Synthesis of 3-octyl-, 3-cyclohexylmethyl- and 3-carboxy-3-(prop-2-ynyl)pyrrolidine-2,5-diones required as potential aromatase inhibitors

摘要

J. CHEM. soc. PERKIN TRANS. 1 1993 Synthesis of 3-Octyl-, 3-Cyclohexylmethyl- and 3-Carboxy-3-(prop-2-ynyl)-pyrrolidine-2.5-diones Required as Potential Aromatase Inhibitors Lawrence W. L. Woo, H. John Smith, Kevin J. Barrel1 and Paul J. Nicholls Welsh School of Pharmacy, University of Wales, College of Cardiff, King Edward Vll Avenue, Cardiff CF7 3XF, UK Routes are described for the synthesis of 3-alkyl-3- (prop-2-ynyl)pyrrolidine-2,5-diones 5 and 6, which are not available by the literature method for the corresponding prop-2-enyl analogues, and 3-carboxy-3-(prop- 2-ynyl) pyrrol idine- 2.5-d ione 7. 1OP-Prop-2-ynylestr-4-ene-3,17-dioneis a mechanism-based inactivator of aromatase due to oxidation of the prop-2-ynyl group to an electrophilic species.' We are concerned with the preparation of non-steroidal inactivators such as the title compounds where the propynyl group has been introduced into the skeleton of a known reversible inhibitor2 of the enzyme, 3-(4-aminophenyl)pyrolidine-2,5-dione. Battersby and Westwood3 have described the synthesis of 3-methyl-3-(prop-2-enyl)pyrrolidine-2,5-dione4 (Scheme 1).III II1 - II r- R+C02Et R+H CO2Et COpEt COpEt CO2H 1 2 3 iii (4 only)I R-fL 0 Y 0 H 4 R = Me,R' = CH,CH=CH2 5 R = CEH,,, R' = CH2CZCH 6 R = CGH13, R' = CH2CZCH 7 R = CO2H, R' = CH2CXH Scheme 1 Reagents: i, LiCl-DMSO-H,O, heat, 6 h; ii, LDA-THF, -70 OC, BrCH2C02Li, HMPA, H+; iii, SOCl,, heat, NH,OH, KOH, H,O-MeOH (1 :1); H+, Me,COCl, heat We have successfully used this route for the synthesis of other 3-alkyl derivatives and ourfirst plan was to use this procedure for the synthesis of the required diones 5 and 6 starting from the corresponding acetylenic diesters 8 and 9.However, on further consideration, we concluded that protection of the ethyne moiety as its C-trimethylsilyl derivative (e.g. 10) would be necessary particularly in the early stages involving base catalysed reactions. Our reason for this was that although the acetylenic proton (pK, ca. 26-27) is less acidic4 than the acarbon of a mono- R'PC02Et CBH17 ester (pK, = 24.5 for ethyl acetate) or carboxylic acid salt (pK, 24.5 for acetic acid) it is less shielded so that preferential alkylations could well occur on the propynyl terminal carbon, a prediction borne out later.Trimethyl- or triethyl-silylation of the acetylenic diester 8 gave impure products due to difficulties in separation of the product 10 from unchanged starting material. Attempts to mono-deethoxycarbonylate the crude product with lithium chloride and wet dimethyl sulfoxide (DMSO) to give the crude mono-ester 11, in the hope that it might be more readily purified, failed and this route had to be abandoned. In another approach to the required mono-ester 11, the diester 8 was hydrolysed and decarboxylated to give the acetylenic acid 12 which was readily silylated as predicted above, to give the protected acid 13. Repeated attempts to convert the acid 13 into the required ethyl ester 11 with ethanolic triethyl orthoformate in the presence of toluene-p- sufonic acid proved abortive. The successful route (Scheme 2) was developed from ethyl decanoate 14a by sequential addition of the carboxymethyl and trimethylsilypropynyl moieties to the respective anions to give the acid ester 14c.R' Camp;17,+ co2Et C,H17 C0,Et R2 tCONHi iL14a R' = R2 = H iiL14b R' = H, R2 = CHzC02H iii 14c R' = CH2C,CSiMe3, R2 = CH2C02H Scbeme 2 Reagents: i, LDA-THF, BrCH,CO,Li, HMPA, -70 OC, H'; ii, 2 LDA, THF, -70 "C,then BrCH,C=CSiMe,; H,O+; iii, Et,N, ClCO,Et, NH,OH; iv, 2 KOH-H,OMeOH (1 :1) The order of addition was based on a previous observation that the trimethylsilylpropynyl group is unstable to lithium diisopropylamide (LDA) as evidenced by tar formation in these reactions and the reversed addition gives ethyl 2-(3-trimethylsilylprop-2-yny1)decanoate which darkens on addi-tion of 1 mol equiv.of LDA. An attempt to convert the acid ester 14 into its amide 15 by heating with concentrated ammonia was unsuccessful and the route via a mixed anhydride was carried out. Treatment of the CO2Et resulting amide 15 with 2 equiv. of potassium hydroxide in 8 R = H,R' = CeH17 11 R = SiMe3,R' = Et aqueous methanol (1 :1) removed the protecting group and unexpectedly yielded the required octyl dione 5. 9 R = H, R' = CeHlamp;H2 10 R = SiMe3,R' = C8H17 13 R = SiMe3,R' = H 12 R=R'=H The corresponding cyclohexylmethyl 2,s-dione 6 was also prepared by this route, starting from the acetylenic diester 9.--Br 16 17 20 19 18 viii, ixI/ H 21 X=Bd 7 X=H Scheme 3 Reagents: i, NaC(CO,Et),-DMF-toluene (1 :l), 80 "C; ii, NaOEt-THF, 20deg;C; iii, KOH-EtOH; iv, DCC, DMAP, Bu'OH, CH,Cl,; v, KOH-H,O-MeOH (1 :1); vi, 2 LDA, THF, -50-+4 "C, ClCH,CO,Et, 18 h, H,O+; vii, ClCO,Et, Et,N, NH,, 4 "C; viii, KOH-MeOH-H,O (1 :l), 20 "C, 3 h;ix, CF,C02H, PhH, 80 "C, 2 h An alternative and successful route to the synthesis of the 3-carboxy analogue 7as set out in Scheme 3, avoided protection of the ethyne grouping and also involved in its final stage, acid- catalysed generation of the free carboxylic acid. In this manner the use of relatively severe alkaline conditions in removal of the protecting groups, which would have undoubtedly led to concomitant ring opening, was avoided.It became clear from early experiments that the success of this route depended primarily on obtaining the starting acetylenic diester 16 in a high state of purity since the first readily purified crystalline intermediate was the amidic diester 20 some 5 steps later. It has been our experience that the standard alkylation procedures for the preparation of low molecular weight monoalkyl malonic esters in a high state of purity requires the use of sophisticated fractionating equipment unavailable to us, a situation even more difficult in the case of the diethyl ester of 16which would have been the ideal starting diester. We chose, therefore, Rappoport's ingenious procedure whereby the readily purified triethyl alkylmethanetricarboxyl-ates are treated with ethanol-free sodium ethoxide to yield the corresponding monoalkyl malonates.Application of this procedure using prop-2-ynyl bromide furnished the acetylenic diester 16 in a very high overall yield and satisfactory state of purity. Partial hydrolyses and a re-esterification with tert-butyl alcohol converted the acetylenic diester 16 into the tert-butyl hydrogen malonate 18which was transformed into the homo- logous diester acid 19 via its dianion. Conversion into its crystalline sharp melting amide 20 as before followed by exposure to aqueous methanolic potassium hydroxide yielded the crystalline dioxo ester 21,which was smoothly dealkylated to the required 2,5-dioxopyrrolidine-3-carboxylicacid 7 by treatment with trifluoroacetic acid in boiling benzene.Experimental 'H NMR spectra were recorded on a Perkin-Elmer R32 (90 MHz) instrument and 13C NMR on a JEOL-FX 9OQ Fourier Transformer (90 MHz) spectrophotometer using CDC1, as solvent and tetramethylsilane (TMS) as internal J. CHEM. soc. PERKIN TRANS. 1 1993 standard, unless otherwise stated. J values are given in Hz. JMOD was performed using standard JEOL software. Mass spectra were determined using high resolution EI at the SERC Mass Spectrometry Service Centre, University College of Swansea and elemental analysis at the School of Pharmacy, University of London. Melting points were determined on an electrothermal instrument and are uncorrected.Infrared spectra were determined in KBr discs unless otherwise stated using a Perkin-Elmer 68 1 Infrared Spectrophotometer. Ether refers to diethyl ether and light petroleum to those fractions with b.p. 40-60 "C. (RS)-3-Ethoxycarbonyl-3-(3-trimethylsilylprop-2-ynyl)unde-canoic Acid 14a.-(RS)-3-Ethoxycarbonylundecanoic acid 14b. To a stirred solution of lithium diisopropylamide (LDA) (74.88 mmol), in tetrahydrofuran (THF) (50 cm3) at -75 "C under nitrogen, was added ethyl decanoate 14a(1 5.0 g, 74.88 mmol) at a rate such that the reaction temperature remained -60 "C, and the pale yellow solution was then stirred at -75 "C for 1 h. Separately, bromoacetic acid (1 1.45 g, 82.37 mmol) in THF (12 cm3) was added dropwise under nitrogen to a stirred suspension of finely powdered lithium hydride (1.3 g, 0.1647 mol) in THF (8 cm3) at 0 "C.After the evolution of hydrogen had ceased, hexamethylphosphoramide (HMPA) (1 6.5 cm3) was added to the suspension. The resulting solution was then added dropwise to the solution of the ester enolate at a rate such that the reaction temperature remained -55 "C. The reaction mixture was then gradually warmed to room temperature, stirred overnight and poured onto ice containing an excess of hydrochloric acid (3 mol dm-,). The organic phase was separated and the aqueous phase was extracted with dichloromethane (3 x 100 cm3). On evaporation of the com- bined organic portions, the residue obtained was fractionated on a column of dry silica (100 g, 0.04-0.063 mm) using ether.The eluent collected was washed with water (4 x 100 cm'), dried (MgS04) and evaporated to give a yellow oil (1 7.4 g). The oil (8.8 g) was then eluted down an Amberlite CG-400 (90 g, basic form) resin with acetone-water mixture (3 :1) under mild suction and then light petroleum (5 x 100 cm3). The eluent collected was acidified with hydrochloric acid (3 mol dm-,) and the organic layer separated, dried (MgSO,) and evaporated to give a yellow liquid (2.3 g). Spectroscopic studies on this liquid indicated that it consisted of a mixture of ethyl decanoate and its self-condensed product, ethyI 2-octyl-3-oxododecanoate. The remaining resin bed was triturated with hydrochloric acid (3 mol dmP3; 300 cm3) and allowed to stand overnight.After filtration, the resin cake obtained was washed under mild suction with light petroleum (5 x 100 cm3). All the filtrates and washes obtained were combined and the organic layer separated, dried (MgSO,) and evaporated to give the acidester 14b(6.5 g, 66.4) as a pale yellow liquid; R, =0.79 (ether), 0.49 (light petroleum+ther, 1: 1) (Found: C, 65.0; H, 10.3; (M+H)+, 259.1932. C14H2604 requires C, 65.1; H, 10.15; (A4+H)', 259.1909); vma,(filrn)/cm-' 3700-2500 (CO,H), 1740 (C0,Et) and 1710 (C0,H); 6, 0.47-2.17 20 H, m, C8H, ,CH(CH,CO2H)CO2CH2CH3, 2.32-3.12 3 H, m, CsH, ,CH(CH2CO,H)CO,CH,CH3, 4.16 (2 H, q, J 7, CO,CH,CH,) and 11.59 (1 H, s, C0,H). A solution of LDA (82.84 mmol) was generated under nitrogen at -60deg;C in THF (85 cm3) with the reaction temperature maintained -40 "C.The acid ester 14b (10.7 g, 41.42 mmol) in THF (11 cm3) was then added dropwise to the base at such a rate that the internal temperature was kept -60 "C. The yellow mixture was stirred at -70 "C for 1 h after which 3-bromo-1-trimethylsilylprop-1-yne(8.08 g, 42.25 mmol) in THF (8 cm3) was added to it. The greenish yellow solution was gradually warmed to room temperature, stirred overnight and poured onto ice containing an excess of J. CHEM. SOC. PERKIN TRANS. 1 1993 hydrochloric acid (3 mol dm-,). The organic layer was separated, and the aqueous layer extracted with dichloro- methane (4 x 50 cm3). The combined organic extracts were evaporated to give a reddish brown oil (15.5 g) which was taken up in light petroleum (300 cm3) washed with saturated aqueous sodium hydrogen carbonate (5 x 50 cm3), dried (MgSO,) and evaporated to give an orange-yellow oil (15.3 g).The oil (7.5 g) was then fractionated on a column of wet silica (150 g, 0.04-0.063 mm) using initially light petroleum-ether (20: I) as eluent and then neat ether after the first fraction had been separated. Evaporation of the ethereal eluent gave the trimethylsilyl acid ester 14c (6.54 g, 87.4) as a pale yellow oil, R, = 0.90 (ether) (Found: C, 65.0; H, 10.0. C20H3604Si requires C, 65.2; H, 9.85); v,,,(film)/cm-' 37062300 (CO,H), 2190 (Sics), I740 (CO,Et), 171 5 (CO,H), 845 and 760 (Sic); 6,(no TMS) 0.00 9 H, s, Si(CH,),, 0.41-1.96 (20 H, m, CH, and CH, of octyl, C0,CH,CH3), 2.67 (4 H, br, s, SiC=CH,, CH,CO,H), 4.00 (2 H, q, J 7, CO,CHCH,) and 11.20 (1 H, br, s, C0,H); 6,-(JMOD, noTMS)0.000 C=CSi(CH,),, 14.O14(CH3 ofoctyl andester), 22.667, 23.885, 24.860, 29.187, 29.796, 31.868, 36.620, 39.301, 46.674, 60.567 and 60.872 (C, aliphatic) 75.801, 77.202 and 78.664 (CDCI,), 87.683 (Sics), 103.099 (SiCEC), 174.269 and 177.255 (C=Oof acid and ester).(RS)-3-Ethoxycarbonyl-3-(3-trimethylsilylprop-2-ynyl)undec-255 1 3.02 (4 H, C2.36 (dd,JBA 17 and JXA 2, HXCSCHAHB), 2.56 (d, JBA 18 CHAHBCONHCO), 2.65 (dd, JAB 17 and JxB 2, HXCS-CHAHB), 2.88 (d, JAB 18, CHAf?BCONHCO)) and 9.07-9.37 (1 H, br, s, CONHCO). (RS)-3-Cyclohexylmethyl-3-~rop-2-ynyl)pyrrolidine-2,5-dione 6.-This dione was obtained similarly (Scheme 2) via the intermediates described below as colourless crystals, m.p.97.4- 98.5 "C; R, = 0.71 (ether), 0.62 (light petroleum-ether, 1 :3) (Found:C,71.85;H,8.2;N,6.l.Cl,H,,NO,requiresC,72.l;H, 8.2; N, 6.0); v,,,(KBr)/cm-' 3300 (=CH, 3200), 3 180 (NH) and 1775 and 1715 (W,imide); 6,0.43-1.84 (13 H, m, CH, and CH of cyclohexylmethyl), 2.05 (1 H, t, J2.5, HCSCH,), 2.23- 2.63 (2 H, C2.37 (dd, JBA 17 and JXA 3, HXCSCHAHB), 2.62 (dd,JAB 17 and JXB 3, HxC~CHAHB))' 2.63-3.03 (2 H c2.64 (d, JBA 18, CHAHBCONHCO), 2.89(d, JABI ~,CHAHBCONHCO)} and 9.15 (1 H, br s, CONHCO). (RS)-1-Ethyl Hydrogen 2-Cyclohexylsuccinate.-A pale yellow oil, R, = 0.62 (light petroleum-ether, 1 :3), 0.50 (light petroleumther, 1 :1) (Found: C, 63.9; H, 9.15.C,,H,,O, requires C, 64.45; H, 9.15); v,,,(film)/cm~' 37062350 (CO,H), 1730 (C0,Et) and 1710 (C0,H); 8, 0.56-2.13 (16 H, m, CH, and CH of cyclohexylmethyl, CO,CH,CH,), 2.30-3.10 3 H, m, CH(CH,CO,H)CO,Et, 4.12 (2 H, q, J 7, CO,CH,CH,) and 11.28 (I H, s, C0,H); 6,-(JMOD) 0.000 (TMS), 14.197, 21.753, 26.323, 26.686, 33.208, 33.452, 35.524, 36.499,38.814 and 39.789 (C, aliphatic), 60.567 (CO,CH,CH,), 75.922,77.324 and 78.786 (CDCI,), 175.122and 177.742 (C0,H and CO,CH,CH,). (RS)-1 -Ethyl 2-Cyclohexylmethyl-2-(3-trimethylsilylprop-2-anamide 15.-Ethyl chloroformate (96.5; 0.66 cm3, 6.755 mmol) in dichloromethane (7 cm3) was added to a stirred mixture of the trimethylsilyl acid ester 14c (2.49 g, 6.755 mmol) and triethylamine (0.95 cm3, 6.755 mmol) in dichloromethane (7 cm3) at 0 "C.After the reaction mixture had been stirred at 0 "C for an additional 1.5 h, concentrated ammonia solution (d 0.88; 2.54 cm3, 54.04 mmol) was added to it dropwise. The resulting suspension was stirred at room temperature overnight, acidified with hydrochloric acid (3 mol dm-,) and the organic layer separated and evaporated. The residue was taken up in light petroleum (100 cm3) and washed with aqueous potassium carbonate (l, 4 x 50 cm3) and then with water until neutral. The organic layer was dried (MgSO,) and evaporated to give a bright yellow oil (2.64 g) which was then fractionated on a column of wet silica (93 g, 0.04-0.063 mm) using ether as eluent.Evaporation of the eluent of the second fraction collected gave the amido ester 15 (1.86 g, 74.9) as a pale yellow oil, R, = 0.59 (ether) (Found: C, 65.5; H, 10.1; N, 3.8. C,,H,,NO,Si requires C, 65.35; H, 10.15; N, 3.8); v,,,(film)/cm-l 3440,3360 and 3200 (NH), 2180 (SiC=C), 1730 (CO,Et), 1670 (CONH,), 1610 (CONH,), 845 and 760 (Sic); 6,(no TMS) 0.00 9 H, s, Si(CH,),, 0.50-1.80 (20 H, m, CH, and CH, of octyl, CO,CH,CH,), 2.52 and 2.63 (4 H, two s, SiC=CCH,, CH,CONH,), 4.03 (2 H, q, J7, CO,CH,CH,) and 5.40-6.05 (2 H, br, s, CH,CONH,). (RS)-3-Octyl-3-(prop-2-ynyl)pyrrolidine-2,5-dione 5.-A solution of potassium hydroxide (85; 0.47 g, 7.120 mmol) in water (10 cm3) was added portionwise to a solution of the amido ester 15 (1.05 g, 2.856 mmol) in methanol (10 cm3) and the reaction mixture was stirred at room temperature overnight.It was then diluted with water (80 cm3) and extracted with chloroform (5 x 25 -an3).The combined extracts were evaporated and the residue taken up in light petroleum (75 an3)and the solution washed with saturated aqueous sodium hydrogen carbonate (2 x 25 cm3) and water (3 x 25 cm3), dried (MgS0,) and evaporated to give the dione 5 (0.65 g, 91.3) as a pale yellow syrup. This solidified to a colourless wax with time at room temperature in a desiccator, R, = 0.67 (ether) (Found: C, 71.8; H, 9.1; N, 5.7. C15H23N02 requires C, 72.25; H, 9.30; N, 5.62); v,,,(film)/cm-' 3280 (NH and SH, 2140 (CS), 1785 and 1725 (W,imide);6, 0.37-1.87 (17 H, m, CH, and CH, of octyl), 2.05 (1 H, t, J 2.5, HCSCH,), 2.25- yny1)succinate.-A bright yellow syrup, R, = 0.79 (ether) (Found: C, 64.7; H, 9.2.Cl9H3,O4Si requires C, 64.7; H, 9.15); v,,,(film)/cm-' 3700-2400 (CO,H), 2 190 (SiCSH), 1730 (CO,Et), 1710 (C0,H) and 845 and 765 (Sic); amp;(no TMS) 0.00 9 H, s, Si(CH,),, 0.662.02 (16 H, m, CH, and CH of cyclohexylmethyl, CO,CH,CH,), 2.68 (4 H, s, SiCgH,, CH,CO,H), 3.99 (2 H, q, J7 CO,CH,CH,) and 10.69 (1 H, s, co2H). (RS)-3-Cyclohexylmethyl-3-ethoxycarbonyl-6-trimethylsilyl hex-5-ynamide.-Colourless crystals, m.p. 96.5-96.9 "C, R,= 0.48 (light petroleum-acetone, 3 :1) (Found: C, 65.5; H, 9.6; N, 4.0. C,,H,,NO,Si requires C, 64.9; H, 9.5; N, 4.0); v,,,(KBr)/cm-' 3420, 3360, 3200, 3010 (NH), 2180 (SiCgH), 17 15 (CO,Et), 1680 (CO,NH,), 1625 (CO,NH,), 845 and 765 (Sic); amp;(no TMS) 0.00 9 H, s, Si(CH,),, 0.62-2.02 (16 H, m, CH, and CH of cyclohexylmethyl, CO,CH,CH,), 2.51 (2 H, s, SiCZCH,), 2.66 (2 H, s, CH,CONH,), 4.01 (2 H, q, J 7, CO,CH,CH,) and 5.73 and 6.17 (2 H, two br s, CONH,).Diethyl Prop-2-ynylmalonate 16.-Triethyl but-3-yne- 1,1,1- tricarboxyIate.-3-Bromopropyne (80 wt. solution in toluene; 28.5 cm3, 0.1904 mol) was added to a solution of triethyl sodiomethanetricarboxylate (24.20 g, 95.21 mmol) in toluene- dimethylformamide (1 :1,240 cm3) and the mixture was stirred and heated at 80 "C for 1.5 h. The resultant, cooled yellow suspension was filtered and the residue washed with toluene (5 x 20 cm3).The combined filtrates were washed with water (5 x 50 cm3), evaporated and dried (azeotropically with propan-2-01) to give a brown liquid (26.60 g) which on distillation gave the tricarboxylate (24.57 g, 95.5) as a pale yellow liquid, b.p. 96-98 "C/0.20 mmHg (Found: C, 57.7; H, 6.8. C1 3H1806 requires C, 57.75; H, 6.7); v,,,(film)/cm~' 3290 (ZH), 2130 (CS) and 1745 (C0,Et); 6, 1.30 (9 H, t, J 7 C02CH2CH3), 2.08 (1 H, t, J2, HCSH,), 3.01 (2 H, d, J2, HCSH,) and 4.28 (6 H, q, J 7, CO,CH,CH,). Triethyl but-3-yne-l , 1,l -tricarboxylate (24.40 g, 90.28 mmol) in THF (30 cm3) was added portionwise to a suspension of sodium ethoxide powder (7.6 g, 0.1 128 mol) in THF (260 cm3). After being stirred at room temp. for 1 h, the reaction mixture was acidified with hydrochloric acid (1 mol dm-3) and the aqueous layer separated and extracted with dichloromethane (4 x 50 cm3).The combined extracts were dried (MgSO,) and evaporated to give a brown liquid (18.71 g) which on distillation gave the title compound 16 (16.20 g, 90.5) as a pale yellow liquid, b.p. 71-72 "C/O.l5 mmHg Found: C, 60.45; H, 7.0; (M + NH,)', 216.1236. C10H1404 requires C, 60.6; H, 7.1; (M + NH4)+, 216.12361; v,,,(film)/cn-' 3290 (CSH), 2130 (WH), 1750 (C02Et) and 1740 (C0,Et); SHl.28 (6 H, t, J 7, 2 x CO,CH,CH3), 2.06 (1 H, t, J 2, HMCH,), 2.79 (2 H, dd, JYH 7 and JXH 3, HxC=CCH,CHy), 3.58 (1 H, t, J 8, CH,CHCO,Et) and 4.24 (4 H, q, J 7, 2 x CO,CH,CH,); B,(JMOD), 14.075 (2 x C02CH,CH3), 18.462 (WCH,), 51.305 (CHCO,Et), 61.664 (2 x C0,CH,CH3), 70.560 and 80.127 (HCK) and 167.810 (2 x C0,Et).(RS)-Ethyl Hydrogen 2- Propyny lmalona te 17.-Potassium hydroxide(85; 6.60 g, 0.10 mol) in absolute ethanol (1 50 cm3) was added to the above ester 16 (19.83 g, 0.10 mol) in ethanol (30 cm3) and the mixture stirred at room temp. for 2 h. The mixture was stored overnight after which the resulting potas- sium salt was collected, washed with light petroleum (5 x 25 cm3)and dried in uacuo overnight at 60deg;C to give a creamy white solid (17.34 8). The salt was then dissolved in water (100 cm3) and the solution acidified with hydrochloric acid (3 mol dmP3) and extracted with dichloromethane (5 x 50 an3).The combined organic extracts were dried (MgSO,) and evaporated to give the acid 17 (12.69 g, 74.6) as a pale yellow liquid (Found: C, 56.05; H, 5.85.C8H1004 requires C, 56.45; H, 5.9); v,,,(film)/cm-' 370G2400 (CO,H), 3300 (=CH), 21 30 (CS) and 1735 (GO); 1.30 (3 H, t, J 7, CO,CH,CH,), 2.126, (1 H, t, J 2, HCSH,), 2.81 (2 H, dd, JYH 7 and JXH 2.5, HxCSCH,CHy), 3.68 (1 H, t, J 7, CH,CHCO,Et), 4.27 (2 H, q, J 7, CO,CH,CH,) and 10.98 (1 H, s, C0,H).(RS)-tert-Butyl 2-Ethoxycarbonylpent-4-ynoate.-l,3-Dicy-clohexylcarbodiimide in dichloromethane (67.4 cm3, 65.10 mmol) was added to 2-ethoxycarbonylpent-4-ynoic acid 17 (10.07 g, 59.18 mmol), 2-methylpropan-2-01 (1 6.8 cm3, 0.1775 mol) and 4-dimethylaminopyridine (0.72 g, 5.9 18 mmol) in dichloromethane (120 cm3) at 0 "C. The white suspension formed was stirred at room temp.overnight, collected and washed with dichloromethane (4 x 50 cm3). The combined filtrates and washes were evaporated and the residue taken up in light petroleum (200 cm3) and the solution washed with dilute hydrochloric acid (4 x 50 cm3) followed by aqueous potassium carbonate (1; 4 x 50 cm3). The organic layer was dried (MgSO,) and evaporated to give a pale yellow liquid (13.00 g) which on distillation in the presence of anhydrous potassium carbonate ( -0.2 g) gave the ester (9.89 g, 73.9) as a colourless liquid b.p. 82-83 "C/0.50 mmHg Found: (M + NH,)', 244.1548. C12H,,N0, requires (M + NH,)+, 244.15491; vmax(film)/cm-l3300 (C=CH), 2140 (Camp; and NS-N), 1745 (M) BH 1.29 (3 H, t, J 7, C02CH2CH3), 1.49 and 1730 (W); 9 H, s, CO,C(CH,),, 2.04 (1 H, t, J2, HMCH,), 2.73 (2 H, dd, JYH 8 and JXH 3, H,CCH,CH,), 3.48 (1 H, t, J 7.5, HC=euro;CH,CH) and 4.23 (2 H, q, J 7, CO,CH,CH,).The crude ester was used for the following reaction without further purification. (RS)-2-(tert-Butoxycarbonyl)pent-4-ynoicacid 18.-A solu-tion of potassium hydroxide (85; 4.53 g, 68.67 mmol) in water (45 cm3) was added to a solution of the crude ester (12.43 g, J. CHEM. SOC. PERKIN TRANS. 1 1993 54.93 mmol) in methanol (45 cm3). After the mixture had been stirred at room temp. overnight it was diluted with water (90 cm3) and the resulting mixture was washed with dichloro- methane (5 x 25 cm3). The aqueous layer was acidified with hydrochloric acid (3 mol drn-,) and extracted with dichloro- methane (5 x 25 an3).The combined organic extracts were dried (MgS0,) and evaporated to give the acid ester 18(10.24 g, 94.0) as a colourless oil Found: (M + NH4)+, 216.1236.C1,H 804N requires (M+ NH,) ,2 16.12361; v,,(film)/cm-' + 3700-2500 (CO,H), 3310 (SH), 2130 (M)and 1735 (GO); SH 1.50 9 H, S, CO,C(CH3)3, 2.05 (1 H, t, J 3, CH,C=CH), 2.77 (2 H, dd, JYRand JXH 2, HxC=CCH2CH,), 3.55 (1 H, t, J 7, HC=CCH,CH) and 10.89 (1 H, s, C0,H). The crude acid ester was used for the next reaction without further purification. (RS)-1-tert-Butyl4-Ethyl2-Carboxy-2-propynylsuccinate19.-To a stirred solution of the crude acid ester 18 (9.68 g, 48.86 mmol) and diisopropylamine (13.7 cm3, 97.72 mmol) in THF (100 cm3) at -60 "C under nitrogen was added butyllithium (1.6 mol dmP3 solution in hexanes; 61.1 cm3, 97.72 mmol) at a rate such that the reaction temperature did not exceed -50 OC. The resulting pale yellow solution was warmed to 4OC and maintained at this temperature for an additional 15 min before ethyl chloroacetate (97, 5.38 cm3, 48.86 mmol) in THF (5 cm3) was added to it dropwise.The mixture was then stirred overnight at room temperature, acidified with hydrochloric acid (1 mol dm-3) and extracted with dichloromethane (4 x 25 cm3). The combined extracts were evaporated and the residue was treated with aqueous potassium carbonate (2; 350 cm3), washed with dichloromethane (5 x 50 cm3), acidified with hydrochloric acid (3 mol drn-,) and extracted with dichloro- methane (5 x 50 cm3).The combined organic extracts were dried (MgSO,) and evaporated to give the diester 19 (12.58 g, 90.6) as a thick yellow oil Found: C, 59.1; H, 7.15; (M + H) +, 285.1338. C,,H,,O, requires C, 59.1; H, 7.1; (A4+ H)', 285.13381; vmax(film)/cm-l 3700-2400 (CO,H), 3290 (=CH), 21 30 (C=C) and 1735 (GO);SH 1.24 (3 H, t, J 7, CO,CH,CH,), 1.48 9 H, S,CO,C(CHs),, 2.08 (1 H, t, J2, HWCH,), 2.95 (2 H,d,J2,HC=CCH2),3.12(2H,s,CH2CO,Et),4.12(2H,q,J7, C02CH2CH3) and 10.17 (1 H, s, C0,H). 1 -tert-Butyl 4-Ethyl 2-Carbamoyl-2-propynylsuccinate20.-Ethyl chloroformate (2.97 cm3, 29.91 mmol) in dichlorome- thane(l0 cm3) was added to a stirred solution of triethylamine (4.35 cm3, 31.34 mmol) and the acid diester 19 (8.10 g, 28.49 mmol) in dichloromethane (1 00 cm3) at 4 "C.After the mixture had been stirred for 30 min, gaseous ammonia (calcium chloride dried) was bubbled slowly into it for 1.5 h. The resulting white suspension was stirred overnight at room temp. col-lected and washed with dichloromethane (4 x 25 cm3). The combined organic layers were evaporated and the residue taken up in ether (100 cm3) and washed successively with dilute sulfuric acid (5 x 25 cm3), aqueous potassium carbonate (2, 5 x 25 cm3) and water (2 x 25 cm3). The ethereal layer was dried (MgSO,) and evaporated to give a pale yellow oil which was dissolved in hot light petroleumther (2 :1). On cooling, the amid0 diester 20 (4.23 g, 52.4) separated as colourless crystals, m.p.102.1-104.4"C Found: C, 59.15; H, 7.65; N, 4.85; (M + H)+,284.1498. C,,H,,O,NrequiresC, 59.35; H, 7.45;N, 4.95; (M + H)', 284.14981; v,,(KBr)/cm-' 3420 and 3330 (NH), 3280 (SH), 1735 (GO,esters), 1680 (CONH,) and 1620 (CONH,); SH 1.25 (3 H, t, J 7, CO,CH,CH3), 1.46 (9 H, S, CO,C(CH3)3, 2.11 (1 H, t, J 2, HCSCH,), 2.55-2.95 (2 H C2.71 (dd, JBA 16 and JXA 3, HxC=CCHAHB), 2.93 (dd, JAB 16andJx~3,HxWCHAHB)),3.00-3.30{2H,2.96(d, JBA 16, CHAHBCOZEt), 3.17 (d, JAB 16, CHAHBCO~E~)), 4.10 (2 H, 9, J 7, C02CH,CH3) and 5.75-6.40 and 7.05-7.65 (2 H, 2 x br s, CONH,. J. CHEM. SOC. PERKIN TRANS. 1 1993 (RS)-3-(tert-Butoxycarbonyl)-3-(prop-2-ynyl)pyrroZidine-2,5-dione 21.-Potassium hydroxide (85; 0.69 g, 10.50mmol) in water (1 5 cm3)was added to a solution of the amido diester 20 (2.38g, 8.400mmol) in methanol (1 5 cm3).After being stirred at room temp. for 3 h, the solution was acidified with dilute hydrochloric acid (1 mol dm-3) and the product extracted with dichloromethane (5 x 25 cm3). The combined organic extracts were dried (MgSO,) and evaporated to give a colourless crystalline solid (1.74g), m.p. 110.8-1 11.4 "C.Upon cooling a solution in hot light petroleum-ether (2:1) the dione 21 (1.68g, 84.3) separated as a colourless crystalline solid, m.p. 1 11.1-112.0"C,R, = 0.73 (acetone-ether, 1 :1) (Found: C,60.4;H, 6.5;N,5.85.C,,H,,N04requires C,60.75;H,6.35;N,5.90); v,,,(KBr)/cm-' 3280 (CH),3240 (NH),1780 (GO,imide), 1735 (C0,Bu') and 1720 (GO, imide); 6, 1.47 9 H,s, CO,C(CH,),, 2.09 (1 H,t, J 3, HC=CCH2),2.65-3.00 (2 H, C2.77 (dd, JBA 16 and JXA 3, HXCSCHAHB),3.01 (dd, JAB 16 and JXB 3, HxCZCHAHB)},3.01-3.28 (2 H,C2.94(d, JBA 18, CHAHBCONHCO),3.19 (d, JAB 18, CH,H,CONHCO)} and 9.02-9.57(1 H,br s, CONHCO). (RS)-3-Carboxy-3-(prop-2-ynyl)pyrrolidine-2,5-dione7.-Tri-fluoroacetic acid (1.99 an3, 25.29 mmol) was added to a solution of the dione 21 (1 .OO g, 4.215 mmol) in benzene (20cm3) and the mixture was heated and stirred at 80 OC for 2 h.The crude reaction mixture was evaporated and the residue (0.70g) dissolved in ethyl acetate (50 cm3). This solution was washed with water (3 x 25 cm3) and extracted with saturated aqueous sodium hydrogen carbonate (50 cm3).The aqueous layer was separated, acidified with dilute hydrochloric acid (1 mol dm-3) and extracted with ethyl acetate (2 x 25 cm3). The combined extracts were dried (MgSO,) and evaporated to give the acid dione 7 (0.50 g, 65.5) as a viscous pale yellow syrup Found: C, 52.7; H, 4.1; N, 7.55; (M + NH,)+, 199.0720. C8H,N04requires C, 53.04; H,3.89;N, 7.73; (A4+ NH,)', 199.07201.v,,,(film)/cm-l 3700-2500 (CO,H),3300 (SH),1785 (W, imide) and 1730 (W);6, (C2H6acetone) 2.53 (1 H, t, J3,HWCH,),2.73-3.03 (2 H, C2.83 (dd, JBA 17 and JXA 2, H,CSCHAHB), 3.13 (dd, JAB 17 and JXB 2, HxCamp;CHAHB)},3.03-3.43 (2 H,c2.94(d, JBA 18, CHAHBCONHCO),3.24(d, JAB 18, CHAHBCONHCO)}and 10.27-10.78(1 H,br s, CONHCO)and 11.30(1 H,br s, C02H); dH(D,O, 3-(trimethylsily1)propane-1 -sulfonic acid, sodium salt hydrate) 2.48 (1 H,t, J 2, HWCH,),2.92 (2 H,d, J 2, HCSCH,),3.01 (1 H,d, JBA 18, CHAHBCONHCO),3.36(1 H, d, JAB 18, CHAHBCONHCO). References 1 B. W. Metcalf, C. L. Wright, J. P. Burkhart and J. 0.Johnston, J. Am. Chem. SOC.,1981,103,322 1. 2 M. J. Daly, G. W. Jones, P. J. Nicholls, H. J. Smith, M. G. Rowlands and M. A. Bunnett, J. Med. Chem., 1986,29,520. 3 A. R. Battersby and S. W. Westwood, J. Chem. SOC.,Perkin Trans. I, 1987,1679. 4 L. Brandsma, Preparation Acetylenic Chemistry, Elsevier, London, 1970, p. 15. 5 R. G. Pearson and R. L. Dillon, J. Am. Chem. Soc., 1953,75,2439. 6 A. P. Krapcho, J. F. Weinmaster, J. M. Eldridge, E. G. E. Jahngen, A. J. Lovey and W. P. Stevens, J. Org. Chem., 1978,43, 138. 7 H. C. Padgett, I. G. Csendes and H. Rappoport, J. Org. Chem., 1979, 44,3492. 8 R. B. Miller, Synth. Comm., 1972,2,267. Paper 3/03489E Received 17th June 1993 Accepted 29th June 1993