yloxy) hexanal (Ic) .-To a stirredsuspension of pyridinium chlorochromate (60 g) andanhydrous sodium acetate (5.3 g) in dry dichloromethane(100 ml) was added 6-(tetrahydropyran-2-yloxy)hexanol*$ B.p. 130-150" at 0.02 mmHg; prepared as for the corres-ponding 6-bromopentyl compound by the method of R. Mayer,G.Wenschuh, and W. Topelmann, Chem. B e y . , 1958, 91, 1616.J. Colonge, L. Cottier, and G. Descotes, Compt. rend., 1969,268C, 1155.(50 g ) in dry dichloromethane (50 ml), dropwise over 5 min.After 2 h ether (100 ml) was added and the supernatantwas decanted from the black residue. The residue wasthoroughly washed with ether (3 x 100 ml) and the com-bined organic solutions were filtered through Hyflo Supercel,washed with water, dried (MgSO,), and evaporated. Thecrude product was purified by column chromatography onKieselgel 60 (500 g; Merck) (eluant ether-ethyl acetate-n-hexane, 3 : 1 : 1) to give the aldehyde (Ic) (26.25 g,52.4%), v,, 1040, 1080, 1 120, 1140, 1730, and 2 738cm-1 (Found: C, 65.6; H, 10.4. C,,H,,O, requires C,66.0; H, 10.1%).2- (7-Hydroxyhe~tyZ)cycZo~ent-2-enone (IIIa) .-7-Hydroxy-heptanal (Ia) (390 g) and the morpholine enamine of cyclo-pentanone (598 g ) in cyclohexane (750 ml) were heatedunder reflux in an atmosphere of nitrogen, the waterformed being continuously removed with a Dean-Starkapparatus.When separation of water was complete (4 h),the solution was treated a t 30-40 "C over 15 min with amixture of concentrated hydrochloric acid (375 ml) andwater (375 ml). Toluene (375 ml) was added, the mixturewas stirred for 1.5 h, and the two (upper) organic layerswere separated from the (lower) aqueous layer. Thelatter was extracted with toluene (2 x 375 ml) and thecombined organic layers were evaporated. The residuewas treated with butan-1-01 (9.9 1) and concentrated hydro-chloric acid (240 ml) and heated a t 90 "C with stirringunder nitrogen for 5 h.The cooled mixture was treatedwith sodium hydrogen carbonate (305 g), filtered, anddistilled t o give the enone (IIIa) (340 g, 58%), b.p. 149-155" at 0.1 mmHg; the sample for analysis had b.p. 160-162" a t 0.3 mmHg (Found: C, 72.8; H, 10.7. C1,H,,O,requires C, 73.4; H, 10.3%). Am= (EtOH) 227 nm (E 9 800),vmx: 1 630, 1 695, and 3 440 cm-1.Similarly the Thp ether (Ib) (23.2 g) gave this enone(IIIa) (10.7 g, 50%). and the Thp ether (Ic) (15 g) gave theenone (IIIc) (4.1 g, 30y0), b.p. 118-122" a t 0.08 mmHg,Amx. (EtOH) 228 nm (E 9 030), vma, 1630, 1700, and3450 cm-l (Found: C, 72.0; H, 10.0. Cl1H,,O2 requiresC, 72.5; H, 10.Oyo).2-( 7-A cetoxyhepty1)cycloPentanone.- 2-( 7-Bromohepty1)-cyclopentanone (1 80 g) ,I potassium acetate (1 45 g), glacialacetic acid (6 ml), and ethanol (396 ml) were heated underreflux for 24 h.The ice-cooled mixture was filtered andevaporated and the residue was extracted with ether. Theextract was washed with water, dried (MgSO,), and distilledto give 2-(7-acetoxyhe~tyZ)cycZo~entanone (130 g, 79y0), b.p.125-130" a t 0.05 mmHg, vmax. 1040, 1 155, 1240, 1370,and 1740 cm-l (Found: C, 69.3; H, 10.2. C,,H,,O,requires C, 70.0; H, 10.1%).Enol Acetate of 2-(7-Acetoxyheptyl)cyc2opentanone.-2- (7-Acetoxyhepty1)cyclopentanone ( 133 g) , isopropenyl acetate(215 g), and toluene-p-sulphonic acid (2.8 g) were heatedunder reflux for 24 h while the acetone formed was allowedto distil off slowly.The excess of isopropenyl acetate wasthen removed in Z~UCUO, the residue was dissolved in di-chloromethane (500 ml), and the solution was washed withaqueous sodium hydrogen carbonate and water, dried(Na,SO,), and distilled to give the enol acetate (144 g, 92y0),b.p. 145-150" a t 0.2 mmHg, v,,,. 1175, 1210, 1235,1 685, and 1 725 cm-l (Found: C, 67.9; H, 9.4. C,,H,,O,requires C, 68.1; H, 9.3%).R. A. Smiley and C. Arnold, J . Org. Chem., 1960, 25, 257. * F. Bohlmann, R. Jeute, and R. Reinecke, Chem. Ber., 1969,102, 3283J.C.S. Perkin I2- (7-AcetoxyheptyZ)cyclopent-2-enone (IIIb) .-To a vigor-ously stirred solution of the above enol acetate (193 g) indry carbon tetrachloride (1.62 1) below -10 "C was added,dropwise, bromine (37.5 ml) in carbon tetrachloride (400ml).The mixture was stirred, without cooling, for 1 11,washed successively with aqueous sodium disulphite andaqueous sodium carbonate, dried (MgSO,), and evaporatedin vacuo (acetone-solid CO,). A solution of potassiumcarbonate (740 g) in water (1.04 1) was added to the residueand the mixture was stirred for 36 h ; more potassiumcarbonate (760 g) was then added and the stirring continuedfor a further 24 h. The mixture was extracted with ether,dried (Na,SO,), and distilled to give the enone (IIIb) (91 g,56%), b.p. 140-155" a t 0.1 mmHg, v,,, 1 240, 1 630,1695, and 1 730 cm-1. A sample was purified by t.1.c. onsilica gel (ether-ethyl acetate-n-hexane, 3 : 1 : 1) (Found :C , 70.6; H, 9.3.C1&,03 requires C, 70.6; H, 9.3%)2- (7-Hydroxyheptyl)-3-oxocycZopentanecarboni€riZe (IVa) .-The enone (IIIa) (30 g), acetone cyanohydrin (15.1 g),aqueous 6% sodium carbonate (30 ml), and methanol(89 ml) were heated under reflux with stirring for 5 11.Methanol was removed in vacuo, water (12 ml) was added,and the mixture was extracted with ether. The extractswere dried (MgSO,) and distilled t o give the nitrile (IVa)(28 g, 82yo), b.p. 175-195" a t 0.05 mmHg, vmax 1735,2 240, and 3 450 cm-l; the sample for analysis had b.p.202-208" a t 0.6-0.7 mmHg (Found: C , 69.9; H, 9.7;N, 5.9. C13H,1N0, requires C, 69.9; H, 9.5; N, 6.3%).Similarly the enone (IIIc) (10.5 g) afforded the nitrile(IVc) t (8.26 g, 68%), b.p. 135-178" a t 0.15 mmHg, vmx.1 730, 2 230, and 3 400 cm-l, and the enone (IIIb) (110 g)gave the nitrile * (In) (83 g, 68%), b.p.160-195" a t0.1-0.15 mmHg, vmaZ 1 245, 1 730, and 2 240 cm-l.6-( 7-Hydroxyheptyl) - 1,4-dioxaspiro [4.4]nonaute- 7-carbo-nitrile (Va).-Method A . The nitrile (IVa) (20 g), ethyleneglycol (5.6 g), toluene-p-sulphonic acid (1 g), and benzene(160 ml) were heated under reflux for 3.5 h with continuousremoval of water. The cold mixture was shaken with anexcess of anhydrous sodium carbonate, filtered, anddistilled to give the acetal (Va) (19.3 g, 80.6yo), b.p. 166-182" a t 0.1 mmHg, vmX 950, 2 240, and 3 450 cm-l; thesample for analysis had b.p. 177-179" a t 0.1 mmHg(Found: C , 67.1; H, 9.2; N, 4.9. C,,H,,N03 requires C,67.4; H, 9.4; N, 5.2%).Method B.By method A, the oxo-nitrile (IVb) (53 g)gave the acetal (Vb) t (38.2 g, 62%), b.p. 170-186" a t0.15 mmHg, vmX 950, 1 240, 1 730, and 2 250 cm-l. Com-pounds (Vb) (36.1 g ) in methanol (200 ml) were treated withstirring a t 10-20 "C with a solution of sodium borohydride(5.3 g) in aqueous 0.2n.-sodium hydroxide (70 ml). Stirringwas continued for a further 2 h, methanol was removedin vacuo, water (50 ml) was added, and the mixture wasextracted with ether. The extracts were dried (MgSO,)and distilled to give the acetal (Va) (29.7 g, 94y0), identi-fied by g.1.c. comparison with a sample prepared bymethod A.1-( 6- (7-Hydroxy1zej~tyZ)- lI4-dioxasPiro [4.4]nonan- 7-yZ)oct-l-en-3-one (VIb) .-A solution of di-isobutylaluminiumhydride (49 g) in dry benzene (135 ml) was added, withrapid stirring, to the acetal nitrile (Va) (40 g) in dry ether(400 ml) a t 0 "C.After 15 min the mixture was addedcautiously, with stirring, to aqueous 2~-acetic acid (900 ml)* Not obtained analytically pure.9 F. S . Alvarez and D. Wren, Tetrahedron Letters, 1973, 569.a t 0 "C. The organic phase was separated and the aqueousphase was extracted with ether. The combined organiclayers were washed with aqueous sodium hydrogencarbonate, dried (Na,SO,), and evaporated to give the crudealdehyde (VIa) (40 g, 89yo), vmsx. 1 715, 2 750, and 3 450~ i i i - ~ , suitable for the next stage.Dimethyl (2-oxoheptyl)phosplionate (16.7 g ; Aldrich) indry tetrahydrofuran (50 ml) was added, dropwise, t o astirred suspension of sodium hydride (1.9 g) in tetrahydro-furan (300 ml) under nitrogen.The mixture was stirredfor 16 h and then treated dropwise with the aldehyde (VIa)(20.3 g) in tetrahydrofuran (100 ml) and stirred for afurther 4 h under nitrogen. The mixture was filtered andthe filtrate was evaporated in uacuo. The residue wasextracted with ether and the extract washed with waterand dried (MgSO,) to give the crude enone (VIb) (27.2 g,99%). A sample was purified on silica gel plates (ether-ethyl acetate-n-hexane, 3 : 1 : 1); A,,,. (EtOH) 230 nm(E 15 500); vmx. 950, 990, 1 045, 1 630, 1 670, and 3 470cm-l (Found: C, 71.7; H, 10.8. C,,H3@4 requires C ,72.1; H, 10.4%).(&)-l l-Deoxy-PGE, (VIIIa) and (rf)-ll-Deoxy-15-epi-PGE, (VIIIb).-Chromium trioxide (15 g; dried iut zlacuoover silica gel) was added in portions to a stirred solutionof the enone (VIb) (13.7 g) in dry dimethylformaniide(200 ml) a t 3-10 "C.Concentrated sulphuric acid (5 ml)in dry dimethylformamide (100 ml) was added below 10 "Cand the solution was stirred for 1.5 11. Ether (200 ml) andwater (100 ml) were then added; the organic layer wasseparated and the aqueous layer was extracted with ether.The combined ether layers were washed with water andextracted into 2~-sodium carbonate (75 ml). The lattersolution was washed with ether, and then covered with alayer of ether and acidified to pH 4 with concentratedhydrochloric acid. The ethereal layer was separated, theaqueous layer was extracted with ether, and the combinedethereal extracts were dried (MgSO,) and evaporated t ogive the crude enone acid (VII) (8.9 g), vmx.945, 985,1630, 1 665, and 1 710 cm-l. A 2% aqueous solution ofsodium citrate (750 ml) was added t o the foregoing product(8.9 g) in methanol (75 ml) a t -5 "C. Potassium boro-hydride (18.9 g) was then added in portions with stirring,pH 8 being maintained by addition, when required, ofaqueous 10% citric acid. The solution was stirred foranother 1.5 h, enough acetone was added to destroy theexcess of borohydride, the pH was adjusted to 4 withcitric acid, and the mixture was extracted with ether andevaporated. The residue was stirred a t 55 "C with N-hydrochoric acid for 4 h and extracted with ether. Thework-up was completed by extraction into aqueous 10%sodium carbonate followed by acidification with hydro-chloric acid, extraction with ether, and drying (MgSO,) togive the products (VIIIa and b) (7.6 g), of which a sample(4 g) was chromatographed on a silica column (ICieselgel60; Merck) (ethyl acetate-toluene, 1 : 4) to give (f)-15-epi-ll-deoxy-PGE, (1.35 g) (VIIIb) (faster-moving com-ponent) and (f)-ll-deoxy-PGE, (VIIIa) (0.9 g) as oils.The latter crystallised from ether-light petroleum (b.p.40-60') to give white needles (0.6 g), n1.p.85-86O ( l i t . , O82.5-85"). The epi-compound crystallised only withdifficulty; a sample was recrystallised (3 X ) from ether-light petroleum (b.p. 40-60"); m.p. 5&51" (lit.,g 53-56O).9,15-Dioxoprost- 13-enoic Acid (VIIIg) .-(A) Di-isobutyl-aluminium hydride (40 g) in dry benzene (350 i d ) wasadded with rapid stirring to the nitrile (IVa) (20 g) in dr1976 2555ether (350 ml) at 5-15 "C.The solution was stirred for1 h at room temperature and added to aqueous 2~-aceticacid (400 ml), and the work-up was completed as in thepreparation of the aldehyde (VIa) to give the crude aldehyde(Xa) (18.3 g, 88%), vmx. 1 710, 2 720, and 3 400 cm-1. Thealdehyde ( 18.3 g) and 2-oxoheptylidenetriphenylphos-phorane 2 (32 g) in dry tetrahydrofuran (165 ml) washeated under reflux for 17 h. The solution was evaporatedin VUGUO and the residue was agitated with light petroleum(b.p. 40-60 "C) until the triphenylphosphine oxide hadcrystallised out, The mixture was filtered and evaporatedto give the crude enone (27 g), v- 980, 1 620, 1 665, and3 400 cm-l.Jones reagent (8N; 13.5 ml) was added dropwise to astirred solution of the enone (10 g) in acetone (66 ml) a t15-25 "C a t a rate such that the initial red colour hadchanged to green before the next addition.The mixturewas diluted with water and extracted with ether (2 x ), andthe combined extracts were washed with 2~-sulphuric acid.Work-up was completed by extraction with base as for(VIIIa and b) to give the dioxo-acid (VIIIg) (4.7 g). Asample was subjected to preparative t.1.c. on silica gel(benzene-dioxan-acetic acid, 65 : 15 : 1) (Found: C, 70.9;H, 9.5. C20H3204 requires C, 71.4; H, 9.6y0), &= (EtOH)228 nm ( E 12 loo), vmz 990, 1630, 1670, 1700, and 1735cm-1, 6 (CDC1,) 9.6 (s, CO,H), 6.8 (2d, J 16 and 7.5 Hz,CE-I-CHC=O), 6.17 (d, J 16 Hz, CH%H*C=O), and 0.9(t, J 5 Hz, CH2CH,).(B) The crude acid (VII) [from (VIb) (3.66 g)] on stirringwith N-hydrochloric acid (50 ml) at 55 "C for 2 h and work-up gave the dioxo-acid (VIIIg) (2.56 8).As for ( A ) above,the nitrile (IVc) (8.8 g) gave the aldehyde (Xb) (8.6 g),vmS. 1 710, 2 700, and 3 400 cm-l, and then the enone,vmak 1620 and 1660 cm-l, and the dioxo-acid (VIIIh)(4.62 g) (Found: C , T0.4; H, 9.3. C,,H,,O, requires C,70.8; H, 9.4%), A,, (EtOH) 228 nm ( E 13 200), vmz1 625, 1 670, 1 700, and 1 730 cm-1.(&)-1 1-Dsoxy-PGF,, aad Epimers (VIIIc-f).-(a) 11-Deoxy-PGE, (VIIIa) (0.34 g) reduced with potassiumborohydride (0.81 g) in aqueous 2% sodium citrate (50 ml),under the conditions used for the enone acid (VII), gave amixture of the epimers (VIIIc and d) (0.34 g).Separationby t .l.c. on silica gel (ethyl acetate-cyclohexane-formicacid, 40 : PO : 1) and then recrystallisations from ether-lightpetroleum (b.p. 40-60 "C) gave ( f)-11-deoxy-PGF,,(VIIIc) (faster-moving band), m.p. 96-96' (lit.,g 97-98.5"), and ( -J-)-ll-deoxy-PGFIB (VIIId),Q m.p. 67-68'(lit.,Q 69-70.5").Similarly (f)-15-epi-11-deoxy-PGE1 (VIIIb) (0.51 g)gave the epimer mixture (VIIIe and f ) (0.52 g), whichafforded ( &)-15-e$i-ll-deoxy-PGFla (VIIIe),9 m.p. 102-104" (lit.,, 102-103.5"), and ( f)-15-epi-ll-deoxy-PGFl~(VIIIf),g m.p. 58-60' (lit.,, 59-60.5').(b) (&)-11-Deoxy-PGE, (VIIIa) (0.34 g) was added to a1M-solution of ' L-Selectride ' in tetrahydrofuran (2 nil) a t-78 "C and the mixture stirred a t this temperature for0.5 h and then a t room temperature for 2.5 h.Aqueous3~-sodium hydroxide (1.5 ml) and 30% hydrogen peroxide(1 ml) were added a t 0 "C; the mixture was stirred for0.5 h, washed with ether, acidified to pH 1 with 2~-hydro-chloric acid, and extracted with ether. The extract wasdried (MgSO,) and the crude product was recrystallisedlo R. G. Curtis, Sir Ian Heilbron, E. R. H. Jones, and G. F.Woods, J . Chem. Soc., 1953, 457.(3 x ) as in (a), to give (f)-ll-deoxy-PGF1, (VIIIc)(0.13 g), m.p. 95-97'. Similarly (f)-15-epi-11-deoxy-PGE, (VIIIb) (0.34 g) gave (f)-15-e$i-l l-deoxy-PGF1,(VIIIe) (0.17 g), m.p. 102-104".(c) Under the reaction conditions described in (b), thedioxo-acid (VIIIg) (0.84 g) gave the epimer mixture(VIIIc and e) (0.85 g) ; separation of a sample (0.5 g) as in(a) afforded (&)-ll-deoxy-PGF,, (VIIIc) (60 mg), m.p.94-96', and the lbepimer (VIIIe) (90 mg), m.p.104-105'.(f)-13,14-Dihydro-ll-deoxy-PGE, (IXa) .-( -J-)-ll-De-oxy-PGE, (VIIIa) (0.1 g) in ethanol (25 ml) was hydrogen-ated a t 70 lb in-2 over 5% palladium-charcoal and chro-rnatographed as in (a) above to give the dihydro-compound(IXa) 4 (40 mg) as an oil, vma= 1 710, 1 740, and 3 460 cni-l.Similarly the 15-epimer (VIIIb) (0.1 g) gave the dihydro-compound (IXb) (30 mg) .nitrile (XIIIb) .-Dihydropyran (73 g) was added dropwisewith stirring at 40 "C to the nitrile (IVa) (10 g) and con-centrated hydrochloric acid (4 drops).The temperaturewas allowed to rise to 65 "C and held a t that level for 1 h.Benzene (50 ml) was added and the cooled solution waswashed with aqueous sodium hydrogen carbonate andwater, dried (MgSO,), and evaporated t o give the crudeThp ether (15 g), v,, 1 040, 1 080, 1 120, 1 140, 1 740, and2 230 cm-l. To an ice-cold solution of the latter (15 g) anddiethyl oxalate (15.9 g) in dry benzene (110 nil) was addedsodium methoxide (5.9 g), and the mixture was set aside atroom temperature for 24 h. Ice-water was added and theorganic layer was separated. The aqueous layer waswashed with benzene and then added to aqueous 30%sodium dihydrogen phosphate (150 ml) at 0 "C. Theorganic layers were extracted with ice-cold aqueous 4%sodium hydroxide and the alkaline extracts were added tothe sodium dihydrogen phosphate solution which was thenstirred at 0 'C for 15 min and extracted with ether.Thecombined extracts were washed with water, dried (MgSO,),and evaporated to give the crude ethoxalyl compound(XIIIa) (11.2 g), vmX. 1 605, 1 670, and 1 720 cm-l. Asolution of the latter, anhydrous potassium carbonate(22 g), and methyl iodide (67 ml) in acetone (450 ml) wasstirred and heated under reflux for 22 h. The cold mixturewas filtered, the solvent was removed in vacuo, and theresidue was treated with water and extracted with ether.The combined extracts were washed successively with2~-sodium hydroxide and water, and then evaporated.Aqueous 60% perchloric acid (6 drops) was added to theresidue (8.4 g) in ethanol (35 ml) and the solution was setaside for 24 h. Chloroform was added and the solutionwas washed with aqueous 2~-sodium carbonate, and thenwith brine, and dried (hTa,SO,). Distillation at 140-200 "C and 0.15 mmHg gave a diastereoisomeric mixture ofnitriles (XIIIb) (3.5 g), vmax. 1455, 1465, 1 730, 2 230, and3 450 cm-l (Found: C, 70.2; H, 10.0; N, 5.4. C,,H,,NO,requires C, 70.8; H, 9.8; N, 5.9%).(&)-1 l-Deo,~y-lO-PPzelhyLPGE, and (-+)-1 l-Deoxy-10-methyZ-15-epi-PGEl (XVa and b).-By the method used toconvert the nitrile (IVa) into the aldehyde (VIa), thenitrile (XIIIb) (3.5 g) afforded the crude acetal aldehyde(XIV) (2.4 g, 57%), vmX. 955, 1040, 1710, 2 700, and 3 400cm-l. Wittig reaction of the latter (2.4 g) with 2-0x0-heptylidenetriphenylphosphorane (3,8 g) in tetrahydro-furan (25 ml), as for the preparation of the enone (VIIIg),and then oxidation and reduction with borohydride as for2- ( 7- Hydroxyheptyl) -5-methyl-3-oxocyclo~e~taneca~boJ.C.S. Perkin Iconversion of the enone (VII) into the acids (VIIIa and b)and t.1.c. (ethyl acetate-cyclohexane-formic acid, 40 : 40 : 1)gave a mixture of (f)-ll-deoxy-lO-methyl-PGE, (XVa) andthe 15-epimer (XVb) (Found: C, 71.7; H, 10.7. C,,H,,04requires C , 71.8; H, 10.Oyo).We thank Dr. K. R. H. Wooldridge for his interest andencouragement, T. A. Donovan, M. J. Durgan, and C . J.Hidden for technical assistance, S. Bance and his staff forthe analyses and i.r. spectra, and Drs. T. L. Threlfall andB. J. Peart for the U.V. and n.m.r. spectra.[6/872 Received, 6th May, 1976
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