Alkenylzirconium reagents useful for prostaglandin analog synthesis

Alkenylzirconium reagents of the general structural formula IX, ##STR1## are useful in the syntheses of prostaglandin analogs. In the preceding structural formula J is bromo or chloro, R.sub.1 is hydrogen, methyl, ethyl, vinyl, 1-propenyl, or cyclopropyl, R.sub.4 is alkyl of 2-7 carbon atoms, and R.sub.3 is a protecting group such as tetrahydropyranyl, 1-ethoxyethyl, or C.sub.1 -C.sub.4 -trialkylsilyl.

BACKGROUND OF THE INVENTION 
The prostaglandins are currently of great interest because of the broad 
physiological responses which they elicit in animals, including man. 
Development of the potential application of both natural and synthetic 
prostaglandins relies upon efficient chemical synthetic methods being 
available. See, Mitra, "The Synthesis of Prostaglandins", Wiley, N.Y. 
1977. 
Processes for preparing prostaglandins and their analogs via conjugate 
addition of an alkenyl moiety to the unsaturated ketone functionality of a 
substituted cyclopentenone have been described in U.S. Pat. Nos. 
3,965,143, 3,950,406 and 4,233,231, and Tet. Letters, 2063 (1977); 
Prostaglandins, 10,733 (1975) and J. Amer. Chem. Soc., 97, 857 (1975). 
Such reactions usually involve the use of alkenyl lithium compounds as 
intermediates in the formation of alkenylcuprates, the latter being 
capable of the desired conjugate addition reaction. Extensive research has 
been done aimed at developing species which could duplicate beneficial 
aspects of cuprate chemistry while not relying on lithium reagent 
precursors. Implementation of lithium-based cuprate processes is often 
hampered by the tedious preparation of these organolithium precursors. In 
the special case of alkenylcuprates, important to the synthesis of various 
natural products, it is necessary to generate and maintain 
stereochemically pure alkenyl species. Alkenyllithium reagents used to 
prepare the corresponding cuprates are obtained by metal-halogen exchange 
with the corresponding alkenylhalide or by reaction of these organic 
halides with lithium metal. Although the conversion of alkenylhalides to 
alkenyllithium reagents occurs predominantly with retention of 
configuration, some loss of double-bond stereochemistry can occur. Lastly, 
alkenylcuprate species are generally utilized at low temperatures since 
they are thermally unstable. 
The possibility of activating organozirconium species toward conjugate 
addition using a second metallic species catalytically, and the use of the 
activated species for the synthesis of 15-hydroxy prostaglandin analogs 
were realized by J. Schwartz, et al., J. Amer. Chem. Soc. 102 1333 (1980). 
However, the prior art does not disclose an organozirconium species useful 
in a conjugate addition reaction directed to the preparation of 
15-deoxy-16-hydroxy-16-substituted prostaglandins. 
DETAILED DESCRIPTION OF THE INVENTION 
Alkenylzirconium reagents of the formula IX: 
##STR2## 
where J is bromo or chloro, R.sub.1 is hydrogen, methyl, ethyl, vinyl, 
1-propenyl or cyclopropyl; R.sub.4 is alkyl of 2-7 carbon atoms, and 
R.sub.3 is a hydroxyl-protecting group such as tetrahydropyranyl (THP), 
1-ethoxyethyl, or C.sub.1 -C.sub.4 trialkylsilyl; are useful as key 
intermediates in a conjugate addition process with racemic or optically 
active 2-cyclopenten-1-ones of the general formula IV: 
##STR3## 
where R is CO.sub.2 R.sub.8 wherein R.sub.8 is C.sub.1 -C.sub.6 alkyl or a 
protecting group such as tetrahydropyranyl, 1-ethoxyethyl, or C.sub.1 
-C.sub.4 -trialkylsilyl; or is a protected hydroxymethylcarbonyl moiety 
such as: 
##STR4## 
where R.sub.9 is trimethylsilyl or triethylsilyl, and R.sub.10 is methyl 
or ethyl; Z is --(CH.sub.2)n-- or 
##STR5## 
where n is 5-7 (preferably 6) and p is 2-4 (preferably 3); and R.sub.5 is 
hydrogen, tetrahydropyranyloxy, 1-ethoxyethoxy, C.sub.1 -C.sub.4 
-trialkylsiloxy or OC(R.sub.10).sub.2 OCH.sub.3 where R.sub.10 is methyl 
or ethyl. The conjugate addition reaction, followed by removal of the 
protecting groups by exposure of the crude reaction mixture to dilute 
aqueous acid affords pharmaceutically useful racemic or optically-active 
analogs of the general formula X: 
##STR6## 
where R.sub.6 is --CH.sub.2 OH, hydroxy, or alkoxy of one to six carbon 
atoms; R.sub.7 is H or hydroxy, Y is --OCH.sub.2 CH.sub.2 O-- or O, and Z, 
R.sub.1 and R.sub.4 are as hereinabove defined. 
Formula X is represented as having the R configuration at C.sub.11 and the 
RS configuration at C.sub.16. Optically-pure prostaglandins of the type X 
of the 11R, 16S or 11R, 16R configuration are obtained by employing 
optically-pure cyclopentenones of structure IV-R: 
##STR7## 
where Z and R are as described hereinabove, which are protected and 
reacted with racemic alkenylzirconium reagents of type IX in the conjugate 
addition reaction. In such a reaction it is believed that the lower side 
chain enters in an orientation trans to the C.sub.11 -hydroxy and trans to 
the .alpha.-side chain of the cyclopentenone ring. Deprotection of the 
crude reaction mixture yields mixtures consisting of prostaglandin analogs 
of the general formulae: 
##STR8## 
where R.sub.6, Y, Z, R.sub.1 and R.sub.4 are as hereinabove described and 
which may be separated by careful chromatographic techniques. If 
optically-pure cyclopentenones of the structure IV-S: 
##STR9## 
where Z and R are as hereinabove described, are protected and employed in 
the conjugate addition reaction, deprotection of the crude reaction 
mixture yields mixtures of optically-pure prostaglandin analogs of the 
general formulae: 
##STR10## 
where R.sub.6, Y, Z, R.sub.1 and R.sub.4 are as hereinabove described, and 
which may generally be separated by chromatography. 
Racemic 4-hydroxy-1-alkynes may be resolved into optically-pure 4R- and 
4S-hydroxy-1-alkynes by the general procedures of Examples 140-142 of U.S. 
Pat. No. 4,254,285, which is incorporated herein by reference. When an 
optically-pure 4-hydroxy-1-alkyne is protected and used to form the 
corresponding alkenylzirconium reagent which is in turn reacted with a 
cyclopentenone of type IV-S or IV-R, only one optically-pure prostaglandin 
analog is obtained, depending upon the particular 
alkenylzirconium-cyclopentenone pair chosen. For example, reaction of IV-R 
with the optically-pure zirconium reagent formed from protected 
4-methyl-4S-hydroxy-1-octyne provides only optically-pure X-S wherein 
R.sub.1 is methyl and R.sub.4 is n-butyl after deprotection and optional 
chromatography. 
If racemic cyclopentenones of the general formula IV-RS 
##STR11## 
where Z and R are as above described are protected and employed in the 
conjugate addition reaction with optically-pure alkenylzirconium reagents 
prepared as described above, deprotection of the crude reaction mixture 
yields prostaglandin analog pairs having either the 16R- or 16S- 
configuration in conjunction with a racemic center at C-11. For example, 
reaction of the optically-pure zirconium reagent formed from 
4-methyl-4S-hydroxy-1-octyne with protected IV-RS, followed by 
deprotection of the crude reaction mixture affords optically-pure 
prostaglandin analogs of the general formulae: 
##STR12## 
where Z, R.sub.6 and Y are as hereinabove defined, R.sub.1 is methyl and 
R.sub.4 is n-butyl, which may be separated by careful chromatography. 
Thus, a pure analog incorporating any of the four possible combination of 
stereochemical configuration at C.sub.11 and C.sub.16 may be obtained by 
the appropriate combination of alkenylzirconium reagents of the type IX 
with protected cyclopentenones of type IV. Procedures for formation of 4S- 
and 4R-cyclopentenones of type IV are described in U.S. Pat. Nos. 
4,254,285 and 4,061,670 which are incorporated herein by reference. If 
protected cyclopentenones of general formula IV-RS are employed in the 
conjugate addition reaction with racemic IX, a mixture of the racemic 
analog pairs dl-X-S and dl-ent-X-S is formed. 
If cyclopentenones of type IV, wherein R.sub.5 is H and Z and R are as 
hereinabove defined, are employed in the conjugate addition reaction with 
racemic IX, a mixture of two chromatographically separable, racemic pairs 
of prostaglandin analogs of formulae X-nat. and X-ent. type is obtained 
wherein R.sub.6, Y, R, and R.sub.4 are as hereinabove described, in which 
the 16-hydroxy substituent is of the RS configuration in each: 
##STR13## 
If optically-pure alkenylzirconium reagents are formed as described above 
and employed in the conjugate addition reaction, a mixture of two 
separable, optically-pure analogs of the type X-nat. and X-ent. is 
obtained both havng either the 16R- or 16S- configuration at C-16. 
Flowchart A outlines a preferred procedure for preparing protected 
cyclopentenone compounds of structure IV, where Z and R.sub.10 are as 
hereinabove defined. 
##STR14## 
For example, treatment of cyclopentenone I, wherein Z is --(CH.sub.2).sub.6 
-- with a large excess of 2,2-dimethoxypropane (II wherein R.sub.10 is 
methyl) and a catalytic amount of para-toluene-sulfonic acid (TsOH) 
produces hemiketal IIIa where Z is --(CH.sub.2).sub.6 -- and R.sub.10 is 
methyl. IIIa may be used in the conjugate addition reaction with 
alkenylzirconium reagents of type IX, or alternatively, may be rearranged 
to dioxolane IVa having Z and R.sub.10 as defined above by treatment with 
4A molecular sieves. 
##STR15## 
Intermediate IIIa wherein R.sub.10 =methyl and Z=--(CH.sub.2).sub.6 is 
disclosed by U.S. Patent No. 4,254,485, which is incorporated herein by 
reference. 
The final composition of the product as determined by .sup.13 C nuclear 
magnetic resonance spectroscopy ("NMR") was 20% IIIa and 80% IVa. Pure IVa 
can be isolated by column chromatography using anhydrous solvents and 
activated silica gel. Pure IVa was found to be stable for several months 
when stored at 0.degree. C. in an airtight container. In solution at 
25.degree. C., a slow, nonhydrolytic decomposition takes place. 
3,3-diethoxypentane has been substituted for 2,2-dimethoxypropane in the 
above reaction sequence, affording compound IVb, wherein R.sub.10 is ethyl 
and Z is 
##STR16## 
Other preferred cyclopentenone compounds of the type IV which may be 
employed include those depicted in Table I below. Each of the publications 
and U.S. patents listed under the caption "Ref." in Table I below is 
incorporated herein by reference. 
TABLE I 
__________________________________________________________________________ 
Cyclopentenone Intermediates of Type IV 
Compound Number 
Ref. 
__________________________________________________________________________ 
##STR17## IVc J. Amer. Chem. Soc. 95 1676 
(1973) 
##STR18## IVd Tet. Let. 2312 (1973) 
##STR19## IVe Tet. Let. 2435 (1972) 
##STR20## IVf J. Org. Chem. 38 3413 (1973) 
##STR21## IVg U.S. Pat. No. 4,254,285 
##STR22## IVh U.S. Pat. No. 4,254,285 
##STR23## IIIb U.S. Pat. No. 4,254,285 
##STR24## IIIa U.S. Pat. No. 4,254,485 
__________________________________________________________________________ 
Flowchart B outlines the preparation of the preferred 
dicyclopentadienylzirconium chloride (VIII), and its reaction with a 
protected alkynol of type VI wherein R.sub.1, R.sub.3, and R.sub.4 are as 
hereinabove defined. 
##STR25## 
Dicyclopentadienyl zirconium chlorohydride VIII, the hydrozirconation 
reagent, is available commercially, but is expensive and hard to handle, 
since it is light and air-moisture sensitive. It has been found more 
satisfactory to generate the reagent in situ by the reduction of 
dicyclopentadienyl zirconium dichloride (VII) to zirconium chlorohydride 
VIII. The reduction is preferably accomplished by dissolving VII in 
tetrahydrofuran (THF) and adding an equivalent of Vitride.RTM. reducing 
agent, bis-(2-methoxyethoxy) aluminum hydride (70% solution in toluene), 
under an inert atmosphere. The resulting precipitate of VIII is washed and 
solvents removed by vacuum filtration under argon pressure. The solid VIII 
(71-78% yield) is resuspended in THF and a protected alkynol VI, wherein 
R.sub.1, R.sub.3 and R.sub.4 are as hereinabove defined, is added to the 
stirred suspension at 20.degree.-30.degree. C. The reaction is complete 
after 20-30 minutes and the resultant solution of IX, where R.sub.1, 
R.sub.3 and R.sub.4 are as hereinabove defined, is filtered into another 
reaction vessel under argon. The following summarizes the .sup.13 C-NMR 
spectrum of a preferred embodiment of reagent IX, IXa, obtained in 
benzene-d.sub.6. (Carbon-13 Chemical shifts [ppm from tetramethyl-silane] 
for the Zirconium Alkenyl Reagent IXa in Benzene-d.sub.6): 
##STR26## 
Due to moisture-sensitivity of the reagent, it is best prepared just prior 
to use. 
The alkenylzirconium reagents of type IX wherein R.sub.1, R.sub.3 and 
R.sub.4 are as hereinabove defined are reacted with 2-cyclopenten-1-ones 
of type IV wherein R.sub.5 is H (branch A) or protected hydroxy (branch 
B), and Z and R are as hereinabove defined, in the presence of a catalytic 
amount of a reduced nickel catalyst. The crude products are treated with 
dilute aqueous acid to yield prostaglandin analog mixtures of type X, 
wherein R.sub.1, R.sub.4, R.sub.6, Y and Z are as above defined. These 
reactions are outlined in Flowchart C. Chromatography of X mixtures as 
described above allows isolation of pure isomer pairs X-R and X-S, X-ent. 
and X-nat. 
##STR27## 
Table II summarizes preferred embodiments of the conjugate addition 
reaction, showing the results of a number of reactions between IXa and 
racemic IVa in the presence of reduced nickel catalyst, followed by 
deprotetction of crude adduct to yield racemic analog Xa. 
TABLE II 
__________________________________________________________________________ 
##STR28## 
##STR29## 
Deprotection with 
3:1:1 HOAc:H.sub.2 O:THF Purity (% Real Xa) 
Reaction 
ml/ Neutralization 
% Yield of Real Xa 
of 
Protecting Groups 
Temp. 
Time 
mmols 
NaHCO.sub.3 
NH.sub.4 OH 
Crude 
Hexane 
Chromato- 
Hexane 
Chromato- 
Reaction 
R in IXa 
R.sub.10 in IVa 
(.degree.C.) 
(hrs.) 
(scale) 
(equiv.) 
(equiv.) 
Product 
Insol's 
graphed 
Insol's 
graphed 
__________________________________________________________________________ 
A Et.sub.3 Si 
Me 8 19 7.8 lrg. -- -- 60.7 
57.5 73.0 
96.5 
excess 
B Me.sub.3 Si 
Me 8 17 4.0 -- 1 -- 37.3 
-- 41.0 
-- 
C Et.sub.3 Si 
Me 8 16 5.9 1 -- -- 62.5 
-- 72.6 
-- 
-- 58.2 
-- 69.8 
-- 
D Et.sub.3 Si 
Et 8 18 5.8 -- 1 -- 48.8 
-- 57.3 
-- 
E Et.sub.3 Si 
Et 8 19 6.0 -- 1 40.4 44.8 
-- 54.7 
-- 
F Et.sub.3 Si 
Et 8 17 6.6 -- 1 44.4 -- -- -- -- 
G Et.sub.3 Si 
Et 8 20 6.0 -- 1 34.5 27.9 
-- 36.7 
-- 
H Et.sub.3 Si 
Me 8 18 6.5 -- 1 49.9 49.9 
36.0 64.7 
106.8 
__________________________________________________________________________ 
The conjugate addition reaction is carried out by combining a mixture of IX 
with IV in an ethereal solvent, preferably THF, with a freshly prepared 
solution of pre-reduced nickel catalyst with ice bath cooling. The reduced 
nickel catalyst is prepared as described in J. Schwartz, et al., J. Amer. 
Chem. Soc. 102 1333 (1980) which is incorporated herein by reference. When 
the combination is complete, the selected reaction temperature is 
established and the reaction is held at that temperature for the desired 
length of time. The reaction is terminated by the addition of an aqueous 
solution of ammonium chloride. The crude products are isolated by 
extraction and, to remove the protecting groups, are treated with a 
deprotection medium consisting of dilute aqueous acid, preferably acetic 
acid, THF and water. The deprotected crude X is prepurified by treatment 
with hexane. Final purification and optional separation of analog pairs 
are accomplished by chromatography on silica gel or silicic 
acid-Celite.RTM.. 
In the following examples all glass apparatus used is dried at 140.degree. 
C. for at least two hours, and then permitted to cool to 25.degree. C. 
under argon prior to use. Solvents (tetrahydrofuran [THF], methylene 
chloride, hexane, ethyl acetate) are dried by adding a 30 ml bulk volume 
of activated 4A molecular sieves to each 1-pint bottle which is then 
provided with an argon atmosphere and sealed with a rubber septum. The 
bottles are allowed to stand for 3-4 days before use of the solvents. 
Intermediates are identified by .sup.13 C-nuclear magnetic resonance 
("NMR") spectroscopy. Assays of final product mixtures for their content 
of analog X are carried out by high pressure liquid chromatography 
techniques (HPLC) and based on quantification by comparison with standard 
samples. A 4.6.times.25 mm ZORBAX ODS (duPont) column is used in a 
Spectra-Physics Model 350B liquid chromatograph, eluting with 
methanol-acetonitrile-water in a ratio of 3:3:4 (v/v). Preparative HPLC is 
carried out using a Water's Associates Prep. LC/System 500 chromatograph 
equipped with Prep Pak 500/Silica columns, and eluting with 
ethyl-acetate-hexane-ethanol in a ratio of 160:40:3 (v/v). 
Chromatographic silica gel or silicic acid is dehydrated by heating to 
170.degree.-180.degree. for a minimum of 24 hours. 
Nickel acetylacetonate hydrate (Aldrich Chemical Co.) is dehydrated by 
heating in vacuo for 18 hours at 90.degree.-95.degree. C. The dehydrated 
solid is dissolved in a quantity of anhydrous ethyl ether, then stirred 
for 1 hr. with anhydrous magnesium sulfate, then filtered. The ether is 
evaporated in vacuo to afford anhydrous nickel acetylacetonate as a green 
solid.

The invention will be described with reference to the following detailed 
examples. 
EXAMPLE 1 
Preparation of 4-methyl-4-triethylsilyloxy-1-octyne(Vla, R.sub.1 =methyl, 
R.sub.3 =triethylsilyl, R.sub.4 =n-butyl). 
A solution of 175.8 g of 4-hydroxy-4-methyl-1-octyne (U.S. Pat. No. 
4,233,231 ), 112.1 g of imidazole and 625 ml of dry dimethylformamide 
(DMF) was stirred under dry nitrogen and 207.9 g of triethylchlorosilane 
added. The resulting homogenous solution was stirred at 
50.degree.-55.degree. for 19 hours, then cooled to 25.degree. C. and 
partitioned between hexane and water. The hexane layer was washed three 
times with water, then dried over anhydrous magnesium sulfate 
(MgSO.sub.4), and hexane evaporated in vacuo. The concentrate was 
distilled to yield 94.7% of the title compound as a colorless liquid, bp 
60.degree.-61.degree. C. (0.20 mm Hg). 
EXAMPLES 2-6 
The 4-hydroxy-1-alkynes of Table III which are disclosed in U.S. Pat. No. 
4,254,285 are converted into the 4-protected-1-alkynes of the table by the 
procedure of Example 1. 
TABLE III 
______________________________________ 
Ex. 4-hydroxy-1-alkyne 
4-Protected-1-alkyne 
______________________________________ 
2 5,5-dimethyl-4-hydroxy- 
5,5-dimethyl-4-triethylsiloxy- 
1-octyne 1-octyne 
3 4-cyclopropyl-4-hydroxy- 
4-cyclopropyl-4-triethylsiloxy- 
1-octyne 1-octyne 
4 4-(1-propenyl)-4-hydroxy- 
4-(1-propenyl)-4-triethylsiloxy- 
1-octyne 1-octyne 
5 4-vinyl-4-hydroxy-1-octyne 
4-vinyl-4-triethylsiloxy- 
1-octyne 
6 4-ethyl-4-hydroxy-1-octyne 
4-ethyl-4-triethylsiloxy- 
1-octyne 
______________________________________ 
EXAMPLE 7 
Preparation of 
1-(2,2-Dimethyl-4-methoxy-1,3-dioxolan-4-yl)-7-[3R-(1-methoxy-1-methyletho 
xy)-5-oxocyclopent-1-en-yl]-hexane IVa. 
In a 1000 ml reaction flask equipped with a mechanically driven stirrer and 
in which an atmosphere of dry argon was maintained were combined 24.0 of I 
(Z=--(CH.sub.2).sub.6 --) (U.S. Pat. No. 4,254,485) and 350 ml of 
2,2-dimethoxypropane (II, R.sub.10 =methyl). To the resultant stirred 
suspension was added 475 mg of p-toluene-sulfonic acid (TsOH), and the 
yellow solution stirred for 90 min. at 25.degree. C. A bulk volume of 135 
ml of activated 4A molecular sieves was introduced and stirring continued 
for 5 hours. Anhydrous potassium carbonate (300 mg) was added and stirring 
continued for 50 minutes. The reaction mixture was filtered under argon 
pressure. The residue of molecular sieves was washed 2-3 times with 50-70 
ml of 2,2-dimethoxypropane and the filtered wash solutions combined with 
the original filtrate. Evaporation of solvents yielded 34-36 g of a 4-1 
mixture of IVa and IIIa (R.sub.10 =methyl, Z=--(CH.sub. 2).sub.6 --) 
(90-95% yield). Chromatography on silica gel with ethyl acetate-hexane 
mixtures yielded pure title compound in 55-65% yield, pure by C.sup.13 
-NMR. 
EXAMPLE 8 
Preparation of 
1-(2,2-Diethyl-4-methoxy-1,3-dioxolan-4-yl)-7-[3R-(1-methoxy-1-ethylpropox 
y)-5-oxo-1-cyclopent-1-enyl]hexane IVb. 
Repeating in a similar manner the procedure of Example 2 above, but 
replacing 2,2-dimethoxypropane with 3,3-diethoxypentane yields the title 
compound IVb. 
EXAMPLES 9-14 
The cyclopentenones of the table which are disclosed in U.S. Pat. No. 
4,254,285, are converted into the protected cyclopentenones of the table 
by the procedures of Examples 7 or 8. 
TABLE IV 
__________________________________________________________________________ 
Protected Cyclopentenones 
Procedure 
Protected 
Ex. 
Cyclopentenones 
of Example 
Cyclopentenone 
__________________________________________________________________________ 
9 1-hydroxy-8-(5-oxocyclo- 
7 1-(2,2-dimethyl-4- 
penten-1-yl)octan-2-one 
methoxy-1,3-dioxolan- 
4-yl)-6-(5-oxocyclo- 
pent-1-enyl)hexane 
10 1-hydroxy-8-(5-oxocyclo- 
8 1-(2,2-diethyl-4-methoxy- 
penten-1-yl)octan-2-one 
1,3-dioxolan-4-yl)-6-(5- 
oxocyclopent-1-enyl)hexane 
11 1-hydroxy-8-(5-oxocyclo- 
7 1-(2,2-dimethyl-4-methoxy- 
penten-1-yl)oct-6-cis-en- 
1,3-dioxolan-4-yl)-6- 
2-one (5-oxocyclopent-1-enyl) 
hex-4-cis-ene. 
12 1-hydroxy-8-(5-oxocyclo- 
8 1-(2,2-diethyl-4-methoxy- 
penten-1-yl)oct-6-cis-en- 
1,3-dioxolan-4-yl)-6- 
2-one (5-oxocyclopen-1-enyl)- 
hex-4-cis-ene. 
13 1-hydroxy-8-(3R--hydroxy- 
7 1-(2,2-dimethyl-4-methoxy- 
5-oxo-cyclopenten-1-yl)- 
1,3-dioxolan-4-yl)-6-[3R-- 
oct-6-cis-en-2-one (1-methoxy-1-methylethoxy)- 
5-oxocyclopent-1-enyl]- 
hex-4-cis-ene. 
14 1-hydroxy-8-(3R--hydroxy-5- 
8 1-(2,2-diethyl-4-methoxy-1, 
oxo-cyclopenten-1-yl)oct- 
3-dioxolan-4-yl)-6-[3R--(1- 
6-cis-en-2-one methoxy-1-ethylpropoxy)-5-oxo- 
1-cyclopent-1-enyl]hex-4- 
cis-ene 
__________________________________________________________________________ 
EXAMPLE 15 
Preparation of chloro-bis(.eta..sup.5 
-2,4-cyclopentadien-1-yl)-(4-methyl-4-triethylsiloxy-1-trans-octenyl)zirco 
nium(IXa, R.sub.1 =methyl, R.sub.3 =triethylsilyl, R.sub.4 -n-butyl). 
A 2 1, round-bottomed reaction flask fitted with a fritted-glass filter was 
charged with 63.1 g of dichlorobis-(.eta..sup.5 
-2,4-cyclopentadien-1-yl)zirconium (Alfa-Ventron) under argon, followed by 
addition of 650 ml of dry tetrahydrofuran (THF). To the resulting solution 
was added slowly via syringe 30.2 ml of 3.58 M bis(2-methoxy-ethoxy) 
aluminum hydride in toluene (Vitride.RTM. reducing agent) (Realco), with 
external cooling as necessary to maintain a reaction temperature of 
25.degree. C. The resulting suspension of VIII was stirred an additional 
30 min., filtered, and the white residue washed three times with 215 ml of 
dry THF. The washed residue, VIII, was resuspended in 650 ml of dry THF in 
the original flask. Into the stirred suspension was injected 45.3g of 
4-methyl-4-triethylsiloxy-1-octyne VIa. The reaction mixture was stirred 
for 30 min. at 25.degree. C. to complete the formation of a solution of 
the title compound which was used as described in Example 27. 
EXAMPLES 16-21 
The 4-protected-1-alkynes of the table which are disclosed in U.S. Pat. No. 
4,254,385 and those of Table III are converted into the alkenylzirconium 
reagents of the table by the procedure described in Example 15. 
TABLE V 
______________________________________ 
Zirconium Reagents 
Protected 4- Chloro-bis(.eta..sup.5 -2,4-cyclopenta- 
Hydroxy- dienyl)-(4-protected- 
Ex. 1-Alkyne (IV) 
1-trans-alkenyl)-zirconium (IX) 
______________________________________ 
16 5,5-dimethyl-4-tri- 
chloro-bis(.eta..sup.5 -2,4-cyclopentadien- 
methylsiloxy-1- 
1-yl)-(5,5-dimethyl-4-trimethyl- 
octyne siloxy-1-trans-octenyl)zirconium 
17 4-methyl-4-tri- 
chloro-bis(.eta..sup.5 -2,4-cyclopentadien- 
methylsiloxy-1- 
1-yl)-(4-methyl-4-trimethylsiloxy- 
octyne 1-trans-octenyl)zirconium 
18 4-cyclopropyl-4- 
chloro-bis(.eta..sup.5 -2,4-cyclopentadien- 
trimethylsiloxy-1- 
1-yl)-(4-cyclopropyl-4-trimethyl- 
octyne siloxy-1-trans-octenyl)zirconium 
19 4-(1-propenyl)-4- 
chloro-bis(.eta..sup.5 -2,4-cyclopentadien-1- 
trimethylsiloxy-1- 
yl)-[4-(1-propenyl)-4-trimethyl- 
octyne siloxy-1-trans-octenyl]zirconium 
20 4-vinyl-4-trimeth- 
chloro-bis(.eta..sup.5 -2,4-cyclopentadien- 
ylsiloxy-1-octyne 
1-yl)-(4-vinyl-4-trimethylsiloxy-1- 
trans-octenyl)zirconium 
21 4-ethyl-4-trimeth- 
chloro-bis(.eta..sup.5 -cyclopentadien-1-yl)- 
ylsiloxy-1-octyne 
(4-ethyl-4-trimethylsiloxy-1- 
trans-octenyl)zirconium 
22 Ex. 2 chloro-bis(.eta..sup.5 -2,4-cyclopentadien-1- 
yl)-(5,5-dimethyl-4-triethylsiloxy- 
1-trans-octenyl)zirconium 
23 Ex. 3 chloro-bis(.eta..sup.5 -2,4-cyclopentadien-1- 
yl)-(4-cyclopropyl-4-triethylsiloxy- 
1-trans-octenyl)zirconium 
24 Ex. 4 chloro-bis(.eta..sup.5 -2,4-cyclopentadien-1-yl)- 
[4-(1-propenyl)-4-triethylsiloxy-1- 
trans-octenyl]zirconium 
25 Ex. 5 chloro-bis(.eta..sup.5 -2,4-cyclopentadien-1-yl)- 
(4-vinyl-4-triethylsiloxy-1-trans- 
octenyl)zirconium 
26 Ex. 6 chloro-bis(.eta..sup.5 -2,4-cyclopentadien-1-yl)- 
(4-ethyl-4-triethylsiloxy-1-trans- 
octenyl)zirconium 
______________________________________ 
EXAMPLE 27 
Preparation of 1-hydroxymethyl-1,9-dioxo-11R, 
16S-dihydroxy-16-methylprost-13-trans-ene(Xa-S) and 
1-hydroxymethyl-1,9-dioxo-11R, 
16-dihydroxy-16-methylprost-13-trans-ene(Xa-R). 
A solution of 5.5 g of anhydrous nickel acetylacetonate in 650 ml of dry 
THF was stirred under argon, cooled to 0.degree. C. and 21.6 ml of 1 M 
diisobutylaluminum hydride in hexane (Aldrich Chemical Co). injected. 
A solution of chloro-bis(.eta..sup.5 
-2,4-cyclopentadien-1-yl)-(4-methyl-4-triethylsiloxy-1-trans-octenyl)zirco 
nium, IXa, R.sub.1 =methyl, R.sub.3 =triethylsilyl, R.sub.4 -n-butyl, 
freshly prepared as described in Example 15, was combined with 41.5 g of 
1-(2,2-diethyl-4-methoxy-1,3-dioxolan-4-yl)-6-[3RS-(1-methoxy-1-ethylpropo 
xy)-5-oxo-cyclopenten-1-yl]hexane IVb-RS in 430 ml of dry THF. This 
solution was cooled to 0.degree. C. and added to the stirred solution of 
prereduced nickel catalyst over 35 min. The reaction flask was cooled to 
8.degree. C. with external cooling and the mixture stirred under argon for 
18 hours. Saturated aqueous ammonium chloride (1750 ml) was added and the 
reaction mixture stirred 50 minutes. The organic phase was added to 3.7 1 
of stirred hexane. The mixture was filtered, the filtrate dried over 
anhydrous magnesium sulfate, then filtered and evaporated to yield 83.5 g 
of an oil. 
The oil was stirred with a mixture of 420 ml glacial acetic acid, 140 ml of 
THF and 140 ml of water for 5.0 hours at 25.degree. C. The reaction 
mixture was cooled in an ice bath and one liter of ethyl ether was added, 
followed by 407 g of 29.9% aqueous ammonia (NH.sub.4 OH) in 648 ml of 
water. The ether layer was isolated and dried over anhydrous magnesium 
sulfate with added sodium bicarbonate (NaHCO.sub.3). The ether solution 
was filtered and evaporated in vacuo to yield 68.0 g of a crude mixture of 
the title compounds as a viscous oil (162%, 30.3% pure by HPLC assay). 
A solution of 67.8 g of crude product in 100 ml of methyl ethyl ketone was 
added to 15.0 l of stirred hexane. The mixture was stirred for 1 hour. The 
hexane was removed by siphoning and the coalesced, viscous residue 
dissolved in 500 ml of methylene chloride. The solution was dried over 
anhydrous magnesium sulfate, filtered, and methylene chloride removed in 
vacuo to yield 76% of the title compounds (64.7% pure by HPLC assay). 
Further purification of the crude product was achieved by preparative 
HPLC. A solution of 31.6 g of crude product in 150 ml ethyl acetate was 
chromatographed in three runs to yield 13.8 g of a mixture of the pure 
racemic title compounds as a pale yellow oil which was identified by HPLC 
assay against a known sample and by spectral analysis. Use of 3R-IVb and 
application of further chromatography can be employed to isolate 
approximately equal portions of Xa-S and Xa-R. 
EXAMPLES 28-60 
The protected cyclopentenones Table I or Table IV are reacted with the 
alkenylzirconium reagents of Table V to yield the prostaglandin analogs 
(substituted prostanes) of the table by the procedures of Example 27. 
TABLE VI 
______________________________________ 
Prostaglandin Analogs 
Protected 
Alkenyl- 
Cyclo- zirconium 
pente- Reagent 
Ex. none of Example 
Prostaglandin analogs 
______________________________________ 
28 Ex. 9 or 15 or 17 nat-1-hydroxymethyl-1, 
Ex. 10 9-dioxo-16RS--hydroxy-16- 
methylprost-13-trans-ene 
and ent-1-hydroxymethyl-1, 
9-dioxo-16RS--hydroxy-16- 
methylprost-13-trans-ene 
29 Ex. 9 or 18 or 23 nat-1-hydroxymethyl-1, 
Ex. 10 9-dioxo-16RS--hydroxy- 
16-cyclopropylprost-13- 
trans-ene and ent-1-hydroxy- 
methyl-1,9-dioxo-16-RS-- 
hydroxy-16-cyclopropylprost- 
13-trans-ene 
30 Ex. 9 or 20 or 25 nat-1-hydroxymethyl-1, 
Ex. 10 9-dioxo-16RS--hydroxy- 
16-vinylprost-13-trans-ene 
and ent-1-hydroxymethyl-1, 
9-dioxo-16RS--hydroxy-16- 
cyclopropylprost-13-trans-ene 
31 Ex. 11 or 
15 or 17 nat-1-hydroxymethyl-1, 
12 9-dioxo-16RS--hydroxy-16- 
methylprosta-5-cis-13-trans- 
diene and ent-1-hydroxymethyl- 
1,9-dioxo-16RS--hydroxy-16- 
methylprosta-5-cis-13-trans- 
diene 
32 Ex. 11 or 
18 or 23 nat-1-hydroxymethyl-1, 
12 9-dioxo-16RS--hydroxy-16- 
cyclopropylprosta-5-cis- 
13-trans-diene and ent-1- 
hydroxymethyl-1,9-dioxo- 
16RS-- hydroxy-16-cyclopropyl 
prosta-5-cis,13-trans-diene 
33 Ex. 11 or 
20 or 25 nat-1-hydroxymethyl-1, 
12 9-dioxo-16RS--hydroxy-16- 
vinylprosta-5-cis,13-trans 
diene and ent-1-hydroxy- 
methyl-1,9-dioxo-16RS--hydroxy- 
16-vinylprosta-5-cis,13-trans 
diene 
34 Ex. 13, 15 or 17 1-hydroxymethyl-1,9-dioxo- 
14 or 11R,16S--dihydroxy-16-methyl- 
IIIb prosta-5-cis,13-trans-diene 
and 1-hydroxymethyl-1,9-dioxo- 
11R,16R--dihydroxy-16-methyl- 
prosta-5-cis,13-trans-diene 
35 Ex. 13, 16 or 22 1-hydroxymethyl-1,9-dioxo- 
14 or 11R,16S--dihydroxy-17,17- 
IIIb dimethylprosta-5-cis,13-trans- 
diene and 1-hydroxymethyl-1, 
9-dioxo-11R,16R--dihydroxy- 
17,17-dimethylprosta-5-cis, 
13-trans-diene 
36 Ex. 13, 18 or 23 1-hydroxymethyl-1,9-dioxo- 
14 or 11R,16S--dihydroxy-16-cyclo- 
IIIb propylprosta-5-cis,13-trans- 
diene and 1-hydroxymethyl-1, 
9-dioxo-11R,16R--dihydroxy- 
16-cyclopropylprosta-5-cis, 
13-trans-diene 
37 Ex. 13, 19 or 24 1-hydroxymethyl-1,9-dioxo- 
14 or 11R,16S--dihydroxy-16-(1-pro- 
IIIb penyl)prosta-5-cis,13-trans- 
diene and 1-hydroxymethyl-1, 
9-dioxo-11R,16R--dihydroxy- 
16-(1-propenyl)prosta-5-cis, 
13-trans-diene 
38 Ex. 13, 20 or 25 1-hydroxymethyl-1,9-dioxo 
14 or 11R,16S--dihydroxy-16-vinyl- 
IIIb prosta-5-cis,13-trans-diene 
and 1-hydroxymethyl-1,9-dioxo- 
11R,16R--dihydroxy-16-vinyl- 
prosta-5-cis,13-trans-diene 
39 Ex. 13, 21 or 26 1-hydroxymethyl-1,9-dioxo- 
14 or 11R,16S--dihydroxy-16- 
IIIb ethylprosta-5-cis,13-trans- 
diene and 1-hydroxymethyl-1,9- 
dioxo-11R,16R--dihydroxy-16- 
ethylprosta-5-cis,13-trans- 
diene 
40 Ex. 7, 15 or 17 1-hydroxymethyl-1,9-dioxo- 
8 or IIIa 11R,16S--dihydroxy-16-methyl- 
prost-13-trans-ene and 1- 
hydroxymethyl-1,9-dioxo-11R, 
16R--dihydroxy-16-methylprost- 
13-trans-ene 
41 Ex. 7, 16 or 22 1-hydroxymethyl-1,9-dioxo- 
8 or IIIa 11R,16S--dihydroxy-17,17- 
dimethylprost-13-trans-ene 
and 1-hydroxymethyl-1,9- 
dioxo-11R,16R--dihydroxy-17,17- 
dimethylprost-13-trans-ene 
42 Ex. 7, 18 or 23 1-hydroxymethyl-1,9-dioxo- 
8 or IIIa 11R,16S--dihydroxy-16-cyclo- 
propylprost-13-trans-ene and 
1-hydroxymethyl-1,9-dioxo-11R, 
16R--dihydroxy-16-cyclopropyl- 
prost-13-trans-ene 
43 Ex. 7, 19 or 24 1-hydroxymethyl-1,9-dioxo- 
8 or IIIa 11R,16S--dihydroxy-16- 
(1-propenyl)prost-13-trans- 
ene and 1-hydroxymethyl-1,9 
dioxo-11R,16R--dihydroxy-16- 
(1-propenyl)prost-13-trans- 
ene 
44 Ex. 7, 20 or 25 1-hydroxymethyl-1,9-dioxo- 
8 or IIIa 11R,16S--dihydroxy-16-vinyl- 
prost-13-trans-ene and 1- 
hydroxymethyl-1,9-dioxo-11R, 
16R--dihydroxy-16-vinylprost- 
13-trans-ene 
45 Ex. 7, 21 or 26 1-hydroxymethyl-1,9-dioxo-11R, 
8 or IIIa 16R--dihydroxy-16-ethyl-prost- 
13-trans-ene and 1-hydroxy- 
methyl-1,9-dioxo-11R,16R-- 
dihydroxy-16-ethylprost-13- 
trans-ene 
46 IVc 15 or 17 methyl 9-oxo-11R,16S--dihydroxy- 
16-methylprost-13-trans-enoate 
and methyl 9-oxo-11R,16R--di- 
hydroxy-16-methylprost-13- 
trans-enoate 
47 IVc 18 or 23 methyl 9-oxo-11R,16S-- 
dihydroxy-16-cyclopropylprost- 
13-trans-enoate and methyl 
9-oxo-11R,16R--dihydroxy-16- 
cyclopropylprost-13-trans 
enoate 
48 IVc 20 or 25 methyl-9-oxo-11R,16S--di- 
hydroxy-16-vinylprost-13- 
trans-enoate and methyl 9- 
oxo-11R,16R--dihydroxy-16- 
vinyl-prost-13-trans-enoate 
49 IVd 15 or 17 methyl 9-oxo-11R,16S--di- 
hydroxy-16-methyl-prosta- 
5-cis,13-trans-dienoate 
and methyl 9-oxo-11R,16R-- 
dihydroxy-16-methyl-prosta- 
5-cis,13-trans-dienoate 
50 IVd 18 or 23 methyl 9-oxo-11R,16S--dihydroxy- 
16-cyclopropylprosta-5-cis, 
13-trans-dienoate and methyl 
9-oxo-11R,16R--dihydroxy-16- 
cyclopropyl-prosta-5-cis, 
13-trans-dienoate 
51 IVd 20 or 25 methyl 9-oxo-11R,16S--dihy- 
droxy-16-vinylprosta-5-cis, 
13-trans-dienoate and methyl 
9-oxo-11R,16R--dihydroxy-16- 
vinylprosta-5-cis,13-trans- 
enoate 
52 IVe 15 or 17 methyl nat-9-oxo-16RS-- 
hydroxy-16-methyl-prost-13- 
trans-enoate and methyl ent- 
9-oxo-16RS--hydroxy-16-methyl- 
prost-13-trans-enoate 
53 IVe 18 or 23 methyl nat-9-oxo-16RS--hydroxy- 
16-cyclopropyl-prost-13-trans- 
enoate and methyl ent-9-oxo- 
16RS--hydroxy-16-cyclopropyl- 
prost-13-trans-enoate 
54 IVe 20 or 25 methyl nat-9-oxo-16RS--hydroxy- 
16-vinyl-prost-13-trans-enoate 
and methyl ent-9-oxo-16RS-- 
hydroxy-16-vinyl-prost-13- 
trans-enoate 
55 IVf 15 or 17 methyl nat-9-oxo-16RS--hydroxy- 
16-methyl-prosta-5-cis-13- 
trans-dienoate and methyl ent- 
9-oxo-16RS--hydroxy-16-methyl- 
prosta-5-cis,13-trans-dienoate 
56 IVf 18 or 23 methyl nat-9-oxo-16RS-- 
hydroxy-16-cyclopropyl-prosta- 
5-cis-13-trans-dienoate and 
methyl ent-9-oxo-16RS--hydroxy- 
16-cyclopropyl-prosta-5-cis, 
13-trans-dienoate 
57 IVf 20 or 25 methyl nat-9-oxo-16RS--hydroxy- 
16-vinylprosta-5-cis,13-trans- 
dienoate and methyl ent-9- 
oxo-16RS--hydroxy-16-vinylprosta- 
5-cis,13-trans-dienoate 
58 IVh 15 or 17 1-hydroxymethyl-1,9-dioxo- 
11R,16S--dihydroxy-16-methyl- 
prosta-5-cis,13-trans-diene 
1-ethylene ketal and 1-hydroxy- 
methyl-1,9-dioxo-11R,16R-- 
dihydroxy-16-methylprosta-5- 
cis,13-trans-diene 1-ethylene 
ketal 
59 IVh 18 or 23 1-hydroxymethyl-1,9-dioxo-11R, 
16S--dihydroxy-16-cyclopropyl- 
prosta-5-cis,13-trans-diene 
1-ethylene ketal and 1-hydroxy 
methyl-1,9-dioxo-11R,16R-- 
dihydroxyl-16-cyclopropylprosta- 
5-cis,13-trans-diene 1- 
ethylene ketal 
60 IVh 20 or 25 1-hydroxymethyl-1,9-dioxo- 
11R,16S--dihydroxy-16-vinyl- 
prosta-5-cis,13-trans-diene 
1-ethylene ketal and 1-hydroxy- 
methyl-1,9-dioxo-11R,16R-- 
dihydroxy-16-vinylprosta-5- 
cis,13-trans-diene 1-ethylene 
ketal 
61 IVg 15 or 17 nat-1-hydroxymethyl-1,9- 
dioxo-16RS--hydroxy-16-methyl- 
prost-13-trans-ene 1-ethylene 
ketal and ent-1-hydroxymethyl- 
1,9-dioxo-16RS--hydroxy-16- 
methyl-prost-13-trans-ene 
62 IVg 18 or 23 nat-1-hydroxymethyl-1,9- 
dioxo-16RS--hydroxy-16-cyclo- 
propylprost-13-trans-ene 
1-ethylene ketal and ent-1- 
hydroxymethyl-1,9-dioxo-16RS-- 
hydroxy-16-cyclopropylprost- 
13-trans-ene 
63 IVg 20 or 25 nat-1-hydroxymethyl-1,9- 
dioxo-16RS--hydroxy-16-vinyl- 
prost-13-trans-ene and ent-1- 
hydroxymethyl-1,9-dioxo- 
16RS--hydroxy-16-vinylprost- 
13-trans-ene 
______________________________________ 
This invention has been described in terms of specific embodiments set 
forth in detail herein, but it should be understood that these are by way 
of illustration only and that the invention is not necessarily limited 
thereto. Modifications and variations will be apparent from the disclosure 
and may be resorted to without departing from the spirit of this 
invention, as those skilled in the art will understand. Accordingly, such 
variations and modifications of the disclosed invention are considered to 
be within the scope of this invention and the following claims.