Hydration of Acetylenic Esters: Synthesis of β-Keto-Esters

Molecules 1996, 1, 72 – 78 © Springer-Verlag 1996 Hydration of Acetylenic Esters: Synthesis of β-Keto-Esters Mauricio Gomes Constantino,*,1 Ivone Carvalho,2 Gil Valdo José da Silva1 and Fernando Costa Archanjo2 1 Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes 3900, 14040-901 - Ribeirão Preto-SP, Brazil. Phone +55/16 633 1010. Fax +55/16 633 8151. (mgconsta@usp.br) 2 Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café s/n, 14040-903 - Ribeirão Preto-SP, Brazil Received: 19 August 1996 / Accepted: 4 October 1996 / Published: 14 October 1996 Abstract Acetylenic esters, which are easily prepared by carbethoxylation of terminal acetylenes, can be hydrated regioselectively to β-keto-esters. In this paper, the terminal acetylenes were prepared by addition of lithium acetylide (complexed with ethylenediamine) to epoxides of cyclopentane derivatives to produce compounds oxygenated at the same position as certain natural products from Otoba parvifolia. The hydration was carried out by two different processes, producing either δ-oxygenated or γ,δ-unsaturated β-keto-esters. Keywords: Acetylenic esters, hydration, β-keto-esters, cyclopentane derivatives, lithium acetylide Introduction The Brazilian plant Otoba parvifolia from the Amazon valley has proved to be a rich source of cyclopentane-based natural products with novel and unusual structures, such as 1, which shows the typical oxygenation pattern.[1] We have been interested for some time in the synthesis of these natural products, and one route we have been exploring to 1 is via the corresponding β-keto-esters. We describe here our results on the synthesis of cyclopentyl and cyclopentenyl substituted β-keto esters related to 1. O H Farnesyl HO OEt CO2Me 1 * To whom correspondence should be addressed Molecules 1996, 1 73 OBn OBn OBn MCPBA + 85% 2 O O 3a 3b 2:3 R2 3a or 3b HC R1 R2 1. BuLi 2. ClCO2Et C(en)Li DMSO R2 R1 KOH O MeOH/H2O HO EtOCO HO CO2H CO2Et 5a, R1=OBn, R2=H, 55% 5b, R1=H, R2=OBn, 61% 4a, R1=OBn, R2=H, 83% 4b, R1=H, R2=OBn, 81% 6a, R1=OBn, R2=H,73% 6b, R1=H, R2=OBn,76% OBn OBn 4a R1 1. BuLi 2. ClCO2Et Me3SiCl Et3N 92% RO Me3SiO CO2Et 7 Scheme 1. Preparation of acetylenic esters Our general approach is outlined in Scheme 1. Hydroboration-oxidation of cyclopentadiene was performed by the procedure described by Allred,[2] with minor modifications, and treatment of the resulting cyclopentenol with sodium hydride in dioxane, followed by benzyl chloride, [3] produced the ether 2. Oxidation of 2 with m-chloroperbenzoic acid [4] furnished, as expected, a mixture of two stereoisomers 3a and 3b in a ratio of 2:3. The isomers were separated by column chromatography and the subsequent reactions were performed exclusively with pure isomers. Treatment of the epoxides 3a or 3b either with sodium acetylide or with the anions from methyl propiolate or from 8a, R = SiMe3, 17% 8b, R = H, 17% 5a, R = CO2Et, 16% propiolic acid resulted only in the recovery of starting material, thus confirming the conclusion by Murray [5] that simple acetylide anions are not suitable for the nucleophilic opening of epoxides of cyclic olefins. By contrast, use of lithium acetylide complexed with ethylenediamine in DMSO resulted in a clean and smooth reaction with the epoxides 3a or 3b to give compounds 4a and 4b in yields of 83 and 81%, respectively.[6] Although direct carboxylation of the dianion from either 4a or 4b could not be effected, carbethoxylation of the same dianions with ethyl chloroformate [7] proved easy. Compounds 5a and 5b, the desired acetylenic esters, were obtained after the original cyclopentanol hydroxyl group was converted to a carbonate ester. We have also demonstrated that compounds 6a and 6b, the expected products 74 Molecules 1996, 1 R2 R1 4% HgSO4 R2 R1 + H H2O/EtOH R3O R3O O CO2Et CO2Et 9a: R1 = OBn, R2 = H, R3 = CO2Et 9b: R1 = H, R2 = OBn, R3 = CO2Et 9c: R1 = OBn, R2 = H, R3 = H N H R2 OBn R1 SiO2 R3O N CHCl3 CO2Et 10a: R1 = OBn, R2 = H, R3 = CO2Et (Z+E) 10b: R1 = H, R2 = OBn, R3 = CO2Et (Z+E) Scheme 2. Hydration of acetylenic esters of direct carboxylation of 4a and 4b, can be prepared in good yield by saponification of 5a and 5b. The acetylenic ester 8a, which contains the trimethylsilyloxy group at the δ-position, was prepared in a similar way by carbethoxylation of the silyl ether 7, itself easily obtained from 4a. A small amount (16%) of the carbonate ester 5a was also formed during the reaction, but formation of the alcohol 8b probably occurred during purification by column chromatography. Hydration of the acetylenic esters was performed as summarized in Scheme 2 and Table 1, either by treatment with mercuric sulfate and acid [8], or by conjugate addition of piperidine followed by acid hydrolysis of the resulting enamine.[9] It is worth noting that, in preliminary experiments using a slightly different starting material (containing -OTHP instead of -OBn), we found that formic acid is a poor hydrating agent for these acetylenic esters, in contrast to the O CO2Et 11 good results we had previously obtained with formic acid in the hydration of diacetylenic compounds.[10,11] The hydration with acidic aqueous/ethanolic mercuric sulfate proved to be an efficient reaction for each of the acetylenic esters we used. When methanol was used as solvent, some ester exchange was observed. The carbonate group (R3) is stable under these hydration conditions, as is the benzyloxy group, but the trimethylsilyl group is, as expected, hydrolysed during the reaction. The two-step hydration protocol, which consists of conjugate addition of piperidine to produce a diastereo-isomeric (Z + E) mixture of enamines followed by acidic hydrolysis, while using very mild conditions in the first step, invariably proceeded with elimination of the carbonate group during the hydrolysis of the enamine. Even with the very gentle conditions of silica gel and chloroform, 11 was still the only product that could be isolated. γ,δ-unsaturated compounds, such as 11, should prove to be useful intermediates in the synthesis of many natural products. However, if δ-oxygenated β-ketoesters of the type 1 are desired, then clearly hydration of the corresponding Molecules 1996, 1 75 Table 1. Hydration of Acetylenic Esters (see Scheme 2) Starting Material A R1 R2 R3 Product Yield, % Yield of 11, % HgSO4 5a 5b 8a 8b OBn H OBn OBn H OBn H H CO2Me CO2Me SiMe3 H 9a 9b 9c 9c 71 74 96 90 - piperidine 5a OBn H CO2Me 5b H OBn CO2Me 10a (Z+E) 10b (Z+E) 100 (crude) 100 (crude) 77 77 75 Reagent acetylenic esters should be by treatment with mercuric sulfate. The high regioselectivity of the hydration reaction is remarkable, and is determined by the ester group.[11] No α-keto esters were observed in any of our hydration reactions. Yield 24.6 g (0.293 mol, 21 % based on the amount of diborane). IR (neat film) 3375, 1610, 1107 cm-1; 1H-NMR (CDCl3, 80 MHz) δ 2.05-2.80 (4H, dd), 3.95 (1H, br.s), 4.254.55 (1H, m), 5.60 (2H, s); 13C-NMR (CDCl3, 20 MHz) δ 42.0 (CH2), 70.9 (CH), 127.9 (CH). 3-Benzyloxy-l-cyclopentene (2) [3] Experimental section NMR spectra were measured using a Bruker AC-80 (80 MHz 1H-NMR, and 20 MHz 13C-NMR) or a Varian EM360L (60 MHz; 1H-NMR) instrument; deuterochloroform and carbon tetrachloride were used as solvents, and tetramethylsilane as the internal standard. IR spectra were measured with a Perkin-Elmer 1430 or a Perkin-Elmer 1600 FT spectrometers. TLC was performed on precoated silica gel 60 F254 plates (0.25 mm thick, Merck), and for column chromatography silica gel 60 70-230 mesh (Merck) was used. 3-Cyclopentenol [2] Diborane, produced as described by Zweifel and Brown [13] from NaBH4 (13.6 g, 0.358 mol) and BF3.Et2O (104 g, 0.732 mol) in diglyme, was passed through a solution of freshly distilled cyclopentadiene ( 159 g, 2.41 mol) in THF (400 mL) maintained at 0°C with mechanical stirring. After the addition of diborane was completed, the reaction mixture was stirred at room temperature for 1 h. The solvent and excess cyclopentadiene were removed under vacuum and the viscous residue was cooled with an ice bath and treated with a 3 N aqueous solution of NaOH (200 mL) followed by a 30% solution of H2O2 (220 mL). The product was extracted with ether and the organic phase was dried with MgSO4. After removing the solvent under vacuum, the residue was distilled at 71-73°C (30 mm Hg). To sodium hydride (3.15 g of a 60 % dispersion in mineral oil, previously washed with hexane, 78.7 mmol), maintained under nitrogen atmosphere, was added a solution of 3-cyclopentenol (3.0 g, 35.7 mmol) in dry dioxane (320 mL). The reaction mixture was heated to reflux for 2 h and then cooled with an ice bath, benzyl chloride (5.7 g, 45.0 mmol) was added dropwise and the mixture was heated again to reflux for 21 h. After cooling to room temperature, the reaction mixture was poured onto ice, and the product was extracted with ether. The organic layer was separated and dried with MgSO4. The solvent was removed under vacuum and the residue was distilled at 100°C (5 mmHg). Yield 4.6 g (26.7 mmol, 75 %). IR (neat film) 1610, 1095, 1072, 735, 696 cm-1; 1H-NMR (CCl4, 80 MHz) δ 2.352.60 (4H, m), 4.05-4.40 (1H, m), 4.45 (2H, s), 5.60 (2H, s), 7.25 (5H, s); 13C-NMR (CDCl3, 20 MHz) δ 39.3 (CH2), 70.8 (CH2 ), 78.8 (CH), 127.4 (CH), 127.7 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 138.8 (C). cis-3-(Benzyloxy)-6-oxabicyclo[3.1.0]hexane (3a) and trans-3-(Benzyloxy)-6-oxabicyclo[3.1.0]hexane (3b) [4, 14] To an ice-cooled solution of compound 2 (874 mg, 5.02 mmol) in methylene chloride (3.7 mL) was added a solution of m-chloroperbenzoic acid (1.14 g of 80% MCPBA, 6.60 mmol) in methylene chloride (11.3 mL) from a dropping funnel. The ice bath was removed and the stirring 76 was continued for 2 h at room temperature. The resulting mixture was treated with 10% sodium sulfite (40 mL) and stirred for 30 min. The organic phase was separated and washed with 5% NaHCO3, water and saturated aqueous NaCl. The mixture was dried (MgSO4) and concentrated to dryness under reduced pressure. The residue was applied to a silica gel column and eluted with (7:3) hexaneethyl acetate. The trans and cis isomers were isolated in 472 mg (2.48 mmol, 49 %) and 340 mg (1.79 mmol, 36 % ) yield, respectively. cis-Isomer 3a: IR (neat film) 1095, 790, 738, 698 cm-1; 1H-NMR (CCl4, 80 MHz) δ 1.6-2.25 (4H, m), 3.30 (2H, s), 3.85-4.15 (1H, m), 4.30 (2H, s), 7.15 (5H, s); 13C-NMR (CCl4, 20 MHz) δ 34.9 (CH2), 56.7 (CH), 70.3 (CH2), 78,5 (CH), 126.9 (CH), 127.2 (CH), 127.9 (CH), 138.6 (C). trans-Isomer 3b: IR (neat film) 1111, 791, 738, 699 cm-1; 1H-NMR (CCl4, 80 MHz) δ 1.40-1.75 (2H, dd), 2.20-2.60 (2H, dd), 3.30 (2H, s), 3.55-3.95 (1H, m), 4.35 (2H, s), 7.20 (5H, s), 13C-NMR (CCl4, 20 MHz) δ 34.3 (CH2), 54.6 (CH), 71.5 (CH2), 75.8 (CH), 127.2 (CH), 127.2 (CH), 128.0 (CH), 138.5 (C). (1S, 2R, 4S)-2-Ethynyl-4-benzyloxy-cyclopentanol (4a) and its enantiomer (racemic mixture) [5] To a solution of compound 3a (265 mg, 1.39 mmol) in dry DMSO (0.9 mL) under nitrogen was added lithium ethylenediamine (400 mg, 4.4 mmol) all at once. The mixture was stirred at room temperature for 20 h and then was hydrolysed with a saturated aqueous NH4Cl and extracted with ether. The ether fractions were washed with saturated aqueous NH4Cl, dried over MgSO4 and evaporated under reduced pressure. The product was purified by column chromatography (silica gel), eluting with (7:3) chloroformdiisopropyl ether. Yield 249 mg (1.15 mmol, 83 %). IR (neat film) 3400, 3300, 2114, 1096, 738, 698 cm-1; 1H-NMR (CCl4, 80 MHz) δ 1.60-2.45 (5H, m), 2.65-3.10 (2H, m), 3.85-4.20 (2H, m), 4.40 (2H, s), 7.20 (5H, s); 13C-NMR (CCl4, 20 MHz) δ 37.6 (CH), 40.0 (CH2), 69.9 (CH), 70.6 (CH2), 77.7 (CH), 78.4 (CH), 86.2 (C), 126.7 (CH), 127.4 (CH), 128.0 (CH), 138.1 (C). Molecules 1996, 1 (1S, 2R, 4S)-2-Carbethoxyethynyl-4-benzyloxy-cyclopentyl carbonate (5a) and its enantiomer (racemic mixture [7]) To a stirred solution of compound 4a (796 mg, 3.68 mmol) in THF (6.0 mL) and HMPA (2.25 mL) cooled to -78°C was added n-butyllithium in hexane (9.22 mL, 10.6 mmol, 1.15 M). Stirring was then continued for 1 h, after which was added a solution of ethyl chloroformate (1610 mg, 14.9 mmol) in anhydrous THF (4 mL), previously cooled to 78°C. The mixture was stirred for 2 h and then the temperature was allowed to rise gradually to room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl and then extracted with ether. The ether extract was washed with saturated NH 4Cl solution and water, dried with MgSO4 and concentrated under reduced pressure. The residue was purified on a silica gel column eluting with (7:3) hexane-ethyl acetate. Yield 723 mg (2.00 mmol, 55 %). IR (neat film) 2237, 1745, 1711, 1261, 751, 698 cm-1; 1H-NMR (CCl4, 80 MHz) δ 1.10-1.40 (6H, dt), 1.70-2.65 (4H, m), 3.00-3.50 (1 H, m), 3.90-4.30 (5H, m), 4.45 (2H, s), 4.75-5.10 (1H, m), 7.20 (5H, s); 13C-NMR (CCl4, 20 MHz) δ 14.0 (CH3), 14.1 (CH3), 34.4 (CH), 37.1 (CH2), 38.0 (CH2), 60.8 (CH2), 63.2 (C), 70.5 (CH2), 77.0 (CH), 80.8 (CH), 86.6 (C), 127.1 (CH), 128.0 (CH), 138.0 (C), 152.1 (CO), 153.9 (CO). (1S, 2R, 4R)-2-Carbethoxyethynyl-4-benzyloxy-cyclopentyl carbonate (5b) and its enantiomer (racemic mixture) This compound was prepared in a manner identical with that of 5a, starting with compound 4b. Yield 814 mg (2.25 mmol, 61 %). IR (neat film) 2236, 1747, 1711, 1256, 751, 698 cm-1, 1H-NMR (CCl4, 80 MHz) δ 1.10-1.40 (6H, t), 1.752.60 (4H, m), 2.75-3.05 (1H, m), 3.90 - 4.30 (5H, m), 4.40 (2H, s), 4.95-5.20 (1H, m), 7.20 (5H, s); 13C-NMR (CCl4, 20 MHz) δ 14.0 (CH3), 14.2 (CH3), 34.6 (CH), 36.7 (CH2), 38.5 (CH2), 60.8 (CH2), 63.3 (C), 70.7 (CH2), 77.3 (CH), 81.2 (CH), 87.0 (C), 127.0 (CH), 127.3 (CH), 128.1 (CH), 138.1 (C), 153.5 (CO), 154.2 (CO). (1S, 2R, 4R)-2-Ethynyl-4-benzyloxy-cyclopentanol (4b) and its enantiomer (racemic mixture) (1S,2R,4S)-2-Carboxyethynyl-4-benzyloxy-cyclopentanol (6a) and its enantiomer (racemic mixture) This compound was prepared as described for 4a, starting with oxirane 3b but stirring at room temperature for a longer time (40 h). Yield 244 mg (1.13 mmol, 81%). IR (neat film) 3400, 3300, 2115, 1100, 738, 698 cm-1 ; 1H-NMR (CCl4, 80 MHZ) δ 1.50-2.60 (6H, m), 3.40 (1H, br.s), 3.804.40 (2H, m), 4.45 (2H, s), 7.20 (5H, s), 13C-NMR (CC14, 20 MHz) δ 37.5 (CH), 40.3 (CH2), 70.0 (CH), 70.7 (CH2), 76.9 (CH), 86.0 (C), 127.3 (CH), 127.4 (CH), 128.1 (CH), 138.4 (C). A mixture of compound 5a (94 mg, 0.261 mmol), 3.9% aqueous solution of KOH (0.47 mL) and MeOH (0. 12 mL) was refluxed for 75 min, after which the MeOH was removed under reduced pressure from the mixture. Water was added to the residue and the aqueous layer was washed three times with ether and then acidified with conc. HCl. The product was extracted with ether, the ether fraction was dried with MgSO 4 and the solvent was evaporated. Yield 49 mg (0.187 mmol, 73 %). IR (neat film) 3380, 2236, 1710, 738, 698 cm-1; 1H-NMR (CDCl3, 80 MHz) δ 1.702.50 (4H, m), 2.90-3.20 (1H, m), 3.95-4.40 (2H, m), 4.50 (2H, s), 6.60 (1H, br.s), 7.30 (5H, s). Molecules 1996, 1 (1S, 2R, 4R)-2-Carboxyethynyl-4-benzyloxy-cyclopentanol (6b) and its enantiomer (racemic mixture) This compound was prepared as described for 6a, starting with compound 5b but stirring at reflux temperature for a longer time (4 h). Yield 52 mg (0.198 mmol, 76 %). IR (neat film) 3400, 2230, 1705, 745, 698 cm-1, 1H-NMR (CDCl3, 80 MHz) δ 1.60-2.85 (5H, m), 3.90-4.25 (2H, m), 4.45 (2H, s), 6.65 (1H, br.s), 7.30 (5H, s); 13C-NMR (CDCl3, 20 MHz) δ 36.7 (CH), 37.4 (CH2), 40.1 (CH2), 71.2 (CH2), 76.8 (CH), 91.7 (CH), 127.9 (CH), 128.5 (CH), 137.7 (C), 156.1 (CO). (1S, 2R, 4S)-1-Trimethylsilyloxy-2-ethynyl-4-benzyloxycyclopentane (7) and its enantiomer (racemic mixture)[15] To a solution of compound 4a (216 mg, 1.0 mmol) in dry THF (2.2 mL) was added Et3N (121 mg, 1.20 mmol) and Me3SiCl (109 mg, 0.13 mL, 1.0 mmol). The reaction mixture was stirred for 7 h at room temperature, after which it was concentrated under reduced pressure. The crude product was diluted with ether, filtered to remove Et3NH+Cl-, and concentrated under reduced pressure. Yield 266 mg (0.923 mmol, 92%). 1H-NMR (CDCl3, 80 MHz) δ 0.15 (9H, s), 1.50-3.00 (6H, m), 3.80-4.20 (2H, m), 4.45 (2H, s), 7.30 (5H, s). (1S, 2R, 4S)-1-Trimethylsilyloxy-2-carbethoxyethynyl-4benzyloxy-cyclopentane (8a) and its enantiomer (racemic mixture) [8] The reaction was performed as previously described for the compound 5a, using compound 7 (266 mg, 0.922 mmol) in THF (0.8 mL), HMPA (0.55 mL), n-butyllithium in hexane (0.59 mL, 1.31 mmol, 2.25 M) and a solution of ethyl chloroformate (200 mg, 1.84 mmol) in THF (0.8 mL). The crude product (266 mg, 0.737 mmol, 80 %) was purified by column chromatography on silica gel with (7:3) hexane-ethyl acetate. Yield 57 mg (0.157 mmol, 17 %). 1H-NMR (CDCl , 80 MHz) δ 0.15 (9H, s), 1.15-1.40 (3H, 3 t), 1.50-2.55 (4H, m), 2.75-3.00 (1 H, m), 3.80-4.35(4H, m), 4.40 (2H, s), 7.30 (5H, s). (1S, 2S, 4S)-2-Carbethoxyacetyl-4-benzyloxy-cyclopentyl carbonate (9a) and its enantiomer (racemic mixture) [7] To a solution of 5a (300 mg, 0.83 mmol) in ethanol (4.3 mL) was added an aqueous solution of 4% HgSO4 (1.3 mL), previously prepared by dissolving red HgO (2.0 g) in H2O (39.5 mL) and conc. H2SO4 (10.5 mL). The reaction mixture was stirred for 2 h at room temperature and then the ethanol was removed under reduced pressure. Water was added to the residue and the mixture was extracted with chloroform. The organic extract was dried over MgSO4 and concentrated under reduced pressure. The product was purified by column chromatography eluting with (7:3) 77 hexane-ethyl acetate. Yield 223 mg (0.589 mmol, 71%). IR (neat film) 1740-1710, 730, 690 cm-1; 1H-NMR (CCl4, 80 M-Hz) δ 1.10-1.40 (6H, dt), 1.70-2.55 (4H, m), 2.602.90 (1H, m), 3.60 (2H, s), 3.90-4.40 (5H, m), 4.50 (2H, s), 5.00-5.30 (1H, m), 7.35 (5H, s). 13C-NMR (CDCl3, 20 MHz) δ 14.0 (CH3), 14.1 (CH3 ), 34.8 (CH2), 38.2 (CH2), 49.0 (CH2), 55.7 (CH), 61.3 (CH2), 64.0 (CH2), 70.6 (CH2), 77.7 (CH), 79.2 (CH), 127.5 (CH), 128.3 (CH), 138.1 (C), 154.9 (CO), 166.8 (CO), 202.9 (CO). (1S, 2S, 4R)-2-Carbethoxyacetyl-4-benzyloxy-cyclopentyl carbonate (9b) and its enantiomer (racemic mixture) This compound was prepared in a manner identical with that of 9a, starting with compound 5b. Yield 232 mg (0.613 mmol, 74%) IR (neat film) 1750-1710, 735, 698 cm-1, 1HNMR (CCl4, 80 MHz) δ 1.10-1.45 (6H, dt), 1.80-2.40 (4H, m), 2.50-2.85 (1H, m), 3.45 (2H, s), 3.95-4.35 (5H, m), 4.40 (2H, s), 4.80-5.30 (1H, m), 7.20 (5H,s). (1S, 2S, 4S)-2-Carbethoxyacetyl-4-benzyloxy-cyclopentanol (9c) and its enantiomer (racemic mixture) The reaction was performed as previously described for the compound 9a, using compound 8a (57 mg, 0.157 mmol) in EtOH (1.0 mL) and aqueous solution of 4%HgSO4 (0.5 mL). Yield 46 mg (0.151 mmol, 96 %). 1H-NMR (CDCl3, 80 MHz) δ 1.05-1.40 (3H, t), 1.65-1.80 (4H, m), 2.65 (1H, br.s), 3.10-3.50 (1H, m), 3.55 (2H, s), 3.95-4.40 (4H, m), 4.40 (2H, s), 5.05 (1H, s), 7.30 (5H, s). (Z)- and (E)-(1S, 2S, 4S)-2-[ 1-(1-Piperidinyl) ]-carbethoxyethenyl-4-benzyloxy-cyclopentyl carbonate (10a) and their enantiomers (racemic mixtures) [9] Piperidine (246 mg, 2.89 mmol) was added to a solution of 5a (517 mg, 1.437 mmol) in anhydrous ether (1.9 mL). The mixture was stirred for 4 h at room temperature. The excess of the reagent and the solvent was removed under reduced pressure and the crude product was isolated as a mixture of Z + E diastereoisomers. Yield 641 mg (1.44 mmol, 100 %). IR (neat film) 1740, 1690, 1265, 750, 698 cm-1; 1H-NMR (CDCl3, 60 MHz) δ 1.00-1.90 (12H, m), 1.90-2.90 (4H, m), 2.95-3.30 (4H, m), 3.40-3.65 (1H, m), 3.70-4.30 (5H, m), 4.45 (2H, s), 4.60-4.75 (1 H, s), 5.105.60 (1H, m), 7.25 (5H, s). (Z)-and (E)-(1S, 2S, 4R)-2-[1-(1-Piperidinyl)]-carbethoxyethenyl-4-benzyloxycyclopentyl carbonate (10b) and their enantiomers (racemic mixtures) These compounds were prepared in a manner identical to that of 10a, starting with compound 5b, also resulting in a mixture of Z + E diastereoisomers. Yield 641 mg ( 1.44 mmol, 100 %). IR (neat film) 1743, 1692, 1262, 750, 698 78 Molecules 1996, 1 cm-1; 1H-NMR (CCl4, 80MHz) δ 1.05-1.40 (6H, m), 1.401.70 (6H, m), 1.70-2.90 (4H, m), 2.90-3.30 (4H, m), 3.403.70 (1H, m), 3.75-4.30 (5H, m), 4.45 (2H, d), 4.60, 4.70 (1H, s), 5.10-5.60 (1H, m), 7.20(5H, s). 2-Carbethoxyacetyl-4-benzyloxy-cyclopentene (11) The compound 10a (234 mg, 0.526 mmol) was applied to a silica gel column (15 mL) eluting with CHCl3;. Yield 117 mg (0.406 mmol, 77 %). IR (neat film) 1742, 1653, 735, 698 cm-1; 1H-NMR (CDCl3, 80 MHz) δ 1.10-1.40 (6H, dt), 2.50-2.80 (4H, m), 3.50 (2H, s), 4.00-4.30 (5H, m), 4.45 (2H, d), 4.95 (1 H, s), 6.40-6.70 (1 H, m), 7.25 (5H, s); 13CNMR (CDCl3, 20 MHz), keto form δ 14.0 (CH3), 37.3 (CH2), 41.0 (CH2), 45.7 (CH2), 61.0 (CH2), 70.7 (CH2), 77.6 (CH), 127.5 (CH), 128.3 (CH), 138.1 (C), 142.6 (CH), 142.7 (C), 167.3 (CO), 190.0 (CO); enol form δ 14.1 (CH3), 37.7 (CH2), 40.1 (CH2), 60.0 (CH2), 70.7 (CH2), 78.2 (CH), 88.9 (CH), 127.5 (CH), 128.3 (CH), 134.1 (CH), 135.7 (C), 138.2 (C), 167.6 (CO), 172.8 (CO). 2. 3. 4. 5. 6. 7. 8. 9. 10. Acknowledgements The authors wish to thank the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ) and the Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for financial support. 11. 12. 13. References 1. Ferreira, A. G., Motidome, M.; Gottlieb, O. R.; Fernandes, J. B.; Vieira, P. C., Cojocaru, M.; Gottlieb, H. E. Phytochemistry 1989, 28, 579-583; see also syntheses of model compounds in Ferreira, J. T. B., Boscaini, R. C., Marques, F.A., Zukerman-Schpector, J. Nat. Prod. Lett. 1993, 1, 305-310; Ferreira, J. T. B., Boscaini, R. C., Marques, F.A. Nat. Prod. Lett. 1993, 2, 313-316. 14. 15. Allred, E. L.; Sonnenberg, J.; Winstein, S. J. Org. Chem. 1960, 25, 26-29. Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis, Wiley, New York, 1967, Vol. 1, p. 1079. David, F. J. Org. Chem. 1981, 46, 3512-3519. Murray, T. F.; Samsel, E. G; Varma, V.; Norton, J. R. J. Am.Chem. Soc. 1981, 103, 7520-7528. The relative stereochemistry between the acetylenic group and the hydroxyl group determined by this epoxide ring opening reaction is not the same as required for the natural product. However, in a synthesis of 1 the stereochemistry of the final product would be determined later, while introducing the farnesyl group. Pflieger, D.; Muckensturm, B. Tetrahedron 1989, 45, 2031-2040. Stacy, G. W.; Mikulec, R. A. In Organic Synthesis; Rabjohn, N., Ed.; Wiley, New York, 1963, Collect. Vol. IV, p. 13. Henbest, H. B.; Jones, E. R. H. J. Chem. Soc. 1950, 3628-3633. Constantino, M. G.; Donate, P. M.; Petragnani, N. Tetrahedron Lett. 1982, 23, 1051-1054. Constantino, M. G.; Donate, P. M.; Petragnani, N. J. Org. Chem. 1986, 51, 387-390. Stetter, H. In Houben Weyl Methoden der Organischen Chemie, Georg Thieme Verlag, Stuttgart, 1973, Vol. 7/2a, p. 837. Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1959, 81, 247. Asami, M. Bull. Chem. Soc. Jpn. 1990, 63, 1402-1408. Greene, T. W. Protective Groups in Organic Synthesis, Wiley, New York, 1981, p. 40. Molecules (electronic publication) - ISSN 1420-3049