G. Zanoni et al. / Tetrahedron 66 (2010) 7472e7478
7477
25.9 (3ꢂq), 25.8 (3ꢂq), 25.0 (t), 24.7 (t), 22.6 (t), 18.3 (s), 17.8 (s),
14.0 (d), ꢀ4.3 (q), ꢀ4.6 (q), ꢀ4.7 (q), ꢀ4.9 (q); HRMS-ESI, m/z for
C32H64O5Si2 [MþH]þ calcd 585.4370, found 585.4388.
(d), 72.5 (d), 54.9 (d), 54.9 (d), 47.1 (t), 38.3 (t), 34.1 (t), 32.5 (t), 30.0
(t), 29.5 (t), 28.3 (t), 27.3 (t), 25.9 (t), 25.5 (t), 23.4 (t), 14.3 (q);
HRMS-ESI, m/z for
C
20H34O5 [MþH]þ calcd 355.2484, found
355.2467.
4.9. Oxidation of hydroxyacid 14
4.12. Synthesis of PGF2
5
a
DesseMartin periodinane (28 mg, 0.066 mmol) was added in
one portion to
a
solution of the hydroxyacid 14 (33 mg,
Aqueous HF (48%, 0.096 mL) was added to a stirred solution of
bis-silyl ether 12 (30 mg, 0.051 mmol) in MeCN (2 mL) in a PE test
tube. After 7 h phosphate buffer (pH 6.8, 6 mL) was added. The
layers were separated and the aqueous phase was extracted with
EtOAc (6ꢂ5 mL). The combined organic phases were washed with
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The resulting residue was purified by flash chromatog-
raphy on silica gel. Elution with EtOAc/MeOH (90:10) gave pure
0.057 mmol) in dry DCM (2 mL) at rt. The solution was stirred for
2 h and then quenched with dry Et2O (4 mL). The resulting sus-
pension was filtered over short pad of silica washed with 15 mL of
1:1 (dry)-hexane/(dry)-Et2O. The solvents were removed under
reduced pressure without heating over 30 ꢁC. The crude ketone was
purified by flash chromatography on silica gel. Elution with hexane/
AcOEt (8:2) gave pure ketone 14a as pale yellow oil (30 mg, 90%), Rf
(hexane/AcOEt) 0.25; [
20
a]
ꢀ45.2 (c 0.5, CH2Cl2); nmax (film) 2950,
PGF2a 5 (16.3 mg, 90%) as a colorless oil, Rf (3% MeOH in AcOEt) 0.2;
D
20
2931, 2853, 1746, 1707, 1462, 1361, 1253, 1075, 1002, 966, 833,
[a
]
þ25.3 (c 0.7, THF); nmax (film) 3383, 3004, 1742 cmꢀ1
; dH
D
780 cmꢀ1
;
dH (300 MHz, CD2Cl2) 5.67e5.50 (m, 2H), 4.18e4.05 (m,
(300 MHz, CD3COCD3) 5.60e5.46 (m, 3H), 5.41e5.28 (m, 1H), 4.12
(td, J¼5.2, 1.6 Hz, 1H), 4.04 (dd, J¼12.0, 5.7 Hz, 1H), 3.87 (ddd, J¼7.8,
6.0, 4.5 Hz, 1H), 2.42e1.99 (m, 8H), 1.74e1.58 (m, 3H), 1.57e1.18 (m,
9H), 0.90 (t, J¼6.8 Hz, 3H); dC (75 MHz, CD3COCD3) 174.6 (s), 136.1
(d), 132.9 (d), 130.5 (d), 129.7 (d), 78.1 (d), 72.9 (d), 72.2 (d), 56.2 (d),
51.2 (d), 44.4 (t), 38.5 (t), 33.6 (t), 32.6 (t), 27.2 (t), 26.1 (t), 26.0 (t),
25.6 (t), 23.3 (t),14.3 (q); HRMS-ESI, m/z for C20H34O5 [MþH]þ calcd
355.2484, found 355.2501.
2H), 2.64 (ddd, J¼18.2, 7.0, 1.2 Hz, 1H), 2.46 (dt, J¼11.1, 7.5 Hz, 1H),
2.36 (td, J¼7.5, 2.2 Hz, 2H), 2.18 (ddd, J¼18.2, 8.3, 2.4 Hz, 1H), 1.96
(dt, J¼11.1, 5.6 Hz, 1H), 1.68e1.23 (m, 18H), 0.94e0.90 (m, 21H),
0.10e0.06 (m, 12H); dC (75 MHz, CD2Cl2) 215.4 (s), 178.9 (s), 135.8
(d), 128.7 (d), 72.9 (d), 72.4 (d), 53.4 (d), 53.2 (d), 47.2 (t), 38.2 (t),
33.5 (t), 31.5 (t), 29.1 (t), 28.5 (t), 27.4 (t), 26.4 (t), 25.3 (3ꢂq), 25.2
(3ꢂq), 24.7 (t), 24.3 (t), 22.3 (t), 17.7 (s), 17.5 (s), 13.5 (d), ꢀ4.9 (q),
ꢀ5.2 (q), ꢀ5.3 (q), ꢀ5.3 (q); HRMS-ESI, m/z for C32H62O5Si2 [MþH]þ
calcd 583.4214, found 583.4210.
4.13. Synthesis of propargylic acetate 15
4.10. Synthesis of PGE2 1
n-BuLi (1.6 M in hexane, 0.153 mL, 1.15 equiv) was added to
a solution of 4-phenyl-1-butyne (0.038 mL, 0.26 mmol, 1.25 equiv)
in dry THF (3 mL) at ꢀ78 ꢁC. After stirring at ꢀ78 ꢁC for 30 min
aldehyde 6b (75 mg, 0.21 mmol, 1 equiv) in dry THF (2 mL) was
added via cannula, followed, after 30 min, by excess Ac2O
(0.036 mL, 0.38 mmol, 1.8 equiv) and a catalytic amount of DMAP
(2 mg). The resulting mixture was allowed to reach rt and stirred
for 15 min, followed by the addition of a saturated solution of NH4Cl
(5 mL). The layers were separated and the aqueous phase was
extracted with Et2O (3ꢂ10 mL). The combined organic phases were
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The resulting residue was purified by flash chromatography
on silica gel. Elution with hexane/EtOAc (8:2) gave the desired di-
astereomeric mixture 15 (93 mg, 85%) as a colorless oil, Rf (1:1
Aqueous HF (48%, 0.111 mL) was added to a stirred solution of
ketone 12a (45 mg, 0.077 mmol) in MeCN (4.5 mL) in a PE test tube.
After 6 h phosphate buffer (pH 6.8, 8 mL) was added. The layers
were separated and the aqueous phase was extracted with EtOAc
(6ꢂ6 mL). The combined organic phases were washed with brine,
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The resulting residue was purified by flash chromatography
on silica gel. Elution with EtOAc/MeOH (90:10) gave pure PGE220
(23 mg, 86%) as a colorless oil, Rf (3% MeOH in AcOEt) 0.2; [
ꢀ71.4 (c 0.7, EtOH); nmax (film) 3379, 2931, 2856, 1732, 1709, 1398,
1204, 1158, 1120, 1084, 1033, 973 cmꢀ1
dH (300 MHz, CD3CN) 5.59
(dd, J¼3.7, 2.6 Hz, 2H), 5.48e5.04 (m, 2H), 4.04 (q, J¼9.0 Hz, 2H),
2.63 (dd, J¼18.3, 7.4 Hz, 1H), 2.41e2.19 (m, 5H), 2.18e1.87 (m, 5H),
1.70e1.56 (m, 2H), 1.54e1.19 (m, 7H), 1.04e0.77 (m, 3H); dC
(75 MHz, CD3CN) 215.7 (s), 175.0 (s), 137.5 (d), 131.4 (d), 131.0 (d),
128.0 (d), 72.9 (d), 72.6 (d), 55.0 (d), 53.9 (d), 47.3 (t), 38.3 (t), 33.6
(t), 32.5 (t), 27.2 (t), 26.0 (t), 25.6 (t), 25.5 (t), 23.4 (t), 14.3 (q);
HRMS-ESI, m/z for C20H32O5 [MþH]þ calcd 353.2327, found
353.2353.
1
a
]
D
;
hexane/AcOEt) 0.4; nmax (film) 2360, 1770, 1731, 1715 cmꢀ1
; dH
(300 MHz, CDCl3) 8.07 (dd, J¼8.3, 2.3 Hz, 2H), 7.70e7.62 (m, 4H),
7.51e7.41 (m, 3H), 7.35e7.21 (m, 5H), 5.53 (t, J¼5.6 Hz, 1H),
5.48e5.44 (m,), 5.32e5.26 (m, 1H), 4.88 (dt, J¼13.0, 6.4 Hz, 1H),
2.86e2.79 (m, 4H), 2.61e2.42 (m, 5H), 2.26 (m, 1H), 2.11 (s, 3H); dC
(75 MHz, CDCl3) 176.3 (s), 176.2 (s), 169.6 (s), 169.5 (s), 165.6 (s),
165.5 (s), 146.0 (s), 146.0 (s), 140.0 (s), 139.9 (s), 130.2 (d), 128.9 (d),
128.4 (d), 128.2 (d), 128.2 (d), 127.3 (d), 127.1 (d), 126.5 (d), 87.7 (s),
87.4 (s), 84.4 (d), 84.1 (d), 76.8 (d), 76.6 (d), 75.9 (s), 75.6 (s), 64.5 (d),
63.8 (d), 56.2 (d), 55.6 (d), 40.0 (d), 39.9 (d), 38.9 (t), 38.2 (t), 36.1 (t),
36.0 (t), 34.3 (t), 34.2 (t), 20.9 (d), 20.9 (d), 20.5 (t), 20.4 (q); HRMS-
ESI, m/z for C33H30O6 [MþH]þ calcd 523.2120, found 523.2111.
4.11. Synthesis of Alprostil PGE1 2
Aqueous HF (48%, 0.111 mL) was added to a stirred solution of
ketone bis-silyl ether 14 (45 mg, 0.077 mmol) in MeCN (4.5 mL) in
a PE test tube. After 6 h phosphate buffer (pH 6.8, 8 mL) was added.
The layers were separated and the aqueous phase was extracted
with EtOAc (6ꢂ6 mL). The combined organic phases were washed
with brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The resulting residue was purified by flash
chromatography on silica gel. Elution with EtOAc/MeOH (90:10)
4.14. Synthesis of enone 16
Propargylic acetate 15 (72 mg, 0.138 mmol) was dissolved in
butanone (3 mL) and water (0.03 mL) followed by t-BuOH
(0.047 mL, 0.505 mmol), than was added Au(PPh3)NTf2 (0.7 mol %,
0.7 mg, 0.00096 mmol). The solution was stirred at rt for 23 h, than
Et3N (three drops) was added and the volatiles were removed un-
der reduced pressure, the residue was purified by flash chroma-
tography on silica gel. Elution with hexanes/AcOEt (8:2) gave the
gave pure PGE1 2 (24.5 mg, 90%) as a colorless oil, Rf (3% MeOH in
20
AcOEt) 0.2; [
a
]
D
ꢀ52 (c 0.25, EtOH); nmax (film) 3369, 2937, 2860,
1733, 1710, 1391, 1206, 115, 1120, 1084, 1033, 973 cmꢀ1
; dH
(300 MHz, CD3CN) 5.65e5.51 (m, 2H), 4.06e3.98 (m, 2H), 2.61 (dd,
J¼17.1, 6.3 Hz, 1H), 2.39e1.82 (m, 7H), 1.63e1.20 (m, 19H), 0.91 (br s,
3H); dC (75 MHz, CD3CN) 216.2 (s), 175.1 (s), 137.5 (d), 131.5 (d), 72.9
enone 16 (60 mg, 90 %) as a white solid, mp 130e131 ꢁC, Rf (hexane/
20
AcOEt, 7:3) 0.17 ; [
a
]
ꢀ120.8 (c 1.0, CH3CN); nmax (Nujol) 1771,
D