Synthesis of 11-deoxyprostaglandins

Improved procedures and intermediates for synthesizing 11-deoxyprostaglandins wherein trans-2,3-dicarbomethoxycyclopentanone is subjected to a novel alcoholysis with .beta.,.beta.,.beta.-trichloroethanol to substitute a .beta.,.beta.,.beta.-trichlorocarboethoxy group at the 2-position followed by alkylation to allow for a wide range of upper side chains to be introduced at the 2-position of the cyclopentanone ring. The unwanted .beta.,.beta.,.beta.-trichlorocarboethoxy group at the 2-position can then be removed easily by a zinc induced elimination-decarboxylation sequence. Base catalyzed epimerization of the 2-position side chain to the desired trans-configuration, relative to the carbomethoxy group in the 3-position, is followed by partial reduction of the 2-hexynyl moiety of the side chain to the desired cis-olefinic group of the E.sub.2 -type 11-deoxyprostaglandins, or through total reduction to the alkane upper side chain of E.sub.1 -type prostaglandin analogs. Modification thereafter of the carbonyl group at the 3-position of the cyclopentanone ring by a variety of reagents allows introduction of the lower side chain present in the prostaglandins themselves or a variety of other side chains derived from the 3-carboxy-, 3-hydroxymethyl- or 3-aldehyde-substituted cyclopentanone ring. From the latter, 11-deoxyprostaglandins can be prepared by known procedures.

SUMMARY OF THE INVENTION 
This invention concerns improved methods and intermediates for synthesizing 
11-deoxyprostaglandin precursors. In the new synthetic route, 
trans-2,3-dicarbomethoxycyclopentanone is subjected to a novel alcoholysis 
with .beta.,.beta.,.beta.-trichloroethanol to substitute a 
2-.beta.,.beta.,.beta.-trichlorocarboethoxy group. Any required upper side 
chain thereafter can easily be introduced in its entirety in one step by 
an alkylation procedure. The unwanted 
.beta.,.beta.,.beta.-trichlorocarboethoxy group at the 2-position of the 
resulting compound is readily removed by a zinc-induced 
elimination-decarboxylation sequence. Base catalyzed epimerization of the 
2-position side chain to the desired trans-configuration, relative to the 
carbomethoxy group in the 3-position is followed by partial reduction of 
the 2-hexynyl moiety of the side chain to the desired cis-olefinic group 
of the E.sub.2 -type 11-deoxyprostaglandins, or by total reduction to the 
alkane upper side chain of E.sub.1 -type prostaglandin analogs. 
Thereafter, modification of the carbonyl group at the 3-position of the 
cyclopentanone ring, readily accomplished by a variety of reagents, allows 
introduction of the lower side chain present in the prostaglandins 
themselves or a variety of other side chains derived from the 3-carboxy-, 
the 3-hydroxymethyl- or the 3-aldehyde-substituted cyclopentanone ring. 
From the latter, 11-deoxyprostaglandins are readily synthesized by known 
procedures. 
DESCRIPTION OF SOME PREFERRED EMBODIMENTS 
The starting material used in the novel processes for making the 
intermediates for 11-deoxyprostaglandins is 1,2,4-tricarbomethoxybutane. 
This compound may be prepared by the procedure of U.S. Pat. No. 2,203,628 
by nitric acid oxidation of a .DELTA..sup.3 -cyclohexene which is 
substituted in at least one of the 1- and 2-positions of the cyclohexene 
nucleus by a carboxylic group. Thereafter, the resulting 
1,2,4-tricarboxybutane is esterified to the trimethyl ester with methanol 
in the presence of an acidic catalyst, following well-known procedures. 
The series of reactions involved in the novel synthesis may be depicted by 
the following schematic representation: 
##STR1## 
Step 1 
If trans-2,3-dicarbomethoxycyclopentanone is not available, the first step 
in the synthetic scheme is the conversion of 1,2,4-tricarbomethoxybutane 
to trans-2,3-dicarbomethoxycyclopentanone. This is carried out by reacting 
the starting material with alkali metal hydride, used as a dispersion in 
mineral oil, the reaction medium being dry p-xylene in the presence of a 
trace of anhydrous methanol. The starting material is added stepwise to 
the reaction medium. The reaction temperature is maintained between about 
20.degree. C. and about 40.degree. C. while the reaction mixture is 
stirred. Stirring is continued for a short time after addition of the 
starting material is complete, the resulting viscous mixture is diluted 
with water and the phases are separated. The aqueous phase is immediately 
acidified by addition thereto of citric acid monohydrate with stirring. 
The crude product is extracted several times, advantageously three times, 
with ethyl acetate and the combined organic phases are washed with water 
and twice with sodium chloride brine and dried over anhydrous magnesium 
sulfate. The solution is filtered, treated with decolorizing carbon, again 
filtered and concentrated in vacuo to give crude product which 
crystallizes upon seeding. This material, 
trans-2,3-dicarbomethoxycyclopentanone, 90-95% pure as determined by VPC, 
may be employed directly in the next step. Preferably, it should first be 
recrystallized from ethyl ether/petroleum ether. 
Most prior art procedures for making the product of the first step have 
given a mixture of the first step product and its isomeric cyclization 
product, 2,4-dicarbomethoxycyclopentanone. By the procedure of U.S. Pat. 
No. 4,146,553 just described, virtually none of the unwanted 2,4-isomer 
(&lt;10%) is produced. 
Step 2 
In this step, alcoholysis with .beta.,.beta.,.beta.-trichloroethanol 
provides a trichlorocarboethoxy group in place of the carbomethoxy group 
at the 2-position prior to the introduction at the 2-position of a 
required side chain. This is accomplished by stirring a mixture of 
2,3-dicarbomethoxycyclopentanone with excess 
.beta.,.beta.,.beta.-trichloroethanol in refluxing m-xylene with provision 
for intermittent removal of solvent. Following a total reaction time of 
ca. 115 hours, the solution is concentrated and the residual oil is 
triturated with ligroin. The resulting solid is taken up in boiling 
aqueous methanol, treated with decolorizing carbon and filtered. 
Trans-2-.beta.,.beta.,.beta.-trichlorocarboethoxy-3-carbomethoxycyclopenta 
none, a new compound, crystallizes out. 
Step 3 
In this step, position 2 is alkylated to introduce a required side chain. 
The side chain is introduced in its entirety in one step. Thereby, a wider 
range of side chains can be introduced than has heretofore been possible. 
The introduction of the desired side chain via a nucleophilic displacement 
utilizes any compound NC(CH.sub.2).sub.3 C.tbd.CCH.sub.2 X in which X is a 
good leaving group. Thus, to a mechanically stirred suspension of a 
mineral oil dispersion of sodium hydride in dry dimethoxyethane is added 
during 30 minutes a solution of a substantially equimolar proportion of 
trans-2-.beta.,.beta.,.beta.-trichlorocarboethoxy-3-carbomethoxy 
cyclopentanone in dry dimethoxyethane. Stirring is continued for ca. one 
and one-half hours after addition is complete, during which hydrogen 
evolution ceases. A solution of a substantially equimolar proportion of 
the methane sulfonate of 6-cyano-2-hexyne-1-ol in dry dimethoxyethane is 
added during ca. 10 minutes. The resulting light tan mixture is heated at 
reflux for ca. 24 hours, cooled, diluted with 100 ml of water and 
exhaustively extracted with ethyl acetate. The combined extracts are 
washed several times with NaCl brine and dried over anhydrous magnesium 
sulfate. The filtered solution is concentrated in vacuo to afford, (after 
washing by decantation several times with hexane and removal of residual 
solvent at the stripper) a 96% yield of crude product. Purification is 
accomplished via chromatography on silica gel, using benzene/ethyl 
acetate, (95/5), as solvent. The pure product, (72% yield, typically) is 
obtained as a viscous, colorless oil. 
Other alkylating agents which can be used include compounds having the 
formula NC(CH.sub.2).sub.3 C.tbd.CCH.sub.2 X in which X is bromo, chloro, 
iodo or p-tolylsulfonyl; Br(CH.sub.2).sub.6 CO.sub.2 CH.sub.3, 
Br(CH.sub.2).sub.6 CN and BrCH.sub.2 C.tbd.CCH.sub.2 CH.sub.3. Broadly, 
the following alkylating agents are useful in the alkylation: 
cis-XCH.sub.2 CH.dbd.CH(CH.sub.2).sub.3 CN, 
X(CH.sub.2).sub.3 (CH.sub.2).sub.x CN, 
XCH.sub.2 C.tbd.C--CH.sub.2 Si(CH.sub.3).sub.2 CH.sub.2 CN, 
XCH.sub.2 C.tbd.CCH.sub.2 SCH.sub.2 CN, 
XCH.sub.2 C.tbd.C(CH.sub.2).sub.3 CO.sub.2 R, 
XCH.sub.2 C.tbd.CCH.sub.2 N(CH.sub.3)CH.sub.2 CN, 
XCH.sub.2 C.tbd.CCH.sub.2 OCH.sub.2 CN, 
XCH.sub.2 C.tbd.C(CH.sub.2).sub.x CN, 
XCH.sub.2 C.tbd.C(CH.sub.2).sub.3 SO.sub.2 NHCH.sub.3, 
cis-XCH.sub.2 CH.dbd.CHCH.sub.2 SCH.sub.2 CN, 
XCH.sub.2 C.tbd.CCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 CN and 
XCH.sub.2 C.tbd.CCH.sub.2 N(CH.sub.2 CN).sub.2, 
wherein X is a good leaving group and x is 1 to 10 (.noteq.3). 
The product of Step 3 is a new compound. 
Step 4 
In Step 4, the unwanted .beta.,.beta.,.beta.-trichlorocarboethoxy group at 
the 2-position of the cyclopentanone moiety is readily removed by 
hydrogenolysis with zinc dust in aqueous acetic acid at room temperature 
for 3.5 hours. After filtering with suction, the removed solids are washed 
with several small portions of glacial acetic acid, the combined filtrate 
and washings are concentrated and the residue is partitioned between ethyl 
acetate and water. After washing the organic phase with sodium bicarbonate 
and sodium chloride solutions, the dried solution is concentrated in vacuo 
to produce a 1:1 mixture of cis:trans-isomers of the product, 
2-(6'-cyano-2'-hexynyl)-3-carbomethoxycyclopentanone. 
Step 5 
The cis:trans-isomer mixture from Step 4 is epimerized to the required all 
trans-isomer with a catalytic amount of sodium methoxide in methanol at 
room temperature. Following acidification with glacial acetic acid, the 
mixture is concentrated in vacuo and the residue is taken up in ethyl 
acetate and washed with sodium bicarbonate and sodium chloride solutions. 
The dried solution is then concentrated in vacuo to provide 
trans-2-(6'-cyano-2'-hexynyl)-3-carbomethoxycyclopentanone. 
Step 6 
The compound of Step 5 is catalytically selectively hydrogenated using 5% 
palladium on barium sulfate in pyridine at 25.degree. C. and one 
atmosphere pressure until one mole of hydrogen has been consumed. After 
removal of the catalyst, most of the pyridine is removed in vacuo and the 
residue is taken up in ethyl acetate and washed with dilute hydrochloric 
acid and sodium chloride solutions and dried. The filtered solution is 
concentrated in vacuo and the crude product is purified via silica gel 
chromatography using benzene/ethyl acetate, (93/7), as solvent. The pure 
product, (95% yield), of 
trans-2-(6'-cyano-cis-2'-hexenyl)-3-carbomethoxycyclopentanone, is 
obtained as a colorless oil. 
Step 7 
In Step 7, the carbomethoxy group in the 3-position on the cyclopentanone 
nucleus is saponified with aqueous methanolic sodium carbonate at about 
75.degree. C. to give, upon acidification with concentrated hydrochloric 
acid, the compound 7 having a carboxylic acid group in the 3-position. The 
reaction is a known type reaction. 
Step 8 
In Step 8A, compound 7 is transformed to its acid chloride by reaction with 
thionyl chloride in dry benzene under anhydrous conditions at about 
85.degree.-90.degree. C. and, after recovery, is employed immediately in 
the following step. 
In Step 8B, the diol is prepared from the preceding acid chloride by 
reduction with alkali metal borohydride in p-dioxane/water in a 
conventional reduction at about 0.degree. to 5.degree. C. to give the 
compound trans-2-(6'-cyano-cis-2'-hexenyl)-3-hydroxymethylcyclopentanol. 
Step 9 
In Step 9, the 6'-cyano-cis-2'-hexenyl group in position 2 is transformed 
to the corresponding 6'-carbomethoxy-cis-2'-hexenyl compound by 
hydrolyzing the cyano moiety to carboxylate with aqueous methanolic alkali 
metal hydroxide, liberating the acid from the resulting carboxylate salt 
with concentrated mineral acid, and treating the latter with diazomethane 
to give product 9, 
trans-2-(6'-carbomethoxy-cis-2'-hexenyl)-3-hydroxymethylcyclopentanol as a 
viscous oil. 
Step 10 
In final Step 10, compound 9 is selectively oxidized by adding a solution 
of it in a non-reactive solvent, advantageously methylene chloride, to a 
solution of anhydrous chromium trioxide in a mixture of about two molar 
proportions of anhydrous pyridine in dry methylene chloride. The reaction 
is carried out at about 25.degree. C. At the completion of the reaction, 
compound 10, 
trans-2-(6'-carbomethoxy-cis-2'-hexenyl)-3-formylcyclopentanone is 
recovered. As is well known to art-skilled persons, this compound is 
readily transformed to 11-deoxyprostaglandins via known steps.

The following examples describe completely representative specific 
embodiments of the invention and the best mode contemplated by the 
inventors of carrying out the invention. 
EXAMPLE 1 
Trans-2,3-dicarbomethoxycyclopentanone, 2 
To a mechanically-stirred suspension of 30.5 g, 0.72 mole, of a 57 percent 
mineral oil dispersion of sodium hydride in 450 ml of dry p-xylene was 
added 20 ml of a solution of 142.5 g, 0.60 mole, of 
1,2,4-tricarbomethoxybutane in 125 ml of dry p-xylene and 1 ml of 
anhydrous methanol. After the reaction had commenced, the remainder of the 
ester solution was added at 20.degree.-25.degree. C. during 1.5 hours. 
Stirring was continued for 20 minutes after addition was complete, the 
viscous mixture was diluted with 200 ml of water and the phases were 
separated. The aqueous phase was immediately acidified by addition of a 
stirred solution of 45.0 g, 0.21 mole, of citric acid monohydrate in 125 
ml of water. The crude product was extracted into three 250 ml portions of 
ethyl acetate and the combined organic phases were washed with 100 ml of 
water and with two 100 ml portions of sodium chloride brine and dried over 
anhydrous magnesium sulfate. The filtered solution was treated with 7.0 g 
of decolorizing carbon, filtered again and concentrated in vacuo to afford 
90.0 g, 75 percent, of crude product which crystallized upon seeding. This 
material, which is 90-95% percent pure titular compound via VPC, when 
recrystallized from ether/petroleum ether (30.degree.-60.degree. C.), was 
obtained as colorless needles, m.p. 49.0.degree.-50.0.degree. C. 
Anal. Calc. for C.sub.9 H.sub.12 O.sub.5 : C, 53.99; H, 6.04. Found: C, 
53.92; H, 6.01. 
The 2,4-dinitrophenylhydrazone thereof was obtained as golden felted 
needles, m.p. 145.0.degree.-146.5.degree. C., from methanol. 
Anal. Calc. for C.sub.15 H.sub.16 N.sub.4 O.sub.8 : C, 47.37; H, 4.24; N, 
14.73. Found: C, 47.41; H, 4.24; N, 14.71. 
EXAMPLE 2 
Trans-2-.beta.,.beta.,.beta.-trichlorocarboethoxy-3-carbomethoxycyclopentan 
one, 3 
A magnetically stirred solution of 35.0 g, 0.175 mole, of 
trans-2,3-dicarbomethoxycyclopentanone and 90.0 g, 0.602 mole, of 
.beta.,.beta.,.beta.-trichloroethanol in 700 ml of dry m-xylene was heated 
at reflux with provision for intermittent removal of solvent according to 
the following schedule, (the progress of the reaction may be conveniently 
followed by silica gel TLC utilizing benzene/methanol, (95/5), as solvent. 
______________________________________ 
Time Distillate, ml 
Head Temp., .degree.C. 
______________________________________ 
1.5 hr. 20 128 
Reflux, 48 hr. 
1.0 hr. 70 136 
Reflux, 24 hr. 
2.5 hr. 410 140 
______________________________________ 
An additional 15.0 g, 0.100 mole, of .beta.,.beta.,.beta.-trichloroethanol 
was then added and reflux was continued for forty-three hours. The brown 
mixture was then concentrated at the stripper and, while chilling in an 
ice/salt bath, was triturated with ligroin. The resulting crude solid was 
filtered, washed well with cold ligroin and recrystallized from 
methanol/water, (Norite), as colorless, felted needles, m.p. 
81.0.degree.-83.0.degree. C. The yield of titular product was 36.0 g, 
(64%). 
Anal. Calc. for C.sub.10 H.sub.11 Cl.sub.3 O.sub.5 : C, 37.82; H, 3.40; Cl, 
33.49. Found: C, 37.83; H. 3.60; Cl, 33.43. 
The 2,4-dinitrophenylhydrazone thereof was obtained as golden felted 
needles, m. pt. 103.5.degree.-105.0.degree. C. from methanol. 
Anal. Calc. for C.sub.16 H.sub.15 Cl.sub.3 N.sub.4 O.sub.8 : C, 38.41; H, 
3.04; N, 11.02. Found: C, 38.61; H. 2.94; N, 11.23. 
Concentration of the mother liquors and recrystallization of the residue 
afforded an additional 5.1 g, (9% yield), of slightly less pure product, 
m.p. 79.0.degree.-83.0.degree. C. 
EXAMPLE 3 
2-(6'-Cyano-2'-hexynyl)-2-.beta.,.beta.,.beta.-trichlorocarboethoxy-3-carbo 
methoxycyclopentanone, 4 
To a mechanically stirred suspension of 4.80 g, 0.100 mole, of a 50 percent 
mineral oil dispersion of sodium hydride in 100 ml of dry dimethoxyethane 
was added during 30 minutes a warm solution of 31.80 g, 0.100 mole, of 
trans-2-.beta.,.beta.,.beta.-trichlorocarboethoxy-3-carbomethoxycyclopenta 
none in 150 ml of dry dimethoxyethane. Stirring was continued for 1 hour 
after addition was completed, during which time hydrogen evolution ceased. 
A solution of 20.10 g, 0.100 mole, of the methane sulfonate of 
6-cyano-2-hexyne-1-ol in 20 ml of dry dimethoxyethane was added during 10 
minutes while the mixture was gradually warmed to reflux. The stirred 
mixture was heated at reflux for 24 hours, cooled, diluted with 100 ml of 
water and exhaustively extracted with ethyl acetate. The combined extracts 
were washed with 3.times.75 ml of brine and were dried over anhydrous 
magnesium sulfate. The filtered solution was concentrated in vacuo to 
afford, (after washing by decantation with 3.times.30 ml of hexane and 
removal of residual solvent at the stripper), 40.8 g, (96% yield), of oily 
product. Purification was accomplished via chromatography on 500 g of 
silica gel, using benzene/ethyl acetate, (95/5), as solvent. The pure 
titular product, (30.5 g, 72% yield), was obtained as a viscous, faint 
yellow oil, shown by H'-NMR to exist as a 1:1 mixture of 
cis-trans-isomers. 
I.R.: 2240 (w, --C.tbd.C--, and/or --CN), 1765 (vs, &gt;C.dbd.O, ketone) and 
1735 cm..sup.-1, (vs, &gt;C.dbd.O, ester). 
H'-NMR: .delta.=1.80 (m, 2H, side chain, --C--CH.sub.2 --C--), 2.83 (m, 
broad, 11H, ring, 
##STR2## 
and side chain, --CH.sub.2 C.tbd.CCH.sub.2 CCH.sub.2 CN), 3.72 (s, 3H, 
--OCH.sub.3), 4.60 and 4.70, (2 singlets, cis:trans-isomers, 2H, 
--OCH.sub.2 CCl.sub.3). 
Anal. Calcd. for C.sub.17 H.sub.18 Cl.sub.3 NO.sub.5 : C, 48.30; H, 4.29; 
N, 3.31; Cl, 25.16. Found: C, 48.42; H, 4.48; N, 3.59; Cl, 24.92. 
EXAMPLE 4 
Trans-2-(6'-cyano-2'-hexynyl)-3-carbomethoxycyclopentanone, 5 
(A) Preparation of the cis-/trans-isomers, 5 
A magnetically stirred suspension of 23.0 g of freshly activated zinc dust 
in 300 ml of 90 percent aqueous acetic acid containing 25.0 g, 0.06 mole, 
of the alkylated cyclopentanone 4 was filtered at the pump after 3.5 
hours. The residual zinc was washed with several small portions of glacial 
acetic acid and the combined filtrates were concentrated at the stripper. 
The residual oil was taken up in 125 ml of ethyl acetate, washed with 
2.times.30 ml of 5 percent aqueous sodium bicarbonate solution and with 
3.times.50 ml of brine and finally dried over anhydrous magnesium sulfate. 
Filtration and concentration at the stripper afforded 14.0 g, (95% yield), 
of pure product, shown by H'-NMR to be a 1:1 mixture of 
cis-/trans-isomers, 5. 
(B) Isomerization to the trans-isomer, 5 
The 14.0 g of product obtained in (A) above was magnetically stirred under 
anhydrous conditions with 150 ml of dry methanol containing a pea-sized 
piece of clean sodium metal for eighty-eight hours. The resulting orange 
solution was then quenched with 1.5 ml of glacial acetic acid and 
concentrated at the stripper. The resulting residual oil was taken up in 
100 ml of ethyl acetate, washed with 2.times.30 ml of 5 percent aqueous 
sodium bicarbonate solution and with 3.times.30 ml of brine and dried over 
anhydrous magnesium sulfate. Filtration and concentration at the stripper 
afforded 13.3 g, (95% yield), of pure titular product as a faint yellow 
oil, shown via H'-NMR to be .perspectiveto.95 percent trans-isomer, 5. 
EXAMPLE 5 
Trans-2-(6'-cyano-cis-2'-hexenyl)-3-carbomethoxycyclopentanone, 6 
To a magnetically stirred solution of 12.8 g, 0.052 mole, of 
trans-2-(6'-cyano-2'-hexynyl)-3-carbomethoxycyclopentanone in 150 ml of 
reagent grade pyridine was added 2.0 g of 5% palladium on barium sulfate 
and the mixture was hydrogenated at one atmosphere hydrogen pressure and 
25.degree. C. After 60 minutes, the theoretical amount of hydrogen, (1,185 
ml), was consumed, and the reaction was terminated. The catalyst was 
removed by vacuum filtration through a celite pad and washed with several 
small portions of ethyl acetate. The combined filtrates were concentrated 
at the stripper and, after cooling, the residual oil was taken up in 150 
ml of ethyl acetate and washed with 3.times.60 ml of 1-normal hydrochloric 
acid and with 3.times.75 ml of brine. Drying (MgSO.sub.4), vacuum 
filtration and concentration at the stripper afforded 12.8 g of a somewhat 
viscous, faint yellow oil. Chromatography on 150 g of silica gel using 
benzene:ethyl acetate (93/7) as eluant provided 12.1 g, (95% yield) of 
pure trans-2-(6'-cyano-2'-cis-hexenyl)-3-carbomethoxycyclopentanone as a 
colorless oil. 
I. R.: 2240 (w, --CN) and 1740 cm..sup.-1 (vs, &gt;C.dbd.O, ketone and ester). 
H'-NMR: .delta.=2.15 (m, broad, 14H, 
##STR3## 
and 
##STR4## 
3.70 (s, 3H, --OCH.sub.3) and 5.38, (m, 2H, 
##STR5## 
Anal. Calcd. for C.sub.14 H.sub.19 NO.sub.3 : C, 67.44; H, 7.68; N, 5.62. 
Found: C, 67.34; H, 7.65; N, 5.50. 
EXAMPLE 6 
Trans-2-(6'-cyano-cis-2'-hexenyl)-3-carboxycyclopentanone, 7 
A magnetically stirred mixture of 15.00 g, 0.061 mole, of 
trans-2-(6'-cyano-2'-cis-hexenyl)-3-carbomethoxycyclopentanone in 150 ml 
of 5 percent aqueous sodium carbonate solution and 25 ml of methanol was 
warmed in an oil bath at 75.degree.-80.degree. C. under a slight positive 
nitrogen pressure for 4 hours, cooled, and stirred at 25.degree. C. 
overnight. The resulting solution was washed with three 25 ml portions of 
ethyl acetate and while chilling in an ice bath was acidified with 
concentrated hydrochloric acid. The yellow oil which separated was 
extracted into three 50 ml portions of ethyl acetate and the combined 
extracts were washed with three 30 ml portions of brine and were dried 
over anhydrous magnesium sulfate. Filtration and concentration in vacuo 
afforded 12.6 g, (89 percent), of crude acid as a viscous yellow oil. This 
material may be utilized directly in the following step. 
EXAMPLE 7 
Trans-2-(6'-cyano-cis-2'-hexenyl)-3-hydroxymethylcyclopentanol, 8 
(A) Preparation of the Acid Chloride 
A magnetically stirred solution of 7.00 g 0.030 mole, of 
trans-2-(6'-cyano-cis-2'-hexenyl)-3-carboxycyclopentanone and 6.85 g, 
0.058 mole, of freshly distilled thionyl chloride in 175 ml of dry benzene 
was heated under anhydrous conditions in an oil bath at 
85.degree.-90.degree. C. for 3 hours, cooled and concentrated in vacuo. An 
additional 25 ml of dry benzene was added and again the solution was 
concentrated in vacuo. After storing at 0.1 mm for 2 hours, the 
quantitative yield of crude yellow-brown acid chloride was fully 
characterized by its IR and H'-NMR spectra and was employed immediately in 
the next step. 
(B) Preparation of the Diol, 8 
To a chilled, magnetically stirred suspension of 1.40 g, 0.037 mole, of 
sodium borohydride in 40 ml of p-dioxane and 40 ml of water was added 
during 30 minutes at 0.degree.-5.degree. C. a solution of all of the acid 
chloride obtained in (A) above, in 40 ml of p-dioxane. After addition was 
complete, 0.40 g, 0.010 mole, of sodium borohydride was added cautiously 
and the foaming mixture was stirred at 0.degree.-5.degree. C. for 1 hour, 
after which 0.20 g 0.005 mole, of sodium borohydride was added in one 
portion and stirring at 0.degree.-5.degree. C. was continued for 45 
minutes. The cooling bath was then removed and the stirred mixture was 
warmed during 15 minutes to 25.degree. C. and poured into 100 ml of brine. 
After exhaustive extraction with ethyl acetate, the combined extracts were 
washed with 75 ml of brine, with two 50 ml portions of 10 percent aqueous 
sodium bicarbonate solution and with two 50 ml portions of brine and were 
dried over anhydrous magnesium sulfate. The filtered solution was 
concentrated in vacuo to afford 6.0 g, (96% yield), of crude titular diol 
which was fully characterized by its IR and H'-NMR spectra and was 
employed directly in the next step. 
EXAMPLE 8 
Trans-2-(6'-carbomethoxy-cis-2'-hexenyl)-3-hydroxymethylcyclopentanol, 9 
A magnetically stirred suspension of 4.00 g, 0.018 mole, of 
trans-2-(6'-cyano-cis-2'-hexenyl)-3-hydroxymethylcyclopentanol in a 
solution of 7.00 g, 0.124 mole, of potassium hydroxide in 50 ml of water 
and 5 ml of methanol was heated at reflux for 1 hour, during which time 
the substrate dissolved. After cooling and backwashing with three 25 ml 
portions of ether the yellow basic solution was treated with decolorizing 
carbon, chilled, and acidified with concentrated hydrochloric acid and 
extracted into three 25 ml portions of ethyl acetate. The combined 
extracts were washed with two 25 ml portions of brine, dried over 
anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 
4.00 g, (93% yield), of crude acid product as a viscous, colorless oil. 
A magnetically stirred solution of 3.10 g, 0.013 mole, of the crude acid in 
20 ml of ether and 5 ml of methanol was treated with a slight excess of 
ethereal diazomethane to a persistent faint yellow color and stirred at 
25.degree. C. for 1 hour. The excess diazomethane was quenched by the 
dropwise addition of glacial acetic acid, and the resulting solution was 
diluted with 25 ml of ether, washed with two 15 ml portions of 5 percent 
aqueous sodium bicarbonate solution, and with two 10 ml portions of brine 
and dried over anhydrous magnesium sulfate. The filtered solution was 
concentrated in vacuo to afford 3.15 g, (96% yield), of the titular 
carbomethoxy diol as a viscous colorless oil which on the basis of its 
spectroscopic and silica gel TLC characterization, was employed directly 
in the final step. 
EXAMPLE 9 
Trans-2-(6'-carbomethoxy-cis-2'-hexenyl)-3-formylcyclopentanone, 10 
To a mechanically stirred, chilled solution of 9.84 g, 0.12440 mole of 
anhydrous pyridine in 150 ml of dry methylene chloride was added in 
several portions during 15 seconds 6.320 g, 0.06220 mole, of anhydrous 
chromium trioxide. The cooling bath was removed and the resulting deep 
burgundy solution was stirred under dry nitrogen for 15 minutes. A 
solution of 1.328 g, 0.00518 mole of 
trans-2-(6'-carbomethoxy-cis-2'-hexenyl)-3-hydroxy-methylcyclopentanol in 
3 ml of dry methylene chloride was added in one portion, washed in with an 
additional 1 l of solvent and the resulting black tarry mixture was 
stirred at 25.degree. C. for 20 minutes. The dark solution was decanted 
from the residue, which was washed with two 100 ml portions of ether and 
the combined organic phases were washed with three 100 ml portions of 5 
percent aqueous sodium hydroxide, with 100 ml of 5 percent aqueous 
hydrochloric acid, with 100 ml of 5 percent aqueous sodium bicarbonate 
and finally with two 100 ml portions of brine. After drying with anhydrous 
magnesium sulfate, the filtered solution was concentrated in vacuo to 
afford 1.240 g of crude product which was chromatographed on 20.0 g of 
silica gel using benzene/acetone, (98/2) as eluent. The titular product 
keto-aldehyde, 1.195 g, (92% yield), was obtained as a colorless, mobile 
oil which was pure by TLC and by IR, H'-NMR and mass spectrometry and 
which may be employed directly in subsequent work in known ways to prepare 
11-deoxyprostaglandins.