Efficient Conditions for Conversion of 2-Substituted Furans into 4

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J. Org. Chem. 1998, 63, 7505-7515

7505

Efficient Conditions for Conversion of 2-Substituted Furans into 4-Oxygenated 2-Enoic Acids and Its Application to Synthesis of (+)-Aspicilin, (+)-Patulolide A, and (-)-Pyrenophorin Yuichi Kobayashi,* Miwa Nakano, G. Biju Kumar, and Kiyonobu Kishihara Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan Received May 19, 1998

2-Substituted furans 1a,b,c were found to be conveniently transformed into trans 4-oxo-2-enals 2a,b,c in 62-87% yields by using NBS/pyridine in THF-acetone-H2O (97% (38) Reaction was carried out by T. Okui of our laboratory.

J. Org. Chem., Vol. 63, No. 21, 1998 7511 ee: [R]20D ) +12 to +14) and CuCN (19 mg, 0.21 mmol) in THF (5 mL) was added the above Grignard reagent 14 (19 mL, 0.34 M in THF, 6.5 mmol) between -55 to -60 °C over 40 min. The resulting mixture was stirred below -30 °C for 1 h, warmed to 0 °C over 1 h, and then poured into a mixture of ethyl acetate and saturated NH4Cl with vigorous stirring. After separation of the phases, the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated to give a residue, which was purified by chromatography (hexane/ethyl acetate) to afford 15 (803 mg, 88%). Since ee of the starting epoxide was not given, 15 was transformed to the bis-MTPA ester by the standard procedure39 [(1) (R)-(-)-MTPACl, pyridine/CHCl3 (1: 1), 0 °C to room temperature; (2) Me2N(CH2)3NH2] and ee was determined to be >95%: [R]23D ) +5.2 (c 0.96, CHCl3); bp 120135 °C (1 Torr); IR (neat) 3338, 1641, 993, 908 cm-1; 1H NMR δ 1.18 (d, J ) 6 Hz, 3 H), 1.22-1.52 (m, 19 H), 2.04 (q, J ) 7 Hz, 2 H), 3.73-3.88 (m, 1 H), 4.93 (d, J ) 10 Hz, 1 H), 5.00 (d, J ) 17 Hz, 1 H), 5.82 (ddt, J ) 17, 10, 7 Hz, 1 H); 13C NMR δ 139.3, 114.2, 68.0, 39.3, 33.7, 29.60, 29.55, 29.52, 29.42, 29.1, 28.9, 25.7, 23.3. HRMS (CI) m/z calcd for C14H29O (M + H)+ 213.2218, found 213.2222. Anal. Calcd for C14H28O: C, 79.18; H, 13.29. Found: C, 79.18; H, 13.13. (2S)-13-Tetradecen-2-ol (15) from (R)-Epichlorohydrin (29). To a mixture of (R)-epichlorohydrin (29) (463 mg, 5.0 mmol, 98.8% ee) and CuCN (22 mg, 0.25 mmol) in THF (5 mL) at -50 °C was added slowly a THF solution of 14 (14 mL, 0.46 M, 6.44 mmol), which had been prepared from Mg (800 mg, 0.033 g-atom), 11-bromo-1-undecene (4.9 g, 21 mmol), 1,2dibromoethane (4 drops), and THF (total 40 mL) in a similar manner described above. The mixture was stirred between -20 and -30 °C for 1.5 h and poured into a mixture of saturated NH4Cl and ethyl acetate with vigorous stirring. Extraction and purification as mentioned above afforded (2R)1-chloro-13-tetradecen-2-ol (1.23 g, 100%): IR (neat) 3371, 1641, 993, 910 cm-1; 1H NMR δ 1.15-1.63 (m, 18 H), 2.04 (q, J ) 7 Hz, 2 H), 2.30 (d, J ) 3 Hz, 1 H), 3.47 (dd, J ) 11, 7 Hz, 1 H), 3.63 (dd, J ) 11, 3 Hz, 1 H), 3.75-3.85 (m, 1 H), 4.93 (d, J ) 10 Hz, 1 H), 5.00 (d, J ) 17 Hz, 1 H), 5.81 (ddt, J ) 17, 10, 7 Hz, 1 H); 13C NMR δ 139.4, 114.2, 71.5, 50.5, 34.2, 33.8, 29.52, 29.50, 29.46, 29.44, 29.1, 28.9, 25.5. To an ice-cold solution of the above chloride (1.23 g, 5.0 mmol) in THF (15 mL) was added LiAlH4 (143 mg, 3.77 mmol) portionwise. The mixture was stirred at room temperature overnight and cooled to 0 °C. After sequential addition of ethyl acetate (0.98 mL, 10 mmol), H2O (0.45 mL, 25 mmol), and NaF (1.05 g, 25 mmol), the resulting mixture was stirred at room temperature for 1 h and filtered through a pad of Celite with ethyl acetate. The filtrate was concentrated, and the residue was purified by chromatography (hexane/ethyl acetate) to furnish the title alcohol 15 (1.05 g, 99%), 1H NMR spectrum of which was identical with that obtained from (S)-propylene oxide (13). (2S)-13-Tetradecyn-2-ol (16). To a solution of olefin 15 (2.12 g, 10 mmol) in CHCl3 (15 mL) was added bromine (0.52 mL, 10 mmol) slowly at -50 °C. After 15 min, the solution was poured into a vigorously stirred aqueous Na2S2O3 with Et2O. The organic layer was separated, and the aqueous layer was extracted with Et2O twice. The combined organic layers were concentrated to give the bromine-adduct, which was used for the next reaction without further purification. To a suspension of NaNH2 in liquid NH3 (ca. 200 mL), which had been prepared from sodium metal (1.6 g, 0.070 g-atom) and a catalytic amount of Fe(NO3)3‚9H2O in NH3, was added a solution of the above bromine-adduct in THF (8 mL) slowly. The cooling bath was removed and stirring was continued. After 1 h, a mixture of H2O-THF (ca. 1:1), saturated NH4Cl, and Et2O were added successively, and the resulting mixture was stirred overnight at room temperature. The product was extracted with Et2O several times, and the combined ethereal solutions were dried over MgSO4 and concentrated. The (39) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543-2549.

7512 J. Org. Chem., Vol. 63, No. 21, 1998 residue was purified by chromatography (hexane/ethyl acetate) to afford acetylene 16 (2.01 g, 96% from 15): [R]22D ) +6.3 (c 0.94, CHCl3); IR (neat) 3360, 3311, 2117 cm-1; 1H NMR δ 1.19 (d, J ) 6 Hz, 3 H), 1.22-1.58 (m, 19 H), 1.94 (t, J ) 3 Hz, 1 H), 2.18 (dt, J ) 3, 7 Hz, 2 H), 3.72-3.86 (m, 1 H); 13C NMR δ 84.9, 68.2, 68.1, 39.4, 29.60, 29.54, 29.48, 29.43, 29.1, 28.7, 28.5, 25.7, 23.4, 18.3. HRMS (CI) m/z calcd for C14H27O (M + H)+ 211.2062, found 211.2059. Anal. Calcd for C14H26O: C, 79.94; H, 12.46. Found: C, 79.88; H, 12.42. (13S)-13-[(tert-Butyldimethylsilyl)oxy]-1-tetradecyne (17). A solution of alcohol 16 (2.01 g, 9.57 mmol), TBDMSCl (1.73 g, 11.5 mmol), and imidazole (0.98 g, 14.4 mmol) in DMF (20 mL) was stirred overnight at room temperature and poured into a mixture of hexane and saturated NaHCO3. After being vigorously stirred at room temperature for 30 min, the layers were separated, and the aqueous layer was extracted with hexane twice. The combined hexane solutions were dried over MgSO4 and concentrated to give an oil, which was purified by chromatography (hexane/ethyl acetate) to afford the silyl ether 17 (3.12 g, 100%): [R]21D ) +8.2 (c 0.94, CHCl3); IR (neat) 3313, 2119, 835, 773 cm-1; 1H NMR δ 0.04 (s, 6 H), 0.88 (s, 9 H), 1.11 (d, J ) 6 Hz, 3 H), 1.16-1.60 (m, 18 H), 1.94 (t, J ) 3 Hz, 1 H), 2.18 (dt, J ) 3, 7 Hz, 2 H), 3.70-3.82 (m, 1 H); 13C NMR δ 84.9, 68.7, 68.1, 39.8, 29.70, 29.63, 29.55, 29.49, 29.1, 28.8, 28.5, 25.9, 25.8, 23.8, 18.4, 18.2, -4.5, -4.8. HRMS (CI) m/z calcd for C20H41OSi (M + H)+ 325.2927, found: 325.2918. (1E,13S)-2-(13-[(tert-Butyldimethylsilyl)oxy]-1-tetradecenyl)furan (7). To a solution of acetylene 17 (2.45 g, 7.56 mmol) in THF (8 mL) at -10 °C was added a solution of Sia2BH in THF (30 mL), which had been prepared from BH3 (20 mL, 1 M in THF, 20 mmol) and 2-methyl-2-butene (20 mL, 2 M in THF, 40 mmol) at -10 °C for 2 h. After being stirred at -10 °C for 1 h, 3 N NaOH (4 mL, 12 mmol), 2-bromofuran (10) (3.34 g, 22.7 mmol), and Pd(PPh3)4 (440 mg, 0.38 mmol) were added to the solution. The mixture was stirred under reflux for 5 h. After being cooled to 0 °C, 3 N NaOH (25 mL, 75 mmol) and 35% H2O2 (7.5 mL) were added slowly. Vigorous stirring was continued at room temperature for 2 h, and the mixture was poured into saturated NH4Cl. The product was extracted with hexane several times, and the combined extracts were dried over MgSO4 and concentrated to leave the residue, which was purified by chromatography (hexane/Et2O) to furnish 7 (2.72 g, 92%): IR (neat) 960, 837, 777, 729 cm-1; 1H NMR (500 MHz) δ 0.035 (s, 6 H), 0.89 (s, 9 H), 1.11 (d, J ) 6 Hz, 3 H), 1.17-1.52 (m, 18 H), 2.12-2.21 (m, 2 H), 3.723.81 (m, 1 H), 6.12 (d, J ) 3 Hz, 1 H), 6.16 (dt, J ) 16, 6 Hz, 1 H), 6.19 (d, J ) 16 Hz, 1 H), 6.33 (dd, J ) 3, 2 Hz, 1 H), 7.30 (d, J ) 2 Hz, 1 H); 13C NMR δ 153.6, 141.3, 136.5, 118.6, 111.2, 105.9, 68.8, 39.8, 32.8, 29.70, 29.65, 29.60, 29.5, 29.3, 29.2, 25.9, 25.8, 23.8, 18.2, -4.5, -4.8. HRMS (CI) m/z calcd for C24H45O2Si (M + H)+ 393.3189, found: 393.3195. (1S,2R,13S)-13-[(tert-Butyldimethylsilyl)oxy]-1-(2-furyl)1,2-tetradecanediol (18).38 To an ice-cold mixture of olefin 7 (200 mg, 0.509 mmol), t-BuOH (2.6 mL), and H2O (2.6 mL) were added MeSO2NH2 (48 mg, 0.50 mmol) and AD-mix-β (0.713 g). The mixture was stirred overnight at room temperature and diluted with brine. The product was extracted with ethyl acetate several times. The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by chromatography (hexane/ethyl acetate) to afford diol 18 (198 mg, 91%). Since all of the 1H NMR signals were superimposed with those of the diastereomer 32 of eq 5 (vide infra), diastereomeric purity of 18 was determined by comparison of 1H NMR signals of the corresponding bisMTPA esters, and no isomer was detected in each spectrum. Diol 18: [R]23D ) +10.8 (c 0.93, MeOH); IR (neat) 3369, 835, 773 cm-1; 1H NMR δ 0.03 (s, 6 H), 0.88 (s, 9 H), 1.10 (d, J ) 6 Hz, 3 H), 1.12-1.52 (m, 20 H), 2.47 (br s, 1 H), 2.78 (br s, 1 H), 3.70-3.82 (m, 1 H), 3.82-3.92 (m, 1 H), 4.46 (t, J ) 6 Hz, 1 H), 6.31 (ddd, J ) 3.3, 0.9, 0.6 Hz, 1 H), 6.34 (dd, J ) 3.3, 1.8 Hz, 1 H), 7.38 (dd, J ) 1.8, 1.2 Hz, 1 H); 13C NMR δ 154.4, 142.4, 110.5, 107.8, 73.6, 71.2, 68.7, 39.8, 32.9, 29.69, 29.62, 29.57, 29.54, 29.51, 25.9, 25.8, 25.5, 23.8, 18.1, -4.5, -4.8.

Kobayashi et al. Anal. Calcd for C24H46O4Si: C, 67.55; H, 10.87. Found: C, 67.50; H, 10.79. (1R,2S,13S)-13-[(tert-Butyldimethylsilyl)oxy]-1-(2-furyl)1,2-tetradecanediol (32). In a manner similar to the above experiment, olefin 7 (32 mg, 0.080 mmol), AD-mix-R (113 mg), MeSO2NH2 (8 mg, 0.08 mmol), t-BuOH (0.4 mL), and H2O (0.4 mL) afforded diol 32 (29 mg, 85%), whose 1H NMR was identical with that of 18. No contamination of 18 in the product 32 was confirmed by the method described above for 18. (1S,2R,13S)-2-(13-[(tert-Butyldimethylsilyl)oxy]-1,2bis(methoxymethoxy)-1-tetradecanyl)furan (19). A solution of alcohol 18 (2.36 g, 5.52 mmol), MOMCl (1.68 mL, 22.1 mmol), and i-Pr2NEt (9.62 mL, 55.2 mmol) in CH2Cl2 (18 mL) was stirred overnight between 25 and 30 °C and poured into saturated NaHCO3. After vigorous stirring for 30 min, the mixture was extracted with ethyl acetate twice. The combined organic layers were dried over MgSO4 and concentrated to give an oil, which was purified by chromatography (hexane/ethyl acetate) to furnish the MOM ether 19 (2.62 g, 92%): [R]22D ) -39.3 (c 1.23, CHCl3); IR (neat) 1032, 835, 775 cm-1; 1H NMR δ 0.03 (s, 6 H), 0.87 (s, 9 H), 1.10 (d, J ) 6 Hz, 3 H), 1.10-1.50 (m, 20 H), 3.35 (s, 3 H), 3.36 (s, 3 H), 3.68-3.80 (m, 1 H), 3.833.92 (m, 1 H), 4.58 (d, J ) 7 Hz, 1 H), 4.59 (d, J ) 7 Hz, 1 H), 4.65 (d, J ) 7 Hz, 1 H), 4.68 (d, J ) 7 Hz, 1 H), 4.74 (d, J ) 7 Hz, 1 H), 6.31 (dd, J ) 3, 1 Hz, 1 H), 6.33 (dd, J ) 3, 2 Hz, 1 H), 7.38 (dd, J ) 2, 1 Hz, 1 H); 13C NMR δ 152.2, 142.5, 110.2, 109.1, 97.2, 94.5, 78.9, 73.9, 68.7, 55.7, 55.6, 39.7, 31.4, 29.65, 29.58, 29.52, 29.49, 29.45, 25.9, 25.7, 25.1, 23.8, 18.1, -4.5, -4.8. Anal. Calcd for C28H54O6Si: C, 65.33; H, 10.57. Found: C, 65.31; H, 10.60. (2E,5S,6R,17S)-17-[(tert-Butyldimethylsilyl)oxy]-5,6bis(methoxymethoxy)-4-oxo-2-octadecenal (20). To a mixture of the MOM ether 19 (793 mg, 1.54 mmol) and NaHCO3 (258 mg, 3.08 mmol) in acetone-H2O (10:1, 3 mL) was added NBS (304 mg, 1.69 mmol) dissolved in acetone-H2O (10:1, 1.5 mL) at -15 °C. The mixture was stirred for 40 min, and furan (0.34 mL, 4.7 mmol) was added to quench excess NBS. After 30 min at -15 °C, pyridine (0.24 mL, 3.03 mmol) was added. The mixture was stirred at room temperature overnight and poured into the phosphate buffer (pH 3.6) with ethyl acetate. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated to give the residue, which was purified by chromatography (hexane/ethyl acetate) to furnish aldehyde 20 (584 mg, 71%): IR (neat) 1697, 1032, 835, 775 cm-1; 1H NMR δ 0.03 (s, 6 H), 0.87 (s, 9 H), 1.10 (d, J ) 6 Hz, 3 H), 1.12-1.76 (m, 20 H), 3.26 (s, 3 H), 3.37 (s, 3 H), 3.69-3.81 (m, 1 H), 3.87-3.95 (m, 1 H), 4.27 (d, J ) 3 Hz, 1 H), 4.57 (d, J ) 7 Hz, 1 H), 4.64 (d, J ) 7 Hz, 1 H), 4.70 (d, J ) 7 Hz, 1 H), 4.72 (d, J ) 7 Hz, 1 H), 6.88 (dd, J ) 16, 8 Hz, 1 H), 7.38 (d, J ) 16 Hz, 1 H), 9.77 (d, J ) 8 Hz, 1 H). HRMS (CI) m/z calcd for C24H55O7Si (M + H)+ 531.3717, found: 531.3718. Methyl (2E,5S,6R,17S)-17-[(tert-Butyldimethylsilyl)oxy]-5,6-bis(methoxymethoxy)-4-oxo-2-octadecenoate (6). According to the procedure for the preparation of 3a, aldehyde 20 (173 mg, 0.326 mmol) was converted into the acid 21 (156 mg, 88%) by using NaClO2 (148 mg, purity 85%, 1.63 mmol) in H2O (1 mL), 2-methyl-2-butene (0.52 mL, 4.9 mmol), t-BuOH (2 mL), and the phosphate buffer (pH 3.6, 1 mL): IR (neat) 1699, 835, 775 cm-1; 1H NMR δ 0.03 (s, 6 H), 0.87 (s, 9 H), 1.10 (d, J ) 6 Hz, 3 H), 1.12-1.72 (m, 20 H), 3.25 (s, 3 H), 3.35 (s, 3 H), 3.67-3.82 (m, 1 H), 3.87-3.97 (m, 1 H), 4.26 (d, J ) 3 Hz, 1 H), 4.58 (d, J ) 7 Hz, 1 H), 4.64 (d, J ) 7 Hz, 1 H), 4.67 (d, J ) 7 Hz, 1 H), 4.71 (d, J ) 7 Hz, 1 H), 6.77 (d, J ) 16 Hz, 1 H), 7.53 (d, J ) 16 Hz, 1 H), 9.2 (br peak, 1 H). To a solution of 2-chloro-1-methylpyridinium iodide (363 mg, 1.42 mmol) in CH2Cl2 (1.5 mL) was added a solution of acid 21 (259 mg, 0.474 mmol), MeOH (0.023 mL, 0.57 mmol), and NEt3 (0.16 mL, 1.15 mmol) in CH2Cl2 (1.5 mL). The resulting mixture was refluxed for 4 h, cooled to room temperature, and concentrated. The residue was purified by chromatography (hexane/ethyl acetate) to furnish the methyl ester 6 (172 mg, 65%): [R]22D ) -34.1 (c 0.82, CHCl3); IR (neat) 1732, 1703,

4-Oxygenated 2-Enoic Acids from 2-Substituted Furans 835, 775 cm-1; 1H NMR δ -0.01 (s, 6 H), 0.83 (s, 9 H), 1.06 (d, J ) 6 Hz, 3 H), 1.08-1.70 (m, 20 H), 3.23 (s, 3 H), 3.33 (s, 3 H), 3.76 (s, 3 H), 3.65-3.79 (m, 1 H), 3.86 (dt, J ) 3, 7 Hz, 1 H), 4.20 (d, J ) 3 Hz, 1 H), 4.53 (d, J ) 7 Hz, 1 H), 4.59 (d, J ) 7 Hz, 1 H), 4.63 (d, J ) 7 Hz, 1 H), 4.67 (d, J ) 7 Hz, 1 H), 6.74 (d, J ) 16 Hz, 1 H), 7.46 (d, J ) 16 Hz, 1 H); 13C NMR δ 199.5, 166.0, 136.4, 130.6, 97.2, 96.1, 83.3, 78.1, 68.6, 56.5, 55.9, 52.2, 39.7, 30.5, 29.59, 29.52, 29.46, 29.43, 25.8, 25.7, 25.3, 23.7, 18.0, -4.6, -4.9. HRMS (CI) m/z calcd for C29H57O8Si (M + H)+ 561.3823, found: 561.3817. Methyl (2E,4R,5R,6R,17S)-17-[(tert-Butyldimethylsilyl)oxy]-5,6-bis(methoxymethoxy)-4-hydroxy-2-octadecenoate (22). To a solution of ketone 6 (123 mg, 0.220 mmol) in Et2O (1 mL) was added an ethereal solution of Zn(BH4)2 (4.8 mL, 0.138 M, 0.66 mmol) at -78 °C. The mixture was gradually warmed to -40 °C over 1 h and poured into brine. The resulting mixture was stirred at room temperature for 1 h and then extracted with Et2O several times. The combined ethereal solutions were dried over MgSO4 and concentrated. The residue was purified by chromatography (hexane/ethyl acetate) to furnish alcohol 22 (112 mg, 90%), whose diastereomeric selectivity was determined to be >15:1 by 1H NMR spectroscopy of the crude product: [R]24D ) +9.6 (c 1.31, CHCl3); IR (neat) 3473, 1728, 1658, 835, 775 cm-1; 1H NMR δ 0.04 (s, 6 H), 0.88 (s, 9 H), 1.10 (d, J ) 6 Hz, 3 H), 1.12-1.46 (m, 21 H), 3.41 (s, 6 H), 3.52-3.60 (m, 1 H), 3.74 (s, 3 H), 3.68-3.80 (m, 1 H), 4.02 (d, J ) 6 Hz, 1 H), 4.39-4.46 (m, 1 H), 4.66 (d, J ) 7 Hz, 1 H), 4.68 (d, J ) 7 Hz, 1 H), 4.70 (d, J ) 7 Hz, 1 H), 4.71 (d, J ) 7 Hz, 1 H), 6.19 (dd, J ) 16, 2 Hz, 1 H), 7.08 (dd, J ) 16, 4 Hz, 1 H); 13C NMR δ 167.0, 147.6, 121.5, 98.1, 97.2, 83.1, 78.7, 70.4, 68.6, 56.3, 56.1, 51.5, 39.7, 30.6, 29.63, 29.60, 29.54, 29.47, 25.8, 25.7, 25.3, 23.7, 18.0, -4.6, -4.9. HRMS (CI) m/z calcd for C29H59O8Si (M + H)+ 563.3979, found: 563.3979. Methyl (2E,4R,5S,6R,17S)-17-[(tert-Butyldimethylsilyl)oxy]-4,5,6-tris(methoxymethoxy)-2-octadecenoate (23). According to the procedure for the preparation of 19, alcohol 22 (58 mg, 0.102 mmol) was converted into 23 (52 mg, 84%) by using MOMCl (0.025 mL, 0.33 mmol), i-Pr2NEt (0.090 mL, 0.51 mmol), and CH2Cl2 (1 mL): [R]23D ) -7.1 (c 0.80, CHCl3); IR (neat) 1730, 1660, 835, 775 cm-1; 1H NMR δ 0.03 (s, 6 H), 0.88 (s, 9 H), 1.10 (d, J ) 6 Hz, 3 H), 1.12-1.70 (m, 20 H), 3.37 (s, 3 H), 3.38 (s, 3 H), 3.40 (s, 3 H), 3.61-3.70 (m, 1 H), 3.74 (s, 3 H), 3.70-3.80 (m, 2 H), 4.36-4.41 (m, 1 H), 4.61 (d, J ) 7 Hz, 1 H), 4.63 (d, J ) 7 Hz, 1 H), 4.66 (d, J ) 7 Hz, 1 H), 4.68 (d, J ) 7 Hz, 1 H), 4.73 (d, J ) 7 Hz, 2 H), 6.07 (dd, J ) 16, 1 Hz, 1 H), 6.97 (dd, J ) 16, 7 Hz, 1 H); 13C NMR δ 166.4, 145.3, 123.2, 97.5, 97.0, 94.9, 80.2, 78.0, 75.7, 68.6, 55.98, 55.79, 55.76, 51.5, 39.6, 31.3, 29.58, 29.51, 29.45, 25.8, 25.6, 25.3, 23.7, 18.0, -4.6, -4.9. HRMS (CI) m/z calcd for C27H53O9Si (M - C4H9)+ 549.3459, found: 549.3464. Methyl (2E,4R,5S,6R,17S)-4,5,6-Tris(methoxymethoxy)17-hydroxy-2-octadecenoate (24). A solution of the silyl ether 23 (100 mg, 0.165 mmol) and NBS (30 mg, 0.17 mmol) in DMSO-H2O (19:1, 1.6 mL) was stirred at room temperature overnight and poured into the phosphate buffer (pH 3.6). The mixture was extracted with Et2O three times. The combined ethereal solutions were dried over MgSO4 and concentrated. The residue was purified by chromatography (benzene/ethyl acetate) to afford alcohol 24 (64 mg, 79%): [R]21D ) -6.0 (c 0.64, CHCl3); IR (neat) 3481, 1724, 1660, 1032 cm-1; 1H NMR δ 1.18 (d, J ) 6 Hz, 3 H), 1.2-1.7 (m, 21 H), 3.37 (s, 3 H), 3.38 (s, 3 H), 3.40 (s, 3 H), 3.62-3.70 (m, 1 H), 3.74 (s, 3 H), 3.723.82 (m, 2 H), 4.35-4.42 (m, 1 H), 4.62 (d, J ) 7 Hz, 1 H), 4.63 (d, J ) 7 Hz, 1 H), 4.66 (d, J ) 7 Hz, 1 H), 4.68 (d, J ) 7 Hz, 1 H), 4.73 (d, J ) 7 Hz, 2 H), 6.06 (d, J ) 16 Hz, 1 H), 6.98 (dd, J ) 16, 7 Hz, 1 H); 13C NMR δ 166.6, 145.3, 123.3, 97.6, 97.1, 94.9, 80.2, 78.1, 75.8, 68.2, 56.10, 55.91, 55.88, 51.6, 39.3, 31.3, 29.64, 29.58, 29.53, 29.48, 25.7, 25.3, 23.4. HRMS (CI) m/z calcd for C25H49O9 (M + H)+ 493.3377, found: 493.3376. (+)-Aspicilin. A mixture of ester 24 (56 mg, 0.114 mmol) and LiOH‚H2O (36 mg, 0.86 mmol) in MeOH and H2O (6:1, 1.1 mL) was stirred at 40 °C overnight and diluted with the phosphate buffer (pH 3.6). The product was extracted with ethyl acetate several times. The combined organic layers were

J. Org. Chem., Vol. 63, No. 21, 1998 7513 dried over MgSO4 and concentrated to furnish acid 25, which was used for the next reaction without further purification: IR (neat) 1716, 1658, 1032 cm-1; 1H NMR δ 1.19 (d, J ) 6 Hz, 3 H), 1.1-1.7 (m, 20 H), 3.38 (s, 3 H), 3.39 (s, 3 H), 3.40 (s, 3 H), 3.61-3.70 (m, 1 H), 3.72-3.89 (m, 2 H), 4.40-4.48 (m, 1 H), 4.63 (d, J ) 7 Hz, 1 H), 4.65 (d, J ) 7 Hz, 1 H), 4.67 (d, J ) 7 Hz, 1 H), 4.68 (d, J ) 7 Hz, 1 H), 4.74 (d, J ) 7 Hz, 2 H), 6.07 (dd, J ) 16, 1 Hz, 1 H), 7.07 (dd, J ) 16, 6 Hz, 1 H). A solution of the above acid 25 and NEt3 (0.09 mL, 0.65 mmol) in THF (1 mL) was stirred at room temperature for 20 min, and then 2,4,6-trichlorobenzoyl chloride (0.05 mL, 0.19 mmol) in THF (0.5 mL) was added. Stirring was continued at room temperature further 2 h, and the solution was diluted with toluene (ca. 20 mL). The resultant white solid (triethylamine hydrochloride) was removed by filtration through a pad of Celite, and the filtrate was diluted further with toluene (total 50 mL). The toluene solution thus obtained was added over 3 h to a refluxing solution of DMAP (78 mg, 0.64 mmol) dissolved in toluene (10 mL). After the addition, the solution was cooled to room temperature, diluted with Et2O, washed with 1 N HCl and saturated NaHCO3, and dried over MgSO4. Concentration and purification by chromatography (hexane/ ethyl acetate) afforded lactone 26 (31 mg, 53% from 24): IR (neat) 1720, 1657, 920 cm-1; 1H NMR δ 1.0-1.6 (m, 23 H), 3.35 (s, 3 H), 3.39 (s, 3 H), 3.40 (s, 3 H), 3.46-3.56 (m, 1 H), 3.86 (dd, J ) 7, 1.5 Hz, 1 H), 4.43 (d, J ) 8 Hz, 1H), 4.58 (d, J ) 7 Hz, 1 H), 4.61 (d, J ) 7 Hz, 1 H), 4.63 (d, J ) 7 Hz, 1 H), 4.74 (d, J ) 7 Hz, 1 H), 4.78 (d, J ) 7 Hz, 1 H), 4.82 (d, J ) 7 Hz, 1 H), 4.90-5.10 (m, 1 H), 6.01 (d, J ) 16 Hz, 1 H), 6.95 (dd, J ) 16, 8 Hz, 1 H); 13C NMR δ 165.7, 143.4, 125.4, 97.7, 97.4, 93.9, 81.1, 77.8, 74.8, 70.8, 55.94, 55.87, 55.5, 35.3, 31.1, 28.11, 28.06, 27.4, 26.9, 26.6, 26.2, 25.4, 23.5, 20.4; FAB mass, M+ + Na ) 483. To an ice-cold solution of the MOM ether 26 (31 mg, 0.067 mmol) and 1,2-ethanedithiol (0.045 mL, 0.61 mmol) in CH2Cl2 (1 mL) was added BF3‚OEt2 (0.051 mL, 0.41 mmol), and the solution was stirred at room temperature for 3 h. Saturated NaHCO3 and ethyl acetate were added to the solution, and the mixture was stirred for 10 min. The layers were separated, and aqueous layer was extracted with ethyl acetate. The combined extracts were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel with a mixture of benzene and EtOH as an eluent to afford (+)aspicilin (12.3 mg, 56%): [R]22D ) +37.5 (c 0.55, CHCl3) (lit.13e [R]23D ) +37.7 (c 0.22, CHCl3); lit.13f [R]D ) +38.5 (c 1.05, CHCl3)); mp 152-155 °C (recrystallized from hexane/ethyl acetate) (lit.13c,f 154-156 °C; lit.13e 150-152 °C). The following 1H and 13C NMR spectra were identical with the reported13e,f data: 1H NMR (CDCl3 + D2O) δ 1.08-1.60 (m, 23 H), 3.57 (t, J ) 3 Hz, 1 H), 3.74 (dt, J ) 3, 7 Hz, 1 H), 4.52-4.60 (m, 1 H), 5.04 (sextet, J ) 6 Hz, 1 H), 6.12 (dd, J ) 16, 2 Hz, 1 H), 6.90 (dd, J ) 16, 5 Hz, 1 H); 13C NMR δ 165.9, 145.0, 123.2, 74.7, 73.5, 71.3, 70.0, 35.7, 31.9, 28.3, 27.7, 27.5, 27.2, 27.1, 26.3, 24.3, 23.5, 20.4. 2-(5-Bromopentyl)furan (35). To an ice-cold solution of furan (1.38 mL, 14 mmol) and bipyridine (ca. 10 mg) in THF (20 mL) was added n-BuLi (8.44 mL, 1.35 M in hexane, 11.4 mmol) dropwise, and the brown solution was stirred at 0-5 °C for 1 h to generate 2-furyllithium (33). 1-Bromo-5-chloropentane (0.50 mL, 704 mg, 3.80 mmol) was added to the solution. After 14 h at room temperature, the solution was poured into a mixture of hexane and saturated NH4Cl with vigorous stirring. Hexane layer was separated, and the aqueous layer was extracted with hexane. The combined hexane solutions were dried over MgSO4 and concentrated to give an oil, which was purified by chromatography (hexane/ Et2O) to afford 34 (621 mg, 95%): bp 95-100 °C (3 Torr); IR (neat) 1597, 1508, 732 cm-1; 1H NMR δ 1.42-1.55 (m, 2 H), 1.62-1.73 (m, 2 H), 1.73-1.88 (m, 2 H), 2.63 (t, J ) 7 Hz, 2 H), 3.55 (t, J ) 6.5 Hz, 2 H), 5.99 (d, J ) 3.5 Hz, 1 H), 6.28 (dd, J ) 3.5, 2 Hz,1 H), 7.31 (d, J ) 2, 1 H); 13C NMR δ 155.8, 140.6, 109.9, 104.7, 44.7, 32.2, 27.7, 27.2, 26.3. A mixture of 34 (5.45 g, 31.6 mmol), LiBr (5.48 g, 63.1 mmol), and trioctylmethylammonium chloride (640 mg, 1.6 mmol) was stirred at 100 °C for 2 days, cooled to room

7514 J. Org. Chem., Vol. 63, No. 21, 1998 temperature, and filtered through a pad of silica gel with hexane. The filtrate was concentrated to give the bromide 35 (6.46 g, 97% conversion by 1H NMR, 94% yield), which was distilled for the next reaction: bp 80-90 °C (1 Torr); IR (neat) 1600, 1510, 734 cm-1; 1H NMR δ 1.42-1.57 (m, 2 H), 1.591.73 (m, 2 H), 1.82-1.97 (m, 2 H), 2.64 (t, J ) 7 Hz, 2 H), 3.41 (t, J ) 7 Hz, 2 H), 5.98 (d, J ) 3 Hz, 1 H), 6.28 (dd, J ) 3, 2 Hz, 1 H), 7.29 (d, J ) 2 Hz, 1 H). (2R)-8-(2-Furyl)-2-octanol (38). To a mixture of Mg (1.34 g, 0.055 g-atom) and THF (7 mL) was added 1,2-dibromoethane (5 drops) to activate Mg, and a solution of 35 (4.0 g, 18.4 mmol) in THF (10 mL) was added slowly to prepare the Grignard reagent 36. After the addition, the solution was diluted with THF (20 mL). The Grignard reagent 36 thus prepared was used for the next reaction immediately. According to the procedure for the preparation of 15, (S)(+)-epichlorohydrin (29) (2.17 mL, 27.7 mmol) of 98.9% ee, the above Grignard reagent 36, CuCN (164 mg, 1.83 mmol), and THF (36 mL) afforded 37 (3.83 g, 90%): IR (neat) 3390, 1597, 1508, 725 cm-1; 1H NMR δ 1.24-1.70 (m, 10 H), 2.14 (d, J ) 5 Hz, 1 H), 2.61 (t, J ) 7.5 Hz, 2 H), 3.47 (dd, J ) 11, 7 Hz, 1 H), 3.64 (dd, J ) 11, 3 Hz, 1 H), 3.74-3.85 (m, 1 H), 5.97 (m, 1 H), 6.28 (m, 1 H), 7.29 (m, 1 H); 13C NMR δ 156.5, 140.7, 110.1, 104.7, 71.5, 50.6, 34.3, 29.3, 29.1, 28.0, 25.5. Dechlorination of 37 (427 mg, 1.85 mmol) was carried out using LiAlH4 (70 mg, 1.85 mmol) in THF (10 mL) at room temperature overnight to afford the furan 38 (337 mg, 93%): bp 100 °C (1 Torr); [R]23D ) -6.1 (c 0.94, CHCl3); IR (neat) 3400, 1632, 1539, 753 cm-1; 1H NMR δ 1.18 (d, J ) 6 Hz, 3 H), 1.25-1.53 (m, 9 H), 1.57-1.71 (m, 2 H), 2.61 (t, J ) 7.5 Hz, 2 H), 3.72-3.84 (m, 1 H), 5.97 (d, J ) 3 Hz, 1 H), 6.27 (dd, J ) 3, 2 Hz, 1 H), 7.29 (d, J ) 2 Hz, 1 H); 13C NMR δ 156.6, 140.7, 110.1, 104.6, 68.2, 39.4, 29.4, 29.2, 28.06, 28.02, 25.7, 23.6. Anal. Calcd for C12H20O2: C, 73.42; H, 10.26. Found: C, 73.10; H, 10.45. (2E,11R)-11-Hydroxy-4-oxo-2-dodecenoic Acid (40). To a solution of the furan 38 (190 mg, 0.968 mmol) and pyridine (0.16 mL, 1.93 mmol) in THF-acetone-H2O (5:4:2, 7 mL) was added NBS (259 mg, 1.46 mmol) dissolved in THF-acetoneH2O (5:4:2, 3 mL) at -20 °C. After being stirred at -20 °C for 1 h and then at room temperature for 4 h, the solution was poured into a mixture of ethyl acetate and aqueous Na2S2O3 with vigorous stirring. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by chromatography (hexane/ethyl acetate) to give aldehyde 39 (150 mg, 73%): IR (neat) 3450, 1720 cm-1; 1H NMR δ 1.19 (d, J ) 6 Hz, 3 H), 1.26-1.74 (m, 11 H), 2.70 (t, J ) 7 Hz, 2 H), 3.74-3.86 (m, 1 H), 6.78 (dd, J ) 16, 7 Hz, 1 H), 6.88 (d, J ) 16 Hz, 1 H), 9.79 (d, J ) 7 Hz, 1 H). According to the procedure for preparation of 3a, a mixture of 39 (299 mg, 1.41 mmol), NaClO2 (225 mg, purity 85%, 2.49 mmol), and 2-methyl-2-butene (1.5 mL, 14 mmol) in t-BuOH (10 mL), the phosphate buffer (pH 3.6, 5 mL), and H2O (5 mL) was stirred at room temperature for 1.5 h to furnish acid 40 (281 mg, 87%). IR and the following 1H NMR spectra of 40 were identical with the reported14h data: 1H NMR δ 1.20 (d, J ) 6 Hz, 3 H), 1.2-1.7 (m, 10 H), 2.65 (t, J ) 7 Hz, 2 H), 3.753.90 (m, 1 H), 6.42 (br s, 2 H), 6.67 (d, J ) 16 Hz, 1 H), 7.14 (d, J ) 16 Hz, 1 H); 13C NMR δ 199.8, 169.1, 140.6, 130.1, 68.4, 41.5, 39.0, 29.2, 29.0, 25.4, 23.5, 23.2. EthyleneKetalof(2E,11R)-11-Hydroxy-4-oxo-2-dodecenoic Acid (41). A solution of acid 40 (29 mg, 0.13 mmol), HC(OEt)3 (67 mg, 0.63 mmol), ethylene glycol (78 mg, 1.26 mmol), and p-TsOH‚H2O (3 mg, 0.02 mmol) in benzene (1.5 mL) was stirred at 35 °C overnight and then poured into a mixture of ethyl acetate and brine. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate repeatedly. The combined organic layers were dried over MgSO4 and concentrated to give a mixture of 41 and its ethyl ester which, without separation, was treated with 2 N LiOH (0.63 mL, 1.26 mmol) in MeOH (6 mL) at room temperature overnight. The solution was acidified to pH 4 with 1 N HCl and poured into brine with ethyl acetate. The organic layer

Kobayashi et al. was separated and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by chromatography (benzene/ethyl acetate) to furnish the ketal acid 41 (20 mg, 62%): [R]26D ) -2.2 (c 0.6, CHCl3). The following 1 H NMR spectra of 41 were in good agreement with the reported14b data: 1H NMR δ 1.18 (d, J ) 6 Hz, 3 H), 1.2-1.8 (m, 11 H), 3.75-3.84 (m, 1 H), 3.84-4.02 (m, 4 H), 6.08 (d, J ) 16 Hz, 1 H), 6.83 (d, J ) 16 Hz, 1 H). (3S)-3-[(tert-Butyldiphenylsilyl)oxy]-1-iodobutane (43). A solution of alcohol 42 (536 mg, 4.54 mmol, 86% ee determined by 1H NMR spectroscopy of the corresponding MTPA ester), TBDPSCl (1.42 mL, 5.46 mmol), and imidazole (927 mg, 13.6 mmol) in DMF (7 mL) was stirred for 18 h at 53 °C, cooled to room temperature, and poured into saturated NaHCO3 with hexane. After 30 min of vigorous stirring, the organic layer was separated, and the aqueous layer was extracted with hexane. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by chromatography (hexane/ethyl acetate) to afford methyl (3S)-3-[(tertbutyldiphenylsilyl)oxy]butanoate (1.62 g, 100%): 1H NMR δ 1.04 (s, 9 H), 1.12 (d, J ) 6 Hz, 3 H), 2.39 (dd, J ) 15, 7 Hz, 1 H), 2.57 (dd, J ) 15, 7 Hz, 1 H), 3.59 (s, 3 H), 4.23-4.37 (m, 1 H), 7.32-7.48 (m, 6 H), 7.60-7.75 (m, 4 H). To a solution of the above product (1.30 g, 3.64 mmol) in THF (15 mL) was added DIBALH (9.1 mL, 1 M in hexane, 9.1 mmol) at -70 °C dropwise. The solution was gradually warmed to -15 °C over 3 h and, after being cooled again to -40 °C, EtOH (2.14 mL, 36.4 mmol) was added slowly to destroy excess hydride. After 15 min, the cooling bath was removed, and the solution was poured into an ice-cold mixture of hexane and 1 N HCl with vigorous stirring. The phases were separated, and the aqueous phase was extracted with hexane twice. The combined organic layers were washed with saturated NaHCO3, dried over MgSO4, and concentrated. The residue was purified by chromatography (hexane/ethyl acetate) to afford (3S)-3-[(tert-butyldiphenylsilyl)oxy]-1-butanol (1.08 g, 91%), whose 1H and 13C NMR data were identical with those reported.34 To a solution of the above alcohol (291 mg, 0.886 mmol), imidazole (147 mg, 2.16 mmol), and PPh3 (341 mg, 1.30 mmol) in benzene (10 mL) was added iodine (440 mg, 1.73 mmol). The resulting red brown solution was stirred at room temperature for 1 h and poured into a mixture of aqueous Na2S2O3 and hexane with vigorous stirring. The hexane layer was separated, and the aqueous layer was washed with hexane. The combined organic layers were dried over MgSO4 and concentrated. The residue was dissolved in THF (40 mL), and aqueous 35% H2O2 (8.4 mL) was added to destroy PPh3 recovered. After being stirred at room temperature for 30 min, brine and hexane were added to the mixture. The organic layer was separated, and the aqueous layer was extracted with hexane. The combined organic layers were dried over MgSO4 and concentrated to furnish the crude product, which was purified by chromatography (hexane/Et2O) to give iodide 43 (337 mg, 88%), whose IR and 1H NMR data were identical with those reported.34 (3S)-2-(3-[(tert-Butyldiphenylsilyl)oxy]butyl)furan (44). According to the procedure for preparation of 34, iodide 43 (2.02 g, 4.59 mmol), furan (1.00 mL, 13.7 mmol), n-BuLi (6.19 mL, 1.48 M in hexane, 9.16 mmol), bipyridine (ca. 10 mg), and THF (35 mL) afforded 44 (1.62 g, 94%): bp 135 °C (1 Torr); IR (neat) 1596, 1509, 1430, 707 cm-1; 1H NMR δ 1.06 (s, 9 H), 1.08 (d, J ) 6 Hz, 3 H), 1.69-1.90 (m, 2 H), 2.57-2.75 (m, 2 H), 3.85-3.97 (m, 1 H), 5.85 (br s, 1 H), 6.24 (br s, 1 H), 7.327.47 (m, 7 H), 7.62-7.75 (m, 4 H); 13C NMR δ 156.3, 140.7, 135.99, 135.95, 134.9, 134.5, 129.6, 129.5, 127.6, 127.5, 110.1, 104.6, 69.0, 37.6, 27.2, 23.9, 23.2, 19.4. Anal. Calcd for C24H30O2Si: C, 76.14; H, 7.99. Found: C, 76.22; H, 8.25. (2E,7S)-7-[(tert-Butyldiphenylsilyl)oxy]-4-oxo-2-octenoic Acid (46). To a solution of the furan 44 (676 mg, 1.79 mmol) and pyridine (0.58 mL, 7.2 mmol) in THF-acetoneH2O (5:4:2, 8 mL) was added NBS (383 mg, 2.15 mmol) dissolved in THF-acetone-H2O (5:4:2, 2 mL) at -20 °C. The solution was stirred for 1 h at -20 °C and then at room

4-Oxygenated 2-Enoic Acids from 2-Substituted Furans temperature for 5 h and poured into a mixture of ethyl acetate and aqueous Na2S2O3 with vigorous stirring. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by chromatography (hexane/ethyl acetate) to afford aldehyde 45 (450 mg, 64%): IR (neat) 1695, 1112, 707 cm-1; 1H NMR δ 1.05 (s, 9 H), 1.11 (d, J ) 6 Hz, 3 H), 1.65-1.89 (m, 2 H), 2.59-2.80 (m, 2 H), 3.88-4.01 (m, 1 H), 6.64 (dd, J ) 16, 7 Hz, 1 H), 6.74 (d, J ) 16 Hz, 1 H), 7.31-7.47 (m, 6 H), 7.61-7.70 (m, 4 H), 9.73 (d, J ) 7 Hz, 1 H). According to the procedure for preparation of 3a, a mixture of 45 (342 mg, 0.867 mmol), NaClO2 (139 mg, purity 85%, 1.31 mmol), 2-methyl-2-butene (0.74 mL, 7.0 mmol) in t-BuOH (8 mL), the phosphate buffer (pH 3.6, 4 mL), and H2O (4 mL) was stirred at room temperature for 1 h to give acid 46 (296 mg, 83%) after purification by chromatography (hexane/ethyl acetate): IR (neat) 1701, 1111, 702 cm-1; 1H NMR δ 1.06 (s, 9 H), 1.10 (d, J ) 6 Hz, 3 H), 1.66-1.88 (m, 2 H), 2.55-2.78 (m, 2 H), 3.88-3.99 (m, 1 H), 6.57 (d, J ) 16 Hz, 1 H), 7.04 (d, J ) 16 Hz, 1 H), 7.34-7.48 (m, 6 H), 7.63-7.72 (m, 4 H). Ethylene Ketal of (2E,7S)-7-[(tert-Butyldiphenylsilyl)oxy]-4-oxo-2-octenoic Acid (47). According to the procedure for preparation of 41, a solution of 46 (84 mg, 0.20 mmol), HC(OEt)3 (113 mL, 1.03 mmol), p-TsOH‚H2O (5 mg, 0.03 mmol), and ethylene glycol (128 mg, 2.06 mmol) in benzene (3.5 mL) was stirred at 35 °C overnight to afford a mixture of

J. Org. Chem., Vol. 63, No. 21, 1998 7515 47 and its ethyl ester, which, without further purification, was treated with 2 N LiOH (1.05 mL, 2.1 mmol) in MeOH (8 mL) at room temperature overnight to furnish 47 (64 mg, 70%), whose 1H NMR data was in good agreement with the reported15c data: 1H NMR δ 1.04 (s, 9 H), 1.06 (d, J ) 6 Hz, 3 H), 1.411.60 (m, 2 H), 1.62-1.90 (m, 2 H), 3.79-3.98 (m, 5 H), 6.04 (d, J ) 16 Hz, 1 H), 6.79 (d, J ) 16 Hz, 1 H), 7.33-7.45 (m, 6 H), 7.64-7.70 (m, 4 H).

Acknowledgment. We gratefully acknowledge the generous supply of (S)- and (R)-epichlorohydrin from Daiso Co. Ltd. We thank Prof. Tadashi Eguchi and Dr. Hiroshi Ikeda of this institute for the mass spectrum of 26 and 500 MHz 1H NMR spectrum of 7, respectively. We also thank Mr. Yasumasa Tashiro of Nippon Chemiphar for measuring the high resolution mass spectra. Supporting Information Available: 1H NMR spectra of compounds lacking elemental analyses (16 pages). This material is contained in libraries on microfiche, immediately follows this article in the microfilm version of the journal, and can be ordered from the ACS; see any current masthead page for ordering information. JO980942A