Prostanoids: Synthesis of enantiomers of 15-deoxy-16-hydroxy-16-methylprostaglandin E1

Article abstract of DOI:10.1135/cccc19971325

Four optically pure isomers of methyl 11,16-dihydroxy-16-methyl-9-oxoprost-13-enoate (1a-1d) were synthesized using an approach reverse to the classical Corey procedure, the key intermediates being the easily accessible (-)- and (+)-enantiomers of the Corey lactone, 2a and 2b.

Full text of DOI:10.1135/cccc19971325

Prostanoids
1325
PROSTANOIDS: SYNTHESIS OF ENANTIOMERS OF
15-DEOXY-16-HYDROXY-16-METHYLPROSTAGLANDIN E1
1
2
3
Miroslav TERINEK , Vaclav KOZMIK and Jaroslav PALECEK
Institute of Organic Chemistry, Prague Institute of Chemical Technology, 166 28 Prague 6,
Czech Republic; e-mail: 1 miroslav.terinek@vscht.cz, 2 vaclav.kozmik@vscht.cz,
3 jaroslav.palecek@vscht.cz
Received February 6, 1997
Accepted April 30, 1997
Dedicated to Dr Jaromir Plesek on the occasion of his 70th birthday.
Four optically pure isomers of methyl 11,16-dihydroxy-16-methyl-9-oxoprost-13-enoate (1a–1d)
were synthesized using an approach reverse to the classical Corey procedure, the key intermediates
being the easily accessible (–)- and (+)-enantiomers of the Corey lactone, 2a and 2b.
Key words: Prostaglandins; Enantiomeric resolution.
Cytoprotective analogues of prostaglandin E1 modified in the ω-chain are recently used
as active components in preparations controlling the secretion of gastric juice and pre-
venting or curing gastric intestinal tract (GIT) ulcers induced by nonsteroidal antiin-
flammatory drugs (NSAIDs)1–5. In this group of compounds, methyl ester of
(+/–)-15-deoxy-(16RS)-16-hydroxy-16-methylprostaglandin E1 (INN misoprostol, 1)1,2
plays an important role. This derivative is a mixture of four enantiomers 1a
(8R,11R,12R,16R), 1b (8S,11S,12S,16R), 1c (8R,11R,12R,16S) and 1d (8S,11S,12S,16S),
however, only the enantiomer 1c (with the natural PG E1 configuration) bears the main
biological activity.
1
O
COOCH
3
9
HO
CH
3
11
16
HO
1
a, (8R, 11R, 12R, 16R)
b, (8S, 11S, 12S, 16R)
c, (8R, 11R, 12R, 16S)
d, (8S, 11S, 12S, 16S)
During the last 15 years much effort has been devoted to the synthesis of these com-
pounds using two- or three-component conjugate additions of organocuprate reagents
with modified ω-chain to the corresponding cyclopentene system2,6–8. These at the first
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

1326
Terinek, Kozmik, Palecek:
glance simple and convergent procedures suffer from several drawbacks. In addition to
relatively complicated synthesis of intermediates, these methods do not allow to pre-
pare the biologically active enantiomer 1c in the required 98–99.5% enantiomeric ex-
cess9,10. The aim of our present study was to synthesize the said enantiomers 1a–1d
using an approach “reverse” to the classical highly stereoselective and flexible Corey
synthesis11. This approach had not been fully realized even using racemic intermedi-
ates12,13. Contrary to previous syntheses11–13 we prepared the pure enantiomers 1a–1d
starting from the easily accessible (–)-enantiomer (natural) of lactone 2a and from the
(+)-enantiomer of the Corey lactone 2b. We employed standard procedures which in
several steps were modified and optimized. For the sake of clarity, the reaction pathway
is depicted only for the levorotatory lactone 2a as the starting compound.
This lactone was almost quantitatively converted into the corresponding derivative 3a by
reaction with tert-butyldimethylsilyl chloride in dimethylformamide in the presence of
imidazole (Scheme 1). Removal of the 4-phenylbenzoyl protecting group by treatment
with sodium methoxide in methanol gave hydroxy derivative 4a which was converted
into a mixture of diastereoisomers 5a by reaction with 3,4-dihydro-2H-pyran catalyzed
with p-toluenesulfonic acid. In addition to the desired product (62%) we isolated also
the starting compound 4a (10–12%), the bistetrahydropyranyl derivative 6a (17%) and
the diol 7a (4–6%). Therefore, we tried to optimize this step using other catalysts14
(Dowex 8 WX, Amberlyst H-15, pyridinium p-toluenesulfonate) and varying the reac-
tion conditions. An excellent result (about 90% of 5a, without 4a, 6a and 7a) was
O
O
O
O
OH
OTBDMS
4-PhPhCOO
RO
R = 4-PhPhCO
R = H
2
3,
4,
O
OH
O
O
1
OR
OTBDMS
RO
THPO
1
R = 4-THP; R = TBDMS
5,
6,
7,
8
1
R = THP; R = THP
1
R = H; R = H
In formulae 2-8
a, (3aR, 4S, 5R, 6aS)
b, (3aS, 4R, 5S, 6aR)
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

Prostanoids
1327
achieved with anhydrous pyridinium p-toluenesulfonate as catalyst. The lactone 5a was
reduced with diisobutylaluminium hydride (DIBAL) in toluene at a temperature below
–75 °C and the obtained lactol 8a (90–95%) was converted into acid 9a by treatment
with ylide generated in situ from 4-(carboxybutyl)triphenylphosphonium bromide with
potassium tert-butoxide. Without isolation, the acid 9a was reacted with methyl iodide
and anhydrous potassium carbonate in acetone to give methyl ester 10a (Scheme 2) in
overall yield over 80%.
1
R O
CH COO
3
COOR
COOCH
3
8
OTBDMS
OH
THPO
THPO
1
12
R = H; R = H
1
9,
10,
11,
R = CH ; R = H
3
1
R = CH ; R = COCH
3
3
CH COO
3
CH COO
3
COOCH
3
COOCH
3
OH
R
RO
THPO
R = THP
R = H
13,
14,
R = CHO
15,
16,
R = COOH
In formulae 9-14
In formulae 15-16
a, (1R, 2S, 3R, 5S)
b, (1S, 2R, 3S, 5R)
a, (1R, 2R, 3R, 5S)
b, (1S, 2S, 3S, 5R)
SCHEME 2
In the next step, the free C-9 hydroxy group (PG-numbering) was acetylated with
acetic anhydride in pyridine in the presence of catalytic amount of 4-dimethylamino-
pyridine. The acetyl derivative 11a was obtained in high yield (about 90%). Attempted
catalytic hydrogenation of acetate 11a over 10% Pd/C in ethyl acetate was unsuccessful
because of immediate deactivation (precipitation) of the catalyst. Only after removal of
the tert-butyldimethylsilyl protecting group with tetrabutylammonium fluoride in tetra-
hydrofuran, the primary alcohol 12a was smoothly hydrogenated under the described
conditions. After consumption of the theoretical amount of hydrogen we isolated the
saturated alcohol 13a in high yield (95%) and purity. We found that prolonged hy-
drogenation resulted in higher consumption of hydrogen due to hydrogenolysis of the
tetrahydropyranylgroup14 under formation of diol 14a. To obtain an optimal yield of the
relatively little stable aldehyde 15a, we tried to oxidize the primary C-13 hydroxy
group in alcohol 13a with various reagents. Application of the chromium trioxide–pyridine
complex (Collins reagent15; sixfold molar excess, dichloromethane, 0 °C, 30 min) gave
the product 15a in about 45% yield, oxidation with in situ prepared N-chlorosuccin-
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

1328
Terinek, Kozmik, Palecek:
imide–thioanisole complex (Corey reagent16, threefold molar excess, dichloromethane,
20 °C, 210 min) afforded only 15% of the aldehyde and mainly the acid 16a (35%), and
reaction with periodate (Dess–Martin17, dimethyl sulfoxide, 1.5 molar excess, 20 °C, 40 min)
furnished 67% of the product. On the other hand, oxidation with the in situ prepared
complex of dimethyl sulfoxide and oxalyl chloride (Swern reagent18, threefold molar
excess, dichloromethane, –75 °C, 60 min) gave very pure product 15a in 92% yield
(Scheme 2).
In the next step, the bottom chain was introduced by reaction of aldehyde 15a with
ylide, generated in situ from (3-hydroxy-3-methylheptyl)triphenylphosphonium iodide
and butyl lithium in tetrahydrofuran. Surprisingly, in addition to the expected methyl
esters 17a + 17c, this reaction gave also the butyl esters 18a + 18c whose structure was
1
unequivocally confirmed by elemental analysis and spectral (IR, H NMR and MS)
methods (Scheme 3). The amount of the butyl esters increased with increasing reaction
time. So far, we are not able to explain this side reaction. Removal of the acetyl pro-
tecting group by treatment of these esters with excess of anhydrous methanol and cal-
cined potassium carbonate was accompanied by simultaneous transesterification and
the desired mixture of methyl esters 19a + 19c was obtained in very good yield (86%).
In addition, preparative chromatography of the reaction mixture afforded minor quan-
tity of another product whose molecular formula was C29H50O7, according to its
1
elemental analysis and molecular ion (m/z 510). As followed from H NMR, 13C NMR
and IR spectral analysis, this side product may be the Claisen condensation product
20a + 20c.
CH COO
3
HO
COOCH
COR
3
15
HO
CH
HO
CH
3
3
THPO
THPO
R = CH
17,
18,
3
R = OCH
19,
3
R = C H
4
9
R = CH COOCH
20,
2
3
O
COOCH
3
1
HO
CH
3
THPO
In formulae 17-20
a, (8R, 9S, 11R, 12R, 16R) c, (8R, 9S, 11R, 12R, 16S)
21
b, (8S, 9R, 11S, 12S, 16R)
d, (8S, 9R, 11S, 12S, 16S)
In formulae 21
a, (8R, 11R, 12R, 16R)
b, (8S, 11S, 12S, 16R)
c, (8R, 11R, 12R, 16S)
d, (8S, 11S, 12S, 16S)
SCHEME 3
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Prostanoids
1329
The C-9 secondary hydroxyl in 19a + 19c was oxidized with chromium trioxide–pyridine
complex in dichloromethane and the resulting oxo derivatives 21a + 21c were obtained
in 80–90% yield. The tetrahydropyranyl protecting group was removed by treatment
with 1 M hydrochloric acid in tetrahydrofuran and the reaction gave the diastereo-
isomeric pair (11R,16R)-1a and (11R,16S)-1c, together with minor quantity (about 3–5%)
of the corresponding isomers PG A1. Preparative HPLC afforded individual highly pure
epimers 1a and 1c. The other two diastereoisomers 1b and 1d were prepared analo-
gously starting from the (+)-enantiomer 2b (see Experimental).
The spectral data of the prepared compounds 1a–1d are in good accord with the
published ones9,19,20. The observed small differences in the optical rotation values
(Table I) can be explained by different enantiomeric purity and conditions of the meas-
urements. We assigned configuration to individual isomers on the basis of these data
and configuration of the starting lactone 2. The structure of all the prepared compounds
1
is in accord with the elemental analyses (Table I), infrared spectra (Table II) and H
NMR spectra (Table III) and in some cases was also verified by 13C NMR and mass
spectra (see Experimental).
EXPERIMENTAL
The temperature data are uncorrected. Melting points were determined on a Boetius block. Infrared
spectra were measured on a Nicolet 740 FT-IR spectrometer in chloroform (unless stated otherwise),
1H and 13C NMR spectra were obtained with Varian 300 and Bruker 400 instruments in deuteriochlo-
roform (unless stated otherwise). The chemical shifts are given in δ (ppm) and coupling constants J
in Hz. Optical rotations were determined on a Jasco digital polarimeter DIP-370. Mass spectra were
measured on a Finnigan MAT-90 spectrometer, using FAB or ES (electrospray) methods; the ion
species are described by m/z units (relative intensity, %). Column chromatography was performed on
Kieselgel 60 (Merck, 0.063–0.100 mm), TLC analyses were carried out on plates coated with Kiesel-
gel GF254 (Fluka); spots were detected by UV light or spraing with 1% solution of cerium(IV) am-
monium nitrate in 10% sulfuric acid and subsequent heating. The mixtures of isomers 1a + 1c or 1b + 1d
were separated by high pressure liquid chromatography on a Thermo Separation Products instrument,
using a P 1000 gradient pump, a Spectra Monitor 3200 UV-detector, and a Rheodyne 7125 injection
valve. Preparative chromatography was carried out on a Biospher SI 100 column (7 µm, 25 × 250 mm)
in hexane–ethanol (96 : 4); analytical separation was done on a Separon SGX column (7 µm, 4 × 250 mm)
in hexane–ethanol (95 : 5).
Chemicals. Optically pure (–)-enantiomer of Corey lactone 2a (m.p. 128–130 °C, [α]2D0 = –86.8°
(CHCl3, c 1.0)) and the (+)-enantiomer 2b (m.p. 133–135 °C, [α]2D0 = +88.5° (CHCl3, c 0.2)) was
obtained by resolution of the racemic lactone 2 (Spolana, Neratovice) according to a described pro-
cedure21. (3-Hydroxy-3-methylheptyl)triphenylphosphonium iodide was prepared as described in a
patent22
.
(–)-(3aR,4S,5R,6aS)-4-[(tert-Butyldimethylsilyloxy)methyl]-5-(4-phenylbenzoyloxy)hexahydro-2H-
cyclopenta[b]furan-2-one (3a)
Imidazole (11.01 g, 162 mmol) and tert-butyldimethylsilyl chloride (9.96 g, 66.1 mmol) were added
to a solution of lactone 2a (13.6 g, 38.6 mmol) in N,N-dimethylformamide (20 ml). The reaction
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

1330
Terinek, Kozmik, Palecek:
Calculated/Found
TABLE I
Optical rotations and elemental analyses of compounds 1–21
Formula
M.w.
[α]2D0, °(CHCl3)
c, g/100 ml
Compound
% C
% H
3a
3b
4a
4b
5a
5b
6a
6b
7a
7b
8a
8b
9a
9b
10a
C27H34O5Si
466.7
–81.5
0.8
69.49
68.95
7.34
7.09
C27H34O5Si
466.7
+81.3a
0.8
69.49
69.65
7.34
7.60
C14H26O4Si
286.4
–14.7
0.9
58.70
58.58
9.15
9.19
C14H26O4Si
286.4
+12.6b
0.8
58.70
58.82
9.15
9.43
C19H34O5Si
370.6
–66.2
0.7
61.58
61.93
9.25
9.45
C19H34O5Si
370.6
+27.2
0.7
61.58
61.87
9.25
9.04
C18H28O6
340.4
–
–
–
–
63.51
63.32
8.29
8.08
C18H28O6
340.4
63.51
63.20
8.29
8.11
C8H12O4
172.2
55.81
55.72
7.02
6.88
C8H12O4
172.2
55.81
55.56
7.02
7.11
C19H36O5Si
372.6
–19.7c
0.3
61.25
61.33
9.74
9.27
C19H36O5Si
372.6
+25.6
0.4
61.25
61.35
9.74
9.82
C24H44O6Si
456.7
+25.6
0.7
63.12
63.54
9.71
9.73
C24H44O6Si
456.7
–26.9
0.2
63.12
63.65
9.71
9.68
C24H46O6Si
470.7
+27.8d
0.2
63.79
63.40
9.85
9.95
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

Prostanoids
1331
TABLE I
(Continued)
Calculated/Found
Formula
M.w.
[α]2D0, °(CHCl3)
c, g/100 ml
Compound
% C
% H
10b
C24H46O6Si
470.7
–23.7e
0.3
63.79
63.74
9.85
9.84
11a
C27H48O7Si
512.8
+24.6
0.3
63.25
62.72
9.44
8.97
11b
C27H48O7Si
512.8
–26.7
0.3
63.25
63.55
9.44
9.49
12a
C21H34O7
398.5
+37.1
0.4
63.30
63.72
8.60
8.67
12b
C21H34O7
398.5
–42.5
0.5
63.30
63.35
8.60
8.85
13a
C21H36O7
400.5
+29.7
0.1
62.98
62.38
9.06
9.25
13b
C21H36O7
400.5
–49.2
0.4
62.98
63.26
9.06
9.35
14a
C16H26O6
314.4
–
61.13
59.84
8.34
8.11
14b
C16H26O6
314.4
–
61.13
59.66
8.34
8.06
15a
C21H34O7
398.5
+42.7
0.4
63.30
63.08
8.60
8.57
15b
C21H34O7
398.5
–47.3
0.3
63.30
62.31
8.60
8.70
17a + 17c
17b + 17d
18a + 18d
18b + 18d
C29H50O7
510.7
+59.8
0.2
68.20
68.68
9.87
10.06
C29H50O7
510.7
–53.6
0.1
68.20
68.76
9.87
10.03
C32H58O7
554.8
+44.5
0.2
69.28
68.83
10.54
10.34
C32H58O7
554.8
–40.9
0.1
69.28
69.62
10.54
10.05
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

1332
Terinek, Kozmik, Palecek:
Calculated/Found
TABLE I
(Continued)
Formula
M.w.
[α]2D0, °(CHCl3)
c, g/100 ml
Compound
% C
% H
19a + 19c
19b + 19d
20a + 20c
20b + 20d
21a + 21c
21b + 21d
1a
C27H48O6
468.7
+13.1
0.1
69.19
68.79
10.32
10.34
C27H48O6
468.7
–19.9
0.9
69.19
68.60
10.32
10.31
C29H50O7
510.7
–
68.20
68.02
9.87
10.12
C29H50O7
510.7
–
68.20
67.94
9.87
9.92
C27H46O6
466.7
–8.4
0.2
69.49
69.57
9.94
9.79
C27H46O6
466.7
+50.1
1.0
–57.8f
0.5
69.49
68.94
9.94
10.29
C22H38O5
382.5
69.08
68.31
10.01
9.92
1b
C22H38O5
382.5
+80.4g
0.4
69.08
68.20
10.01
10.14
1c
C22H38O5
382.5
–75.1h
0.2
69.08
68.24
10.01
9.99
1d
C22H38O5
382.5
+62.5i
1.0
69.08
68.30
10.01
9.84
a
b
c
d
[α]D20, °: Ref.23 +78.0 (CHCl3). Ref.23 +13.6 (CHCl3). Ref.24 –28.0 (c 1.98, CHCl3). Ref.24
+22.0 (c 1.84, CH3OH). e Ref.23 –26.0 (CHCl3). f Ref.9 –55.5 (CH3OH). g Ref.9 +47.5 (CH3OH). Ref.9
h
–71.8 (c 1.0, CH3OH). Ref.9 +56.5 (CH3OH).
i
mixture was stirred at room temperature under exclusion of air for 1 h. After partition between toluene
(150 ml) and water (100 ml), the organic layer was washed with saturated solution of sodium hy-
drogen carbonate (2 × 80 ml), water (2 × 80 ml), dried over anhydrous magnesium sulfate and the
solvent was evaporated. Crystallization of the crude residue (17.9 g) from ethyl acetate–hexane (1 : 7)
afforded 16.9 g (94%) of silyl ether 3a; white crystals, m.p. 74–76 °C (reported23 m.p. 83–84.5 °C
(ether–hexane).
(+)-(3aS,4R,5S,6aR)-4-[(tert-Butyldimethylsilyloxy)methyl]-5-(4-phenylbenzoyloxy)hexahydro-2H-
cyclopenta[b]furan-2-one (3b)
Silyl ether 3b was obtained analogously in 97% yield; white crystals, m.p. 81–83 °C.
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

Prostanoids
1333
(–)-(3aR,4S,5R,6aS)-4-[(tert-Butyldimethylsilyloxy)methyl]-5-hydroxy-hexahydro-2H-
cyclopenta[b]furan-2-one (4a)
Freshly prepared sodium methoxide (62.6 mmol) in methanol (80 ml) was added to a solution of
compound 3a (16.2 g, 34.7 mmol) in anhydrous methanol (30 ml). After stirring under nitrogen at
room temperature for 80 min, the reaction mixture was partitioned between chloroform (150 ml) and
water (150 ml). The chloroform layer was washed with saturated solutions of calcium chloride (2 × 80 ml)
and sodium chloride (2 × 80 ml), dried over anhydrous magnesium sulfate and the solvent was evaporated.
Pressure chromatography (0.5% triethylamine in chlorofom with gradient 2–4% methanol) of the
residue (14.2 g) afforded 6.69 g of the product which was crystallized from toluene–hexane (1 : 10)
to give 6.44 g (65%) of alcohol 4a as white crystals, m.p. 57–59 °C (reported23 m.p. 61–62.5 °C).
(+)-(3aS,4R,5S,6aR)-4-[(tert-Butyldimethylsilyloxy)methyl]-5-hydroxy-hexahydro-2H-cyclo-
penta[b]furan-2-one (4b)
The title alcohol was prepared in the same manner as described above in 65% yield. White crystals,
m.p. 57–59 °C.
(–)-(3aR,4S,5R,6aS)-4-[(tert-Butyldimethylsilyloxy)methyl]-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexa-
hydro-2H-cyclopenta[b]furan-2-one (5a)
To a solution of alcohol 4a (5.65 g, 19.7 mmol) in 1,2-dichloroethane (40 ml) were successively
added 3,4-dihydro-2H-pyran (10.9 ml, 120 mmol) and pyridinium p-toluenesulfonate (3.74 g, 14.9 mmol).
The suspension was stirred at room temperature in an inert atmosphere for 2 h and then partitioned
between 1,2-dichloroethane (40 ml) and water (40 ml). The organic layer was washed with saturated
sodium hydrogen carbonate solution (3 × 70 ml), water (2 × 70 ml) and saturated sodium chloride
solution (2 × 70 ml). After drying over anhydrous magnesium sulfate the solvent was evaporated and
the crude residue (6.97 g) was column chromatographed (pressure, eluent toluene–tert-butyl methyl
ether (6 : 1) with 0.5% triethylamine). Yield 6.56 g (90%) of pure lactone 5a as a viscous oil.
(+)-(3aS,4R,5S,6aR)-4-[(tert-Butyldimethylsilyloxy)methyl]-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexa-
hydro-2H-cyclopenta[b]furan-2-one (5b)
The title lactone 5b was prepared in the same manner as lactone 5a. Yield 82%, yellow oil.
(–)-(2RS,3aR,4S,5R,6aS)-4-[(tert-Butyldimethylsilyloxy)methyl]-5-[(tetrahydro-2H-pyran-2-yl)oxy]-
hexahydro-2H-cyclopenta[b]furan-2-ol (8a)
A solution of diisobutylaluminium hydride (1 M, 24.0 ml, 24.0 mmol) was added dropwise under
nitrogen at –75 °C during 10 min to a solution of compound 5a (3.39 g, 9.15 mmol) in toluene (40 ml).
After stirring at –70 °C for 45 min under nitrogen, anhydrous methanol (4.5 ml) was added and the
mixture was allowed to warm to about 5 °C. Water (26 ml) was added and the mixture was stirred
for 80 min at 5 °C. The precipitated aluminium salts were filtered off and washed with toluene (3 × 25 ml),
the combined organic filtrates were washed with saturated solution of sodium chloride (2 × 90 ml)
and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 3.20 g (94%) of pure
lactol 8a as a yellowish viscous oil.
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

1334
Terinek, Kozmik, Palecek:
TABLE II
Absorption maxima in IR spectra of compounds 1–21
Compound
ν(OH)
ν(C–H)
ν(C=O)
ν(C–O)
3a
–
–
3 027 w, 2 956 w, 2 888 w, 2 858 w 1 769 s, 1 712 s 1 277 s
3 026 w, 2 956 w, 2 898 w, 2 859 w 1 769 s, 1 712 s 1 279 s
3b
4a
3 607 w, 3 523 w 3 025 w, 2 956 m, 2 900 m, 2 859 m 1 768 s
3 608 w, 3 507 w 3 024 w, 2 956 m, 2 899 w, 2 859 m 1 766 s
–
4b
–
5a
–
–
–
–
3 013 w, 2 954 m, 2 932 m, 2 858 m 1 765 s
3 024 w, 2 954 m, 2 932 m, 2 858 m 1 785 s
–
–
5b
6a
2 985 w, 2 935 m, 2 892 w
2 990 w, 2 940 m, 2 890 w
2 978 w, 2 935 m, 2 887 w
2 980 w, 2 938 m, 2 889 w
1 750 s
1 755 s
1 737 s
1 739 s
1 212 s
1 210 s
1 205 s
1 208 s
–
6b
7a
3 365 m
3 368 m
7b
8a
3 600 w, 3 385 w 3 012 m, 2 952 s, 2 932 s, 2 858 m
3 600 w, 3 389 w 3 011 m, 2 952 s, 2 932 s, 2 858 m
–
–
8b
–
9a
3 519 w
3 518 w
3 523 w
3 522 w
3 017 m, 2 952 s, 2 930 s, 2 857 m
3 010 m, 2 952 s, 2 932 s, 2 857 s
3 005 w, 2 953 s, 2 931 s, 2 857 m
3 010 m, 2 953 s, 2 932 s, 2 858 m
1 709 m
1 709 s
1 731 m
1 731 m
–
9b
–
10a
10b
11a
11b
12a
12b
13a
13b
14a
14b
15a
15b
–
–
–
–
3 025 w, 2 953 m, 2 932 m, 2 858 m 1 729 s
3 023 w, 2 953 m, 2 932 m, 2 858 w 1 729 s
1 255 s
1 255 s
1 254 m
1 255 m
1 256 m
1 257 m
1 254 m
1 253 m
1 250 m
1 250 m
1 253 m
1 260 m
1 254 m
1 260 m
–
3 460 w
3 023 w, 2 951 m, 2 869 w
1 730 s
1 729 s
1 729 s
1 729 s
1 730 s
1 730 s
1 731 s
1 729 s
1 730 s
1 730 s
1 727 s
1 727 s
1 731 m
1 731 s
3 508 w, 3 448 w 3 022 m, 2 951 m, 2 869 w
3 460 w
3 447 w
3 450 w
3 453 w
3 023 w, 2 938 m, 2 860 w
3 022 m, 2 939 m, 2 860 w
3 024 w, 2 935 m, 2 859 w
3 026 w, 2 935 m, 2 861 w
3 023 w, 2 941 m, 2 860 w
3 023 m, 2 942 m, 2 860 w
3 014 w, 2 934 s, 2 860 m
3 013 m, 2 936 s, 2 862 m
3 012 w, 2 935 m, 2 861 w
3 012 w, 2 935 s, 2 861 m
–
–
17a + 17c 3 486 w
17b + 17d 3 474 w
18a + 18c 3 486 w
18b + 18d 3 482 w
19a + 19c 3 607 w, 3 521 w 3 011 m, 2 934 s, 2 859 m
19b + 19d 3 606 w, 3 515 w 3 019 m, 2 934 s, 2 859 m
20a + 20ca 3 607 w, 3 512 w 3 019 m, 2 935 m, 2 860 m
20b + 20da 3 606 w, 3 514 w 3 018 m, 2 934 m, 2 860 m
21a + 21c 3 605 w, 3 479 w 3 017 w, 2 936 m, 2 860 w
21b + 21d 3 606 w, 3 477 w 3 019 w, 2 936 m, 2 860 w
–
1 740 m, 1 717 m
1 741 m, 1 718 m
1 737 s
–
–
–
1 737 s
–
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

Prostanoids
1335
TABLE II
(Continued)
Compound
ν(OH)
ν(C–H)
ν(C=O)
ν(C–O)
1a
1b
1c
1d
3 601 w, 3 407 w
3 605 w, 3 403 w
3 603 w, 3 407 w
3 602 w, 3 405 w
3 019 w, 2 935 m, 2 860 w
3 018 w, 2 935 m, 2 860 w
3 020 w, 2 935 m, 2 861 w
3 018 w, 2 935 m, 2 861 w
1 737 s
1 738 s
1 738 s
1 738 s
–
–
–
–
a Neat.
(+)-(2RS,3aS,4R,5S,6aR)-4-[(tert-Butyldimethylsilyloxy)methyl]-5-[(tetrahydro-2H-pyran-2-yl)oxy]-
hexahydro-2H-cyclopenta[b]furan-2-ol (8b)
Lactol 8b was prepared in the same manner as compound 8a, yield 91%, viscous oil.
Methyl-(+)-7-{(1R,2S,3R,5S)-2-[(tert-butyldimethylsilyloxy)methyl]-5-hydroxy-3-[(tetrahydro-2H-
pyran-2-yl)oxy]cyclopent-1-yl]}hept-5(Z)-enoate (10a)
A solution of potassium tert-butoxide in tetrahydrofuran (2.26 mol l–1; 43.1 ml, 97.4 mmol) was
added dropwise at about 5 °C (external cooling with ice) to a suspension of 4-(carboxybutyl)triphe-
nylphosphonium bromide (21.6 g, 48.7 mmol) in tetrahydrofuran (80 ml). The reaction mixture, con-
taining the deep orange ylide, was stirred at 5 °C for 15 min. Then a solution of lactol 8a (5.20 g,
14.0 mol) in tetrahydrofuran (30 ml) was added in one portion. The reaction mixture was stirred at
the same temperature for 60 min and then mixed with a solution of potassium carbonate (0.850 g,
6.15 mmol) in water (50 ml), ether (30 ml), ethyl acetate (30 ml) and benzene (60 ml). After separ-
ation, the aqueous layer was extracted with ether–ethyl acetate (1 : 1) (2 × 60 ml) and the combined
organic layers were washed with water (3 × 60 ml). The aqueous phases, containing the salt of acid
9a (TLC), were combined, cooled (ice) to about 5 °C, and under constant stirring acidified with satu-
rated solution of sodium hydrogen sulfate (to pH about 6). The reaction mixture was extracted with
diethyl ether (3 × 60 ml), the combined ethereal phases were washed with water (20 ml) and satu-
rated sodium chloride solution (20 ml) and dried over anhydrous magnesium sulfate. A part of the
filtrate was evaporated and subjected to column chromatography (gradient elution with 5–10% methanol
in chloroform) which gave 0.086 g of acid 9a for analytical purposes. The rest of the filtrate was
coevaporated with potassium carbonate (7.66 g, 55.4 mmol) and the obtained crude potassium salt of
acid 9a (14.5 g) was slurried in acetone (60 ml). Methyl iodide (20.5 ml, 329 mmol) was added and
the reaction mixture was stirred at room temperature under exclusion of moisture. After 15 h the
separated inorganic salts were removed by filtration and washed with acetone (3 × 20 ml) and the
combined acetone washings were evaporated on a rotatory evaporator in vacuo. The crude residue
was diluted with diethyl ether–ethyl acetate (1 : 1, 30 ml), the precipitated crystals were collected
and washed with the same solvent mixture (2 × 20 ml). The combined organic portions were evap-
orated and the residue (5.52 g) was subjected to column chromatography. Yield 5.25 g (80% from
the lactol 8a) of methyl ester 10a as a yellowish oil.
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

1336
Terinek, Kozmik, Palecek:
TABLE III
1
Characteristic shifts of signals in the H NMR spectra of compounds 1–21
1H NMR spectrum, ppm
Compound
3a
3b
4a
4b
5a
5b
6a
6b
7aa
7ba
8a
8b
9a
0.08 s, 6 H (2 × CH3); 0.91 s, 9 H ((CH3)3C); 7.39–8.09 m, 9 H (H-arom)
0.08 s, 6 H (2 × CH3); 0.91 s, 9 H ((CH3)3C); 7.40–8.09 m, 9 H (H-arom)
0.07 s, 6 H (2 × CH3); 0.89 s, 9 H ((CH3)3C); 2.28 d, 1 H (OH)
0.07 s, 6 H (2 × CH3); 0.89 s, 9 H ((CH3)3C); 2.24 d, 1 H (OH)
0.04 s, 6 H (2 × CH3); 0.88 s, 9 H ((CH3)3C)
0.04 s, 6 H (2 × CH3); 0.88 s, 9 H ((CH3)3C)
3.90 m, 1 H (CH–O); 4.83 dt, 1 H (CH–O)
3.88 m, 1 H (CH–O); 4.82 dt, 1 H (CH–O)
3.92 m, 1 H (CH–O); 4.63 t, 1 H (OH); 4.74 d, 1 H (OH); ; 4.90 dt, 1 H (CH–O)
3.90 m, 1 H (CH–O); 4.61 t, 1 H (OH); 4.73 d, 1 H (OH); 4.87 dt, 1 H (CH–O)
0.05 s, 6 H (2 × CH3); 0.89 s, 9 H ((CH3)3C)
0.04 s, 6 H (2 × CH3); 0.89 s, 9 H ((CH3)3C)
0.04 s, 6 H (2 × CH3); 0.89 s, 9 H ((CH3)3C); 2.36 t, 2 H (CH2–CO); 5.40–5.49 m,
2 H (CH=CH)
9b
0.05 s, 6 H (2 × CH3); 0.89 s, 9 H ((CH3)3C); 2.36 t, 2 H (CH2–CO); 5.40–5.48 m,
2 H (CH=CH)
10a
0.04 s, 6 H (2 × CH3); 0.89 s, 9 H ((CH3)3C); 2.33 t, 2 H (CH2–CO); 3.67 s, 3 H
(OCH3); 5.40–5.49 m, 2 H (CH=CH)
10b
11a
11b
12a
12b
0.03 s, 6 H (2 × CH3); 0.87 s, 9 H ((CH3)3C); 2.31 t, 2 H (CH2–CO); 3.65 s, 3 H
(OCH3); 5.38–5.47 m, 2 H (CH=CH)
0.04 s, 6 H (2 × CH3); 0.88 s, 9 H ((CH3)3C); 2.03 s, 3 H (CO–CH3); 2.30 t, 2 H
(CH2–CO); 3.67 s, 3 H (OCH3); 5.29–5.42 m, 2 H (CH=CH)
0.02 s, 6 H (2 × CH3); 0.85 s, 9 H ((CH3)3C); 2.00 s, 3 H (CO–CH3); 2.27 t, 2 H
(CH2–CO); 3.63 s, 3 H (OCH3); 5.23–5.41 m, 2 H (CH=CH)
2.04 s, 3 H (CO–CH3); 2.31 t, 2 H (CH2–CO); 3.67 s, 3 H (O–CH3); 5.29–5.44 m,
2 H (CH=CH)
2.02 s, 3 H (CO–CH3); 2.29 t, 2 H (CH2–CO); 3.65 s, 3 H (O–CH3); 5.24–5.41 m,
2 H (CH=CH)
13a
13b
14a
2.04 s, 3 H (CO–CH3); 2.29 t, 2 H (CH2–CO); 3.66 s, 3 H (O–CH3)
2.04 s, 3 H (CO–CH3); 2.29 t, 2 H (CH2–CO); 3.66 s, 3 H (O–CH3)
2.06 s, 3 H (CO–CH3); 2.30 t, 2 H (CH2–CO); 3.66 s, 3 H (O–CH3); 5.29–5.45 m,
2 H (CH=CH)
14b
15a
15b
2.06 s, 3 H (CO–CH3); 2.29 t, 2 H (CH2–CO); 3.67 s, 3 H (O–CH3); 5.22–5.40 m,
2 H (CH=CH)
2.06 s, 3 H (CO–CH3); 2.28 t, 2 H (CH2–CO); 3.65 s, 3 H (O–CH3); 9.77 dd, 1 H
(CH=O)
2.04 s, 3 H (CO–CH3); 2.26 t, 2 H (CH2–CO); 3.63 s, 3 H (O–CH3); 9.75 dd, 1 H
(CH=O)
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

Prostanoids
1337
TABLE III
(Continued)
1H NMR spectrum, ppm
Compound
17a + 17c 0.92 t, 3 H (CH3); 1.16 s, 3 H (CH3); 2.05 s, 3 H (CO–CH3); 2.29 t, 2 H (CH2–CO);
3.67 s, 3 H (O–CH3); 5.31–5.64 m, 2 H (CH=CH)
17b + 17d 0.90 t, 3 H (CH3); 1.13 s, 3 H (CH3); 2.03 s, 3 H (CO–CH3); 2.26 t, 2 H (CH2–CO);
3.64 s, 3 H (O–CH3); 5.25–5.62 m, 2 H (CH=CH)
18a + 18c 0.94 t, 3 H (CH3); 1.16 s, 3 H (CH3); 2.05 s, 3 H (CO–CH3); 2.29 t, 2 H (CH2–CO);
4.07 t, 2 H (O–CH2); 5.32–5.64 m, 2 H (CH=CH)
18b + 18d 0.93 t, 3 H (CH3); 1.15 s, 3 H (CH3); 2.04 s, 3 H (CO–CH3); 2.27 t, 2 H (CH2–CO);
4.06 t, 2 H (O–CH2); 5.31–5.63 m, 2 H (CH=CH)
19a + 19c 0.92 t, 3 H (CH3); 1.15 s, 3 H (CH3); 2.30 t, 2 H (CH2–CO); 3.67 s, 3 H (O–CH3);
5.34–5.61 m, 2 H (CH=CH)
19b + 19d 0.92 t, 3 H (CH3); 1.15 s, 3 H (CH3); 2.30 t, 2 H (CH2–CO); 3.67 s, 3 H (O–CH3);
5.35–5.61 m, 2 H (CH=CH)
20a + 20c 0.92 t, 3 H (CH3); 1.15 s, 3 H (CH3); 2.51 t, 2 H (CH2–CO); 3.44 s, 3 H (O–CH3);
3.74 s, 2 H (CO–CH2–CO); 5.35–5.58 m, 2 H (CH=CH)
20b + 20d 0.92 t, 3 H (CH3); 1.15 s, 3 H (CH3); 2.52 t, 2 H (CH2–CO); 3.45 s, 3 H (O–CH3);
3.74 s, 2 H (CO–CH2–CO); 5.35–5.58 m, 2 H (CH=CH)
21a + 21c 0.92 t, 3 H (CH3); 1.16 s, 3 H (CH3); 2.29 t, 2 H (CH2–CO); 3.66 s, 3 H (O–CH3);
5.44–5.75 m, 2 H (CH=CH)
21b + 21d 0.91 t, 3 H (CH3); 1.16 s, 3 H (CH3); 2.28 t, 2 H (CH2–CO); 3.66 s, 3 H (O–CH3);
5.42–5.72 m, 2 H (CH=CH)
1a
1b
1c
1d
0.92 t, 3 H (CH3); 1.18 s, 3 H (CH3); 3.67 s, 3 H (O–CH3); 5.39–5.80 m, 2 H (CH=CH)
0.90 t, 3 H (CH3); 1.16 s, 3 H (CH3); 3.65 s, 3 H (O–CH3); 5.36–5.74 m, 2 H (CH=CH)
0.92 t, 3 H (CH3); 1.18 s, 3 H (CH3); 3.67 s, 3 H (O–CH3); 5.39–5.80 m, 2 H (CH=CH)
0.90 t, 3 H (CH3); 1.16 s, 3 H (CH3); 3.65 s, 3 H (O–CH3); 5.36–5.74 m, 2 H (CH=CH)
a Measured in (CD3)2CO.
Methyl (–)-7-{(1S,2R,3S,5R)-2-[(tert-butyldimethylsilyloxy)methyl]-5-hydroxy-3-[(tetrahydro-2H-
pyran-2-yl)oxy]cyclopent-1-yl]}hept -5(Z)-enoate (10b)
The title methyl ester 10b was prepared as a yellowish oil from the lactol 8b in 79% yield in the
same manner as described for 10a.
Methyl (+)-7-{(1R,2S,3R,5S)-5-acetyloxy-2-[(tert-butyldimethylsilyloxy)methyl]-3-[(tetrahydro-2H-
pyran-2-yl)oxy]cyclopent-1-yl]}hept-5(Z)-enoate (11a)
Freshly distilled acetic anhydride (6.10 ml, 64.7 mmol) was added at 5 °C (external cooling) to a
mixture of alcohol 10a (5.06 g, 10.7 mmol), 4-dimethylaminopyridine (0.096 g, 0.786 mmol) and dry
pyridine (40 ml). The solution was stirred under exclusion of moisture at diminished temperature for
10 min and then at room temperature for 60 min. The reaction mixture was cooled, decomposed with
water (50 ml) and extracted with ethyl acetate (4 × 50 ml). The combined organic extracts were sub-
sequently washed with water (50 ml), 0.5 M hydrochloric acid (50 ml), saturated solution of sodium
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

1338
Terinek, Kozmik, Palecek:
hydrogen carbonate (3 × 50 ml), water (50 ml) and saturated sodium chloride solution (50 ml). After
drying over anhydrous magnesium sulfate and evaporation of the solvent, the crude product (5.19 g)
was repeatedly coevaporated with toluene (5 × 10 ml) to remove the remaining pyridine. Column
chromatography in hexane–ethyl acetate (4 : 1) afforded 4.94 g of ester 11a (90%) as a yellowish oil.
Methyl (–)-7-{(1S,2R,3S,5R)-5-acetyloxy-2-[(tert-butyldimethylsilyloxy)methyl]-3-[(tetrahydro-2H-
pyran-2-yl)oxy]cyclopent-1-yl]}hept-5(Z)-enoate (11b)
The title ester was obtained as a viscous oil from alcohol 10b in 88% yield in the same manner as
described for 11a.
Methyl (+)-7-{(1R,2S,3R,5S)-5-acetyloxy-2-(hydroxymethyl)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-
cyclopent-1-yl]}hept-5(Z)-enoate (12a)
To a solution of silyl ether 11a (4.92 g, 9.60 mmol) in tetrahydrofuran (60 ml) 1 M tetrabutylam-
monium fluoride in tetrahydrofuran (50.0 ml, 50.0 mmol) was added at 5 °C (external ice-cooling) in
the course of 5 min. After stirring under nitrogen at 10 °C for 2 h, the reaction mixture was diluted
with ethyl acetate (100 ml), the solution was washed with water (4 × 50 ml) and saturated sodium
chloride solution (2 × 50 ml), and the organic layer was dried over anhydrous magnesium sulfate.
The solvent was evaporated and the residue (4.56 g) purified by column chromatography in hexane–
ethyl acetate (1 : 1) to give 3.55 g of unsaturated alcohol 12a (93%) as a viscous oil. Mass spectrum
•
(ES): 421.0 ([M + Na]+, 100).
Methyl (–)-7-{(1S,2R,3S,5R)-5-acetyloxy-2-(hydroxymethyl)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-
cyclopent-1-yl]}hept-5(Z)-enoate (12b)
The title compound was prepared as a yellowish oil in 98% yield from 11b as described above.
Methyl (+)-7-{(1R,2S,3R,5S)-5-acetyloxy-2-(hydroxymethyl)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-
cyclopent-1-yl]}heptanoate (13a)
Unsaturated alcohol 12a (3.39 g, 8.51 mmol) was hydrogenated in ethyl acetate (110 ml) over 10%
Pd/C (0.443 g) at atmospheric pressure and room temperature in a standard apparatus. After con-
sumption of the theoretical amount of hydrogen, the catalyst was filtered off and washed with ethyl
acetate (3 × 50 ml). The combined filtrates were evaporated and the crude product (3.30 g) was column
chromatographed in hexane–ethyl acetate (1 : 1) to give 3.28g (96%) of saturated alcohol 13a as a
•
•
yellow oil. Mass spectrum (ES): 423.1 ([M + Na]+, 100), 439.1 ([M + K]+, 10).
Methyl (–)-7-{(1S,2R,3S,5R)-5-acetyloxy-2-(hydroxymethyl)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-
cyclopent-1-yl]}heptanoate (13b)
The saturated alcohol 13b was obtained from 12b as a yellowish oil in 86% yield using an analogous
procedure.
Methyl (+)-7-{(1R,2S,3R,5S)-5-acetyloxy-2-formyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopent-1-yl]}-
heptanoate (15a)
A solution of dimethyl sulfoxide in dichloromethane (5.64 mol l–1, 5.10 ml, 28.8 mmol) was added
at –75 °C to a solution of oxalyl chloride in dichloromethane (1.16 mol l–1, 7.50 ml, 8.70 mmol).
After 10 min at –75 °C, a solution of alcohol 13a (3.28 g, 8.19 mmol) in dichloromethane (7 ml) was
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

Prostanoids
1339
added and the reaction mixture was stirred at –75 °C for 1 h. The complex was decomposed with
triethylamine (6.40 ml, 45.9 mmol), the mixture was allowed to warm to room temperature and then
was diluted with ether (50 ml). The solution was washed with saturated solutions of ammonium
chloride (2 × 30 ml) and sodium chloride (2 × 30 ml) and dried over anhydrous magnesium sulfate.
The solvent was evaporated and the residue (3.16 g) subjected to column chromatography in hexane–
ethyl acetate (1 : 1) to afford 3.01 g (92%) of aldehyde 15a as an oil. In addition, 0.030 g (1%) of
the starting alcohol 13a was recovered.
Methyl (–)-7-{(1S,2R,3S,5R)-5-acetyloxy-2-formyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopent-1-yl]}-
heptanoate (15b)
The title aldehyde 15b (yellow oil) was prepared analogously in 85% yield. Small amount (2%) of
the starting alcohol 13b was also recovered.
Methyl (+)-(8R,9S,11R,12R,16RS)-9-acetyloxy-16-hydroxy-16-methyl-11-[(tetrahydro-2H-pyran-2-yl)-
oxy]prost-13-enoate (17a + 17c)
A solution of butyllithium in hexane (1.86 mol l–1, 15.4 ml, 28.6 mmol) was added dropwise at –75 °C
during 5 min to a suspension of (3-hydroxy-3-methylheptyl)triphenylphosphonium iodide (7.45 g,
14.4 mmol) in tetrahydrofuran (30 ml) in a nitrogen atmosphere. After addition, the cooling bath was
removed and the suspension was stirred at room temperature for 2 h. The mixture was cooled to –40 °C,
stirred at this temperature for 10 min and then a solution of aldehyde 15a (2.81 g, 7.05 mmol) in
tetrahydrofuran (20 ml) was added in one portion. The reaction mixture was stirred under nitrogen at
–30 to –20 °C for 2 h and partitioned between ethyl acetate (80 ml) and water (80 ml). The aqueous
phase was washed with ethyl acetate (2 × 60 ml) and the combined organic phases were washed with
water (50 ml), saturated solutions of ammonium chloride (50 ml) and sodium chloride (50 ml) and
dried over anhydrous magnesium sulfate. After evaporation of the solvent, the crude residue (8.2 g)
was subjected to column chromatography in hexane–ethyl acetate (2 : 1) to give 1.04 g (29%) of
methyl esters 17a + 17c and 0.861 g (22%) of butyl esters 18a + 18c, both as viscous oils.
Methyl (–)-(8S,9R,11S,12S,16RS)-9-acetyloxy-16-hydroxy-16-methyl-11-[(tetrahydro-2H-pyran-2-yl)-
oxy]prost-13-enoate (17b + 17d)
The title methyl esters were obtained as a yellow oil in 28% yield, together with the corresponding
butyl esters 18b + 18d (oil, 22%).
Methyl (+)-(8R,9S,11R,12R,16RS)-9,16-dihydroxy-16-methyl-11-[(tetrahydro-2H-pyran-2-yl)oxy]-
prost-13-enoate (19a + 19c)
Freshly calcined potassium carbonate (2.85 g, 20.6 mmol) was added to a solution of a mixture of
17a + 17c (0.846 g, 1.66 mmol) and 18a + 18c (0.575 g, 1.04 mmol) in anhydrous methanol (80 ml).
After stirring under nitrogen at 45 °C for 3 h, the suspension was diluted with ethyl acetate (80 ml)
and washed with saturated ammonium chloride solution (70 ml). The aqueous layer was extracted
with ethyl acetate (2 × 30 ml) and the combined organic phases were washed with saturated solution
of sodium chloride (2 × 50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated
and the crude product (1.22 g) was subjected to column chromatography to give 0.887 g (68%) of
product 19a + 19c as a viscous oil, together with the Claisen condensation product 20a + 20c (0.128 g;
•
•
9%; oil). Mass spectrum of 19a + 19c (FAB): 469.4 ([M]+, 6), 85.1 (THP, 100), 385.4 ([M – THP]+, 23),
•
•
•
367.4 ([M – THP – H2O]+, 85), 349.4 ([M – THP –2H2O]+, 64), 331.3 ([M – THP – 3H2O]+, 52).
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

1340
Terinek, Kozmik, Palecek:
•
+
20a + 20c (ES): 533.2 ([M + Na] , 100).
Mass spectrum of
13C NMR spectrum of 20a + 20c (characteristic shifts): 167.98 s
(CH
2COCH2); 203.04 s (CH2COOCH3).
Methyl (–)-(8S,9R,11S,12S,16RS)-9,16-dihydroxy-16-methyl-11-[(tetrahydro-2H-pyran-2-yl)oxy]-
prost-13-enoate (19b + 19d)
Prepared as a yellowish oil in 65% yield in the same manner as above. The Claisen condensation
product 20b + 20d was isolated in 11% yield as an oil.
Methyl (–)-(8R,11R,12R,16RS)-16-hydroxy-16-methyl-9-oxo-11-[(tetrahydro-2H-pyran-2-yl)oxy]-
prost-13-enoate (21a + 21c)
Collins reagent (2.12 g, 8.21 mmol) was added in one portion at 0 °C (external cooling) to a solution
of 19a + 19c (0.515 g, 1.10 mmol) in dichloromethane (50 ml). The cooling bath was removed and
the suspension was stirred under exclusion of moisture at room temperature for 2 h. The inorganic
salts were removed by filtration and washed with chloroform (3 × 15 ml). The combined filtrates
were evaporated on a rotatory evaporator, the residue was codistilled with toluene (3 × 20 ml) and
the obtained crude product (0.540 g) was purified by column chromatography in hexane–ethyl acetate
(1 : 1). Yield 0.435 g (85%) of oily product 21a + 21c.
Methyl (+)-(8S,9R,11S,12S,16RS)-16-hydroxy-16-methyl-9-oxo-11-[(tetrahydro-2H-pyran-2-yl)oxy]-
prost-13-enoate (21b + 21d)
Prepared in the same manner as above in 83% yield as a viscous oil.
Methyl (8R,11R,12R,16R)-(–)-11,16-Dihydroxy-16-methyl-9-oxo-prost-13-enoate (1a) and
Methyl (8R,11R,12R,16S)-(–)-11,16-Dihydroxy-16-methyl-9-oxo-prost-13-enoate (1c)
Dilute hydrochloric acid (1 mol l–1; 13.4 ml, 13.4 mmol) was added during 5 min to a solution of
acetal 21a + 21c (0.364 g, 0.780 mmol) in tetrahydrofuran (8 ml). The solution was stirred at room
temperature for 30 min and then partitioned between ethyl acetate (25 ml) and water (25 ml). The
aqueous phase was extracted with ethyl acetate (3 × 15 ml), the combined organic layers were
washed with water (20 ml), saturated sodium hydrogencarbonate solution (20 ml), again water (20 ml),
and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue (0.284 g)
was subjected to column chromatography (eluent 3% methanol + 1% triethylamine in chloroform).
The chromatography afforded 0.260 g (87%) of oily alcohol 1a + 1c (mixture of epimers 1a and 1c
of misoprostol 1), 0.014 g (5%) of prostaglandin A derivative formed by elimination of water, and
0.013 g (4%) of the starting acetal 21a + 21c. Preparative HPLC in hexane–ethanol (95 : 5) separated
the mixture 1a + 1c into the individual desired epimers 1a (0.117 g) and 1c (0.122 g).
Methyl (8S,11S,12S,16R)-(+)-11,16-Dihydroxy-16-methyl-9-oxo-prost-13-enoate (1b) and
Methyl (8S,11S,12S,16S)-(+)-11,16-Dihydroxy-16-methyl-9-oxo-prost-13-enoate (1d)
The title compounds (mixture of epimers 1b and 1d of misoprostol 1) were prepared in 85% yield
analogously. A prostaglandin A derivative was also isolated (7%) and some of the starting acetal 21b + 21d
was recovered (7%). Preparative HPLC in hexane–ethanol (95 : 5) afforded the individual epimers 1b
and 1d.
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

Prostanoids
1341
The authors are indebted to the staff of Central Laboratories of the Institute of Chemical Technology
for measurement of the IR and 13C NMR spectra and for elemental analyses. Their thanks are also due
to Dr V. Havlicek (Microbiological Institute, Academy of Sciences of the Czech Republic) for taking the
mass spectra.
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