New 7-oxabicycloheptane compounds which have the general formula ##STR1## wherein each R is independently hydrogen or hydroxy, at least one R being hydroxy; R.sup.1 is hydrogen or lower alkyl; R.sup.3 is ##STR2## are useful as cardiovascular agents.

SUMMARY OF THE INVENTION 
This invention relates to a group of compounds of the PGH.sub.2 type which 
are cardiovascular agents useful, for example, in the treatment of 
thrombolytic disease. These compounds have the structural formula 
##STR3## 
In formula I, and throughout the specification, the symbols are as defined 
below. 
Each R is independently hydrogen or hydroxy, provided at least one R is 
hydroxy; 
R.sup.1 is hydrogen or lower alkyl; and 
R.sup.3 is keto 
##STR4##

DETAILED DESCRIPTION OF THE INVENTION 
The sequence of reactions described below yields a series of 
7-oxabicycloheptane derivatives of the PGH.sub.2 type. 
Not only can members of the group be derived from other members and thus 
have utility as intermediates, but they also have physiological activity 
themselves. 
The compounds of formula I are prepared using 3-benzyloxyfuran or 
3,4-dibenzyloxyfuran as a starting material; i.e., a compound having the 
formula 
##STR5## 
In formula IV, and throughout the specification, each R.sup.4 is 
independently hydrogen or benzyloxy, provided at least one R.sup.4 is 
benzyloxy. 
The starting materials of formula IV can be prepared using art-recognized 
procedures. For example, 3-benzyloxyfuran can be prepared from the benzyl 
ether of isomaltol using the procedure disclosed by Fisher et al, J. Org. 
Chem., 29:776(1964), for the preparation of 3-methoxyfuran. 
3,4-Dibenzyloxyfuran can be prepared from 3,4-dibenzyloxy-2,5-furan 
dicarboxylic acid following the procedure used by Olivard et al., J. Med. 
Chem., 19:729(1976) for the synthesis of 3,4-dimethoxyfuran. The 
3,4-dibenzyloxy-2,5-furan dicarboxylic acid can be prepared from 
3,4-dihydroxy-2,5-dicarbomethoxyfuran by alkylation with benzyl chloride 
using the procedures described by Hoehn, Iowa State Coll. J. Sci., 11:66 
(1936) for the synthesis of 3,4-dimethoxy-2,5-dicarbomethoxyfuran. 
When maleic anhydride is reacted with a substituted furan of formula IV, 
e.g., in ether solution at room temperature, a compound having the formula 
##STR6## 
is obtained. 
Chemical reduction of a compound of formula V with a borohydride reducing 
agent, such as sodium borohydride or zinc borohydride, in a solvent, such 
as tetrahydrofuran, yields a compound having the formula 
##STR7## 
In the instance wherein only one of the R.sup.4 groups is benzyloxy, 
compound VI will be obtained as a mixture of isomers which can be 
separated using conventional techniques. These isomers have the formulas 
##STR8## 
Hydrogenation of a compound of formula VI in the presence of a catalyst 
such as palladium-charcoal saturates the carbon-carbon double bond, and 
yields the corresponding mono- or dihydroxy derivative. The reduced 
compounds having the formula 
##STR9## 
The hydroxy group(s) in the compound of formula VII will be endo; this is 
represented by the broken line. 
Before proceeding further with the reaction sequence, it is necessary to 
protect the hydroxy group(s) in the compounds of formula VII. Any base 
stable protecting group is suitable. An exemplary protecting group is 
dimethyl-t-butyl silyl ether. If both R groups are hydroxy it is also 
possible to form cyclic acetal or ketal derivatives such as the acetonide 
derivative. The protected derivatives of the compounds of formula VI can 
be represented by the formula 
##STR10## 
In formula VIIa, and through the specification, each R.sup.5 group is 
independently hydrogen or a protected hydroxy group, provided at least one 
R.sup.5 group is a protected hydroxy group. 
Treatment of a compound of formula VIIa with diisobutylaluminum hydride or 
diisobutylborane yields a compound having the formula 
##STR11## 
which then is submitted to Wittig reaction conditions e.g., with an 
(alkoxymethyl)triphenylphosphonium halide like 
(methoxymethyl)triphenylphosphonium chloride in the presence of an alkali 
metal alkylamide like lithium diisopropylamide, a lithium alkyl like 
sec-butyl lithium in an inert organic medium like toluene, tetrahydrofuran 
or the like, at a temperature in the range of about -10.degree. to 
25.degree. C. This reaction produces a compound having the formula 
##STR12## 
The compound of formula IX is acylated, e.g., with an acylpyridinium halide 
like N-acetylpyridinium chloride in the presence of an acid acceptor like 
pyridine, oxidized with an oxidizing agent like mercuric acetate in an 
organic medium like tetrahydrofuran, then demetalated with a reducing 
agent like potassium iodide to yield a compound having the formula 
##STR13## 
The compound of formula X is subjected to a Wittig reaction, e.g., with a 
carboxyalkyl triphenylphosphonium halide followed by hydrolysis, e.g., 
with sodium carbonate and aqueous methanol to obtain a compound having the 
formula 
##STR14## 
wherein R.sup.1 is hydrogen. The corresponding compound of formula XI 
wherein R.sup.1 is lower alkyl can be obtained by esterifying the product 
of formula XI, e.g., with a diazoalkane like diazomethane in an inert 
organic solvent like ether, or with a substituted diazoalkane like 
diphenyldiazomethane. 
The hydroxymethyl group in the 3-position of a compound of formula XI 
wherein R.sup.1 is lower alkyl can be oxidized, e.g., with chromium 
trioxide in pyridine, to obtain an aldehyde having the formula 
##STR15## 
wherein R.sup.1 is lower alkyl. 
Subjecting a compound of formula XII to a Horner-Wittig reaction using a 
beta ketophosphonate such as dimethyl 2-oxoheptylphosphonate and a base 
such as sodium hydride, in an inert organic solvent such as 
dimethoxyethane, or alternatively a Wittig reaction using a beta keto 
phosphorous ylide such a tributyl or triphenyl 2-oxoheptylidine 
phosphorane, in an organic solvent such as tetrahydrofuran, provides a 
compound having the formula 
##STR16## 
wherein R.sup.1 is lower alkyl. 
The compound of formula XIII can be chemically reduced, e.g., with lithium 
diisobutyl aluminum hydride, with zinc borohydride, sodium borohydride or 
sodium cyanoborohydride to yield a product having the formula 
##STR17## 
wherein R.sup.1 is lower alkyl. The corresponding free acid (formula XIV, 
R.sup.1 is hydrogen) can be obtained by treatment of one of the esters 
with a base such as lithium hydroxide, followed by neutralization with an 
acid such as dilute hydrochloric acid. 
The products of formula I wherein the hydroxy group in the 5- and/or 
6-position is endo can be obtained by removing the acid-labile protecting 
group(s) from the corresponding compound of formula XIII or XIV using 
art-recognized procedures. For example, a compound with the hydroxy groups 
protected can be treated with tetrabutyl ammonium fluoride in a solvent 
such as tetrahydrofuran followed by neutralization with a base. 
The product of formula I wherein the hydroxy group(s) in the 5- and/or 
6-position is exo can be obtained from the corresponding compound of 
formula XIV wherein R.sup.1 is lower alkyl. The hydroxy group in the side 
chain is first protected, e.g., by acylation, yielding a compound having 
the formula 
##STR18## 
wherein R.sup.1 is lower alkyl. In formula XV, and throughout the 
specification, R.sup.6 is a protected hydroxy group (preferably an acyloxy 
group) different than R.sup.5. Selective removal of the R.sup.5 protecting 
groups yields a compound having the formula 
##STR19## 
Treatment of a compound of formula XVI with triphenylphosphine and benzoic 
acid, followed by treatment with diethylazodicarboxylate yields the 
corresponding exo hydroxy group in the 5- and/or 6-position "tied-up" as 
the benzoate ester; i.e., a compound having the formula 
##STR20## 
wherein R.sup.1 is lower alkyl. In formula XVII and throughout the 
specification, each R.sup.7 is independently hydrogen or benzoyloxy, 
provided that at least one R.sup.7 group is benzoyloxy. 
Saponification of a compound of formula XVII using conventional techniques 
yields a product having the formula 
##STR21## 
wherein R.sup.1 is hydrogen. Esterification of an acid of formula XVIII 
using the procedure described for the esterification of a compound of 
formula XI, yields the corresponding product of formula XVIII wherein 
R.sup.1 is lower alkyl. 
Compounds of formula I wherein both R groups are hydroxy, one being exo and 
one being endo are also within the scope of this invention. They can be 
prepared by first reacting a compound of formula VIa or VIb with 
m-chloroperbenzoic acid in an organic solvent such as methylene chloride 
to yield the corresponding compound having the formula 
##STR22## 
Hydrogenation of a compound of formula XIXa or XIXb in the presence of a 
catalyst yields the corresponding compound having the formula 
##STR23## 
Chemical reduction of a compound of formula XXa or XXb using, for example, 
a borohydride such as sodium borohydride, yields the corresponding 
compound having the formula 
##STR24## 
wherein one of the hydroxy groups is exo and one is endo. The designation 
" " represents the stereochemistry of the substituent or side-chain; 
depending on the stereochemistry of the precursor the substituent or 
side-chain will be cis (exo) or trans (endo) to the oxa bridge. The solid 
line (--) is used to represent exo and the broken line (-- ) is used to 
represent endo. From these compounds it is possible to prepare the 
products of formula I wherein both R groups are hydroxy, one being exo and 
one being endo, using the procedures described above for the conversion of 
a compound of formula VII to a compound of formula XIII or XIV with 
protecting groups removed. 
When the keto group in the side chain of the compounds of formula XIII is 
reduced to the hydroxy group of formula XIV, a mixture of stereoisomeric 
compounds in which the hydroxy group is either R(.beta.) or S(.alpha.) is 
obtained. The isomers are separable using conventional techniques such as 
column chromatography. 
When the sequence of reactions described above are followed, i.e., reacting 
maleic anhydride with a furan of formula IV, etc., compounds are obtained 
wherein both side chains, i.e., those residues attached to the 2- and 
3-positions on the 7-oxabicyclo[2,2,1]-heptane ring system, are cis to the 
7-oxa bridge; i.e., they are exo. 
It is also possible to prepare the compounds of formula I wherein one R is 
hydroxy and at least one of the side chains in the 2- and/or 3-positions 
on the 7-oxabicyclo[2,2,1]heptane ring system is trans to the 7-oxa 
bridge; i.e., endo. These compounds are prepared utilizing as a starting 
material a compound having the formula 
##STR25## 
This compound is known; see Berson et al; J.A.C.S., 75:1721 (1953). 
Reduction of a compound of formula XXII with borane-tetrahydrofuran 
complex in an organic solvent such as tetrahydrofuran yields a compound 
having the formula 
##STR26## 
Treatment of a compound of formula XXIII with tri-n-butyl tin hydride 
yields a compound having the formula 
##STR27## 
Oxidation of an alcohol of formula XXIV using procedures described for the 
oxidation of a compound of formula XI above yields the corresponding 
aldehyde having the formula 
##STR28## 
Epimerization of the aldehyde function of a compound of formula XXV to a 
compound having the formula 
##STR29## 
can be realized by treating a compound of formula XXV with 
potassium-t-butoxide in t-butanol. 
Using the procedures described above to convert a compound of formula VIII 
to a compound of formula XI an aldehyde of formula XXV or XXVI can be 
converted successively to the corresponding compounds having the formulas 
##STR30## 
An aldehyde of formula XXV or XXVI can also be converted, using procedures 
described above for the conversion of a compound of formula XII to a 
compound of formula XIII, to the corresponding enone having the formula 
##STR31## 
A compound of formula XXIX can be treated with diisobutyl aluminum hydride 
in an organic solvent to obtain the corresponding compond having the 
formula 
##STR32## 
Esterification of a compound of formula XXXI can be effected using 
art-recognized procedures, e.g., by reaction with a diazoalkane in an 
inert organic solvent such as ether, or with a substituted diazoalkane. 
The resulting ester has the formula 
##STR33## 
wherein R.sup.1 is lower alkyl. 
Chemical reduction of an enone of formula XXX using procedures described 
above for the reduction of a compound of formula XIII to a compound of 
formula XIV, yields a corresponding compound having the formula 
##STR34## 
The hydroxy group in a compound of formula XXXIII can be protected with a 
base stable protecting group, e.g., dimethyl-t-butyl silyl ether. The 
compound with protected hydroxy group can be represented by the formula 
##STR35## 
Reduction of a compound of formula XXXIV with diisobutyl aluminum hydride 
in an organic solvent yields the corresponding compound having the formula 
##STR36## 
A compound of formula XXXII can be reacted with a Horner Wittig reagent, 
e.g., dialkyl-oxalkyl phosphonate to obtain a compound having the formula 
##STR37## 
wherein R.sup.1 is lower alkyl. 
A compound of formula XXXVI can be chemically reduced, e.g., with sodium 
borohydride, and then saponified to obtain the corresponding acid having 
the formula 
##STR38## 
A compound of formula XXXVII is obtained as a mixture of stereoisomers in 
which the hydroxy group noted with an asterisk is either R(.beta.) or 
S(.alpha.). The isomers are separable using conventional techniques. 
A compound of formula XXXV can be converted to the corresponding acid 
having the formula 
##STR39## 
which can be in turn converted to the corresponding product having the 
formula 
##STR40## 
A compound of formula XXXIX is obtained as a mixture of stereoisomers in 
which the hydroxy group noted with an asterisk is either R(.beta.) or 
S(.alpha.). After esterification of the carboxyl group, the isomers are 
separable using conventional techinques. The reactions used are the same 
as those described above for the conversion of a compound of formula XXV 
to a compound of formula XXIX. 
A compound of formula XXXII can be treated with an alkali metal alkoxide, 
e.g., sodium methoxide in an alcohol solvent, e.g., methanol to yield a 
compound having the formula 
##STR41## 
wherein R.sup.1 is lower alkyl. 
A compound of formula XL can be converted to the corresponding product 
having the formula 
##STR42## 
A compound of formula XLI is obtained as a mixture of stereoisomers in 
which the hydroxy group noted with an asterisk is either R(.beta.) or 
S(.alpha.). The isomers are separable using conventional techniques. The 
above reaction procedure is the same as described above for the conversion 
of a compound of formula XII to a compound of formula XIV. 
A compound of formula XXXV wherein the side-chain in the 2-position is endo 
can be epimerized to a compound having the formula 
##STR43## 
using the procedure described above for the epimerization of a compound 
having the formula XXXII to a compound having the formula XL. A compound 
of formula XLII can be subjected to Wittig reaction conditions as 
described above to obtain a compound having the formula 
##STR44## 
A compound of formula LXIII can be converted to the corresponding product 
having the formula 
##STR45## 
following the reaction sequence described above for the conversion of a 
compound having the formula XXVII to a compound having the formula XXIX. A 
compound of formula XLIV is obtained as a mixture of stereoisomers in 
which the hydroxy group noted with an asterisk is either R(.beta.) or 
S(.alpha.). 
It is also possible to prepare the compounds of formula I wherein both R 
groups are hydroxys and both of the side chains in the 2- and 3-positions 
on the 7-oxabicyclo[2,2,1]heptane ring system are trans to the 7-oxa 
bridge; i.e., endo. These compounds, wherein both R groups are exo 
hydroxys, are prepared utilizing as a starting material a compound having 
the formula 
##STR46## 
which is described in Can. J. Chem., 53:2701(1975). Saponification of a 
diester of formula XLV yields the corresponding dicarboxylic acid having 
the formula 
##STR47## 
Catalytic hydrogenation of the dicarboxylic acid of formula XLVI yields the 
corresponding compound having the formula 
##STR48## 
To obtain the diacid corresponding to the compound of formula XLVII, but 
having the acetonide groups trans to the 7-oxa bridge, it is necessary to 
utilize a starting compound having the formula 
##STR49## 
which is described in J.A.C.S., 75:1721(1953). Treatment of a compound of 
formula XLVIII with alkali, e.g., sodium hydroxide, in an alcohol-water 
mixture yields a diacid having the formula 
##STR50## 
Reaction of a diol of formula IL with acetone in the presence of an acid 
catalyst yields the acetonide having the formula 
##STR51## 
An acetonide of formula XLVIII or LI can be treated first with an acid 
anhydride, such as trifluoroacetic anhydride, and then with a chemical 
reducing agent, such as sodium borohydride to yield a compound having the 
formula 
##STR52## 
Using the procedures described above for the preparation of a compound of 
formula XIV from a compound of formula VIIa, a compound of formula LI can 
be used to obtain a compound having the formula 
##STR53## 
wherein R.sup.1 is lower alkyl. A compound of formula LII is obtained as a 
mixture of stereoisomers in which the hydroxy group is either R(.beta.) or 
S(.alpha.). The isomers are separable using conventional techniques. 
By treatment with a mixture of acetic acid and water, an acetonide of 
formula LII can be converted to the corresponding product having the 
formula 
##STR54## 
wherein R.sup.1 is lower alkyl and the stereochemistry of the hydroxy 
group noted with an asterisk will depend on the stereochemistry of the 
hydroxy group in the starting reactant. The corresponding free acid, i.e., 
a compound of formula LIII wherein R.sup.1 is hydrogen can be obtained by 
saponification of a corresponding ester. 
It is also possible to prepare the compounds of formula I wherein both R 
groups are hydroxys and one of the side-chains in the 2- or 3-position on 
the 7-oxabicyclo[2,2,1]heptane ring system is trans to the 7-oxa bridge; 
i.e., endo. These compounds can be prepared from an acetonide of formula 
LI. 
An acetonide of formula LI can be converted to a compound having the 
formula 
##STR55## 
wherein R.sup.1 is lower alkyl, using the procedures described above for 
the conversion of a compound of formula VII to a compound of formula XII. 
Epimerization of a compound of formula LIV using the procedures described 
above for the epimerization of a compound of formula XL yields a compound 
having the formula 
##STR56## 
wherein R.sup.1 is lower alkyl. 
An aldehyde of formula LV can be converted to the corresponding compound 
having the formula 
##STR57## 
wherein R.sup.1 is lower alkyl, using the procedures described above for 
the conversion of a compound of formula XII to a compound of formula XIII. 
A compound of formula LVI is obtained as a mixture of stereoisomers in 
which the hydroxy group is either R(.beta.) or S(.alpha.). The isomers are 
separable using conventional techniques. 
An acetonide of formula LVI can be converted to the corresponding product 
of formula I, i.e., a compound having the formula 
##STR58## 
wherein R.sup.1 is lower alkyl, using the procedure described above for 
the preparation of a compound of formula LIII from a compound of formula 
LII. The corresponding free acid, i.e., a compound of formula LVII wherein 
R.sup.1 is hydrogen can be obtained by saponification of a corresponding 
ester. 
An acetonide of formula LI can be converted to the corresponding enone 
having the formula 
##STR59## 
using the procedure described above for the conversion of a compound of 
formula XII to a compound of formula XIII. 
An alcohol of formula LVIII can be converted to the corresponding acetate 
having the formula 
##STR60## 
using the procedure described above for the conversion of a compound 
having the formula IX to a compound having the formula X. 
A compound of formula LIX can be converted to the corresponding compound 
having the formula 
##STR61## 
using the procedures described above for the conversion of a compound 
having the formula XIII to a compound having the formula XIV. A compound 
of formula LX is obtained as a mixture of stereoisomers in which the 
R.sub.5 group is either R(.beta.) or S(.alpha.). 
Deacetylation of a compound of formula LX using the procedure described 
above for the deacetylation of a compound of formula X yields a compound 
having the formula 
##STR62## 
Using the procedures described above for the conversion of a compound of 
formula XXIV to a compound of formula XXVI, a compound of formula LXI can 
be oxidized and epimerized to obtain a compound having the formula 
##STR63## 
An aldehyde of formula LXII can be converted to the corresponding acid 
having the formula 
##STR64## 
using the procedures described above for the conversion of a compound of 
formula VIII to a compound of formula XL 
Removal of the protecting group from a compound of formula LXIII yields the 
corresponding product having the formula 
##STR65## 
Procedures for removal of the protecting group are described above for the 
conversion of a compound of formula LII to a compound of formula LIII. 
It is also possible to prepare the compounds of formula I wherein one R 
group is hydroxy and at least one of the side chains in the 2- and/or 
3-positions on the 7-oxabicyclo[2,2,1]heptane ring system is trans to the 
7-oxa bridge; i.e., endo. These compounds are prepared using as a starting 
material a compound having the formula 
##STR66## 
Compounds of formula LXV are known; see, for example, Eggelte et al., 
Tetrahedron, 29:2491(1973). Treatment of a compound of formula LXV with an 
acid anhydride, such as trifluoroacetic anhydride, and then with a 
chemical reducing agent, such as sodium borohydride yields a compound 
having the formula 
##STR67## 
A hydroxy group can be added to the compound of formula LXVI by reacting it 
with an oxidizing agent, such as mercury acetate. The product is a mixture 
of isomers having the formulas 
##STR68## 
which can be separated using conventional techniques. Protection of the 
hydroxy group of a compound of formula LXVIIa or LXVIIb using the 
procedure described above for protecting the hydroxy group on a compound 
of formula VII, yields a compound having the formula 
##STR69## 
wherein one R.sup.5 group is hydrogen and the other is a protected hydroxy 
group. 
Using the sequence of reactions described above for the conversion of a 
compound of formula VIIa to a compound of formula XIV to treat a compound 
of formula LXVIII yields the corresponding compound having the formula 
##STR70## 
wherein R.sup.1 is lower alkyl and one R.sup.5 group is hydrogen and the 
other is a protected hydroxy. A compound of formula LXIX is obtained as a 
mixture of stereoisomers in which the hydroxy group is either R(.beta.) or 
S(.alpha.). The isomers are separable using conventional techniques. 
Saponification of an ester of formula LXIX yields the corresponding free 
acid (formula LXIX, R.sup.1 is hydrogen). The protecting group can be 
removed from a compound of formula LXIX to yield a product of formula I 
using the procedure described above for removal of the protecting group 
from a compound of formula XIV. 
Using the sequence of reactions described above for the conversion of a 
compound of formula LI to a compound of formula LVII to treat a compound 
of formula LXVIII yields the corresponding compound having the formula 
##STR71## 
wherein R.sup.1 is lower alkyl and one R.sup.5 group is hydrogen and the 
other is a protected hydroxy. A compound of formula LXX is obtained as a 
mixture of stereoisomers in which the hydroxy group is either R(.beta.) or 
S(.alpha.). The isomers are separable using conventional techniques. 
Saponification of an ester of formula LXX yields the corresponding free 
acid (formula LXX, R.sup.1 is hydrogen). The protecting group can be 
removed from a compound of formula LXX to yield a product of formula I 
using the procedure described above for removal of the protecting group 
from a compound of formula XIV. 
Using the sequence of reactions described above for the conversion of a 
compound of formula LI to a compound of formula LXIII to treat a compound 
of formula XLVIII yields the corresponding compound having the formula 
##STR72## 
wherein R.sup.1 is lower alkyl and one R.sup.5 group is hydrogen and the 
other is a protected hydroxy. A compound of formula LXXI is obtained as a 
mixture of stereoisomers in which the hydroxy group is either R(.beta.) or 
S(.alpha.). The isomers are separable using conventional techniques. 
Saponification of an ester of formula LXI yields the corresponding free 
acid (formula LXXI, R.sup.1 is hydrogen). The protecting group can be 
removed from a compound of formula LXXI to yield a product of formula I 
using the procedure described above for removal of the protection group 
from a compound of formula XIV. 
The compounds of this invention are cardiovascular agents useful as 
platelet aggregation inhibitors e.g., for treatment of thrombolytic 
disease such as coronary or cerebral thromboses. They are also selective 
thromboxane A.sub.2 synthetase inhibitors, e.g., having a vasodilatory 
effect for treatment of myocardial ischemic disease such as angina 
pectoris. They can be administered orally or parenterally to various 
mammalian species known to be subject to such maladies, e.g., cats, dogs, 
and the like in an effective amount within the dosage range of about 1 to 
100 mg./kg., preferably about 1 to 50 mg./kg. and especially about 2 to 25 
mg./kg. on a regimen in single or 2 to 4 divided daily doses. 
The active substance can be utilized in a composition such as tablet, 
capsule, solution or suspension containing about 5 to about 500 mg. per 
unit of dosage of a compound or mixture of compounds of formula I. They 
may be compounded in conventional manner with a physiologically acceptable 
vehicle or carrier, excipient, binder, preservative, stabilizer, flavor, 
etc. as called for by accepted pharmaceutical practice. Also as indicated 
in the discussion above, certain members additionally serve as 
intermediates for other members of the group. 
The following examples are specific embodiments of this invention. 
EXAMPLE 1 
[1R-(1.alpha.,2.beta.(5Z),3.beta.(1E,3R),4.alpha.,6.beta.)]7-[3-(3-hydroxy- 
1-octenyl)-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid 
(a) exo-5-Benzyloxy-3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1,3-dione 
A mixture of 3-benzyloxyfuran (17.4 g, 0.1 mole) and maleic anhydride (9.8 
g, 0.1 mole) in ether (200 ml) is kept at room temperature for about 16 
hours. The crystalline precipitate which forms is separated by filtration, 
washed with ether and dried yielding the title compound. 
(b) exo-5-Benzyloxy-3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1(3H)-one 
and exo-(6-Benzyloxy-3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1(3H)-one 
To a slurry of sodium borohydride (3.8 g, 0.1 mole) in dry tetrahydrofuran 
(30 ml) is added a solution of 
exo-5-benzyloxy-3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1,3-dione in 
dry tetrahydrofuran (300 ml) over a 10 minute period with stirring and ice 
cooling. The resulting mixture is stirred under nitrogen for 5 hours and 
then stripped of solvent under vacuum. The residue is treated with 100 ml 
of 10% hydrochloric acid solution while being cooled in an ice-bath. The 
resulting slurry is extracted with dichloromethane (5.times.100 ml), dried 
over sodium sulfate and concentrated to yield the title compound. The 
mixture of isomers is separated by column chromatography on silica gel to 
yield 
exo-5-benzylozy-3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1(3H)-one and 
exo-6-benzyloxy-3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1(3H)-one. 
(c) 
endo-5-Hydroxy-exo-3a,4,7,7a,8-tetrahydro-4,7-epoxyisobenzofuran-1(3H)-one 
A mixture of 
exo-5-benzyloxy-3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1(3H)-one (30 
g), and 5% palladium on charcoal (1.5 g) in ethyl acetate (1.5 L) is 
treated with hydrogen at atmospheric pressure. The reaction is stopped 
after uptake of 1 mole of hydrogen. The catalyst is filtered from the 
reaction mixture and the solvent is stripped under vacuum to yield the 
title compound. 
(d) 
endo-5-t-Butyldimethylsilyloxy-exo-3a,4,7,7a-tetrahydro-4,7-epoxyisobenzof 
uran-1(3H)-one 
A solution of 
endo-5-hydroxy-exo-3a,4,7,7a,8-tetrahydro-4,7-eoxyisobenzofuran-1(3H)-one 
in dimethylformamide (100 ml) is added to a solution of 
t-butyldimethylsilyl chloride (14.1 g, 0.1 mole) and imidazole (17 g, 0.25 
mole) in dimethylformamide (100 ml) at 35.degree. C. and the mixture is 
kept at that temperature for 12 hours. The mixture is poured into water 
(1L) and extracted with ether (three.times.150 ml portions) yielding, 
after drying over sodium sulfate and concentration, the title compound. 
(e) 
endo-5-t-Butyldimethylsilyloxy-exo-3a,4,7,7a-tetrahydro-4,7-epoxyisobenzof 
uran-2-ol 
A solution of 
endo-5-t-butyldimethylsilyloxyexo-3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofu 
ran-1(3H)-one (2.58 g, 10 mmole) in toluene 50 ml) is chilled to 
-78.degree. C. and treated dropwise over 10 minutes with a solution of 
diisobutyl aluminum hydride (20 mmole). The resulting slurry is stirred at 
-78.degree. C. for 20 minutes. The reaction is quenched by adding dropwise 
12 ml of 10% acetic acid and allowing the reaction to warm to room 
temperature. The mixture is poured into 10% hydrochloric acid, saturated 
with sodium chloride (50 ml) and extracted with methylene chloride (eight 
50 ml portions) yielding after drying over sodium sulfate and 
concentration the title compound. 
(f) 
[1R-(1.alpha.,2.beta.,3.beta.,4.alpha.,5.alpha.)]-3-(2-methoxyethenyl)-5-t 
-butyl-dimethyl silyloxy-7-oxabicyclo[2.2.1]heptane-2-methanol 
A solution of methoxymethylenetriphenylphosphorane is prepared by addition 
of lithium diisopropyl amide (10.6 g, 0.1 mole) in dry tetrahydrofuran 
(100 ml) to a slurry of methoxy methyl triphenyl phosphonium chloride 
(34.3 g, 0.1 mole) in dry toluene (400 ml) under nitrogen at 0.degree. C. 
The resulting red Wittig reagent is stirred at 0.degree. C. for 30 minutes 
prior to use. To this solution is added 
endo-5-t-butyldimethylsilyloxy-exo-3a, 
4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-2-ol (14.3 g, 0.05 mole) via a 
solids addition funnel and the resulting mixture is stirred at 25.degree. 
C. for 2 hours. The mixture is acidified to pH 5 with 10hydrochloric acid 
and extracted with ether (three 200 ml portions). The solvents are removed 
under vacuum and the residue is dissolved in ether and this solution 
chilled yielding crystalline triphenylphosphine oxide. The filtrate is 
concentrated yielding the title compound which is purified by column 
chromatography on silica gel. 
(g) [1R-(1.alpha.,2.beta.,3.beta.,4.alpha. 
,5.alpha.)]-2-[2-acetoxymethyl-5-t-butyldimethylsilyoxy-7-oxabicyclo[2.2.1 
]hept-3-yl]ethanal 
A mixture of N-acetylpyridinium chloride is prepared by combination of 
pyridine (56 ml) and acetyl chloride (9.6 ml, 136 mmole) at 0.degree. C. 
To this is added the enol ether of example 1f (1.5 g, 23 mmole) dissolved 
in 15 ml of pyridine the resulting mixture is stirred at 25.degree. C. for 
2 hours and poured into brine. The product is extracted into ether (three 
100 ml portions), washed with 5% hydrochloric acid (two 200 ml portions) 
and brine (200 ml), dried over sodium sulfate and concentrated to yield 
the ester derivative. This product is treated directly with mercury 
acetate (43 g, 135 mmole) and 10% aqueous tetrahydrofuran (700 ml). After 
10 minutes the mixture is poured into a solution of potassium iodide (300 
g) in water (36). After shaking the product is extracted with benzene 
(three 500 ml portions), washed with potassium iodide solution, brine and 
dried over sodium sulfate. Concentration yields the title compound. 
(g) [1R-(1.alpha.,2.beta.,3.beta.(5Z), 
4.alpha.,5.alpha.)]-7-[2-hydroxymethyl-5-t-butyldimethylsilyloxy-7-oxabicy 
clo[2.2.1] hept-3-yl]-5-heptenoic acid 
A solution of sodium methylsulfinylmethide (2 g, 20 mmole) in 
dimethylsulfoxide is added dropwise to a solution of 4-carboxybutyl 
triphenylphosphonium bromide (8.8 g, 20 mmole) in dry dimethylsulfoxide 
100 ml. To the solution of Wittig reagent so produced is added a solution 
of the aldehyde of example 1f (6.6 g, 20 mmole) in dimethylsulfoxide (10 
ml). The resulting mixture is stirred for 45 minutes and quenched by the 
addition of acetic acid (20 mmole). The mixture is poured into brine and 
extracted with ether (three 200 ml portions). Concentration gives an oil 
which is shaken with saturated sodium bicarbonate solution until a 
crystalline solid (triphenylphosphine oxide) appears. This is removed by 
filtration and the filtrate concentrated yielding a product which is 
stirred with excess sodium carbonate in methanol for 24 hours at room 
temperature. The mixture is poured into water and acidified with dilute 
hydrochloric acid. Extractions with ether followed by concentration give a 
product which is purified by column chromatography. 
(h) [1R-(1.alpha.,2.beta.(5Z), 3.beta.,4.alpha.,6.alpha.]- 
8-[3-hydroxymethyl-6-t-butyldimethylsilyloxy-7-oxabicyclo[2.2.1]hept-2-yl] 
-5-heptenoic acid methyl ester 
A solution of the product of example 1 g (3.84 g, 10 mmole) in ether (100 
ml) is treated with an ether solution of diazomethane. The solution is 
kept at room temperature for 15 minutes and the excess diazomethane is 
quenched with acetic acid. Evaporation of the solvents yields the title 
compound which was purified by passage through a short column of silica 
gel. 
(i) 
[1R-(1.alpha.,2.beta.(5Z),3.beta.,(1E),4.alpha.,6.alpha.)]-7-[3-(3-oxo-1-o 
ctenyl)-6-t-butyldimethylsilyloxy-7-oxabicyclo[2.2.1]hept-2-yl]-5heptenoic 
acid methyl ester 
A solution of chromium trioxide-pyridine is prepared in anhydrous methylene 
chloride (from 6 g, 60 mmole of chromium trioxide; 9.6 ml, 120 mmole of 
pyridine and 250 ml of methylene chloride) and stirred at 25.degree. C. 
for 20 minutes, nine gms of dry Celite are added followed by the product 
of example 1h (3.98 g, 10 mmole) dissolved in methylene chloride (15 ml). 
The resulting mixture is stirred under nitrogen for 15 minutes and 
filtered. The filtrate is washed with 5% sodium bicarbonate solution (two 
100 ml portions), 10% hydrochloric acid solution (two 100 ml portions), 5% 
sodium bicarbonate solution (two 100 ml portions), water (200 ml) and 
brine (two 100 ml portions). After drying over sodium sulfate, the 
methylene chloride solution is concentrated yielding the aldehyde 
derivative of the starting material. 
Sodium hydride (50% in oil, 480 mg, 10 mmole) is washed with pentane and 
slurried in dimethoxyethane (200 ml). The slurry is treated dropwise with 
dimethyl (2-oxoheptyl)phosphonate (2.66 g, 13 mmole) and stirred 
vigorously at 25.degree. C. for 2 hours. The thick paste is treated with 
the above aldehyde and the mixture is stirred at 25.degree. C. for an 
additional 2 hours. The reaction is quenched with acetic acid (600 mg) and 
concentrated. The residue is treated with 5% sodium bicarbonate and 
extracted with ether (four 100 ml portions). After drying over magnesium 
sulfate and concentration, the residue is purified by column 
chromatography on silica gel yielding the title compound. 
(j) 
[1R-(1.alpha.,2.beta.(5Z),3.beta.(1E,3R),4.alpha.,6.alpha.]-7-[3-(3-hydrox 
y-1-octenyl)-6-t-butyldimethylsilyloxy-7-oxabicyclo-[2.2.1]-hept-2-yl]-5-he 
ptenoic acid methyl ester 
A solution of the product of example 1i (369 mg, 0.75 mmole) in methanol (2 
l) containing samarium chloride hexahydrate (272 mg, 0.75 mmole) is 
treated with sodium borohydride (27.2 mg, 0.72 mmole) portionwise over 1 
minute. The reaction mixture is stirred at 25.degree. C. for 7 minutes and 
poured into satured ammonium chloride solution (25 ml). The products are 
extracted into ether (two 20 ml portions), the solution dried over 
magnesium sulfate, and concentrated yielding a mixture of isomers which is 
separated by chromatography on silica gel. 
(k) [1R-(1.alpha.,2.beta.(5Z),3.beta.(1E,3R), 
4.alpha.,6.alpha.)]-7-[3-(3-hydroxy-1-octenyl)-6-hydroxy-7-oxabicyclo[2.2. 
1]-hept-2-yl]-5-heptenoic acid 
A solution of the product of example 1j (494 mg, 1 mmole) in dry 
tetrahydrofuran (10 ml) is treated with anhydrous tetrabutylammonium 
fluoride (522 mg, 2 mmole) nd the mixture kept under nitrogen for 24 hours 
at 25.degree. C. The solution is diluted with tetrahydrofuran (75 ml) and 
water (17 ml) and treated with lithium hydroxide (628 mg, 26 mmole) in 
water (17 ml) at 0.degree. C. The mixture is stirred at 0.degree. C. for 6 
hours and then acidified with 10% oxalic acid to pH 2. The mixture is 
extracted with ether (three 100 ml portions), the extracts washed with 
water (two 100 ml portions) and brine (two 100 ml portions ), dried over 
magnesium sulfate and concentrated yielding the title compound which is 
purified by column chromatography on silica gel. 
(1) [1R-(1.alpha.,2.beta.(5Z),3.beta.(1E,3R),4.alpha.,6.alpha. 
)]-7-[3-(3-acetoxy-1-octenyl)-6-hydroxy-7-oxabicyclo[2.2.1]-hept-2-yl]-5-h 
eptenoic acid methyl ester 
A slurry of N-acetyl pyridinium chloride (1.5 mmole) prepared by additiion 
of acetyl chloride (1.5 mmole) to pyridine (10 ml at 0.degree. C. is mixed 
with the product from example 1k (494 mg, 1 mmole) dissolved for 2 hours 
at 25.degree. C. and poured into brine. The product is extracted with 
ether and the ether extracts are washed with 55 hydrochloric acid (two 50 
ml portions), 5% sodium bicarbonate (two 50 ml portions), and brine (50 
ml). After drying over magnesium sulfate the solution is concentrated to 
yield the acetate derivative of the starting material. This is converted 
to the title compound with purification by dissolving in anhydrous 
tetrahydrofuran (10 ml) and addition of tetranbutylammonium fluoride (522 
mg, 2 mmole) followed by 24 hours at 25.degree. under nitrogen. The 
hydroxy acetate product is isolated by evaporation of th solvents followed 
by extraction of the residue with ether. After drying over magnesium 
sulfate and concentration, the product is purified by column 
chromatography on silica gel. 
(m) [1R-(1.alpha.,2.beta.(5Z), 3.beta.(1E,3R), 
4.alpha.,6.beta.)]-7-[3-(3-hydroxy-1-octenyl)-6-hydroxy-7-oxabicyclo[2.2.1 
]-hept-2-yl]-5-heptenoic acid 
A solution of the product of exampl 1L (422 mg, 1 mmole), 
triphenylphosphine (524 mg, 2 mmole), and benzoic acid (244 mg, 2 mmole) 
is prepared in anhydrous tetrahydrofuran under nitrogen at 0.degree. C. To 
this is added diethyll azodicarboxylate (348 mg, 2 mmole) as quickly as 
possible. The resulting solution is stirred at 0.degree. C. for 1 hours 
and concentrated to yield the crude product. Stirring of the crude with 
ether gives triphenylphosphine oxide which is removed by filtration. The 
filtration is washed with 5% sodium bicarbonate (two 50 ml portions), 
brine (100 ml), dried over magnesium sulfate and concentrated yielding an 
intermediate with a protected hydroxy group. This is purified by column 
chromatography and converted directly to the title product. A solution of 
the intermediate in tetrahydrofuran (85 ml) and water (18 ml) is treated 
at 0.degree. C. with lithium hydroxide (628 mg, excess) in water (18 ml) 
and the mixture kept at 0.degree. C. for 6 hours. The mixture is 
acidified to pH 2 with 10% oxalic acid and the product is extracted with 
ether. After drying over sodium sulfate and concentration. The product is 
purified by column chromatography.