Synthesis of Prostaglandin E2 Metabolite
J . Org. Chem., Vol. 67, No. 5, 2002 1611
(M+ + H, 100), 377(65); HRMS Calcd C26H44O6N2Si, 508.2970,
found 508.2966.
7.5 Hz), 1.25 (t, 6H, J ) 7.2 Hz), 1.11 (m, 2H); 13C NMR δ up:
216.0, 174.1, 173.4, 133.8, 60.6 (×2), 47.1, 34.1, 31.4, 28.8, 27.1,
25.3, 24.6; down: 134.1, 132.9 (×2), 129.0, 128.1 (×2), 127.4,
71.0, 53.0, 50.5, 48.7, 14.4 (×2); IR (film) 3448, 2933, 1728,
1374, 1183, 1079, 1028 cm-1; EI MS (m/z) 499 (M+ + Na, 100);
HRMS calcd for C26H36O6S 476.2234, found 476.2213. Further
elution gave the free bicyclic ketone 17 (37.5 mg, 11% yield
from 7) as a colorless oil, TLC Rf (MTBE/petroleum ether )
3/2) ) 0.20; 1H NMR δ 5.60 (dt, 1H, J ) 7.3 and 10.3 Hz), 4.98
(dd, 1H, J ) 9.0 and 10.3 Hz), 4.43 (dd, 1H, J ) 7.3 and 5.8
Hz), 4.12 (quint, 4H, J ) 7.2 Hz), 3.48 (d, 1H, J ) 7.3 Hz),
2.55 (m, 2H), 2.30 (m, 4H), 2.10 (m, 4H), 1.86 (m, 1H), 1.61
(m, 2H), 1.41 (m, 2H), 1.26 (dt, 6H, J ) 7.1 and 8.7 Hz); 13C
NMR δ up: 212.3, 174.6, 173.8, 61.1, 60.5, 44.1, 41.5, 34.3,
32.0, 28.9, 27.6, 24.6, 19.6; down: 134.4, 124.4, 67.9, 41.5, 28.2,
14.4, 14.3; IR (film) 3478, 2934, 1738, 1714, 1583, 1440, 1374,
1182, 1026, 748, 693 cm-1 ; EI MS (m/z): 389 (M+ + Na, 100);
HRMS calcd for C20H30O6 366.2043, found 366.2049.
Dia zok eton e 6 fr om th e F r ee Ald ol 14. To a stirred
solution of the free aldol 14 (100 mg, 0.254 mmol) in CH2Cl2
(4 mL) were added imidazole (51.8 mg, 0.761 mmol), 4-DMAP
(2 mg, cat.), and tert-butylchlorodimethylsilane (76.5 mg, 0.508
mmol). After an additional 18 h, the reaction mixture was
partitioned between CH2Cl2 and, sequentially, saturated aque-
ous NH4Cl and brine. The combined organic extract was dried
(Na2SO4) and concentrated. The residue was chromatographed
to afford the tert-butyldimethylsilyl ether 6 (116 mg, 90% yield
from 14) as a pale yellow oil.
Bicyclic Keton es 7 a n d 15. To a stirred solution of Rh2-
(oct)4 (56 mg, 0.072 mmol) in CH2Cl2 (dried by filtration
through anhydrous K2CO3, 30 mL) at room temperature was
added dropwise over 15 min a solution of the diazoketone 6
(730 mg, 1.44 mmol) in CH2Cl2 (20 mL). After an additional 8
h, the reaction mixture was concentrated. The residue was
chromatographed to afford the mixture of bicyclic ketone 7 (358
mg, 52% yield from 6) and 15 (193 mg, 28% yield from 6) as a
colorless oil, TLC Rf (MTBE/petroleum ether ) 16/84) ) 0.47.
To the mixture of bicyclic ketones 7 and 15 (215 mg, 0.447
mmol) in EtOH (10 mL) at 0 °C was added NaBH4 (50.7 mg,
1.34 mmol). After 40 min, 5 mL of pH ) 7 aqueous buffer was
added. After an additional 1 min, the reaction mixture was
partitioned between EtOAc and brine. The organic extract was
dried (Na2SO4) and concentrated. The residue was chromato-
graphed to afford the alcohol 21 (104 mg, 75% yield from 7),
followed by 22.
Allylic Alcoh ol 18. To a stirred solution of the thioether 8
(268 mg, 0.455 mmol) in CH2Cl2 (18 mL) at -78 °C was added
a solution of 3-chloroperoxybenzoic acid (157 mg, 0.910 mmol)
in CH2Cl2 (2.0 mL). The mixture was stirred for 1 h, after
which a solution of trimethyl phosphite (564 mg, 4.55 mmol)
in EtOH (7 mL) was added. The mixture was stirred at -78
°C for 10 min and then warmed to room temperature. After
an additional 2 h, the reaction mixture was partitioned
between EtOAc and, sequentially, saturated aqueous NaHCO3
and brine. The organic extract was dried (Na2SO4) and
concentrated. The residue was chromatographed to afford the
allylic alcohol 18 (230 mg, 95% yield from 8) as a colorless oil;
TLC Rf (MTBE/petroleum ether ) 3/7) ) 0.16. 1H NMR δ 5.68
(dd, 1H, J ) 6.5 and 15.1 Hz), 5.26 (dd, 1H, J ) 10.4 and 15.1
Hz), 4.21 (d, 1H, J ) 5.4 Hz), 4.12 (m, 5H), 2.92 (t, 1H, J )
9.0 Hz), 2.67 (q, 1H, J ) 7.4 Hz), 2.2-2.5 (m, 6H), 1.3-1.9 (m,
9H), 1.25 (M, 6H), 0.87 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H); 13C
NMR δ up: 217.7, 173.9, 173.6, 60.7, 60.5, 45.8, 36.9, 34.4,
32.2, 25.1, 24.9, 21.1, 18.2; down: 137.6, 126.8, 72.9, 72.2, 52.3,
48.9, 25.9 (×3), 14.4 (×2), -4.6, -4.7; IR (film): 3458, 2930,
2857, 1738, 1254, 1179, 1033, 837, 778 cm-1; EI MS (m/z): 521
(M+ + Na, 100), 503 (6), 481 (5), 349 (4), 303 (5); HRMS:
calcd.C26H46O7Si 498.3014 found 498.3030.
To the solution ofalcohol 21 in CH2Cl2 (3.5 mL) was added
Dess-Martin periodinane (126 mg, 0.260 mmol) at room
temperature. After an additional 1 h, the reaction mixture was
cooled in an ice bath. The resulting precipitate was filtered
and washed with Et2O. Evaporation of the filtrate gave a
residue that was chromatographed to afford the bicyclic ketone
1
7 (98 mg, 95% yield from 21). H NMR δ 5.57 (dt, 1H, J ) 7.4
and 10.3 Hz), 5.05 (dd, 1H, J ) 9.1 and 10.3 Hz), 4.43 (d, 1H,
J ) 4.9 Hz), 4.11 (m, 4H), 2.43 (m, 2H), 2.30 (t, 2H, J ) 7.4
Hz), 2.18 (m, 1H), 2.14 (m, 2H), 1.99 (m, 2H), 1.84 (m, 1H),
1.76 (m, 2H), 1.65 (m, 2H), 1.41 (quint, 2H, J ) 7.6 Hz), 1.25
(dt, 6H, J ) 7.2 and 5.8 Hz), 0.89 (s, 9H), 0.09 (s, 3H), 0.06 (s,
3H); 13C NMR δ up 212.8, 173.8, 173.6, 60.5 (×2), 44.1, 42.1,
34.3, 31.9, 29.0, 27.6, 24.7, 19.6, 18.1; down: 133.8, 124.9, 68.3,
42.3, 27.8, 25.9 (×3), 14.4 (×2), -4.5, -4.6; IR (film): 2931,
2857, 1732, 1254, 1178, 1085, 1058, 836, 777 cm-1; EI MS (m/
z) 503 (M+ + Na, 100), 481 (20), 349 (20), 303 (48), 257 (27);
HRMS: calcd C26H44O6Si 480.2908 found 480.2916.
En on e 19. To a stirred solution of the allylic alcohol 18 (212
mg, 0.426 mmol) in CH2Cl2 (12 mL) at room temperature was
added Dess-Martin periodinane (247 mg, 0.511 mmol). After
an additional 1 h, the reaction mixture was cooled in an ice
bath. The resulting precipitate was filtered and washed with
Et2O. Evaporation of the filtrate gave a residue that was
chromatographed to afford the enone 19 (169 mg, 80% yield
from 18), TLC Rf (MTBE/petroleum ether ) 3/7) ) 0.37. 1H
NMR δ 6.41 (dd, 1H, J ) 10.3 and 15.6 Hz), 6.26 (d, 1H, J )
15.6 Hz), 4.27 (m, 1H), 4.11 (m, 4H), 3.06 (dd, 1H, J ) 8.0 and
9.9 Hz), 2.77 (dd, 1H, J ) 7.5 and 15.6 Hz), 2.54 (m, 3H), 2.40
(m, 2H), 2.31 (m, 2H), 1.98 (m, 1H), 1.65 (m, 5H), 1.51 (m,
1H), 1.25 (m), 0.87 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR
δ up: 216.4, 199.1, 173.6, 173.0, 60.7, 60.5, 45.9, 40.6, 34.2,
32.2, 24.6, 23.4, 21.2, 18.1; down: 141.7, 132.9, 72.1, 52.7, 49.3,
25.9 (×3), 14.4 (×2), -4.6 (×2); IR (film): 2931, 2587, 1739,
1676, 1629, 1464, 1255, 1181, 837, 778 cm-1; EI MS (m/z): 519
(M+ + Na, 100) HRMS calcd C26H44O7Si, 496.2857 found
496.2881.
Th ioeth er 8. To a stirred solution of the bicyclic ketone 7
(474 mg, 0.988 mmol) and thiophenol (326 mg, 2.96 mmol) in
CH2Cl2 (2.0 mL) at -78 °C was added BF3‚OEt2 (561 mg, 3.95
mmol). After 20 min, the mixture was warmed to -45 °C. After
an additional 8 h, the reaction mixture was partitioned
between CH2Cl2 and, sequentially, saturated aqueous NaHCO3
and brine. The organic extract was dried (Na2SO4) and
concentrated. The residue was chromatographed to afford the
thioether 8 (318 mg, 55% yield from 7) as a colorless oil; TLC
Rf (MTBE/benzene ) 2/98) ) 0.42. 1H NMR δ 7.38 (m, 2H),
7.26 (m, 3H), 5.53 (t, 1H, J ) 10.6 Hz), 5.32 (m, 1H), 4.66 (d,
1H, J ) 6.1 Hz), 4.11 (m, 4H), 3.84 (dd, 1H, J ) 5.3 and 10.6
Hz), 2.72 (m, 2H), 2.59 (m, 2H), 2.46 (m, 1H), 2.26 (m, 2H),
2.14 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.4 (M, 3H), 1.25 (t,
6H, J ) 7.1 Hz), 1.05 (M, 1H), 0.87 (s, 9H), 0.10 (s, 3H), 0.09
(s, 3H); 13C NMR δ up: 217.2, 173.6, 173.3, 133.9, 60.5, 60.4,
47.0, 34.2, 33.1, 28.8, 27.0, 24.7, 20.6, 18.1; down: 134.5, 131.1
(×2), 129.5 (×2), 129.1, 129.0, 69.5, 53.1, 49.6, 47.0, 25.9 (×3),
14.4 (×2), -4.5 (×2); IR (film): 2930, 2856, 1736, 1583, 1472,
Dik eton e 9. To a solution of the enone 19 (18. 7 mg, 0.038
mmol) in ethanol (1.2 mL) at room temperature was added
Pd/C (1.0 mg, cat.), and then a hydrogen gas balloon was
attached. After 2 h, the reaction mixture was filtered and
concentrated. The residue was chromatographed to afford the
diketone 9 (18.6 mg, 99% yield from 19) as a colorless oil,TLC
Rf (MTBE/petroleum ether ) 3/7) ) 0.29. 1H NMR δ 4.20
(quint, 1H, J ) 2.9 Hz), 4.13 (q, 4H, J ) 7.1 Hz), 2.62 (q, 1H,
J ) 7.2 Hz), 2.49 (m, 6H), 2.32 (m, 2H), 2.21 (m, 2H), 1.88 (m,
1H), 1.66 (m, 8H), 1.27 (t, 6H, J ) 7.1 Hz), 0.87 (s, 9H), 0.07
(s, 3H), 0.06 (s, 3H); 13C NMR δ up: 217.5, 209.6, 173.6, 173.4,
60.6, 60.5, 45.6, 42.6, 40.7, 34.2, 32.3, 24.6, 23.3, 20.9, 19.9,
18.1; down: 71.1, 49.4, 47.8, 25.9 (×3), 14.4 (×2), -4.5, -4.6;
IR (film): 2930, 2857, 1736, 1253, 1178, 836, 777 cm-1; EI MS
1462, 1438, 1372, 1253, 1180 cm-1; EI MS (m/z): 613 (M+
+
Na, 100), 503 (6), 417 (10); HRMS calcd C32H50O6SiS 590.3099,
found 590.3107; Further elution gave the free thioether 16
(50.4 mg, 11% yield from 7) as a colorless oil, TLC Rf (MTBE/
1
petroleum ether ) 3/2) ) 0.33; H NMR δ 7.46 (m, 2H), 7.29
(m, 3H), 5.42 (m, 2H), 4.35 (m, 1H), 4.22 (dd, 1H, J ) 5.0 and
10.0 Hz), 4.11 (m, 4H), 3.10 (d, 1H, J ) 3.7 Hz), 2.72 (dd, 1H,
J ) 7.1 and 18.4 Hz), 2.52 (m, 1H), 2.35 (m, 2H), 2.26 (m, 2H),
2.20 (m, 2H), 1.84 (m, 2H), 1.64 (m, 2H), 1.47 (quint, 2H, J )