Synthesis of 2-normisoprostol, methyl6-(3-hydroxy-2-((E)-4-hydroxy-4- methyloct-1-enyl)-5-oxocyclopentyl)hexanoate

Article abstract of DOI:10.1080/00397910802664228

Synthesis of 2-normisoprostol, methyl 6-(3-hydroxy-2-((E)-4-hydroxy-4- methyloct-1-enyl)-5-oxocyclopentyl)hexanoate (3), employing two-component coupling strategy based on 1,4-addition followed by DDQ-mediated triethyl silyl deprotection is reported. Desired key intermediates, methyl 6-(3-triethyl silyloxy-5-oxocyclopent-1-enyl)hexanoate (4) and (E)-1-(tributylstannyl)-4- methyloct-1-en-4-yloxy)triethylsilane (5), were prepared from commercially available cycloheptanone and propargyl bromide, and the intermediates were coupled to obtain 3 in a convergent approach.

Full text of DOI:10.1080/00397910802664228

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Synthesis of 2-Normisoprostol,
Methyl 6-(3-Hydroxy-2-((E)-4-
hydroxy-4-methyloct-1-enyl)-5-
oxocyclopentyl)hexanoate
a
a
b
M. Harikrishna , H. Rama Mohan , P. K. Dubey
&
a
Gottumukkala V. Subbaraju
a
Aptuit Laurus Private Limited , Hyderabad, India
b
Department of Chemistry , College of Engineering,
JNT University , Hyderabad, India
Published online: 26 Jun 2009.
To cite this article: M. Harikrishna , H. Rama Mohan , P. K. Dubey & Gottumukkala
V. Subbaraju (2009) Synthesis of 2-Normisoprostol, Methyl 6-(3-Hydroxy-2-((E)-4-
hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl)hexanoate, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
39:15, 2763-2775, DOI: 10.1080/00397910802664228
To link to this article: http://dx.doi.org/10.1080/00397910802664228
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1
Synthetic Communications , 39: 2763–2775, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802664228
Synthesis of 2-Normisoprostol, Methyl
-(3-Hydroxy-2-((E)-4-hydroxy-4-methyloct-
-enyl)-5-oxocyclopentyl)hexanoate
6
1
1
M. Harikrishna, H. Rama Mohan, P. K. Dubey,
1
2
1
and Gottumukkala V. Subbaraju
Aptuit Laurus Private Limited, Hyderabad, India
1
2
Department of Chemistry, College of Engineering, JNT University,
Hyderabad, India
Abstract: Synthesis of 2-normisoprostol, methyl 6-(3-hydroxy-2-((E)-4-hydroxy-
4
-methyloct-1-enyl)-5-oxocyclopentyl)hexanoate (3), employing two-component
coupling strategy based on 1,4-addition followed by DDQ-mediated triethyl
silyl deprotection is reported. Desired key intermediates, methyl 6-(3-triethyl
silyloxy-5-oxocyclopent-1-enyl)hexanoate (4) and (E)-1-(tributylstannyl)-4-
methyloct-1-en-4-yloxy)triethylsilane (5), were prepared from commercially
available cycloheptanone and propargyl bromide, and the intermediates were
coupled to obtain 3 in a convergent approach.
Keywords: 1,4-Addition, normisoprostol, prostaglandins, two-component coupling
INTRODUCTION
Prostaglandins are a group of unsaturated carboxylic acids consisting of
a 20-carbon skeleton with a cyclopentane unit and two side chains. These
[
1]
are biosynthetically derived from arachidonic acid, are present in
virtually every cell of the body, and exhibit a wide variety of biological
functions. Prostaglandins are like hormones in that they act as chemical
messengers but do not move to other sites; they work right within the
Received October 15, 2008.
Address correspondence to H. Rama Mohan, Aptuit Laurus Private Limited,
ICICI Knowledge Park, Turkapally, Shameerpet, Hyderabad 500 078, India.
E-mail: mohan.hindupur@aptuitlaurus.com
2
763

2764
M. Harikrishna et al.
cells where they are synthesized. The bioactivity profile of prostaglandins
include activation of the inflammatory response, production of pain and
fever, induction of labor and other reproductive processes, inhibition of
acid synthesis in the gastrointestinal tract, and stimulation of constriction
and clotting of platelets.
The general synthetic route to the natural prostaglandins was devel-
oped by Corey and his coworkers and involves the key intermediate,
‘
industrial synthesis of prostaglandins. However, several alternate meth-
‘Corey lactone.’’ The approach continues to be the general strategy for
[2]
[
3]
ods have been reported to construct the core structure of prostaglandins.
The two-component coupling strategy, first reported by Syntex
[
4]
group, has been used mainly for the synthesis of racemic prostaglan-
dins, such as misoprostol. The most elegant synthesis, consisting of the
[
5]
three-component coupling, was developed by Noyori et al.
Retrosynthetic analysis revealed that two key units, 4 and 5, could be
readily obtained from commercially available raw materials.
RESULTS AND DISCUSSION
Synthesis of 4 (Scheme 1)
Bayer–Villiger oxidation of cycloheptanone with m-3-chloroperbenzoic
[
acid (CPBA) gave the corresponding lactone (7) in good yield. Hydroly-
6]
sis of lactone 7 was accomplished by BF etherate in methanol to produce
3
the hydroxy ester, 8. Oxidation of primary alcohol in 8 carried out with
conventional methods using pyridinium chlorochromate (PCC) or
[
,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) gave the aldehyde ester
7]
2
9
in good yield. Lithiation of furan in the presence of MgCl using n-BuLi
2
ꢁ
followed by addition of aldehyde ester 9 at ꢀ10 to 30 C gave the desired
[8]
alkylated product 11 in good yield. Intramolecular cyclization of 11 by
reaction with ZnCl provided 3-hydroxy-substituted cyclopentenone deri-
2
vative, 12a, which was converted to the corresponding methyl ester using
methyl iodide to obtain 12b. Isomerization of cyclopentenone derivative
1
tive 13. The secondary hydroxyl group in 13 was protected as triethyl silyl
2b with chloral in triethylamine gave 4-hydroxy cyclopentenone deriva-
[
derivative using chlorotriethylsilane (TESCl) in the presence of triethyla-
9]
mine to obtain the key unit 4 in good yield.
Synthesis of 5 (Scheme 2)
[
10]
Reaction of propargyl bromide in presence of Zn, followed by the
addition of 2-hexanone, gave 15 in reasonable yield. However,

Normisoprostol
2765
Scheme 1. Reagents: (a) mCPBA, DCM, 20 h, 55%; (b) BF
1
3
etherate, methanol,
ꢁ
6 h, 94%; (c) TEMPO, NaOCl, DCM, rt, 75%; (d) MgCl
2
, THF, n-BuLi, ꢀ10 C;
(
e) ZnCl
2
, dioxane, MeI, acetone, reflux, 16 h; (f) chloral, toluene, TEA, reflux,
h, 31% for three-step conversion from 11 to 13; and (g) TESCl, TEA, THF,
6
rt, 3 h, 66%.
Mg-mediated Grignard reaction did not give the desired product.
Protection of hydroxyl group in 15 by triethylsilane (TES) ether followed
by reaction of terminal alkyne with tributyl tin hydride in the presence of
0
2,2 -azobis(2-methylpropionitrile (AIBN) gave the stannane derivative 5,
which was used for 1,4-addition without further purification.
2
-Normisoprostol (3)
Condensation of 4 with stannane derivative 5 under Lipshutz condi-
[
9]
tions through the generation of mixed cuprate gave the 1,4-addition
product, which was subjected to purification by column chromatography
to give product 17 in good yield (Scheme 3).
Scheme 2. Reagents: (a, b) Zn, DMF, 2-hexanone, rt, 5 h, 57%; (c) TESCl,
ꢁ
imidazole, DMF, rt, 6 h, 75%; (d) Bu SnH, AIBN, 100 C, 85%.
3

2766
M. Harikrishna et al.
ꢁ
ꢁ
Scheme 3. Reagents: (a) THF, MeLi, CuCN, ꢀ70 C to ꢀ75 C, 55%; and (b)
2
DDQ, AcCN, H O, 60%.
Deprotection of triethyl silyl groups in 17 was achieved under neutral
conditions by employing 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
in acetonitrile to obtain the desired 2-normisoprostol (3) in good yield. The
spectral data of 3 corroborated well with the structure proposed.
CONCLUSION
We have obtained 2-normisoprostol, 3, a rearranged prostaglandin, in 2.6%
overall yield starting from commercially available cycloheptanone and
propargyl bromide utilizing an efficient two-component coupling strategy.
The synthesis can be scaled up to produce 3 for the bioactivity studies.
EXPERIMENTAL
Materials and Methods
All the reactions that were moisture- and air-sensitive were carried out using
dried glassware under an argon or nitrogen atmosphere. The progress of the
reactions was monitored by thin-layer chromatography (TLC) over silica gel
60F (E. Merck) in a thin layer (0.25mm). The chromatograms were visua-
lized by irradiation with ultraviolet (UV) light or by heat staining with
poly-phosphoric acid and p-anisaldehyde in ethanol=sulfuric acid. Silica
gel (230–400 mesh), (Spectrochem) was used for flash chromatography,
and solvents used were lab reagent (LR) grades from spectrochem and
RanKem without further purification. NMR spectra were recorded on a
Bruker DPX 200 instrument with tetramethylsilane (TMS) as internal
standard. The chemical shifts are reported in d values (ppm).

Normisoprostol
2767
Oxocan-2-one (7)
Cycloheptanone (40 g, 35.71 mmol) and m-chloroperbenzoic acid (70%,
5
2
0 mmol) were dissolved in dichloromethane (400 mL) and stirred for
0 h at room temperature. The resulting cloudy mixture was washed with
saturated sodium carbonate solution (3 ꢂ 250 mL) and brine solution
(
3
250 mL). The organic layer was dried (Na SO ) and concentrated at
2 4
ꢁ
5–40 C in vacuo to get crude (7), which was purified by column chroma-
tography on silica gel (60–120 mesh) with an EtOAc=hexane step
gradient as eluent. The selected fractions were combined, and the solvent
ꢁ
was removed in vacuo at 40–45 C to give 25 g of 7 (19.53 mmol, 55%) as a
colorless oil.
1
H NMR (200 MHz, CDCl ): d 4.25 (2 H, t, J 5.5 Hz, C8-H ), 2.45
3
2
(
2 H, t, J 6.0 Hz, C3-H ), 1.38–1.82 (8H, br, C4-C7-(H ) ) 2CH .
2 2 4 2
Methyl 7-Hydroxyheptanoate (8)
Compound 7 (24.5 g, 19.14 mmol) was dissolved in methanol (250 mL)
under a nitrogen atmosphere, and boron trifluoride etherate (0.1 eq)
was added to the reaction mass at room temperature. The resulting
mixture was stirred for 16 h at room temperature, and methanol was then
ꢁ
removed at 40–45 C in vacuo to get the residue, which was dissolved in
2
50 mL of water. The aqueous layer was extracted with ethyl acetate
3 ꢂ 200 mL). The organic layer was washed with 2% sodium bicarbonate
solution (150 mL) and brine (200 mL), dried (Na SO ), and concentrated
(
2
4
ꢁ
at 40–45 C in vacuo to get crude 8. The crude product was purified by
column chromatography on silica gel (60–120 mesh) with an
EtOAc=hexane step gradient as eluent. The pure fractions were com-
ꢁ
bined, and the solvent was removed in vacuo at 40–45 C to give
2
8.75 g of 8 (17.99 mmol, 94%) as colorless oil.
1
H NMR (200 MHz, CDCl ): d 3.67 (3H, s, OCH ), 3.41 (2H, t, J
3
3
8
OCH CH C H CH ), 1.08–1.29 (4H, m, HOC H C H ).
.0 Hz, CH OH), 2.14 (2H, t, J 7.0 Hz, CH CO), 1.29–1.54 (4H, m,
2
2
2
2
2
4
2
2
4
2
4
Methyl 6-Formylhexanoate (9)
A mixture of compound 8 (28 g, 17.5 mmol), dichloromethane (DCM;
420 mL), water (200 mL), and sodium bromide (18.23 g 17.7 mmol) was
ꢁ
taken in a round-bottom flask (2.0 L) and cooled to 0 C. TEMPO
(0.179 g, 0.115 mmol) was added in one lot, followed by addition of
sodium hypochlorite (4–6%) (16.48 g, 22.15 mmol) in 6% sodium

2768
M. Harikrishna et al.
ꢁ
bicarbonate solution (250 mL) at 0–5 C. The resulting mixture was
stirred for 15 min, at which TLC indicated complete conversion of 8 to
ꢁ
9
. The reaction mass was quenched by water (300 mL) at 0–5 C, and
the DCM layer was separated. The aqueous layer was extracted twice
with DCM (400 mL, total), and combined extracts were washed with
1
0% KHSO4 solution (250 mL), 2.5% sodium thiosulphate solution
200 mL), and brine solution (100 mL); dried (Na SO ); and filtered.
(
Filtrate was concentrated at 40–45 C in vacuo to give 26 g of crude 9,
which was purified by high vacuum distillation at 75–85 C under 0.5 to
1
2
4
ꢁ
ꢁ
mm of Hg vacuum to give 21 g of 9 (13.2 mmol, 75.9%).
1
H NMR (200 MHz, CDCl ): d 9.76 (s, 1 H, –CHO), 3.67 (s, 3 H,
3
CH O), 2.48–2.28 (m, 4H, J 7.2 Hz 2CH ), 1.73–1.36 (m, 6H, J 7.2 Hz
3
2
3
CH ); mass: 157 (Mꢀ1).
2
Methyl 7-(Furan-2-yl)-7-hydroxyheptanoate (11)
A solution of furan (15.8 g, 133 mmol) in THF (200 mL) was cooled to
ꢁ
ꢀ
10 C, and a solution of 1.6 M n-butyl lithium in hexane (95.7 mL,
46.3 mmol) was added dropwise while the reaction temperature was
1
ꢁ
ꢁ
maintained at less than 0 C. The solution was stirred at 0 C for
0 min, and anhydrous MgCl2 (13.93 g, 146.3 mmol) was added in
one portion. The mixture was warmed to room temperature for 1.5 h
3
ꢁ
and then cooled to ꢀ25 C. A solution of aldehyde ester 9 (20 g,
1
33 mmol) in THF (40 mL) was added, and the mixture was stirred
ꢁ
at ꢀ25 C for 30 min. The progress of the reaction was monitored by
gas chromatography (GC). After completion of the reaction as shown
by GC analysis, the reaction mixture was quenched by dropwise addi-
tion of saturated aqueous NH Cl solution (100 mL) and diluted with
4
EtOAc (100 mL). The layers were separated, and the aqueous layer
was extracted three times with EtOAc (3 ꢂ 100 mL). The combined
extracts were dried (Na SO ), filtered, and concentrated in vacuo to
2
4
give 27.2 g of crude hydroxy ester 11, which was used without further
purification.
An analytical sample of 11 was prepared via chromatography over
silica gel with an EtOAc=hexane step gradient as eluent. The pure frac-
tions (R 0.15; 20=80 EtOAc=hexane) were combined, and the solvent
f
was removed in vacuo to give a pale yellow oil.
1
H NMR (200 MHz, CDCl ): d 7.36 (d, 1H), 6.32 (d, 1H, J 1.8 Hz),
3
6
.22 (d, 1H, J 3.4 Hz), 4.66 (t, 1H), 3.65 (s, 3H, OCH ), 2.33–2.26 (t, 2H,
3
J 7.2 Hz), 1.95–1.56 (m, 5H, J 6.8 Hz), 1.49–1.25 (m, 4H); mass: 227
M þ 1).
(

Normisoprostol
2769
Methyl 6-(2-Hydroxy-5-oxocyclopent-3-enyl)hexanoate (12)
A solution of 11 (26 g, 115 mmol) and ZnCl2 (78.2 g, 575 mmol) in
,4-dioxane (312 mL) and water (210 ml) was refluxed for 16 h (TLC
1
analysis indicated the complete disappearance of starting material). The
mixture was cooled to room temperature, acidified to pH 2 with 6 N
HCl, and extracted with EtOAc (300 mL). The extract was dried with
over anhydrous Na SO , filtered, and concentrated in vacuo to give
2
4
2
8 g of a product mixture that contained 12a as the major component.
The crude mixture was dissolved in acetone (416 mL) and treated with
K CO (79.38 g, 575 mmol) and methyl iodide (81.68 g, 575 mmol). The
2
3
mixture was refluxed for 12 h (TLC indicated complete conversion of
2a to 12b). The mixture was filtered, and the filtrate was concentrated
1
in vacuo to give 27 g of crude cyclopentenone 12b, which was used
without further purification.
An analytical sample of 12b was prepared by chromatography over
silica gel (60–120 mesh) with EtOAc=hexane step gradient as eluent.
Selected fractions (R 0.16; 50=50 EtOAc=hexane) were combined, and
f
the solvent was removed in vacuo to give pale yellow oil.
1
H NMR (200 MHz, CDCl ): d 7.50 (dd, 1H, J 3.8 Hz), 6.20 (d, 1H, J
3
5
.8 Hz), 4.67 (m, 1H), 3.66 (s, 3H), 2.87–2.74 (dd, 1H, J 6.2 Hz), 2.35–2.16
(m, 4H, J 7.4 Hz), 1.88–1.32 (m, 7H, J 7.4 Hz); mass: 227 (M þ 1).
Methyl 6-(3-Hydroxy-5-oxocyclopent-1-enyl)hexanoate (13)
A solution of 12b (26 g, 115 mmol), Et N (17.46 g, 172 mmol), anhydrous
3
ꢁ
chloral (8.47 g, 57.5 mmol), and toluene (340 mL) was heated to 70–75 C
for 6 h (TLC analysis indicated complete conversion of 12b to 13). The
mixture was added to a slurry of anhydrous LiBr (260 g) in heptane
(
312 mL) and toluene (200 mL). The resulting mixture was stirred for
ꢁ
2
atmosphere and washed with a mixture of toluene (200 mL) and heptane
h at 30 C. The LiBr complex was collected by filtration under nitrogen
(
100 mL). The isolated LiBr complex was added portion wise to a mixture
ꢁ
of water (800 mL) and toluene (400 mL) at 0 C and stirred for 30 min.
The layers were separated, and the aqueous layer was extracted one time
with toluene (200 mL). The combined organic extracts were dried
(Na SO ), filtered, and concentrated in vacuo to give 18 g of crude 13,
2 4
which was purified by column chromatography over silica gel (60–120
mesh) with EtOAc=hexane step gradient as eluent. Selected fractions
(
removed in vacuo at 40–45 C to give 8.0 g of compound 13 (35 mmol,
R , 0.15; 50=50 EtOAc=hexane) were combined, and the solvent was
ꢁ
f
3
1% yield) as a pale yellow oil.

2770
M. Harikrishna et al.
1
H NMR (200 MHz, CDCl ): d 7.16 (d, 1H), 4.93 (br, 1H), 3.66 (s,
3
3
1
H), 2.87–2.75 (dd, 2H, J 6.2, 18.3 Hz), 2.34–2.16 (m, 4H, J 7.4 Hz),
1
3
.71–1.34 (m, 7H, J 7.2 Hz); mass: 227 (M þ 1). C NMR (200 MHz,
CDCl ): 206.6 (C¼O), 174.19 (COOCH ), 156.56 (CH), 147.17, 67.91
3
3
(CH-OH), 51.25 (OCH ), 44.57, 33.7, 28.59, 26.92, 24.47, 24.03.
3
Methyl 6-(3-Triethyl silyloxy-5-oxocyclopent-1-enyl)hexanoate (4)
A solution of 13 (5 g, 22 mmol) and Et N (33 g, 330 mmol) in dimethylfor-
3
ꢁ
mamide (DMF, 50 mL) was cooled to 10 C, and chlorotriethylsilane
(
4.31 g, 28 mmol) was slowly added dropwise over a period of 10 min.
The mixture was allowed to warm to room temperature and stirred for
h (TLC indicated complete conversion of 13 to 4). Reaction mass was
6
quenched by the addition of ice-cold water (25 mL) and extracted five
times with heptane (250 mL, total), and the combined extracts were
washed twice with saturated aqueous NaCl solution (200 mL total), dried
(Na SO ), and filtered. The filtrate was concentrated in vacuo to give 7 g
2 4
of crude 4, which was purified by chromatography over silica gel (60–120
mesh) with EtOAc=hexane step gradient as eluent. The pure fractions (Rf,
0
.52; 30=70 EtOAc=hexane) were combined, and the solvent was removed
in vacuo to give 5 g (14 mmol, 66%) of silyl ether 4 as pale yellow oil.
1
H NMR (200 MHz, CDCl ): d 7.04 (m, 1H), 4.88 (m, 1H), 3.66 (s,
3
3
2
9
H), 2.80–2.68 (dd, 1H, J 6.2, 18.4 Hz), 2.28 (dd, 1H, J 5.6, 18.4 Hz),
.35–2.16 (m, 4H, J 4.6 Hz), 1.88–1.32 (m, 6H, J 6.8 Hz), 1.02–0.94 (q,
1
3
H, J 7.6 Hz), 0.70–0.62 (t, 6H, J 7.6 Hz); mass: 341 (M þ 1).
C
NMR (200 MHz, CDCl ): 205.4 (C¼O), 173.5 (COOCH ), 156 (CH),
3
3
1
2
46.6, 68 (CH-OSi), 50.85 (OCH ), 45.08, 33.51, 28.58, 26.84, 24.38,
3
3.97, 6.27, 4.38.
4
-Methyloct-1-yn-4-ol (15)
Zn (13.1 g, 20 mmol) and DMF (100 mL) were added to a mixture of
-hexanone (10 g, 10 mmol) at room temperature under an N atmo-
sphere; 14 (23.6 g, 20 mmol) was added dropwise over a period of
2
2
25 min (reaction is exothermic and external cooling is required to main-
ꢁ
tain temperature at 30 C). The mixture was stirred for 5 h, at which time
GC analysis indicated complete conversion of 2-hexanone to 15. The
reaction mass was quenched by the addition of saturated NH Cl
4
ꢁ
(
100 mL) at 10–20 C, stirred for 10 min, and filtered. The filtrate was
extracted with three times with DCM (300 mL, total), and combined
extracts were washed twice with water (200 mL, total), dried (Na SO ),
2
4

Normisoprostol
2771
and filtered. The filtrate was concentrated in vacuo to give 13 g of crude
ꢁ
1
3
5, which was purified by high vacuum distillation at 48–54 C under
–4 mm of Hg vacuum to get 8 g of 15 (5.7 mmol, 57%) as an oil.
1
H NMR (200 MHz, CDCl ): d 6.48 (br, OH), 2.41–2.30 (dq, 2H, J
3
2
.8, 16.4 Hz, CH CCH), 1.96 (t, 1H, J 2.8 Hz, CH), 1.65–1.5 (m, 2H,
1
2
3
CH ), 1.38–1.28 [m, 7H, CH (CH ) ]; mass: 141 (M þ 1). C NMR
2
3
2 2
(
(
200 MHz, CDCl ): 82.04 (CCH), 75.05, 69.79 (CH), 41.63, 32.61, 27.48
3
CCH ), 26.05, 23.13, 14.07 (CH CH ).
3
2
3
4
-Methyloct-1-yn-4-yloxy)triethylsilane (16)
A mixture of compound 15 (7 g, 5 mmol) and imidazole (6.8 g, 10 mmol)
ꢁ
in DMF (50 mL) was cooled to 10 C, and chlorotriethylsilane (11.3 g,
7
.5 mmol) was added dropwise over a period of 10 min. The mixture
was allowed to warm to room temperature and stirred for 6 h (TLC indi-
cated complete conversion of 15 to 16). The reaction mass was quenched
by the addition of water (100 mL) and extracted two times with DCM
(
(
200 mL, total), and the combined extracts were washed twice with water
200 mL, total), dried (Na SO ), and filtered. The filtrate was concen-
2
4
trated in vacuo to give 12 g of crude 16, which was purified by chromato-
graphy over silica gel (60–120 mesh) with EtOAc=hexane step gradient as
eluent. Selected fractions were combined, and the solvent was removed in
ꢁ
vacuo at 35 C to give 9.5 g (3.74 mmol, 75%) of silyl ether 16 as a pale
yellow oil.
1
H NMR (200 MHz, CDCl ): d 2.41–2.30 (dq, 2H, J 2.8, 16.4 Hz,
3
CH CCH), 1.96 (t, 1H, J 2.8 Hz, CH), 1.65–1.5 (m, 2H, CH2),
2
1
7
.38–1.28 [m, 7H, CH (CH ) ], 1.05–0.82 (m, 9H), 0.65–0.58 (q, 6H, J
3 2 2
1
3
.6 Hz); mass: 255 (M þ 1).
C NMR (200 MHz, CDCl ): 81.96
3
(
CCH), 74.86, 69.79 (CH), 41.63, 32.61, 27.48 (CCH ), 26.05, 23.13,
3
1
4.07 (CH CH ), 7.03, 6.79.
2 3
(E)-1-(Tributylstannyl)-4-methyloct-1-en-4-yloxy)triethylsilane (5)
A mixture of 16 (8.5 g, 3.3 mmol), AIBN (0.38 g, 0.23 mmol), and tribu-
ꢁ
tyltinhydride (9.73 g, 3.3 mmol) was heated to 110 C and stirred for
2
hexane). Reaction mass was cooled to 30 C, and 50 mL of n-hexane were
h, at which time TLC indicated complete conversion of 16 to 5 (100%
ꢁ
ꢁ
added. Filtrate was concentrated at 40 C in vacuo to give 15.5 g of 5
(2.83 mmol, 85%) as a pale yellow liquid, which was used in the next step
without purification.

2772
M. Harikrishna et al.
Methyl 6-(3-Triethylsilyloxy-2-((E)-4-triethylsilyloxy-4-methyloct-
-enyl)-5-oxocyclopentyl)hexanoate (17)
1
A solution of CuCN (2.31 g, 25 mmol) in THF (60 mL) in a flame-dried
flask was degassed with a vacuum and placed under Ar by releasing
ꢁ
the vacuum with Ar. The solution was cooled to ꢀ5 to 0 C, and a solu-
tion of 1.6 M methyl lithium in diethyl ether (40 mL, 51 mmol) was added
ꢁ
through the cannula at ꢀ5 to 0 C. The resulting solution was stirred for
1
5 min and a solution of 5 (14.1 g, 25 mmol) in THF (20 mL) was added
ꢁ
slowly to the reaction mass at ꢀ5 to 0 C. The resulting mixture was stir-
ꢁ
ꢁ
red for 1.5 h at 25–30 C, cooled to ꢀ75 C, and stirred for 5 min. Solution
of 4 (4 g, 11 mmol) in THF (20 mL) was added to the reaction mass at
ꢁ
ꢀ
75 C and and stirred for 1 h (TLC indicated complete conversion of
3 to 16). The reaction mixture was poured into a mixture of saturated
aqueous NH C1=NH OH solution (9:1, 100 mL). The mixture was
4
4
vigorously stirred for 30 min, and the layers were separated. The aqueous
phase was extracted twice with EtOAc (2 ꢂ 50 mL), and the combined
organic phases were washed twice with a mixture of 9=1 saturated
aqueous NH Cl=NH OH solution (100 mL total). The organic phase
4
4
was dried (Na SO ), filtered, and concentrated in vacuo to give 5.26 g
4
2
of crude 17, which was purified by column chromatography over silica
gel (230–400 mesh) with EtOAc=hexane step gradient as eluent. Selected
fractions were combined, and the solvent was removed in vacuo to give
3
.8 g of 17 (6.4 mmol, 55%).
1
H NMR (200 MHz, CDCl ): d 5.77–5.73 (m, 1H), 5.46–542 (m, 1H),
3
4
(
1
.06 (q, 1H), 3.66 (s, 3H), 2.80–2.67 (dd, 1H, J 18.0, 7.2 Hz), 2.39–2.14
m, 6H, J 7.6 Hz), 2.04–1.93 (m, 1H, J 6.2), 1.67–1.17 (m, 17H),
.05–0.82 (m, 21H), 0.65–0.58 (t, 12H); ES-MS: 369 (M þ 1). C NMR
3 3
1
3
(
7
2
200 MHz, CDCl ): 216.1 (C¼O), 174 (COOCH ), 132, 129.9 (CH),
3.1, 72.9 (CH), 54.5 (CH), 53.9 (CH), 51.4, 47.6, 45.7, 42.2, 34, 29.3,
7.7, 27.6, 26.4, 26.1, 24.7, 23.2, 14.1, 7.1, 6.9, 6.6, 5.7, 5.3, 4.7.
Methyl 6-(3-Hydroxy-2-(E)-4-hydroxy-4-methyloct-1-enyl)-5-
oxocyclopentyl)hexanoate (3)
The compound 17 (3.0 g, 0.5 mmol) was dissolved in acetonitrile (42 mL)
and water (21 mL) at room temperature. The solution was treated with
ꢁ
DDQ (0.114 g, 0.05 mmol) and stirred for 4 h at 25–30 C, at which time
TLC indicated complete conversion of 17 to 3. Most of the acetonitrile
ꢁ
was removed in vacuo at 30–35 C, and methyl-tert-butyl ether (MTBE)
(50 mL) was added at room temperature. The organic layer was sepa-
rated, and the aqueous layer was extracted twice with MTBE (100 mL,

Normisoprostol
2773
total). Combined extracts were dried (Na SO ), filtered, and concen-
2
4
ꢁ
trated in vacuo at 25 C to give crude 2 (2.8 g). The crude sample was pur-
ified by column chromatography over silica gel (230–400 mesh) with an
MTBE=n-hexane step gradient as eluent. Selected fractions (R , 0.40,
f
1
at 25 C to give 1.1 g of compound 3 (0.29 mmol, 60%), characterized
00% MTBE) were combined, and the solvent was removed in vacuo
ꢁ
1
by NMR, mass, and C NMR.
3
1
H NMR (200 MHz, CDCl ): d 5.77–5.73 (m, 1H), 5.46–542 (m, 1H),
3
4
6
3
.06 (q, 1H), 3.66 (s, 3H), 2.80–2.67 (dd, H, J 18.0, 7.2 Hz), 2.39–2.14 (m,
H, J 7.6 Hz), 2.04–1.93 (m, 1H, J 6.2), 1.67–1.17 (m, 19H), 0.95–0.88 (t,
1
3
H, J 7.2 Hz); ES-MS: 369 (M þ 1). C NMR (200 MHz, CDCl ): 216.1
3
(
C¼O), 174 (COOCH ), 132, 129.9 (CH), 73.1, 72.9 (CH), 54.5 (CH),
3
5
2
3.9 (CH), 51.4, 47.6, 45.7, 42.2, 34, 29.3, 27.7, 27.6, 26.4, 26.1, 24.7,
3.2, 14.1.
ACKNOWLEDGMENT
The authors thank Dr. C. Satyanarayana, CEO, Aptuit Laurus, for his
encouragement.
REFERENCES
1
. (a) Nicolaou, K. C.; Barnette, W. E.; Magolda, R. L. Synthesis of (5Z)- and
5E)-6,9-thiaprostacyclins. J. Am. Chem. Soc. 1981, 103, 3472–3480; (b) Peng,
(
S.; McGingly, C. M.; Van der Donk, W. A. Synthesis of site-specifically
labeled arachidonic acids as mechanistic probes for prostaglandin H synthase.
Org. Lett. 2003, 6, 349–352; (c) Peng, S.; Okeley, N. M.; Tsai, A.-L.; Wu, G.;
Kulmacz, R. J.; Van der Donk, W. A. Structural characterization of a penta-
dienyl radical intermediate formed during catalysis by prostaglandin H
synthase-2. J. Am. Chem. Soc. 2001, 123, 3609–3610; (d) Rokach, J.;
Khanapure, S. P.; Hwang, S. W.; Adiyaman, M.; Schio, L.; FitzGerald, G.
A. The isoprotanes, a new class of natural products: Synthesis and biosynth-
esis. Synthesis 1998, 569–580.
2
. (a) Renaud, P.; Vionnet, J. P. Radical additions to 7-oxabicyclo[2.2.1]hept-5-
en-2-one: Facile preparation of all-cis-Corey lactone. J. Org. Chem. 1993, 58
(
22), 5895–5896; (b) Bonini, C.; Iavarone, C.; Trogolo, C.; Di Fabio, R.
One-pot conversion of 6-hydroxy-D7-iridoid glucosides into cis-2-
oxabicyclo[3.3.0]oct-7-enes and transformation into Corey’s lactone analog.
J. Org. Chem. 1985, 50 (7), 958–961; (c) Davini, E.; Lavarone, C.; Mataloni,
F.; Trogolo, C. Conversion of aucubin to a useful Corey lactone analog for
the synthesis of 11-methyl PGA2. J. Org. Chem. 1988, 53 (9), 2089–2091; (d)
Tomankova, Z.; Setnicka, V.; Urbanova, M.; Matejka, P.; Kral, V.; Volka,
K.; Bour, P. Conformational flexibility of Corey lactone derivatives indicated
by absorption and vibrational circular dichroism spectra. J. Org. Chem. 2004,

2774
M. Harikrishna et al.
69 (1), 26–32; (e) Bernini, R.; Davini, E.; Lavarone, C.; Trogolo, C. Synthesis
of a Corey lactone analog from the iridoid glucoside aucubin and its utilization
in the synthesis of a new 12-epi-PGF2a modified at C-11. J. Org. Chem. 1986,
51 (24), 4600–4603; (f) Rajan Babu, T. V. From carbohydrates to carbocycles,
2: A free radical route to Corey lactone and other prostanoid intermediates. J.
Org. Chem. 1988, 53 (19), 4522–4530.
. (a) Curran, T. T.; Hay, D. A.; Koegel, C. P. The preparation of optically active
3
2-cyclopenten-1,4-diol derivatives from furfuryl alcohol. Tetrahedron 1997, 53,
1983–2004; (b) Myers, A. G.; Hammond, M.; Wu, Y. An improved prepara-
tion
butyldimethylsiloxy-2-cyclopenten-1-one. Tetrahedron Lett. 1996, 37, 3083–
086; (c) Khanapure, S. P.; Najafi, N.; Manna, S.; Yang, J. J.; Rokach, J.
An efficient synthesis of 4(S)-hydroxycyclopent-2-enone. J. Org. Chem. 1995,
0, 7548–7551; (e) Das, S.; Chandrasekhar, S.; Yadav, J. S.; Gree, R. Recent
developments in the synthesis of prostaglandins and analogues. Chem. Rev.
007, 107 (7), 3286–3337.
of
highly
enantiomerically
enriched
(R)-(þ)-4-tert-
3
6
2
4
. (a) Alvarez, F. S.; Wren, D.; Prince, A. Prostaglandins, IX: Synthesis of (þ-)-
prostaglandin E1, (þ)-11-deoxyprostaglandins E1, F1-a and F1-b, and
(þ)-9-oxo-13-cis-prostenoic acid by conjugate addition of vinyl copper
reagents. J. Am. Chem. Soc. 1972, 94, 7823–7827; (b) Kluge, A. F.; Untch,
K. G.; Fried, J. H.; Prostaglandins, X: Synthesis of prostaglandin models
and prostaglandins by conjugate addition of a functionalized organo copper
reagent. J. Am. Chem. Soc. 1972, 94, 7827–7832; (c) Collins, P. W.; Dajani,
E. J.; Driskill, D. R.; Bruhn, M. S.; Jung, C. J.; Pappo, R. J. Synthesis and
gastric antisecretory properties of 15-deoxy-16-hydroxyprostaglandin E ana-
logs. J. Med. Chem. 1977, 20, 1152–1159; (d) Lipishutz, B. A.; Ellsworth, E.
L. Hydrozirconation—transmetalation: A mild, direct route to higher order
vinylic cuprates from mono substituted acetylenes. J. Am. Chem. Soc. 1990,
112, 7440–7441; (e) Okamoto, S.; Yoshino, T.; Sato, F. A practical synthesis
of the x side-chain unit present in mexiprostil and its use for synthesis of mex-
iprostil via two-component coupling process. Tetrahedron: Asymmetry 1991, 2,
35–38.
5. (a) Suzuki, M.; Yanagisawa, A.; Noyori, R. Prostaglandin synthesis, 16: The
three-component coupling synthesis of prostaglandins. J. Am. Chem. Soc.
1988, 110, 4718–4726; (b) Noyori, R.; Suzuki, M. Prostaglandin-Synthesen
durch Dreikomponenten-Kupplung. Angew. Chem. 1984, 96, 854; Prostaglan-
din syntheses by three-component coupling: New synthetic methods. Angew.
Chem Int. Ed. 1984, 23, 847; (c) Johnson, C. R.; Penning, T. D. Triply conver-
gent synthesis of (ꢀ)-prostaglandin E2 methyl ester. J. Am. Chem. Soc. 1988,
110, 4726–4735; (d) Gooding, O. W. An expedient triply convergent synthesis
of prostaglandins. J. Org. Chem. 1990, 55, 4209–4211; (e) Suzuki, M.;
Yanagisawa, A.; Noyori, R. Prostaglandin synthesis, 10: An extremely short
way to prostaglandins. J. Am. Chem. Soc. 1985, 107, 3348–3349; (f)
Donaldson, R. E.; Saddler, J. C.; Byrn, S.; Mckenzie, A. T.; Fuchs, P. L.
Syntheses via vinyl sulfones, 11: A triply convergent total synthesis of L-
(ꢀ)-prostaglandin E2. J. Org. Chem. 1983, 48, 2167–2188; (g) Lipshutz,

Normisoprostol
2775
B. H.; Wood, M. R. A practical, general three-component coupling approach
to prostaglandin and non-prostaglandin-related skeleta. J. Am. Chem. Soc.
1
994, 116, 11689–11702.
6
. (a) Jack, E. B.; Robert, M. A.; Steve, H. R. Intramolecular
palladium-catalysed cross coupling: A direct route to c-oxo-a,b-unsaturated
macrocycles. Tetrahedron 1992, 48, 2957–2976; (b) Guy, S.; Almudena, R.;
Carmen, M. C.; Jose, L. G. R. Asymmetric synthesis of orsellinic acid type
macrolides: The example of lasiodiplodin. Tetrahedron: Asymmetry 1990, 1,
1
87–198.
7
. (a) Enrico, B.; Paolo, F.; Guiseppe, G.; Sergio, I.; Vittorio, M. New synthesis
of methyl 7-oxoheptanoate: An useful intermediate for the preparation of
2
(
-(6-methoxycarbonylhexyl)-cyclopent-2-en-1-one. Synthesis 1983, 942–944;
b) Corey, E. J.; Suggs, W. J. Pyridinium chlorochromate: An efficient reagent
for oxidation of primary and secondary alcohols to carbonyl compounds. Tet-
rahedron Lett. 1975, 2647; (c) Pier Lucio, A.; Carlo, B.; Fernendo, M.; Silvio,
Q. Fast and selective oxidation of primary alcohols to aldehydes or to car-
boxylic acids and of secondary alcohols to ketones mediated by oxoammo-
nium salts under two-phase conditions. J. Org. Chem. 1987, 52, 2559–2562.
. (a) John, H. D.; John, P. A.; Kevin, A. B.; James, R. B.; John, R. M.; John,
S. N.; Joseph, J. W. An efficient synthesis of the antisecretory prostaglandin
enisoprost. J. Org. Chem. 1991, 56, 2549–2552; (b) Piancatelli, G.; Scettri,
A.; Barbadoro, S. A useful preparation of 4-substituted 5-hydroxy-3-oxocyclo-
pentene. Tetrahedron Lett. 1976, 39, 3555–3558.
8
9
. Lipshutz, B. H.; Ellsworth, E. L. Hydrozirconation–transmetalation: A mild,
direct route to higher order vinylic cuprates from mono substituted acetylenes.
J. Am. Chem. Soc. 1990, 112, 7440–7441.