Syntheses of All Phytoprostanes B1 Type I and II
purified by column HPLC (SI-60, 5µm): cyclohexane/ethyl
acetate 50:50; 3.0 mL/min at 254 nm tR: 23 min (29% after
two steps). Rf: 0.53 (cyclohexane/ethyl acetate 40:60). IR ν
(cm-1): 3457 (O-H), 1734 (CdO), 1715 (CdO). 1H NMR (360
MHz, CDCl3) δ: 1.00 (t, J ) 7.5 Hz, 3H), 1.28-1.33 (m, 6H),
1.57-1.64 (m, 2H), 1.37-1.45 (m, 2H), 1.65-1.72 (m, 2H),
2.23-2.33 (m, 4H), 2.42-2.45 (m, 2H), 2.64-2.68 (m, 2H), 3.68
(s, 3H), 4.26-4.31 (m, 1H), 6.27 (dd, J ) 6.0 and 15.7 Hz, 1H),
6.82 (d, J ) 15.7 Hz, 1H). 13C NMR (90 MHz, CDCl3) δ: 9.6,
22.9, 24.8, 25.6, 28.7, 28.9, 29.0, 29.2, 30.2, 33.8, 34.0, 51.4,
(1 × 10-2, MeOH). Anal. Calcd for C11H21ClO3: C, 55.81; H,
8.94. Found: C, 55.96; H, 8.99.
9(S)-Hydroxy-10-iododecanoic Acid Methyl Ester (22a).
A mixture of compound 21a (5.4 g, 26.79 mmol, 1 equiv) and
sodium iodide (9 g, 59.94 mmol, 2.2 equiv) in dry 2-butanone
(70 mL) was refluxed for 2 days. After NaCl was removed by
filtration, the filtrate was concentrated, and the oily residue
was dissolved in ethyl acetate (300 mL) and washed with 10%
Na2S2O3 (3 × 80 mL), saturated NaHCO3 (80 mL), and brine
(80 mL). The organic layer was dried and concentrated. The
crude material was purified by column chromatography (cy-
clohexane/ethyl acetate 90:10) to give compound 22a (5.89 g,
68%). Rf: 0.63 (cyclohexane/ethyl acetate 60:40). IR ν (cm-1):
3453 (OH), 1734 (CdO). 1H NMR (360 MHz, CDCl3) δ: 1.25-
1.34 (m, 6H), 1.37-1.44 (m, 2H), 1.48-1.56 (m, 2H), 1.56-
1.63 (m, 2H), 2.28 (t, J ) 7.5 Hz, 2H), 3.21 (dd, J ) 6.4 and
10.1 Hz, 1H), 3.35 (dd, J ) 3.9 and 10.1 Hz, 1H), 3.45-3.55
(m, 1H). 3.64 (s, 3H). 13C NMR (90 MHz, CDCl3) δ: 16.5, 24.9,
25.5, 28.9, 29.0, 34.0, 36.5, 51.5, 70.9, 174.3. [R]20D ) -3 (1 ×
10-2, MeOH). Anal. Calcd for C11H21IO3: C, 40.26; H, 6.45.
Found: C, 40.32; H, 6.51.
73.6, 124.1, 139.9, 141.4, 163.1, 174.1, 209.5. [R]20 ) +23 (1
D
× 10-2, MeOH). Anal. Calcd for C19H30O4: C, 70.77; H, 9.38.
Found: C, 70.80; H, 9.42.
9(S)-Hydroxy-10-chlorodeca-6-ynoic Acid (19a). To a
stirred solution of 8-heptynoic acid (4 g, 31.70 mmol, 1 equiv)
in tetrahydrofuran (101 mL) at -78 °C was added 2.5 M
n-BuLi in hexane (25.4 mL, 63.4 mmol, 2 equiv), and the
mixture was stirred at -78 °C for 1 h. (S)-Epichlorhydrin (2
g, 21.61 mmol, 0.68 equiv) and BF3‚Et2O (4.0 mL, 31.70 mmol,
1 equiv) were added, and the mixture was stirred at -78 °C
for 1 h and then allowed to warm to room temperature. After
2 h, the reaction was quenched with saturated NaCl (30 mL)
and acidified with 1 N aqueous HCl (25 mL, to pH 2). The
mixture was extracted with ethyl acetate (3 × 60 mL). The
organic extracts were washed with water (20 mL) and brine
(20 mL), dried, and concentrated. The crude material was
purified by column chromatography on silica gel (cyclohexane/
ethyl acetate 70:30) to give compound 19a as a colorless oil
(5.8 g, 74%). Rf: 0.66 (cyclohexane/ethyl acetate 60:40, 2%
acetic acid). IR ν (cm-1): 3050-3450 (COOH), 3453 (OH), 1715
(CdO). 1H NMR (360 MHz, CDCl3) δ: 1.52-1.60 (m, 2H),
1.71-1.78 (m, 2H), 2.18-2.24 (m, 2H), 2.39 (t, J ) 7.2 Hz, 2H),
2.49-2.54 (m, 2H), 3.63 (dd, J ) 6.0 and 11.2 Hz, 1H), 3.71
(dd, J ) 4.6 and 11.2 Hz, 1H), 3.92-3.98 (m, 1H). 13C NMR
(90 MHz, CDCl3) δ: 18.4, 23.8, 24.7, 28.1, 33.4, 48.2, 70.0, 75.1,
2(S)-Hydroxy-10-carbonylnonyltriphenylphospho-
nium Iodide (23a). To a solution of the hydroxy iodide 22a
(4.9 g, 14.93 mmol, 1 equiv) in dry tetrahydrofuran (45 mL)
was added triphenylphosphine (7.83 g, 29.87 mmol, 2 equiv).
The mixture was heated under reflux for 7 days in the absence
of oxygen and then concentrated at reduced pressure. The oily
residue obtained was triturated and washed with dry diethyl
ether to give the title compound 23a as a yellow oil (7.2 g,
86%). Rf: 0.64 (dichloromethane/methanol 95:5). IR ν (cm-1):
3359 (OH), 1739 (CdO). 31P NMR (81 MHz, CDCl3, external
ref: H3PO4) δ: +24.4. 1H NMR (360 MHz, CDCl3) δ: 1.10-
1.25 (m, 4H), 1.25-1.30 (m, 2H), 1.49-1.55 (m, 2H), 1.71-
1.75 (m, 1H), 1.90-2.00 (m, 1-H), 2.29 (t, J ) 7.5 Hz, 2H),
3.20-3.36 (m, 1H), 3.61 (s, 3H), 3.82-3.99 (m, 1H), 4.00-4.10
(m, 1H), 7.65-7.70 (m, 6H), 7.72-7.79 (m, 9H). 13C NMR (90
MHz, CDCl3) δ: 24.8, 25.5, 28.9, 29.0, 31.7 (d, J ) 50.5 Hz),
34.0, 38.7 (d, J ) 13.0 Hz), 51.4 (s, 3H), 66.5 (d, J ) 7.5 Hz),
118.8 (d, J ) 87.7 Hz), 130.3 (d, J ) 12.2 Hz), 134.1 (d, J )
82.9, 179.3. [R]20 ) -12 (1 × 10-2, MeOH). Anal. Calcd for
D
C11H17ClO3: C, 54.92; H, 6.91. Found: C, 54.99; H, 7.00.
9(S)-Hydroxy-10-chlorodeca-6-ynoic Acid Methyl Es-
ter (20a). To a solution of compound 19a (5.77 g, 31.69 mmol,
1 equiv) in methanol (63 mL) was added a solution of acetyl
chloride (0.90 mL, 12.68 mmol, 0.4 equiv) in methanol (22.6
mL) at room temperature, under nitrogen. The reaction
mixture was stirred at reflux for 20 h. The solvent was
removed under reduced pressure and the residue diluted with
ethyl acetate (100 mL) and neutralized with a 10% NaHCO3
solution (60 mL). The organic layer was washed with brine
(30 mL) and water (30 mL), dried, and concentrated under
reduced pressure. The crude material was purified by column
chromatography (cyclohexane/ethyl acetate 80:20) to give
compound 20a (4.2 g, 68%). Rf: 0.72 (cyclohexane/ethyl acetate
60:40). IR ν (cm-1): 3453 (OH), 1734 (CdO). 1H NMR (360
MHz, CDCl3) δ: 1.50-1.58 (m, 2H), 1.70-1.79 (m, 2H), 2.18-
2.24 (m, 2H), 2.35 (t, J ) 7.5 Hz, 2H), 2.50-2.55 (m, 2H), 3.63
(dd, J ) 6.2 and 11.3 Hz, 1H), 3.69 (s, 3H), 3.71 (dd, J ) 4.5
and 11.4 Hz, 1H), 3.92-3.98 (m, 1H). 13C NMR (90 MHz,
CDCl3) δ: 18.4, 24.0, 24.7, 28.2, 33.5, 48.3, 51.5, 70.0, 75.0,
10.3 Hz), 134.8 (d, J ) 2.9 Hz), 174.3. [R]20D ) +35 (1 × 10-2
,
MeOH). Anal. Calcd for C22H24IOP: C, 57.16; H, 9.63. Found:
C, 57.19; H, 9.68.
2-Formyl-5-n-propylfuran (24). To N,N-dimethylforma-
mide (52.3 mL, 703.58 mmol, 1.3 equiv) was added dropwise
freshly distilled phosphorus oxychloride (23.3 mL, 249.66
mmol, 1.1 equiv) at room temperature, under nitrogen. The
mixture was stirred at 70 °C for 1 h and cooled at 10 °C. Then,
a solution of commercially 2-n-propylfuran 6 (25 g, 226.96
mmol, 1 equiv) in dry N,N-dimethylformamide (136.1 mL) was
added dropwise by cannulation, and the resulting mixture was
stirred for 3 h. Ice-cold water (491 mL) was then added, and
the mixture was neutralized with 99.32 g of sodium hydro-
genocarbonate and 97 mL of saturated sodium carbonate. The
aqueous layer was extracted with diethyl ether (3 × 500 mL).
The organic layers were washed with brine (2 × 200 mL),
dried, and concentrated to give the crude material. Fractional
distillation afforded compound 24 (23.10 g, 75%) as a colorless
oil. Bp: 84 °C (8 mbar). Rf: 0.70 (cyclohexane/ethyl acetate
83.0, 173.9. [R]20 ) +13 (1 × 10-2, MeOH). Anal. Calcd for
D
1
80:20). IR ν (cm-1): 1683 (CdO). H NMR (360 MHz, CDCl3)
C11H17ClO3: C, 54.78; H, 7.36. Found: C, 54.87; H, 7.45.
9(S)-Hydroxy-10-chlorodecanoic Acid Methyl Ester
(21a). A mixture of compound 20a (4 g, 20.38 mmol, 1 equiv)
and 10% Pd/C (800 mg) in ethyl acetate (41 mL) was hydro-
genated at 70 psi for 10 h. The mixture was filtered through
Celite and the filtrate concentrated to provide 21a as a
colorless oil which was used in the next step without further
purification. Rf: 0.65 (cyclohexane/ethyl acetate 70:30). IR ν
δ: 0.92 (t, J ) 7.5 Hz, 3H), 1.62-1.72 (m, 2H), 2.64 (t, J ) 7.5
Hz, 2H), 6.19 (d, J ) 3.7 Hz, 1H), 7.13 (d, J ) 3.3 Hz, 1H),
9.46 (s, 1H). 13C NMR (90 MHz, CDCl3) δ: 13.6, 20.9, 30.2,
108.7, 123.5, 151.8, 163.8, 176.8. Anal. Calcd for C8H10O2: C,
69.54; H, 7.30. Found: C, 69.61; H, 7.39.
2-Dimethoxymethyl-5-n-propylfuran (25). To solution of
compound 24 (23.1 g, 167.20 mmol, 1 equiv) in methanol (55.7
mL) were added sequentially at 0 °C, under nitrogen, trimethyl
orthoformate (29.3 mL, 267.54 mmol, 1.6 equiv) and p-
toluenesulfonic acid hydrate (445.3 mg, 2.34 mmol, 0.014
equiv). The reaction mixture was stirred at room temperature
for 2 h, neutralized with sodium hydrogenocarbonate (702.4
mg), and filtered, and solvent was removed under reduced
1
(cm-1): 3453 (OH), 1734 (CdO). H NMR (360 MHz, CDCl3)
δ: 1.29-1.38 (m, 6H), 1.42-1.48 (m, 2H), 1.50-1.56 (m, 2H),
1.58-1.67 (m, 2H), 2.31 (t, J ) 7.5 Hz, 2H), 3.48 (dd, J ) 6.9
and 11.2 Hz, 1H), 3.63 (dd, J ) 3.3 and 11.2 Hz, 1H), 3.67 (s,
3H), 3.76-3.83 (m, 1H). 13C NMR (90 MHz, CDCl3) δ: 24.9,
25.4, 28.9, 29.1, 34.0, 34.1, 50.5, 51.4, 71.4, 174.3. [R]20D ) -8
J. Org. Chem, Vol. 70, No. 3, 2005 995