IMPROVED SYNTHESIS OF (+)-CLOPROSTENOL
393
at 80°C for 2 h, then concentrated in vacuo. Water (50 mL)
and MTBE (50 mL) were added and the organic phase was
discarded, the aqueous phase was acidized to pH ≈ 1.0–1.5
with 1 N hydrochloric acid. The acidic solution was stirred
for 30 min, then extracted with MTBE (50 mL). The organic
phase was washed successively with water (25 mL) and
saturated brine (25 mL), then concentrated in vacuo. The
residue was dissolved in dichloromethane (10 mL) and
cooled to 5°C for 4 h. The formed precipitate was filtered
off, the filtrate was concentrated in vacuo to give crude
product 5 (1.9 g, 87% yield).
Fig. 1. Structures of PGF2α and (+)-cloprostenol.
Preparation of (3aR,4R,5R,6aS)-4-((R,E)-4-(3-chlorophenoxy)-3-
hydroxybut-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl
[1,1′-biphenyl]-4-carboxylate (4). (–)-DIP-Cl as reductant.
3 (3.0 g, 5.8 mmol) in THF (60 mL) was added to a solution
of (–)-B-chlorodiisopinocampheylborane (10.2 mL, 1.7 M in
heptane, 17.4 mmol) in THF (15 mL) at –40°C. The reaction
mixture was stirred at –15°C for 18 h, then acetone (6 mL)
was added. The solution was stirred at 25°C for 1 h, then con-
centrated under reduced pressure. The residue was dissolved
in dichloromethane (60 mL), washed with saturated NH4Cl
(45 mL×3), and saturated brine (45 mL×1) in turn, then cooled
to –5°C for 8 h. The formed precipitate was filtered off, the
filtrate was concentrated in vacuo to give crude product 4
(2.7 g, 88% yield, 92:8 dr).
(R)-Me-CBS as reductant. (R)-2-Methyl-CBS-oxazaboro-
lidine (1.16 mL, 1.0 M in toluene, 1.16 mmol) was charged
along with THF (30 mL) under nitrogen atmosphere. N,N-
Diethylanilineborane (DEANB, 2.6 mL, 14.5 mmol) was
added in a slow stream and stirred for 30 min at 25°C. The
solution was cooled to –15°C, then 3 (3.0 g, 5.8 mmol) in
THF (15 mL) was added in about 5 min. The mixture was
stirred at 0°C for 1 h, then quenched with methanol (30 mL)
and stirred for 10 min. Hydrochloric acid (1.5 N, 60 mL)
was added, and the mixture was stirred at 25°C for 10
min, diluted with ethyl acetate (60 mL) and water (30 mL).
The organic layer was separated, washed with 1.5 N hydro-
chloric acid (30 mL), water (30 mL), and saturated brine
(30 mL) in turn, dried over anhydrous sodium sulfate,
concentrated under vacuum to give crude product 4 (2.7 g,
89% yield, 91:9 dr).
Preparation of (3aR,4R,5R,6aS)-4-((R,E)-4-(3-chlorophenoxy)-3-
hydroxybut-1-enyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-
one (6). A solution of 5 (1.9 g) in toluene (35 mL) was refluxed
for 30 min, then concentrated at atmospheric pressure to a vol-
ume of about 10 mL. The mixture was cooled to 80°C and ethyl
acetate (10 mL) was added. The solution was further cooled to
30°C and n-heptane (10 mL) was added to form some seed
crystal in the mixture. The mixture was stirred at 25°C for 10
min, then n-heptane (15 mL) was added over 5 min. After
stirring for another 1 h, the formed precipitate was filtered and
dried to give compound 6 (1.4 g, 95% yield). Mp 117.9–120.8°C;
20
1
½aꢀD = –7.6 (c=0.5, THF); H NMR (400 MHz, CDCl3) δ: 7.21
(s, 1H), 6.95 (d, J= 25.7 Hz, 2H), 6.81 (s, 1H), 5.71 (s, 2H), 4.92
(s, 1H), 4.53 (s, 1H), 4.01 (s, 2H), 3.89 (d, J= 7.4 Hz, 1H), 2.74
(d, J= 17.6 Hz, 2H), 2.64 (s, 1H), 2.50 (d, J= 15.8 Hz, 3H), 2.37
(s, 1H), 1.99 (s, 1H). 13C NMR (101 MHz, CDCl3) δ: 177.1,
159.1, 134.9, 132.9, 131.3, 130.4, 121.5, 115.1, 113.1, 82.6,
76.3, 71.7, 70.6, 56.2, 42.4, 39.7, 34.2; HRMS (ESI) calcd. for
C17H19ClO5Na [M + Na]+ 361.0813, found 361.0811.
Preparation of (3aR,4R,5R,6aS)-4-((3R,E)-4-(3-chlorophenoxy)-3-
(1-ethoxyethoxy)but-1- enyl)-5-(1-ethoxyethoxy)hexahydro-2H-
cyclopenta[b]furan-2-one (7). 6 (2.0 g, 5.9 mmol) was dissolved
in dichloromethane (30 mL) and placed in a sealable pressure
tube. Then trichloroacetic acid (0.06 g in 10 mL dichlorometh-
ane) and vinyl ethyl ether (17.0 mL, 177.0 mmol) were
added successively. The tube was closed and heated at
45°C for 8 h. Triethylamine (1.0 mL) was added, the mix-
ture was stirred for 10 min, then concentrated in vacuo
to give crude product 7 (3.7 g, >99% yield).
Crude product 4 (3.0 g) was then dissolved in methanol
(6 mL) and isopropyl ether (12 mL) at room temperature.
The formed precipitate was filtered, washed with cold isopro-
pyl ether, and dried to afford pure 4 as a white solid (2.5 g,
Preparation of (3aR,4R,5R,6aS)-4-((3R,E)-4-(3-chlorophenoxy)-3-
(1-ethoxyethoxy)but-1- enyl)-5-(1-ethoxyethoxy)hexahydro-2H-
cyclopenta[b]furan-2-ol (8). A solution of 7 (3.7 g, 5.9 mmol)
in THF (10 mL) was cooled to –40°C and a solution of diiso-
butylaluminium hydride (DIBAL-H, 6.6 mL, 1.5 M in THF,
9.9 mmol) was added. The mixture was stirred for 30 min at
–40°C, then quenched by the addition of ethyl acetate (30 mL)
and aqueous potassium sodium tartrate (20 g in 60 mL H2O).
The mixture was heated at 45°C for 1 h, then cooled to room
temperature. The organic layer was separated and concentrated
in vacuo to give crude product 8 (3.7 g, 95% yield).
1
81% yield, 98:2 dr). Mp 110.0–113.3°C; H NMR (400 MHz,
CDCl3) δ: 8.06 (m, 2H), 7.72-7.64 (m, 2H), 7.64-7.57 (m, 2H),
7.51-7.43 (m, 2H), 7.40 (m 1H), 7.16 (t, J= 8.2 Hz, 1H), 6.98-6.90
(m, 1H), 6.90-6.84 (m, 1H), 6.74 (m, 1H), 5.85 (m, 1H), 5.74
(m, 1H), 5.31 (m, 1H), 5.09 (m, 1H), 4.53 (d, J=3.5 Hz, 1H),
3.94 (m, 1H), 3.83 (m, 1H), 2.95-2.77 (m, 3H), 2.61 (m, 2H),
2.41 (d, J= 4.1 Hz, 1H), 2.29 (m, 1H); 13C NMR (101 MHz,
CDCl3) δ: 176.3, 165.9, 159.1, 146.1, 139.8, 135.0, 130.9, 130.2,
128.9, 128.2, 127.2, 121.5, 115.0, 113.1, 83.3, 79.0, 71.8, 70.0,
54.3, 42.7, 37.6, 34.9; HRMS (ESI) calcd. for C30H27ClO6Na
[M + Na]+ 541.1388, found 541.1387.
Preparation of (Z)-7-((1R,2R,3R,5S)-2-((3R,E)-4-(3-chlorophenoxy)-
3-(1-ethoxyethoxy)but-1-enyl)-3-(1-ethoxyethoxy)-5-
hydroxycyclopentyl)hept-5-enoic acid (9). A suspension
of 4-carboxybutyltriphenylphosphonium bromide (9.6 g, 21.7
mmol) in THF (60 mL) was cooled to –10°C and potassium
tert-butoxide (7.8 g, 69.5 mmol) was added slowly. The mix-
ture was stirred for 1 h, followed by a slow addition of crude
8 (3.7 g, 5.5 mmol) in THF (20 mL) at –10°C. After stirring
for 3 h at 0°C, water (30 mL) was added dropwise followed
Preparation of 2-((1R,2R,3R,5S)-2-((R,E)-4-(3-chlorophenoxy)-3-
hydroxybut-1-enyl)-3,5-dihydroxycyclopentyl)acetic acid (5).
4
(2.5 g, 4.8 mmol) was added to a solution of potassium
hydroxide (2.7 g, 74.0 mmol) in methanol (60 mL) and
water (1.3 mL) at room temperature. The solution was stirred
Chirality DOI 10.1002/chir