Benzyl 3-ethoxycarbonyl-4-oxopentanoate (2).

Method A[88]:

Ethyl acetoacetate (1.30 g, 10 mmol) was added onto the surface of alumina (10.20 g, 0.1 mol) previously impregnated with potassium tert-butoxide (1.12 g, 10 mmol) and stirred for 30 min at room temperature under nitrogen. Benzyl bromoacetate (2.29 g, 10 mmol) was then added and stirring was continued in the solid phase until completion of the reaction (24 h), monitored by TLC. The solid mass was transferred to a column with a short plug of silica gel and eluted with methylene dichloride (100 ml). Evaporation of the solvent furnished practically pure product (2.36 g, 85 %), which was further purified by bulb-to-bulb distillation (temperature 130 - 140 °C, 4.10-2 mm Hg) to give a colourless oil 2 (2.20 g, 79 %).

Preparation of Alumina Impregnated with Sodium or Potassium Alkoxide.[88]

Alumina (10 times the weight of the 1,3-dicarbonyl compound, activated for 4 h at 180 °C under vacuum) was stirred with a freshly prepared solution of potassium tert-butoxide in tert-butyl alcohol, or sodium ethoxide in ethanol for 10 min at room temperature. The solvent was completely evaporated under reduced pressure to leave an easy flowing white powder which was used for alkylation on the same day.

Benzyl 3-ethoxycarbonyl-4-oxopentanoate (2) and dibenzyl 3-acetyl-3-etoxycarbonylpentanedioate (3).

Method B[87]:

Ethyl acetoacetate (1.30 g, 10 mmol) was added to a suspension of sodium hydride (0.44g, 55 - 65 % in mineral oil, 11 mmol) in THF (60 ml) precooled to 0 °C. The mixture was stirred for 10 minutes, then benzyl bromoacetate (2.29 g, 10 mmol) was added. Stirring was continued for 3 h at 0 °C and overnight at room temperature. Addition of 1 N HCl (100 ml) was followed by extraction with ether (3 x 100 ml). The ether extracts were dried over MgSO4 and evaporated. The residue was distilled by bulb-to-bulb distillation (temperature 130 - 140 °C, 4.10-2 mm Hg) to give a colourless oil 2 (1.86 g, 67 %). The residue from the distillation was purified by flash chromatography (silica gel, CHCl3) to give a colourless oil 3 (0.47 g, 11 %).

Benzyl 3-ethoxycarbonyl-4-oxopentanoate (2)B.p. 130-140°/4.10-2 mm Hg. IR (film, KBr): 2984w, 2939w, 1737s, 1720s, 1498w, 1456w, 1410w, 1387w, 1358m, 1320m, 1263m, 1160s, 1097w, 1021w, 957w, 858w, 753w, 699w. 1H-NMR (400 MHz, CDCl3, 298 K): 7.38 - 7.29 (m, 5H, HCarom.); 5.11 (s, 2H, H2C(11)); 4.18 (2q from AB x q, 3J(32,33) = 7.1, 2H, H2C(32)); 3.99 (dd, 3J(3,2A) = 8.1, 3J(3,2B) = 6.4, 1H, HC(3)); 3.02 (dd, 2J(2A,2B) = 17.6, 3J(2A,3) = 8.1, 1H, HAC(2)); 2.89 (dd, 2J(2B,2A) = 17.6, 3J(2B,3) = 6.4, 1H, HBC(2)); 2.33 (s, 3H, H3C(5)); 1.25 (t, 3J(33,32) = 7.1, 3H, H3C(33)). 13C-NMR (100 MHz, CDCl3, 298 K): 202.2 (C(4)); 171.8 (C(1)); 168.9 (C(31)); 136.2 (C(12)); 129.2 (C(14,14')); 129.0 (C(15)); 128.9 (C(13,13')); 67.4 (C(11)); 62.5 (C(32)); 55.3 (C(3)); 33.0 (C(2)); 30.5 (C(5)); 14.6 (C(33)). EI-MS: 278 (4, [M]+), 172 (12), 171 (56), 144 (23), 143 (37), 130 (15), 115 (5), 108 (5), 107 (12), 102 (5), 101 (15), 98 (5), 97 (5), 92 (5), 91 (100), 65 (5), 43 (31).

Dibenzyl 3-acetyl-3-etoxycarbonylpentanedioate (3). IR (film, KBr): 3091w, 3066w, 3034m, 2982m, 2959m, 2907w, 1805m, 1735s, 1604w, 1586w, 1498m, 1456s, 1415m, 1384s, 1349s, 1285s, 1259s, 1168s, 1099m, 1080m, 1018m, 978m, 917w, 860w, 827w, 814w, 751s, 699s, 601w, 580w, 543w, 492w, 486w. 1H-NMR (400 MHz, CDCl3, 298 K): 7.37 - 7.29 (m, 10H, HCarom.); 5.08 (s, 4H, H2C(11 and 51)); 4.13 (q, 3J(32,33) = 7.1, 2H, H2C(32)); 3.22 (d, 2J(2A,2B) = 2J(4A,4B) = 17.1, 2H, HAC(2 and 4)); 3.17 (d, 2J(2B,2A) = 2J(4B,4A) = 17.1, 2H, HBC(2 and 4)); 2.25 (s, 3H, H3C(35)); 1.16 (t, 3J(33,32) = 7.1, 3H, H3C(33)). 13C-NMR (100 MHz, CDCl3, 298 K): 203.0 (C(34)); 171.2 (C(1) and C(55)); 170.4 (C(31)); 136.1 (C(12) and C(52)); 129.2 (C(14,14') and C(54,54')); 129.0 (C(15) and C(55)); 128.9 (C(13,13') and C(53,53')); 67.4 (C(11) and C(51)); 62.9 (C(32)); 60.0 (C(3)); 38.3 (C(2) and C(4)); 27.3 (C(35)); 14.4 (C(33)). EI-MS: 428 (7, [M + 2]+), 427 (21, [M + 1]+), 319 (27), 276 (12), 272 (8), 230 (10), 229 (83), 188 (16), 186 (15), 185 (96), 183 (14), 182 (13), 181 (81), 180 (18), 169 (24), 158 (22), 141 (29), 138 (16), 113 (8), 92 (9), 91 (100).

Ethyl 3-ethoxycarbonyl-4-oxopentanoate (7).

The mixture of benzyl 3-ethoxycarbonyl-4-oxopentanoate (2.78 g, 10 mmol) and Pd on active charcoal (100 mg, 10 %) in ethanol (50 ml) was stirred in an autoclave under H2 (70 atm) for 1 h, then filtered through Celite. Evaporation of solvent furnished practically pure product (1.97 g, 91 %), which was further purified by bulb-to-bulb distillation (temperature 60 - 70 °C, 7.10-2 mm Hg) to give a colourless oil 7[133] (1.88 g, 87 %).

B.p. 60 - 70°/7.10-2 mm Hg. IR (film, KBr): 2985m, 2940w, 2910w, 1736s, 1654w, 1467w, 1448m, 1412m, 1396m, 1370m, 1321m, 1263s, 1163s, 1098m, 1035s, 966w, 935w, 859w, 803w. 1H-NMR (400 MHz, CDCl3, 298 K): 4.16 (q, 3J(11,12) = 7.1, 2H, H2C(11)); 4.07 (q, 3J(32,33) = 7.1, 2H, H2C(32)); 3.93 (dd, 3J(3,2A) = 8.1, 3J(3,2B) = 6.4, 1H, HC(3)); 2.90 (dd, 2J(2A,2B) = 17.5, 3J(2A,3) = 8.1, 1H, HAC(2)); 2.78 (dd, 2J(2B,2A) = 17.5, 3J(2B,3) = 6.4, 1H, HBC(2)); 2.30 (s, 3H, H3C(5)); 1.23 (t, 3J(12,11) = 7.1, 3H, H3C(12)); 1.20 (t, 3J(33,32) = 7.1, 3H, H3C(33)). 13C-NMR (100 MHz, CDCl3, 298 K): 202.3 (C(4)); 171.9 (C(1)); 169.0 (C(31)); 62.4 (C(11)); 61.5 (C(32)); 55.2 (C(3)); 32.9 (C(2)); 30.5 (C(5)); 14.7 (C(12)); 14.6 (C(33)). EI-MS: 218 (9, [M + 2]+), 217 (85, [M + 1]+), 199 (6), 175 (6), 174 (58), 172 (11), 171 (100), 143 (50), 128 (34), 115 (4), 101 (8), 100 (16), 97 (5), 73 (5), 55 (8), 43 (21).

DCI-MS: 235 (12, [M + 19]+), 234 (100, [M + 18]+), 218 (6, [M + 2]+), 217 (66, [M + 1]+), 199 (7), 188 (15), 174 (8), 171 (41), 143 (6).

3-Ethoxycarbonyl-4-oxopentanoic acid (4).

The mixture of benzyl 3-ethoxycarbonyl-4-oxopentanoate (2.78 g, 10 mmol) and Pd on active charcoal (100 mg, 10 %) in ether (50 ml) was stirred in an autoclave under H2 (70 atm) for 1 h, then filtered through Celite and concentrated. The product was purified by flash chromatography (silica gel, heptane/AcOEt 1:1) to give a colourless oil 4[134] (1.58 g, 84 %).

IR (film, KBr): 3199m, 2986m, 2942m, 2670w, 1739s, 1718s, 1467w, 1406m, 1369m, 1265s, 1160s, 1097w, 1021m, 963w, 931w, 858w, 806w, 628w, 492w. 1H-NMR (400 MHz, CDCl3, 298 K): 10.64 (br. s, 1H, HOOC(1)); 4.18 (q, 3J(32,33) = 7.1, 2H, H2C(32)); 3.92 (t, 3J(3,2A) = 3J(3,2B) Å 7.0, 1H, HC(3)); 2.98 (dd, 2J(2A,2B) = 17.9, 3J(2A,3) = 8.0 , 1H, HAC(2)); 2.85 (dd, 2J(2B,2A) = 17.9, 3J(2B,3) = 6.3 , 1H, HBC(2)); 2.31 (s, 3H, H3C(5)); 1.25 (t, 3J(33,32) = 7.1, 3H, H3C(33)). 13C-NMR (100 MHz, CDCl3, 298 K): 202.2 (C(4)); 177.8 (C(1)); 168.8 (C(31)); 62.6 (C(32)); 55.0 (C(3)); 32.6 (C(2)); 30.4 (C(33)); 14.6 (C(5)). EI-MS: 190 (15, [M + 2]+), 189 (5, [M + 1]+), 185 (3), 173 (2), 155 (1), 94 (1), 86 (2), 77 (1), 60 (3), 55 (5), 52 (55), 51 (100), 50 (74).

Methyl 3-acetyl-4-oxopentanoate (8).

The 2,4-pentanedione (1.00 g, 10 mmol) was added slowly at 0 °C to a suspension of sodium hydride (0.44g, 55 - 65 % in mineral oil, 11 mmol) in THF (60 ml). After the mixture was stirred for 10 min, methyl bromoacetate (1.53 g, 10 mmol) was added. Stirring was continued for 3 h at 0 °C and overnight at room temperature. Addition of 1 N HCl (100 ml) was followed by extraction with ether (5 x 50 ml). The ether extracts were dried over MgSO4 and evaporated. The residue was purified by flash chromatography (silica gel, CH2Cl2/ether 4:1) to give a colourless oil 8[90] (oxo/enol 70:30, 1.39 g, 81 %).

IR (film, KBr): 3005m, 2957m, 2850w, 1734s, 1704s, 1605m, 1438s, 1361s, 1325m, 1256s, 1204s, 1162s, 1094w, 1043w, 1004m, 954m, 895w, 841w, 763w, 702w, 612w, 566w, 498w, 457w. 1H-NMR (400 MHz, CDCl3, 298 K): 11.29 (s, 1H, HO-enol); 4.11 (t, 3J(3,2) = 7.2, 1H, HC(3)oxo); 3.67 (s, 3H, H3C(11)enol); 3.64 (s, 3H, H3C(11)oxo); 3.23 (s, 2H, H2C(2)enol); 2.85 (d, 3J(2,3) = 7.2, 2H, H2C(2)oxo); 2.23 (s, 3H, H3C(5)oxo); 2.12 (s, 3H, H3C(5)enol). 13C-NMR (100 MHz, CDCl3, 298 K): 202.3 (C(4)oxo); 191.8 (C(4)enol); 171.9 (C(1)enol); 171.6 (C(1)oxo); 104.2 (C(3)enol); 63.1 (C(3)oxo); 52.0 (C(11)oxo-enol); 33.0 (C(2)enol); 32.2 (C(2)oxo); 29.5 (C(5)oxo); 23.2 (C(5)enol). EI-MS: 173 (12, [M + 1]+), 172 (13), 141 (19), 140 (15), 131 (7), 130 (36), 125 (8), 113 (36), 112 (9), 99 (20), 98 (40), 97 (15), 74 (8), 71 (66), 70 (17), 69 (12), 59 (12), 55 (23), 44 (100), 43 (8), 42 (8).

3-Acetyl-4-oxopentanoic acid (9).

A slowly stirred solution of methyl 3-acetyl-4-oxopentanoate (517 mg, 3 mmol), in 0.1 M (NaH2PO4/Na2HPO4 1:5) buffer (30 ml) at 20 °C was neutralised to pH 7.8 with 0.1 M aqueous NaOH by using a pH-stat. PLE (130 U) was then added, and the pH of the solution was maintained at 7.8. The hydrolysis proceeded until 1 equiv of base (30 ml) had been consumed (3 h), at which point it stopped. A solution of 1.0 M aqueous NaOH was then added to adjust a pH > 9. The resulting solution was immediately washed with chloroform (2 x 20 ml) to remove unreacted ester then acidified to pH < 3 with 2 M hydrochloric acid. It was then extracted with ether (5 x 30 ml). Evaporation of the dried (MgSO4) ether extracts followed by flash chromatography (silica gel, CH2Cl2/ether/AcOH 8:2:1) yielded the product 9[135] (403 mg, 85 %) as a colourless oil.

M.p. 72.0-72.5°. IR (film, KBr): 3008m, 1718s, 1416s, 1363s, 1255s, 1199s, 1162s, 1088w, 1022w, 953m, 834w, 779w, 614w, 572w, 505w. 1H-NMR (400 MHz, CDCl3, 298 K): 11.31 (s, 1H, HO-enol); 10.30 (br. s, 1H, HOOC(1); 4.08 (br. t, 3J(3,2) Å 6.7, 1H, HC(3)oxo); 3.29 (s, 2H, H2C(2)enol); 2.91 (d, 3J(2,3) = 7.2, 2H, H2C(2)oxo); 2.25 (s, 3H, H3C(5)oxo); 2.15 (s, 3H, H3C(5)enol). 13C-NMR (100 MHz, CDCl3, 298 K): 202.3 (C(4,31)oxo); 192.0 (C(4,31)enol); 177.6 (C(1)enol); 176.8 (C(1)oxo); 103.7 (C(3)enol); 62.9 (C(3)oxo); 33.0 (C(2)enol); 32.2 (C(2)oxo); 29.5 (C(5,32)oxo); 23.3 (C(5,32)enol). DCI-MS: 177 (9, [M + 19]+), 176 (93, [M + 18]+), 159 (36), 158 (8), 141 (3), 98 (4), 72 (4), 71 (7), 70 (4), 69 (4), 55 (3), 46 (5), 44 (100), 43 (6), 42 (6), 40 (10).

(E,Z)-Ethyl 2-acetyl-3-(2-furanyl)propenoate (10).

A solution of TiCl4 (22 ml, 0.2 mol) in absolute CCl4 (50 ml) was added dropwise to absolute THF (200 ml) at - 5 °C to form a yellow precipitate. Then a solution of 2-furaldehyde (8.3 ml, 9.6 g, 0.1 mol) and ethyl acetoacetate (12.6 ml, 13 g, 0.1 mol) in THF (50 ml) was added. Then a solution of absolute pyridine (32 ml) in THF (60 ml) was added dropwise during 1 h. The mixture was stirred for 24 h at - 5 °C, warmed up to room temperature and water (50 ml) and ether (50 ml) were added and the aqueous phase was extracted with ether (3 x 50 ml). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue was distilled by bulb-to-bulb distillation (temperature 160 - 170 °C, 12 mm Hg) to give a colourless oil 10[136] (16.0 g, 77 %, E/Z 3:4).

B.p. 160-170°/12 mm Hg. IR (film, KBr): 3127w, 2984w, 2939w, 1719s, 1662m, 1626s, 1548w, 1473m, 1447w, 1423w, 1392m, 1379m, 1344m, 1247s, 1211s, 1179m, 1081m, 1059m, 1023s, 974w, 952w, 933w, 886m, 875w, 760m, 593m, 560w. EI-MS: 209 (12, [M + 1]+), 208 (86, [M]+), 193 (17), 179 (30), 166 (12), 165 (18), 163 (46), 162 (15), 151 (20), 134 (14), 121 (89), 120 (100), 119 (13), 97 (16), 94 (10), 93 (15), 92 (21), 86 (28), 84 (38), 78 (11), 77 (24), 66 (12), 65 (74), 64 (24), 63 (41), 53 (14), 51 (18), 49 (32), 43 (71).

(Z) Ethyl 2-acetyl-3-(2-furanyl)propenoate (10a). 1H-NMR (400 MHz, CDCl3, 298 K): 7.50 (d, 3J(34,33) = 1.8, 1H, HC(34)); 7.26 (s, 1H, HC(3)); 6.78 (d, 3J(32,33) = 3.5, 1H, HC(32)); 6.47 (dd, 3J(33,32) = 3.5, 3J(33,34) = 1.8, 1H, HC(33)); 4.36 (q, 3J(11,12) = 7.1, 2H, H2C(11)); 2.32 (s, 3H, H3C(22)); 1.32 (t, 3J(12,11) = 7.1, 3H, H3C(12)). 13C-NMR (100 MHz, CDCl3, 298 K): 193.9 (C(21)); 167.5 (C(1)); 148.9 (C(31)); 146.4 (C(34)); 129.9 (C(2)); 126.4 (C(3)); 118.7 (C(32)); 112.9 (C(33)); 61.6 (C(11)); 26.4 (C(22)); 14.1 (C(12)).

(E) Ethyl 2-acetyl-3-(2-furanyl)propenoate (10b). 1H-NMR (400 MHz, CDCl3, 298 K): 7.47 (d, 3J(34,33) = 1.8, 1H, HC(34)); 7.31 (s, 1H, HC(3)); 6.71 (d, 3J(32,33) = 3.5, 1H, HC(32)); 6.43 (dd, 3J(33,32) = 3.5, 3J(33,34) = 1.8, 1H, HC(33)); 4.22 (q, 3J(11,12) = 7.1, 2H, H2C(11)); 2.43 (s, 3H, H3C(22)); 1.26 (t, 3J(12,11) = 7.1, 3H, H3C(12)). 13C-NMR (100 MHz, CDCl3, 298 K): 202.1 (C(21)); 164.5 (C(1)); 149.1 (C(31)); 146.1 (C(34)); 129.6 (C(2)); 125.9 (C(3)); 117.7 (C(32)); 112.6 (C(33)); 61.4 (C(11)); 31.0 (C(22)); 14.1 (C(12)).

Ethyl 2-(2-furanylmethyl)-3-hydroxybutanoate (11).

To a suspension of sodium hydroden telluride [103], prepared by stirring tellurium powder (0.31 g, 0.0024 mol) with NaBH4 (0.214 g, 0.0056 mol) in 10 ml of ethanol for 2 h at 25 °C under N2, was added a solution of ethyl 2-acetyl-3-(2-furanyl)propenoate (0.21 g, 0.001 mol) in 1 ml of ethanol. The mixture was stirred for 7 h, then filtered through Celite. Evaporation of the solvent was followed by addition of water (30 ml) and extraction with chloroform (6 x 20 ml). The chloroform extracts were dried over MgSO4 and evaporated under reduced pressure. The residue was preadsorbed on silica gel and purified by flash chromatography (silica gel, CHCl3/MeOH 99:1) to afford of slightly yellow oil 11 (0.17 g, 81 %).

1H-NMR (200 MHz, CDCl3, 298 K): 7.28 (br. d, 3J(25,24) = 1.8, 1H, HC(25)); 6.25 (br. t, 1H, HC(24)); 6.03 (br. t, 3J(23,24) = 3.3, 1H, HC(23)); 4.18 - 3.87 (m, 3H, H2C(11) and HC(3)); 3.04 - 2.98 (m, 2H, H2C(21)); 2.84 - 2.70 (m, 2H, HO and HC(2)); 1.26 - 1.15 (m, 6H, H3C(12) and H3C(4)). 13C-NMR (50 MHz, CDCl3, 298 K): 174.4 and 174.2 (C(1)); 153.1 and 152.6 (C(22)); 141.5 and 141.4 (C(25)); 110.3 (C(23)); 106.6 and 106.3 (C(24)); 67.8 and 67.8 (C(3)); 60.8 (C(11)); 51.5 and 51.4 (C(2)); 27.9 and 26.1 (C(21)); 21.5 and 20.4 (C(4)); 14.2 (C(12)).

Ethyl 2-(2-furanylmethyl)-3-tert-butyldimethylsilyloxybutanoate (12).

To a solution of ethyl 2-(2-furanylmethyl)-3-hydroxybutanoate (56 mg, 0.264 mmol) and imidazole (22 mg, 0.324 mmol) in dry DMF (0.26 ml) was added tert-butyldimethylchlorsilane (44.7 mg, 0.298 mmol) and the mixture was stirred under an atmosphere of N2. When the TLC analysis showed the complete consumption of the starting material (48 h), the reaction mixture was poured into ice/water (1.5 ml), and the resulting suspension was sequentially extracted with diethyl ether (2 x 5 ml) and hexane (2 x 5 ml). The combined organic layers were washed with water (5 ml) and saturated NaCl (5 ml), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, CHCl3/MeOH 99:1) to give a clear colourless oil 12 (71 mg, 83 %).

1H-NMR (200 MHz, CDCl3, 298 K): 7.28 (br. d, 3J(25,24) Å 1.1, 1H, HC(25)); 6.25 (br. dd, 3J(24,23) = 3.3, 3J(24,25) = 1.8, 1H, HC(24)); 6.00 (br. d, 3J(23,24) Å 3.3, 1H, HC(23)); 4.07 (q, 3J(11,12) = 7.2, 2H, H2C(11)); 4.13 - 4.01 (m, 1H, HC(3)); 3.00 - 2.71 (m, 3H, HC(2) and H2C(21)); 1.26 - 1.14 (m, 6H, H3C(12) and H3C(4)); 0.89 and 0.87 (s, 9H, H3C(32)); 0.07 and 0.05 (s, 6H, H3C(31)). 13C-NMR (50 MHz, CDCl3, 298 K): 173.5 and 173.1 (C(1)); 153.7 and 153.5 (C(22)); 141.1 and 141.0 (C(25)); 110.1 (C(23)); 105.9 and 105.8 (C(24)); 69.2 and 69.1 (C(3)); 60.3 and 60.2 (C(11)); 53.1 and 53.1 (C(2)); 27.0 and 26.4 (C(21)); 25.7 and 25.7 (C(32)); 21.8 and 21.1 (C(4)); 18.0 and 17.9 (C(33)); 14.1 (C(12)); -5.0 and -5.1 (C(31)).

Ethyl 2-(2-furanylmethyl)-3-triethylsilyloxy-2-butenoate (13).

To the solution of ethyl 2-acetyl-3-(2-furanyl)propenoate (2.08 g, 10 mmol) and tris(triphenylphosphine)rhodiumchloride (0.093 g, 0.1 mmol, 1 mol %) in dry benzene (10 ml) was added triethylsilane (1.6 ml, 10 mmol), and the mixture was stirred at 55 °C under an atmosphere of N2. When TLC analysis showed the complete consumption of the starting material (24 h), the solvent was removed under reduced pressure to give the crude product 13 (2.98 g). The 1H-NMR spectrum of the reaction mixture showed the exclusive formation of 1,4 adduct 13 (78 %). The crude product contained 16 % of desilylated ethyl 2-(2-furanylmethyl)-3-oxobutanoate 14.

1H-NMR (200 MHz, CDCl3, 298 K): 7.24 (br. d, 3J(25,24) Å 1.0, 1H, HC(25)); 6.23 (br. dd, 3J(24,23) Å 3.1, 3J(24,25) Å 1.9, 1H, HC(24)); 5.89 (br. dd, 3J(23,24) Å 3.1, 4J(23,21) Å 0.9, 1H, HC(23)); 4.14 (q, 3J(11,12) = 7.1, 2H, H2C(11)); 3.68 (br. s, 2H,H2C(21)); 2.36 (s, 3H, H3C(4)); 1.22 (t, 3J(12,11) = 7.1, 3H, H3C(12)); 1.01 - 0.89 (m, 9H, H3C(32)); 0.79 - 0.67 (m, 6H, H2C(31)).

Ethyl 2-(2-furanylmethyl)-3-oxobutanoate (14).

A crude reaction mixture (2.98 g) containing ethyl 2-(2-furanylmethyl)-3-triethylsilyloxy-2-butenoate and ethyl 2-(2-furanylmethyl)-3-oxobutanoate (78:16) was dissolved in a mixture of THF/AcOH/H2O 4:4:1 (90 ml) and was stirred at 45 °C under an atmosphere of N2. When TLC analysis showed the complete consumption of starting material (16 h), the reaction mixture was poured into water (100 ml) and extracted with ether (3 x 30 ml). The combined organic phases were washed with aqueous NaHCO3 (3 x 30 ml), and dried over MgSO4. Evaporation of the solvent furnished practically pure product (1.8 g, 87 % - calculated from ethyl 2-acetyl-3-(2-furanyl)propenoate) which was further purified by flash chromatography (silica gel, heptane/AcOEt 2:1) to give a yellow oil 14[137] (609 mg, 29 %).

IR (film, KBr): 2984m, 2939w, 2877w, 1742s, 1718s, 1650w, 1600w, 1508w, 1467w, 1446w, 1429m, 1361m, 1322m, 1251s, 1203s, 1148s, 1097m, 1080m, 1016m, 962w, 933w, 885w, 860w, 807w, 740m, 600w. 1H-NMR (400 MHz, CDCl3, 298 K): 7.28 (dd, 3J(25,24) = 1.9, 4J(25,23) = 0.8 , 1H, HC(25)); 6.25 (ddt, 3J(24,23) = 3.2, 3J(24,25) = 1.9, 5J(24,21) = 0.3, 1H, HC(24)); 6.03 (ddt, 3J(23,24) = 3.2 , 4J(23,25) = 0.8, 4J(23,21) = 0.9, 1H, HC(23)); 4.18 (2q from AB x q, 3J(11,12) = 7.1, 2H, H2C(11)); 3.86 (dd, 3J(2,21A) = 7.3,3J(2,21B) = 7.6, 1H, HC(2)); 3.18 (ddd, 2J(21A,21B) = 15.6, 3J(21A,2) = 7.3, 4J(21A,23) = 1.2, 1H, HAC(21)); 3.17 (ddd, 2J(21B,21A) = 15.6, 3J(21B,2) = 7.6, 4J(21B,23) = 1.2, 1H, HBC(21)); 2.23 (d, 4J(4,2) = 0.3, 3H, HC(4)); 1.24 (t, 3J(12,11) = 7.1, 3H, H3C(12)). 13C-NMR (100 MHz, CDCl3, 298 K): 201.9 (C(3)); 168.7 (C(1)); 151.8 (C(22)); 141.5 (C(25)); 110.3 (C(24)); 106.6 (C(23)); 61.6 (C(11)); 58.2 (C(2)); 29.3 (C(4)); 26.5 (C(21)); 14.0 (C(12)). EI-MS: 210 (9, [M]+), 168 (5), 167 (24), 139 (6), 137 (13), 136 (7), 122 (8), 121 (51), 94 (9), 91 (5), 82 (5), 81 (42), 69 (6), 68 (13), 66 (7), 65 (8), 46 (6), 44 (100), 42 (10). DCI-MS: 229 (27, [M + 19]+), 228 (100, [M + 18]+), 212 (23), 211 (94), 210 (5), 167 (8), 121 (4), 81 (12).

Methyl 3-methoxymethyl-4-oxopentanoate (16).

To a rapidly stirred mixture of formaldehyde dimethylacetal (0.44 ml, 4.95 mmol) and freshly distilled TiCl4 (2 equiv.,1.1 ml, 9.9 mmol) in dry methylene chloride (30 ml), a methylene chloride (10 ml) solution of silyl enol ether 15[113] (1 g, 4.95 mmol) was added dropwise at -78 °C under an atmosphere of dry N2, and the reaction mixture was stirred at the same temperature for 1 h and then at -20 °C for 47 h. After hydrolysis with saturated solution of NaCl (20 ml) the mixture was extracted with methylene chloride (3 x 30 ml). Evaporation of the dried (MgSO4) methylene chloride extracts followed by flash chromatography (silica gel, hexane/AcOEt 1:1) yielded the product 16 (698 mg, 81 %) as a colourless oil.

IR (film, KBr): 2997w, 2955m, 2933m, 2899m, 2834w, 1738s, 1718s, 1682m, 1636w, 1439s, 1416m, 1360s, 1265m, 1205s, 1166s, 1120s, 1039w, 1010m, 954w, 888w. 1H-NMR (400 MHz, CDCl3, 298 K): 3.64 (s, 3H, H3C(11)); 3.49 (dd, 2J(31B,31A) = 10.6, 3J(31B,3) = 5.9, 1H, HBC(31)); 3.48 (dd, 2J(31A,31B) = 10.6, 3J(31A,3) = 6.0, 1H, HAC(31)); 3.29 (s, 3H, H3C(32)); 3.24 - 3.17 (m, 1H, HC(3)); 2.78 (dd, 2J(2A,2B) = 17.1, 3J(2A,3) = 9.0, 1H, HAC(2)); 2.40 (dd, 2J(2B,2A) = 17.1, 3J(2B,3) = 5.1, 1H, HBC(2)); 2.24 (s, 3H, H3C(5)). 13C-NMR (100 MHz, CDCl3, 298 K): 208.8 (C(4)); 172.6 (C(1)); 72.7 (C(31)); 59.0 (C(32)); 51.7 (C(11)); 48.5 (C(3)); 32.5 (C(2)); 29.9 (C(5)). DCI-MS: 192 (17, [M + 18]+), 176 (5), 175 (53), 160 (5), 143 (11), 110 (4), 101 (3), 100 (3), 61 (2), 52 (10), 36 (55), 35 (100).

3-Methoxymethyl-4-oxopentanoic acid (17).

A slowly stirred solution of methyl 3-methoxy-4-oxopentanoate (523 mg, 3 mmol), in 0.1 M (NaH2PO4/Na2HPO4 1:5) buffer (30 ml) at 20 °C was neutralised to pH 7.8 with 0.1 M aqueous NaOH by using a pH-stat. PLE (130 U) was then added, and the pH of the solution was maintained at 7.8. The hydrolysis proceeded until 1 equiv of base (30 ml) had been consumed (24 h), at which point it stopped. A solution of 1.0 M aqueous NaOH was then added to pH > 9. The resulting solution was immediately washed with chloroform (2 x 20 ml) to remove unreacted ester then acidified to pH < 3 with 2 M hydrochloric acid and was then extracted with ether (5 x 30 ml). Evaporation of the dried (MgSO4) ether extracts followed by flash chromatography (silica gel, hexane/AcOEt 1:1) yielded the product 17 (346 mg, 72 %) as a colourless oil.

IR (film, KBr): 3455m, 2983m, 2932s, 2361w, 1714s, 1387s, 1367m, 1169s, 1118s, 1037w, 960w, 937w, 911w, 688w, 629w, 569w. 1H-NMR (400 MHz, CDCl3, 298 K): 3.52 (dd, 2J(31B,31A) = 11.3, 3J(31B,3) = 5.8, 1H, HBC(31)); 3.51 (dd, 2J(31A,31B) = 11.3, 3J(31A,3) = 5.9, 2H, HAC(31)); 3.31 (s, 3H, H3C(32)); 3.22 - 3.15 (m, 1H, HC(3)); 2.85 (dd, 2J(2A,2B) = 17.4, 3J(2A,3) = 8.9, 1H, HAC(2)); 2.46 (dd, 2J(2B,2A) = 17.4, 3J(2B,3) = 4.9, 1H, HBC(2)); 2.26 (s, 3H, H3C(5)). 13C-NMR (100 MHz, CDCl3, 298 K): 208.7 (C(5)); 177.6 (C(1)); 72.5 (C(31)); 59.1 (C(32)); 48.4 (C(3)); 32.5 (C(2)); 29.8 (C(5)). DCI-MS: 178 (50, [M + 18]+), 162 (12), 161 (100), 160 (13), 149 (5), 146 (29), 144 (6), 143 (71), 142 (8), 129 (28) 128 (15), 111 (14), 110 (9), 101 (18), 85 (6), 71 (5), 68 (5), 58 (5), 45 (14), 43 (11).