New synthesis of important prostanoid intermediate

Article abstract of DOI:10.1135/cccc19961509

New synthesis of intermediates for the preparation of prostaglandin analogs of the E₁ series is described. The simple synthesis starts from commercially accessible Corey acetate 1 and makes use of simultaneous protection of the two hydroxy groups in the form of cyclic acetal. No expensive protecting reagents are required and the synthetic sequence leading to the end product is shorter.

Full text of DOI:10.1135/cccc19961509

Important Prostanoid Intermediate
1509
NEW SYNTHESIS OF IMPORTANT PROSTANOID INTERMEDIATE
a1
a
b
a2
Jiri SVOBODA , Vaclav KOZMIK , Ivan VESELY and Jaroslav PALECEK
a Institute of Organic Chemistry, Prague Institute of Chemical Technology,
166 28 Prague 6, Czech Republic; e-mail: 1 jiri.svoboda@vscht.cz, 2 jaroslav.palecek@vscht.cz
b Spolana, Department for Development, 277 11 Neratovice, Czech Republic
Received January 10, 1996
Accepted February 9, 1996
Dedicated to the memory of Dr Zdenek Arnold.
New synthesis of intermediates for the preparation of prostaglandin analogs of the E1 series is de-
scribed. The simple synthesis starts from commercially accessible Corey acetate 1 and makes use of
simultaneous protection of the two hydroxy groups in the form of cyclic acetal. No expensive pro-
tecting reagents are required and the synthetic sequence leading to the end product is shorter.
Key words: Prostaglandins; Misoprostol; Acetals.
In the course of the last twenty years, the synthesis of prostanoids, particularly analogs
of the E1-series modified in the ω-chain, has been intensively studied1. This group of
compounds exhibits significant cytoprotective activity and some analogues – Misoprostol2,
Riaprostol3, and Mexiprostol4 - are used for curing stomach and duodenal ulcers that
represent an important medicinal problem5. The synthetic scheme for the preparation of
prostaglandins of the series 2, introduced by Corey and coworkers6,7, has not been
successful for compounds of the series 1. These are often synthesized using the so-called
“reversed approach”8,9 that enables the synthesis of pharmacologically important E1
prostaglandin analogs, modified in the bottom chain. Synthesis of important derivative A,
used in these transformations, is described in several papers6,7. In the present communica-
tion we describe a new alternative approach to compounds of the type A, consisting in
simultaneous protection of the two hydroxy groups in lactone 2 as cyclic acetal.
2
OR
COOCH
3
1
R O
CH OR
2
A
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1510
Svoboda, Kozmik, Vesely, Palecek:
In the first step, the starting commercially accessible racemic (±)-(3aα,4α,5β,6aα)-4-
(acetyloxymethyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one (1) was converted
almost quantitatively into (±)-(3aα,4α,5β,6aα)-5-hydroxy-4-(hydroxymethyl)hexahy-
dro-2H-cyclopenta[b]furan-2-one (2) by transesterification with methanol in the
presence of catalytic amount of sodium methoxide at room temperature (Scheme 1).
Attempts to obtain the cyclic acetal by reaction with formaldehyde dimethyl acetal,
catalyzed with p-toluenesulfonic acid were unsuccessful and led to complex mixtures
of products. On the other hand, reaction of the diol 2 with acetaldehyde diethyl acetal
in dichloromethane, catalyzed with p-toluenesulfonic acid, afforded in a high yield
(87%) the desired (±)-(4aβ,4bα,7aα,8aα)-2-methylhexahydrofuro[3′ ,′2 :3,4]cyclo-
penta[1,2-d]-1,3-dioxin-6(4H)-one (3) as a mixture of 2α- and 2β-diastereoisomers (3a
and 3b, respectively). One of the diastereoisomers (3a) was isolated in the crystalline
state (m.p. 104–108 °C). As minor products, column chromatography of the reaction
mixture afforded (±)-(3aα,4α,5β,6aα)-5-(1-ethoxyethoxy)-4-[(1-ethoxyethoxy)methyl]-
hexahydro-2H-cyclopenta[b]furan-2-one (4) (yield 5%), arising by reaction of diol 2 with
two equivalents of the starting diethyl acetal, further the isomeric (±)-(3aα,4α,5β,6aα)-4-
[(1-ethoxyethoxy)methyl]-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one (5) and
O
O
O
O
a
HO
CH OAc
HO
CH OH
2
2
1
2
b
O
O
O
O
O
O
O
O
7a
5
8
4b
4a
8a
4
O
EE-O
CH O-EE HO
CH O-EE EE-O
CH OH
2
2
2
O
2
4
5
6
CH
3
3
EE = 1-ethoxyethyl
a) CH OH, CH ONa; b) CH CH(OC H )
2 5 2
3
3
3
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Important Prostanoid Intermediate
1511
(±)-(3aα,4α,5β,6aα)-5-(1-ethoxyethoxy)-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]fu-
ran-2-one (6) in the yields of 2% and 1%, respectively. We found that even great excess of acetalde-
hyde diethyl acetal (200%) did not convert the side products 4–6 into the desired cyclic
acetal 3. The monoacetals 5 and 6 were not stable at room temperature and on standing
for several days they turned into mixtures of acetals 3–6 and diol 2.
The structure of compounds 4–6 was confirmed by independent syntheses. Treatment
of diol 2 with ethyl vinyl ether in the presence of p-toluenesulfonic acid afforded the
bisacetal 4, reaction of acetate 1 with ethyl vinyl ether, followed by transesterification
with methanol under the above-mentioned conditions, gave compound 6. Analogous
reaction starting from (±)-(3aα,4α,5β,6aα)-4-(hydroxymethyl)-5-[(p-phenylbenzoyl)-
oxy]hexahydro-2H-cyclopenta[b]furan-2-one furnished selectively acetal 5.
The presence of the 2α,2β-diastereoisomeric pair in the product 3 manifests itself by
1
doubling of some proton signals in the H NMR spectra, complicating thus their inter-
1
pretation. Therefore, we performed a H–1H COSY study of the crystalline diastereo-
isomer 3a and assigned unequivocally all the proton signals. By comparison with the
spectrum of the diastereoisomeric mixture it was possible to assign also signals of the
oily isomer 3b. Both pairs differ practically only in the signals of the 1,3-dioxin ring
protons and of the 2-methyl group. The configuration of the 2-methyl group (α or β)
was assigned on the basis of the published 1H NMR spectra and proton chemical shifts
in trans-fused cyclopenta- and cyclohexa-1,3-dioxins10,11. Comparison of the shifts and
coupling constants indicated that the 2-methyl group in the crystalline diastereoisomer
3a occupies an equatorial position on the 1,3-dioxin ring and thus its configuration is
2α. Consequently, the isomer 3b has configuration 2β.
Further synthetic transformations were performed both with mixtures of 2α,2β-dia-
stereoisomers and with the pure diastereoisomer 3a (for easier interpretation of spectral
data). Since the results obtained in both synthetic sequences were identical, only the
conversion of compound 3a and its physicochemical data are described in the Ex-
perimental. The lactone grouping in compound 3a was reduced with diisobutyl-
aluminium hydride (DIBAH) in toluene at –78 °C (Scheme 2). The obtained
(±)-(2α,4aβ,4bα,6αβ,7aα,8aα)-6-hydroxy-2-methylhexahydrofuro[3′ ,2′ :3,4]cyclopenta[1,2d- ]
- 1,3(4H)-dioxin (7) was converted into (±)-(2α,4aβ,5α,6α,7aα)-[6-hydroxy-2-methyl-
hexahydrocyclopenta-1,3(4H)-dioxin-5-yl]-5(Z)-heptenoic acid (8) by Wittig reaction
with (4-carboxybutyl)triphenylphosphorane, generated from (4-carboxybutyl)triphe-
nylphosphonium bromide with potassium tert-butoxide. The crude acid 8 was treated
with anhydrous potassium carbonate and the resulting salt reacted with methyl iodide to
give the corresponding methyl ester 9.
The secondary hydroxyl in the ester 9 was protected by acylation with acetic anhy-
dride in pyridine in the presence of catalytic amount of 4-dimethylaminopyridine and
the obtained acetate 10 was hydrogenated over 10% Pd/C at atmospheric pressure to
afford ester 11.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1512
Svoboda, Kozmik, Vesely, Palecek:
Subsequent deprotection of the acetal with methanol in the presence of p-toluenesul-
fonic acid afforded smoothly methyl (±)-7-[(1α,2β,3α,5α)-5-acetyloxy-3-hydroxy-2-
(hydroxymethyl)cyclopent-1-yl]heptanoate (12) in the yield of 90%. Standard reaction
with chlorotriethylsilane12 converted the diol 12 into the desired product, methyl
(±)-7-[(1α,2β,3α,5α)-5-acetyloxy-3-(triethylsilyloxy)-2-[(triethylsilyloxy)methyl]cyclopent-1-yl]hep-
tanoate (13). Selective oxidation of primary triethylsilyloxy group in the presence of a
secondary one has already been described in detail13–15
.
In this study we also verified the approach (Scheme 3) consisting in introduction of
the 9-oxo group (prostaglandin numbering), characteristic of prostaglandins of the
E-series, under retention of the acetal protecting group. The aim of this approach was
to circumvent the final oxidative conversion16 of analogs of the F-series into those of
OH
1
OR
O
(CH ) COOR
2 3
a
b
3a
O
O
O
O
CH
CH
3
3
7
1
R
R
8
9
H
H
H
CH
3
10
CH COCH
3
3
c
OCOCH
OCOCH
3
3
(CH ) COOCH
(CH ) COOCH
2 6
3
2 6
3
d
RO
CH OR
O
2
O
CH
12, R = H
13, R = Si(C H )
3
11
2
5 3
(C H ) P CH(CH ) COOH; 2. CH I, K CO ; 3. (CH CO) O;
a) DIBAH; b) 1.
3
2
3
3
2
6
5 3
2 3
c) H , Pd-C; d) 1. CH OH, TosOH; 2. (C H ) SiCl
2
3
2 5 3
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Important Prostanoid Intermediate
1513
the E-series which often gives poor yields and is accompanied with side products of the
A-series.
We made use of ester 9 which on standard hydrogenation at atmospheric pressure
over 10% Pd/C in methanol afforded methyl (±)-(2α,4aβ,5α,6α,7aα)-[6-hydroxy-2-
methylhexahydrocyclopenta-1,3(4H)-dioxin-5-yl]heptanoate (14) in an almost quantita-
tive yield. The ester 14 was then oxidized with Jones reagent at –20 to –30 °C to give
the desired methyl (±)-(2α,4aβ,5α,7aα)-[2-methyl-6-oxohexahydrocyclopenta-1,3(4H)-di-
oxin-5-yl]heptanoate (15) in the yield of 92%. Under the described reaction conditions,
the acetal grouping in compounds 14 and 15 was stable.
However, this stability proved to be very disadvantageous in the next step, i.e., in the
deprotection of both hydroxy groups. Commonly used reagents12, such as pyridinium
chloride, pyridinium fluoride, pyridinium trifluoracetate, iron(III) chloride, p-toluene-
sulfonic acid, or dilute hydrochloric or hydrobromic acid, were not effective and there-
fore we resorted to relatively strong acids: trifluroacetic or hydrofluoric acid. The
OH
O
(CH2)6COOCH3
(CH2)6COOCH3
a
b
9
O
O
O
O
CH3
14
H3C
15
c
O
O
(CH2)6COOCH3
+
(CH2)6COOCH3
RO
CH2OR
CH2OH
17
16, R = H
18, R = Si(C2H5)3
a) H2, Pd-C; b) CrO3 ,H2SO4; c) 1. aq. HF/SiO2; 2. (C2H5)3SiCl
SCHEME 3
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1514
Svoboda, Kozmik, Vesely, Palecek:
deprotection of acetal 15 was accompanied with elimination of water and a consider-
able amount of methyl (±)-7-[(1α,2β)-2-(hydroxymethyl)-5-oxo-3-cyclopenten-1-
yl]heptanoate (17) was isolated in addition to the desired methyl (±)-7-[(1α,2β,
3α)-3-hydroxy-2-(hydroxymethyl)-5-oxocyclopent-1-yl]heptanoate (16). Only after using
40% aqueous hydrofluoric acid in the presence of silica gel in methanol we obtained
the diol 16 in a very good yield (81%).
The diol 16 was converted into the corresponding methyl (±)-7-[(1α,2β,3α)-3-(tri-
ethylsilyloxy)-2-[(triethylsilyloxy)methyl]-5-oxocyclopent-1-yl]heptanoate (18), another
important intermediate of the general formula A, suitable for the synthesis of prosta-
noids of the E-series.
We can conclude that we succeeded in elaboration of a novel and simple alternative
preparation of important intermediates used in the synthesis of prostanoids of the series 1,
modified in the ω-chain.
EXPERIMENTAL
The temperature data are uncorrected. The melting points were determined on a Boetius block. IR
spectra were measured on a Nicolet 740 spectrometer in chloroform, wavenumbers are given in cm–1.
Proton and 1H–1H COSY NMR spectra (δ, ppm; J, Hz) were taken on a Bruker 400 instrument in
deuteriochloroform. Mass spectra were obtained with a Jeol DX 300 spectrometer (electron energy
70 eV). The starting lactone 1 was a Spolana (Neratovice) product.
(±)-(3aα,4α,5β,6aα)-5-Hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one (2)
To a solution of compound 1 (40.0 g, 0.187 mol) in dry methanol (250 ml) was added 1.5 M methanolic
sodium methoxide (11 ml). The mixture was stirred at room temperature for 1 h and then neutralized
with 0.85 M methanolic HCl (19.5 ml). The solid was filtered and the filtrate evaporated to dryness
to yield 32.0 g (100%) of compound 2, m.p. 116–117 °C (reported17 m.p. 117–118 °C). Its IR and 1H NMR
spectra were identical with the published ones18
.
Reaction of Diol 2 with Acetaldehyde Diacetal
To a stirred suspension of diol 2 (31.3 g, 0.182 mol) in dry dichloromethane (310 ml) and acetalde-
hyde diethyl acetal (64.3 g, 0.545 mol) was added 40 ml of 0.2 M solution of anhydrous p-toluene-
sulfonic acid in dichloromethane. The mixture was stirred for 1 h at room temperature and then
refluxed for 3.5 h. After cooling, the reaction was quenched by addition of solid potassium carbonate
(5 g), the solid was filtered off and the filtrate was concentrated. The residue was dissolved in di-
chloromethane (200 ml), the solution washed with water and saturated solution of sodium chloride,
and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue crystallized
from hexane–ethyl acetate to give 19.34 g (54%) of crystalline diastereoisomer 3a, m.p. 104–108 °C.
After concentration of the mother liquor, the residue was separated by column chromatography on
silica gel in chloroform–methanol (1–5%). The chromatography afforded another portion (12.06 g) of
compound 3 (mixture of diastereoisomers, total yield 87%), bisacetal 4 (2.70 g, 5%), monoacetal 5
(0.65 g, 2%) and monoacetal 6 (0.56 g, 1%).
Compound 3: For C10H14O4 (198.2) calculated: 60.59% C, 7.12% H; found: 60.47% C, 7.01% H.
1
IR spectrum: 1 768 (CO). H–1H COSY NMR spectrum of diastereoisomer 3a: 1.37 d, 3 H, J = 5.1
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Important Prostanoid Intermediate
1515
(CH3); 1.69 dq, 1 H, J1 = 4.2, J2 = 10.8 (H-4a); 1.88 dt, 1 H, J1 = 4.4, J2 = 11.6 (H-8); 2.33 dtd, 1 H,
J1 = 1.5, J2 = 7.4, J3 = 13.7 (H-4b); 2.41 dd, 1 H, J1 = 1.6, J2 = 18.3 (H-5); 2.65 dt, 1 H, J1 = 7.1, J2 =
13.2 (H-5); 2.70 dd, 1 H, J1 = 9.3, J2 = 18.2 (H-8); 3.41 dt, 1 H, J1 = 7.0, J2 = 11.0 (H-8a); 3.58 t,
1 H, J = 10.7 (H-4); 4.29 dd, 1 H, J1 = 4.3, J2 = 10.7 (H-4); 4.70 q, 1 H (H-2); 4.90 dt, 1 H, J1 =
4.4, J2 = 7.2 (H-7a). 1H NMR spectrum of diastereoisomer 3b: 1.27 d, 3 H, J = 5.1 (CH3); 1.64 m,
1 H, (H-4a); 1.88 dt, 1 H, J1 = 4.4, J2 = 11.6 (H-8); 2.33 dtd, 1 H, J1 = 1.5, J2 = 7.4, J3 = 13.7 (H-4b);
2.41 dd, 1 H, J1 = 1.6, J2 = 18.3 (H-5); 2.65 dt, 1 H, J1 = 7.1, J2 = 13.2 (H-5); 2.70 dd, 1 H, J1 = 9.3,
J2 = 18.2 (H-8); 3.41 dt, 1 H, J1 = 7.0, J2 = 11.0 (H-8a); 3.50 t, 1 H, J = 10.7 (H-4); 4.22 dd, 1 H,
J1 = 4.3, J2 = 10.7 (H-4); 4.64 q, 1 H (H-2); 4.79 dt, 1 H, J1 = 4.4, J2 = 7.2 (H-7a).
Compound 4: For C16H28O6 (316.4) calculated: 60.74% C, 8.92% H; found: 60.46% C, 8.67% H.
IR spectrum: 1 767 (CO). 1H NMR spectrum: 1.18 dt, 6 H (CH3); 1.27 dt, 6 H (CH3); 2.11 m, 1 H;
2.18 m, 1 H; 2.36 m, 1 H; 2.55 m, 1 H; 2.70–2.85 m, 2 H; 3.38 m, 1 H; 3.45 m, 2 H; 3.57 m, 3 H;
3.98 m and 4.13 m, 1 H; 4.67 m, 1 H; 4.73 m, 1 H; 4.96 m, 1 H.
Compound 5: For C12H20O5 (244.3) calculated: 59.00% C, 8.25% H; found: 49.69% C, 8.07% H.
1
IR spectrum: 3 609, 3 471 (OH), 1 767 (CO). H NMR spectrum: 1.20 dt, 3 H (CH3); 1.29 dd, 3 H
(CH3); 2.06 m, 2 H; 2.37 m, 1 H; 2.52 m, 2 H; 2.78 m, 2 H; 3.50 m, 1 H; 3.62 d, 2 H, J = 5.2; 4.05 q
and 4.14 q, 1 H, J = 5.5; 4.74 q, 1 H, J = 5.5; 4.95 dt, 1 H, J1 = 2.3, J2 = 6.8.
Compound 6: For C12H20O5 (244.3) calculated: 59.00% C, 8.25% H; found: 49.77% C, 8.21% H.
1
IR spectrum: 3 625, 3 480 (OH); 1 767 (CO). H NMR spectrum: 1.21 t, 3 H, J = 7.2 (CH3); 1.31 d,
3 H, J = 5.1 (CH3); 1.79 s, 1 H (OH); 2.04 m, 2 H; 2.41 t, 1 H, J = 6.3; 2.47 m, 1 H; 2.64 m, 1 H;
2.82 t, 1 H, J = 8.3; 3.48 m, 2 H; 3.62 m, 2 H; 4.10 q, 1 H, J = 5.9; 4.70 dq, 1 H, J1 = 2.8, J2 = 6.9;
4.94 dt, 1 H, J1 = 2.7, J2 = 7.9.
(±)-(2α,4aβ,4bα,6αβ,7aα,8aα)-6-Hydroxy-2-methylhexahydrofuro[3 ′,2′ :3,4]cyclopenta-
[1,2-d]-1,3(4H)-dioxin (7)
A solution od DIBAH in toluene (26.5 ml of 1 M solution) was added during 20 min at –78 °C to a
stirred solution of compound 3 (5.0 g, 25.2 mmol) in toluene (150 ml) under nitrogen. The mixture
was stirred for 10 min and the reaction quenched by addition of methanol (7 ml). After warming to
0 °C, water (7 ml) was added dropwise and the mixture was stirred for 1.5 h. The solid was collected
and washed with toluene (2 × 100 ml). The combined organic solutions were washed with saturated
solution of sodium chloride (100 ml) and dried over anhydrous magnesium sulfate. Evaporation of
the solvent gave 4.80 g (95%) of compound 7 as a nonvolatile oil. For C10H16O4 (200.2) calculated:
1
59.98% C, 8.05% H; found: 59.86% C, 8.11% H. IR spectrum: 3 395, 3 264 (OH). H NMR spectrum:
1.37 d, 3 H, J = 5.1 (CH3); 1.70 m, 1 H; 1.96 dt, 1 H; 2.22 m, 1 H; 2.35 m, 1 H; 2.46 dt, 1 H; 3.38 dt,
1 H; 3.54 q, 1 H, J = 10.8; 4.30 dd, 1 H, J1 = 4.3, J2 = 10.7; 4.68 m, 2 H; 5.67 dd, 1 H, J1 = 4.4, J2 = 17.0
(CHOH).
Methyl (±)-7-[(2α,4aβ,5α,6α,7aα)-6-Hydroxy-2-methylhexahydrocyclopenta-1,3(4H)-dioxin-5-yl]-
5(Z)-heptenoate (9)
A solution of potassium tert-butoxide (7.3 ml of 1.61 M solution) was added dropwise at 0 °C to a
suspension of (4-carboxybutyl)triphenylphosphonium bromide (2.65 g, 6.0 mmol) in tetrahydrofuran
(20 ml) under nitrogen. After 15 min, a solution of compound 7 (0.48 g, 2.4 mmol) in tetrahydro-
furan (5 ml) was added in a single portion and the mixture was stirred at 0 °C for 3 h. The mixture
was decomposed with water (5 ml), the organic layer was separated, washed with water (2 × 10 ml)
and the combined aqueous layers were washed with benzene (10 ml). The aqueous solution was
mixed with ether (30 ml) and the stirred mixture was adjusted to pH 5 by addition of saturated solution
of sodium hydrogen sulfate. The ethereal layer was separated and the aqueous phase washed with
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1516
Svoboda, Kozmik, Vesely, Palecek:
ether (2 × 20 ml). The combined ethereal solutions were dried over anhydrous magnesium sulfate and
the solvent was evaporated. The obtained crude acid 8 was dissolved in acetone (25 ml), the solution
was mixed with potassium carbonate (1.0 g) and methyl iodide (2 ml, 32 mmol), and the mixture was
stirred at ambient temperature for 8 h. The solid was filtered and washed with acetone, the filtrate
was concentrated and the residue was chromatographed on a column of silica gel in hexane–ethyl
acetate (2 : 1) to give 0.61 g (85%) of oily ester 9. For C16H26O5 (298.4) calculated: 64.41% C,
1
8.78% H; found: 64.26% C, 8.93% H. IR spectrum: 3 613, 3 499 (OH), 1 731 (CO). H NMR spec-
trum: 1.39 d, 3 H, J = 5.1 (CH3); 1.46 m, 1 H; 1.59 m, 1 H; 1.72 m, 2 H; 2.12 m, 4 H; 2.20 m, 1 H;
2.32 t, 2 H, J = 7.4 (CH2CO); 2.58 dt, 1 H, J1 = 7.4, J2 = 13.2; 3.27 dt, 1 H, J1 = 7.6, J2 = 11.0; 3.51 t,
1 H, J = 10.7; 3.68 s, 3 H (OCH3); 4.25 dq, 2 H; 4.70 q, 1 H; 5.40 m, 2 H (CH=CH). Mass spectrum,
m/z (%): 298 (M+, 1), 280 (5), 267 (10), 255 (12), 225 (12), 205 (9), 187 (12), 154 (21), 109 (41),
95 (100), 81 (69), 69 (20), 55 (35).
Methyl (±)-7-[(2α,4aβ,5α,6α,7aα)-6-Acetyloxy-2-methylhexahydrocyclopenta-1,3(4H)-dioxin-5-yl]-
5(Z)-heptenoate (10)
Acetic anhydride (5.5 g, 54 mmol) was added dropwise at 5 °C to a mixture of ester 9 (4.2 g, 14.1 mmol),
pyridine (15 ml) and 4-dimethylaminopyridine (0.1 g). After stirring for 20 min at room temperature,
the reaction mixture was diluted with ice-cold water (200 ml) and extracted with ethyl acetate (4 × 30 ml),
the organic solution was washed with water, saturated solution of of sodium chloride, and dried over
anhydrous magnesium sulfate. Evaporation of the solvent and filtration through a column of silica gel
(eluent hexane–ethyl acetate 2 : 1) afforded 4.34 g (91%) of oily acetate 10. For C18H28O6 (340.4)
calculated: 63.51% C, 8.29% H; found: 63.44% C, 8.13% H. IR spectrum: 1 733 (CO). 1H NMR
spectrum: 1.38 d, 3 H, J = 5.2 (CH3); 1.58 m, 2 H; 1.68 m, 2 H; 1.79 m, 1 H; 2.06 s, 3 H
(CH3COO); 2.07 q, 2 H; 2.18 t (CH2CO), 2 H, J = 6.4; 2.32 t, 2 H, J = 7.4; 2.65 dt, 1 H, J1 = 7.3,
J2 = 13.6; 3.33 ddd, 1 H; 3.52 t, 1 H, J = 10.6; 3.67 s, 3 H (OCH3); 4.27 dd, 1 H, J1 = 4.1, J2 = 10.6;
4.71 q, 1 H; 5.18 m, 1 H; 5.33 m, 2 H (CH=CH).
Methyl (±)-7-[(2α,4aβ,5α,6α,7aα)-6-Acetyloxy-2-methylhexahydrocyclopenta-1,3(4H)-dioxin-5-yl]-
heptanoate (11)
Ester 10 (3.62 g, 10.6 mmol) was hydrogenated in methanol (50 ml) over 10% Pd/C (200 mg) at
atmospheric pressure, using a standard apparatus. After consumption of the theoretical amount of hy-
drogen, the catalyst was filtered off and washed with methanol (10 ml). Evaporation of the solvent
gave 3.35 g (92%) of oily ester 11. For C18H30O6 (342.4) calculated: 63.14% C, 8.83% H; found:
1
63.00% C, 8.77% H. IR spectrum: 1 732 (CO). H NMR spectrum: 1.28 m, 6 H; 1.37 d, 3 H, J = 5.0
(CH3); 1.46 m, 2 H; 1.58 m, 2 H; 1.78 m, 1 H; 2.05 s, 3 H (CH3COO); 2.06 m, 2 H; 2.30 t, 2 H, J = 7.4
(CH2CO); 2.66 dt, 1 H, J1 = 7.3, J2 = 13.6; 3.32 ddd, 1 H; 3.54 t, 1 H, J = 10.7; 3.66 s, 3 H (OCH3);
4.27 dd, 1 H, J1 = 4.1, J2 = 10.5; 4.71 q, 1 H; 5.17 m, 1 H.
Methyl (±)-7-[(1α,2β,3α,5α)-5-Acetyloxy-3-hydroxy-2-(hydroxymethyl)cyclopent-1-yl]heptanoate (12)
Anhydrous p-toluenesulfonic acid (10 mg) was added at room temperature to a stirred solution of
acetal 11 (1.06 g, 3.1 mmol) in methanol (10 ml). After stirring at room temperature for 12 h the
mixture was partitioned between ethyl acetate (20 ml) and saturated solution of sodium chloride. The
aqueous layer was extracted with ethyl acetate (2 × 10 ml) and the combined organic layers were
washed with saturated solution of sodium hydrogen carbonate (10 ml) and saturated solution of sodium
chloride. After drying over anhydrous magnesium sulfate and evaporation of the solvent, the residue
was chromatographed on a silica gel column in chloroform containing 5% methanol. Yield 0.88 g
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Important Prostanoid Intermediate
1517
(90%) of oily diol 12. For C16H28O6 (316.4) calculated: 60.74% C, 8.92% H; found: 60.65% C,
1
8.55% H. IR spectrum: 3 630, 3 453 (OH), 1 730 (CO). H NMR spectrum: 1.28 m, 6 H; 1.42 m, 1 H;
1.61 m, 4 H; 1.72 dd, 1 H, 1.95 m, 1 H; 2.06 s, 3 H (CH3COO); 2.28 t, 2 H, J = 7.4; 2.38 t, 2 H;
3.56 dd, 1 H, J = 10.6; 3.68 s, 3 H (OCH3); 3.91 dd, 1 H; 4.12 m, 1 H; 5.18 m, 1 H.
Methyl (±)-7-[(1α,2β,3α,5α)-5-Acetyloxy-3-triethylsilyloxy-2-[(triethylsilyloxy)methyl]cyclopent-1-yl]-
heptanoate (13)
Chlorotriethylsilane (0.55 g, 3.6 mmol) was added dropwise at room temperature to a solution of diol 12
(0.48 g, 1.53 mmol) in pyridine (6 ml) and the mixture was stirred for 2 h. The reaction was quen-
ched by addition of water (10 ml) and chloroform (10 ml). The aqueous layer was extracted with
chloroform (3 × 10 ml) and the combined chloroform layers were washed with water (10 ml), satu-
rated solution of sodium chloride (10 ml) and dried over anhydrous magnesium sulfate. The solvent
was evaporated and the residue chromatographed on a column of silica gel in hexane–ethyl acetate (4 : 1)
to give 0.80 g (96%) of silylated product 13. For C28H56O6Si2 (544.9) calculated: 61.72% C, 10.36% H;
found: 61.55% C, 10.12% H. IR spectrum: 1 730 (CO). 1H NMR spectrum: 0.58 m, 12 H (CH2Si);
0.94 m, 18 H (CH3); 1.27 m, 6 H; 1.39 m, 1 H; 1.61 m, 3 H; 1.77 m, 2 H; 2.03 s, 3 H (CH3COO);
2.26 m, 3 H; 3.65 s, 3 H (OCH3); 3.65 m, 2 H; 4.13 m, 1 H; 5.05 m, 1 H.
Methyl (±)-7-[(2α,4aβ,5α,6α,7aα)-6-Hydroxy-2-methylhexahydrocyclopenta-1,3(4H)-dioxin-5-yl]-
heptanoate (14)
Ester 9 (0.72 g, 2.4 mmol) was hydrogenated in methanol (15 ml) at atmospheric pressure over 10%
Pd/C (10 mg). After consumption of the theoretical amount of hydrogen, the mixture was filtered and
the catalyst washed with methanol (10 ml). The filtrate was concentrated and the residue chromato-
graphed on a column of silica gel in hexane–ethyl acetate (3 : 2) to give 0.71 g (98%) of ester 14,
m.p. 50.5–52.5 °C. For C16H28O5 (300.4) calculated: 63.97% C, 9.40% H; found: 63.69% C, 9.34% H.
1
IR spectrum: 3 610, 3 499 (OH), 1 730 (CO). H NMR spectrum: 1.31 m, 5 H; 1.38 m, 2 H; 1.38 d,
3 H, J = 5.0 (CH3); 1.50–1.64 m, 5 H; 1.74 m, 1 H; 2.30 t, 2 H, J = 7.4 (CH2CO); 2.59 dt, 1 H, J1 = 7.3,
J2 = 13.3; 3.27 dt, 1 H, J1 = 7.4, J2 = 11.0; 3.52 t, 1 H, J = 10.7; 3.67 s, 3 H (OCH3); 4.24 m, 2 H;
4.70 q, 1 H. Mass spectrum, m/z (%): 300 (M+, 2), 282 (2), 257 (12), 239 (7), 227 (8), 221 (11), 164
(35), 136 (21), 107 (15), 95 (100), 81 (45).
Methyl (±)-7-[(2α,4aβ,5α,7aα)-2-Methyl-6-oxohexahydrocyclopenta-1,3(4H)-dioxin-5-yl]-
heptanoate (15)
Jones reagent (1.65 ml) was added dropwise at –20 to –30 °C to a stirred solution of ester 14 (0.71 g,
2.36 mmol) in acetone and the mixture was stirred for 10 min. The reaction was quenched by addi-
tion of 2-propanol (2 ml) and, after stirring for 5 min, the mixture was partitioned between chloro-
form (50 ml) and saturated solution of sodium chloride (200 ml). The organic phase was separated,
washed with saturated sodium chloride solution (2 × 20 ml), dried over anhydrous magnesium sul-
fate, and the solvent was evaporated. Chromatography of the residue on a column of silica gel in
benzene–ethyl acetate afforded 0.65 g (92%) of keto ester 15. For C16H26O5 (298.4) calculated:
1
64.41% C, 8.78% H; found: 64.34% C, 8.44% H. IR spectrum: 1 745 (CO). H NMR spectrum: 1.30 m,
5 H; 1.40 d, 3 H, J = 5.1 (CH3); 1.46 m, 2 H; 1.58–1.76 m, 4 H; 1.84 m, 1 H; 1.94 m, 1 H; 2.30 t,
2 H, J = 7.5 (CH2CO); 2.33 dd, 1 H, J1 = 11.7, J2 = 17.7; 2.66 dd, 1 H, J1 = 7.2, J2 = 17.5; 3.68 s,
3 H (OCH3), 3.75 t, 1 H, J = 10.5; 3.79 m, 1 H; 4.34 dd, 1 H, J1 = 4.0, J2 = 10.7; 4.92 q, 1 H. Mass
spectrum, m/z (%): 298 (M+, 2), 280 (2), 255 (5), 223 (15), 205 (11), 155 (20), 154 (33), 138 (21),
108 (25), 95 (100), 81 (37), 69 (39), 55 (50).
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1518
Svoboda, Kozmik, Vesely, Palecek:
Methyl (±)-7-[(1α,2β,3α)-3-Hydroxy-2-(hydroxymethyl)-5-oxocyclopent-1-yl]heptanoate (16)
A solution of acetal 15 (2.79 g, 9.35 mmol) in methanol (30 ml) was mixed with silica gel (300 mg)
and then hydrofluoric acid (4 ml of 40% solution) was added dropwise under stirring. The mixture
was stirred at room temperature for 20 min, neutralized with triethylamine (6 ml) and diluted with
chloroform (50 ml) and water (30 ml). The aqueous layer was extracted with chloroform (3 × 25 ml)
and the combined organic solutions were washed with saturated solution of sodium hydrogen carbonate
(30 ml) and saturated solution of sodium chloride, and dried over anhydrous magnesium sulfate. The
solvent was evaporated and the residue chromatographed on a column of silica gel in chloroform–
methanol to give 2.07 g (81%) of oily compound 16. Compound 17 (0.31 g, 13%; oil) was isolated
as side product.
Compound 16: For C14H24O5 (272.3) calculated: 61.74% C, 8.88% H; found: 61.66% C, 8.47% H.
1
IR spectrum: 3 623, 3 468 (OH), 1 737 (CO). H NMR spectrum: 1.30 m, 5 H; 1.42 m, 1 H; 1.62 m,
4 H; 2.03 m, 2 H; 2.25 dd, 1 H, J1 = 11.5, J2 = 17.0; 2.31 t, 2 H, J = 7.5 (CH2CO); 2.71 dd, 1 H, J1 = 7.2,
J2 = 17.8; 3.68 s, 3 H (OCH3); 3.75 m, 1 H; 3.97 d, 1 H, J = 10.2; 4.33 q, 1 H, J = 6.7. Mass
spectrum, m/z (%): 272 (M+, 1), 254 (1), 223 (1), 191 (1), 143 (20), 130 (40), 112 (24), 99 (100), 82
(27), 69 (20), 55 (35).
Compound 17: For C14H22O4 (254.3) calculated: 66.12% C, 8.72% H; found: 65.86% C, 8.54% H.
1
IR spectrum: 3 625, 3 488 (OH), 1 729, 1 702 (CO), 1 590 (CH=CH). H NMR spectrum: 1.28–1.47 m,
7 H; 1.61 m, 2 H; 1.74 m, 1 H; 2.11 m, 1 H; 2.31 t, 2 H, J = 7.5 (CH2CO); 2.84 m, 1 H; 3.66 t, 1 H,
J = 6.8; 3.68 s, 3 H (OCH3); 3.81 dd, 1 H, J1 = 5.3, J2 = 10.5; 3.92 bs, 1 H (OH); 6.18 dd, 1 H, J1 = 1.4,
J2 = 5.7 (CH=); 7.75 dd, 1 H, J1 = 2.2, J2 = 5.7 (=CHCO). Mass spectrum, m/z (%): 254 (M+, 1), 223
(6), 192 (5), 181 (10), 121 (11), 112 (100), 94 (36), 83 (17), 66 (15), 55 (27).
Methyl (±)-7-[(1α,2β,3α)-5-Oxo-[(2-triethylsilyloxy)methyl]-3-(triethylsilyloxy)cyclopent-1-yl]-
heptanoate (18)
Chlorotriethylsilane (2.08 g, 13.8 mmol) was added at 0–5 °C to a solution of ester 16 (1.57 g, 5.77
mmol) in pyridine (20 ml). After stirring at room temperature for 40 min, the reaction mixture was
diluted with water (30 ml) and extracted with chloroform (3 × 30 ml). The extract was dried over
anhydrous magnesium sulfate, the solvent evaporated, and the residue chromatographed on a column
of silica gel in chloroform–methanol to give 2.56 g (89%) of oily silyl derivative 18. For
C26H52O5Si2 (500.9) calculated: 62.35% C, 10.46% H; found: 62.24% C, 10.23% H. IR spectrum:
1
1 735 (CO). H NMR spectrum: 0.55 q, 12 H, J = 8.0 (CH2Si); 0.91 t, 15 H (CH3); 1.23 m, 5 H; 1.38 m,
1 H; 1.54 m, 4 H; 1.92 m, 1 H; 2.09 m, 1 H; 2.12 m, 1 H; 2.24 t, 2 H, J = 7.4 (CH2CO); 2.57 ddd,
1 H, J1 = 1.1, J2 = 7.2, J3 = 17.7; 3.58 dd, 1 H, J1 = 3.8, J2 = 10.2; 3.62 s, 3 H (OCH3); 3.78 dd, 1 H,
J1 = 3.8, J2 = 10.3; 4.27 q, 1 H, J = 6.9. Mass spectrum, m/z (%): 500 (M+, 0.3), 471 (M – C2H5,
90), 339 (60), 217 (40), 205 (35), 189 (43), 161 (20), 151 (40), 133 (31), 117 (68), 115 (64), 103
(31), 87 (100), 75 (41), 67 (27), 59 (48).
Elemental analyses and spectral measurements were carried out at the Prague Institute of Chemical
Technology and the authors are indebted to the staff of the corresponding Departments.
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Important Prostanoid Intermediate
1519
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