CA1198417A - 9-deoxy-9a-methylene isosteres of pgi.sub.2 and process for their preparation - Google Patents

Abstract

ABSTRACT
This invention relates to compounds having the following formula (I) (I) wherein R is chosen from the group a) a free or esterified carboxy group;
b) -C(OR')3, where each R' group is independently C1-C6 alkyl or phenyl;
c) -CH2-R", where R" is hydroxy or C2-C7 alkoxy; d) where Ra and Rb are chosen independently from the group hydrogen, C1-C6 alkyl, C2-C6 alkanoyl and phenyl; e -C?N; f) a radical; g) -CHO; h) a radical where each X' is independently-O- or -S- and the R'a and R'b groups, whether the same or different, are C1-C6 alkyl or together form a straight or branched C2-C6 alkylene chain;
D is chosen from the group: CH2-, , (cis), (trans), -C?C-,, -O-, -S-, and , where Rc may be hydrogen, C1-C6 alkyl or C2-C6 alkanoyl;
one of R1 and R2 and, independently, one or R3 and R4 is hydrogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, phenyl, or aryl-C1-C6 alkyl and the other is hydrogen, hydroxy, C1-C6 alkoxy or aryl C1-C6 alkoxy, or R1 and R2 and, independently, R3 and R4 together form an oxo group;
each R5 and R6, whether the same or different, may be hydrogen, C1-C6 alkyl or halogen, or R5 and R6 and the carbon atom to which they are bound form a or radical;
Y is chosen from the group: -CH2-CH2-, -C?C-, (trans), (cis) where Z is hydrogen or halogen, -NH-CO- and -NH-CH2-;

X is chosen from the group: -(CH2)m3 - in which m3 is zero or 1, (cis), (trans) -O- -S- and ?N-Rc which Rc as defined above;
m1, m2, n1, and n2, whether the same or different may be zero or an integer between 0 and 12 such that each sum m1+m2 and n1+n2 is less than or equal to 15;
p and q are independently zero or an integer between 1 and 3 such that the sum p + q is an integer of 1 to 6;
R7 is chosen from the group. a') hydrogen; b') C1-C4 alkyl; c') a cycloaliphatic radical, either unsubstituted or substituted with one or more C1-C6 alkyl or C1-C6 alkoxy; d') an aryl group either unsubstituted or substituted with one or more of the following: halogen,halo-C1-C6-alkyl, C1-C6-alkyl C1-C6-alkoxy phenyl; e') a saturated or unsaturated heterocyclic ring either unsubstituted or substituted with one or more of the following:
halogen halo-C1-C6-alkyl C1-C6-alkoxy phenyl C1-C6 alkyl;
as well as the lactones derived from compounds with formula (I) and the pharmaceutically or veterinarily acceptable salts thereof. It also relates to a process for the preparation of these compounds and to intermediates use-ful in this process. The compounds of formula (I) are useful in medicine due to their broncho dilator luteolytic anti-ulcerogenic and platelet anti-aggregant activity.

Description

Lo The object of this invention is 9-deoxy-9a-methylene-isosteres of PGI2, also known as oxide ,15(S)-dihydroxy-pro~-ta-S~æ),13(E)-dienoic acid, including a procedure for their preparation as well as pharmaceutical and veterinary compositions containing them.
Compounds covered by -this invention have the following general formula I
CHrJ(CH ) -D-(CH ) -R

(OH ) s C~12) H H

I

3 - (c , R

wherein R is chosen from the group (a) a free or es-terified car boxy group;
(b) -COREY, where each R' group is independently Cl-C6-alkyl or phenol;
(c) -SHARI", where R" is hydroxy or C2-C7-alkoxyi (d) -CON Ray where R
and Rub are chosen independently from the group hydrogen, Cl-C6-alkyl, C2-C6-alkanoyl and phenol; (e) -C-Ni (f) a -C ¦¦ radical; (g) -Chow (h) a OR NH-N
-OH OR radical where each X' is independently -O- or -S- and the R' and Rub groups, whether the same or different, are Cl-C6-alkyl or together form a straight or branched C2-C6-alkylene chain; D is chosen from the group:
-SHEA-, -SHEA, -CH=CH- (is), -CH=CH- (trays), -C-C-, KIWI, -O-, -S-, and NO , where R may be hydrogen, Cl-C6-alkyl or C2-C6-alkanoyli one of Al and R2 and, independently, one of R3 and R4 is hydrogen, Cl-C6~alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenol, or aryl-Cl--C6-alkyl and the other is hydra-gent hydroxy, Cl-C6-alkoxy or aryl-C1-C6-alkoxy, or, Al and R2 and, in depend-entry, R3 and R4 together form an ox group; each R5 and R6, whether -the same or different, may be hydrogen, C1-C6-alkyl or halogen, preferably fluorine, or R5, R6 and the carbon atom to which they are bound form a ,C=CH2 or C I 2 radical; Y is chosen from -the group: -CH2-CH2-, -CHIHUAHUAS- (trays) or -CHIHUAHUAS- (is) where Z is hydrogen; is chosen from -the group -(Chihuahuas) - in which my is zero or 1, -CH=CH- (is), -CH=CH- (trays), -0-, -So and IRE
wherein R is as defined above; ml, my, no and no, whether the same or different, may be zero or an integer between 0 and 12 such tilt each sum ml + my and no -I no is less than or equal -to 15; p and q are independently zero or an integer between 1 and 3 such that sum p -I q is an integer of 1 to 6; R7 is an aureole group, either unsubstituted or substituted with one or more of the following: halogen, halo-Cl-C6-alkyl, Cl-C6-alkyl, C1-C6-alkoxy, phenol.
This invention also covers lactones derived from compounds with formula I, as well as pharmaceutically or veterinarily acceptable salts, optical antipodes, and geometric isomers and diastereoisomers of compounds with formula I, plus their mixtures.
In this discussion, a dashed line (111 ) refers to substituents on a ring in the configuration, that is, below the plane of the ring, to sub-stituents on a bicycle [(p+q-~1).3.0] Al Kane system (composed of condensed rings A and B) in the end configuration, and to substituents on a chain in -the configuration. A wedged line I on the other hand, refers to a ring substituent in the 3 configuration, -that is above the plane of the ring, to a bicycle [(p-~q+1).3.0] Al Kane substituent in the ego configuration, and to a side chain substituent in the R configuration. A wavy line (~) indicates a substituent or undefined stereochemistry: ring substituents may be or 3, bicycloalkane subs-tituents may be end or ego, and side chain subs-tituents may be R or S.
The compounds with formula I and -their derivatives described here have a is junction between condensed rings A and B; the hydrogen atoms bound to the bicyclic system at the junction are both outside the dihedral].
angle formed by the rings in the natural configuration.
The side chain on cyclopentane ring A (the chain) is trays with respect to ring B and ego with respect to the bicyclic system.

.... .
f~J'~ hi - 2 -In the compounds covered by -this invention, there are two possible geometric isomers arising from the configuration of -the double bond ego-cyclic to ring B, depending on whether the chain bowl -to this double bond (chain I) is on the same side as or -the opposite side from the chain on cyclopentane ring A (chain I): in -the firs-t case, the exocyclic double bond is defined as is; in the second, i-t is -trans. In both formula I and -the formulae which follow, the symbol I means -that both geometric isomers are covered by -this invention, both separately and in mixtures.
The above notation refers to natural compounds. However, -the enantiomers covered by this invention show stereochemistry at all asymmetric sites which is the opposite of that found in the natural compounds. They are thus mirror images of the latter, and -their names include -the prefix "en"
to indicate precisely that. do mixtures contain equimolar quantities of the natural compounds and the corresponding enantiomers.
The alkyd, alkenyl, alkynyl, alkoxy and alkanoyloxy groups may be straight or branched, unsubstitu-ted or substituted with one or more of the following: halogen, Cl-C6-alkoxy and aureole, phenol in particular.
R is preferably a free or esterified carboxylic group, or its derivative salt. A Cl-C6-a]kyl group is preferably methyl, ethyl or propel.
A C2-C7-acyloxy group is preferably C2-C6-alkanoyloxy, for example, Aztecs, propionyloxy, or benzoyloxy. A C2-C6-alkanoyl group is preferably acutely or propionyl. A C2-C6-alkylene radical is preferably ethylene or propylene.
A Cl-C6-alkoxy group is preferably methoxy, ethics or propoxy. An aureole-Cl-C6-alkyl group is preferably bouncily. An aureole Cl-C6-alkoxy group is preferably Benelux. A C2-C10-alkenyl group is preferably -CHESHIRE, where R8 is hydrogen or straight or branched Cluck -alkyd, but preferably a vinyl group. A C2-C10-alkynyl group is preferably -C-C-R8, where R8 is as defined above, but preferably an ethanol group. A halo-Cl-C6-alkyl group is pro-fireball trihalo-Cl-C6-alkyl, particularly trifluoromethyl. Preferably R5 and R6 are independently chosen from hydrogen, Cl-C6-alkyl and fluorine.
For R7 aureole, phenol, ~-naphthyl or ~-naphthyl is preferred.
When R is an esterified carboxyl group, -COORS is preferred, where Jo - 3 -Rug is a Cl-Cl2-alkyl radical, particularly methyl, ethyl, propel, hotly or C2-Cl2-alkenyl, ally in particular. Preferably, m , my, no and no are independently zero, l, 2 or 3.
Pharmaceutically or veterinarily acceptable salts of compounds with formula I may be formed with both inorganic and organic acids and bases.
Pharmaceutically or veterinarily acceptable inorganic acids include hydrochloric, hydrobromic and sulfuric while organic acids include citric, fumaric, tartaric mafia, malefic, methanesulfonic and ethansulfonic. Accept-able inorganic bases may be -the hydroxides of alkali or alkaline earth metals, lo zinc and aluminum. Acceptable organic bases may be amine like methyl amine, diethylamine, trimethylamine, ethyl amine, dibutylamine, triisopropylamine, N-me-thylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, phenol-ethyl amine, ~-phenylethylamine, ethylenediamine, diethylenetriamine, and other similar aliphatic, aromatic and heterocyclic amine like piperidine, morpholine, pyrrolidine, piperazine, as well as substituted derivatives like l-methylpiperidine, ~-ethylmorpholine, l-isopropylpyrrolidine, 2-methyl-pyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, hydrophilic derive-lives like moo-, dip and triethanol, 2-amino-2-butanol, 2-amino-l-butanol,

2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris-(hydroxy-methyl)-aminomethane, N-phenylethanolamine, ~-(p-tert.-amylphenyl)-diethanol-amine, ephedrine, procaine and and amino acids like Lawson and arginine.
Under this invention, the preferred salts are compounds with formula I in which R is -Cord, where Rod is a pharmaceutically or veterinary fly acceptable cation derived from one of the bases listed above.
In this discussion, the compounds covered by the invention will be referred to as bicycle [(p+q+1).3.0] Al Kane derivatives, or, preferably, as derivatives of a 20 carbon atom compound, the prostacyclanoic acid, with the following formula:

I

COO
Jo O pa 7 H H
10~ 1 in which the position of -the oxygen atom is called the pa position.
Thrower, a compound with formula I in which pal is a bicycle [3.3.0] octal derivative or, preferably, a derivative of a adieux-ethylene pros-tacyclanoic acid, since a ethylene group has taken the place of the heteroatom in position pa of the prostacyclanoic acid. A compound with formula L in which pi and Al is a bicycle [4.3.0] nonyl derivative, or, preferably, a derivative of 9a-deoxy-9a,9b-dimethylene prostacyclanoic acid, since -two ethylene groups have substituted the heteroatom in position pa of the prostacyclanoic acid. Analogously, a compound with formula I in which pi and Al is a bicycle [5.3.0] dodecyl derivative or, preferably, a derivative of 9a-deoxy-9a,9b,9c-trimethylene prostacyclanoic acid.
Analogous prostacyclanoic acid derivatives in which q--2 or q=3 are called "Amy" or "7a,7b-dihomo" respectively, while compounds with formula I with p or q equal to zero are called "9a-nor-methylene" or "7-nor-methylene"
respectively.
The same notation (home, dummy, nor, donor, etc.) is used to indicate lengthening (the former) or shortening (the latter) of the and chains by one, two or more carbon atoms, relative to the number of carbon atoms in prostacyclanoic acid.
Under this invention, preferred compounds with formula I are those in which R is a free or sulfide car boxy group; R7 is phenol optionally substituted as described above, and the other substi-tuents have the meanings reported above.
The following compounds are particularly preferred under this invention: 5c,13t-il~,15S-dihydroxy-9a-deoxy-9a-methylene-17--phenol-, , - 5 -I

trinor-prostacycla-5,13-dienoic acid; 5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-16-m-trifluorome-thylphenoxy-17,18,19,200--tetranor-prostacycla-5,13-it dunk acid;~,13-t-lla,15S-dihydroxy-9a-deoxy-9a-me-thylene-17phenol-18,19,20-trinor-pxostacycla-5,13-dienoic acid; 5t,13t~ ,]5S-dihydroxy-9a-deoxy-9a-methylene-16-m-tri:Eluoromethylpherloxy-::1,7,18,19,20--tetranor-prosta-cycla-5,13-dienoic acid;5c,13t-:Ll~,15S-dihydroxy-9a-deoxy-7-nor-methylenee-17-phenyl-18,19,20-trinor-prostacycla-5,13-dienoicc acid; 5c,13t-11~,15S-dihydroxy-9a-deoxy-9a,7a-homo-dime-thylene-16-phennoxy-17,18,19,20-tetranor-prostacycla-5,13-dienoic acid; 5t,13t-11~,15S-dihydroxy-9a-deoxy-7-nor-methylene-17-phenyl-18,19,20-trinor-prostacycla-5,dunk acid; 5t,13-t-11~,15S-dihydroxy-9a-deoxy-9a,7a-homo-dimethylene--phonics--tetranor-prostacycla-5,13-dienoic acid; as well as the 11-deoxy-derivatives, the 11-epimers, the 15R-hydroxy isomers and all -the enantiomers of the come pounds indicated above as well as their pharmaceutically or veterinarily acceptable salts.
The compounds covered by this invention are prepared by a process which comprises alkylation of compound II

/ C\
(SHEA) B (SHEA) H H
< A ¦ II

2 _ --5 C-(CH2)n -I X (C 2)n2 7 R' I R6 wherein p, q, Y, no, no, X, R5, R6 and R7 are as defined above; one of R 1 and R'2 and, independently, one of R'3 and R'4 is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenol or aryl-Cl-C6-alkyl and the other is hydrogen, hydroxy, Cl-C6-alkoxy, aryl-Cl-C6-alkoxy or a protecting group bound to the bicyclic system or the side chain through an ether linkage, or 1119~ 7 Al and R'2 and, independently, R'3 and R'4 together form a protecting group for the kitten function, with a compound with formula IT
E-cH-(cH2)m D (SHEA

wherein D, ml and my are as defined above; E is a (C6HS)3P- or a (R 0)2P-~(0)- group where each R may independently be C1-C6-alkyl or phenol;
R"' is (a") a carboxylic group, free, esterified or as its salt;
(b") -COREY, where R' is as defined above; (c") -SHARI , where R is C2-C7-acyloxy or a protecting group bound to -SHEA- through an ether linkage;
(d') -CON R where Ray and Rub are as defined above; (e") -CON; (f") a I radical; (g") a -OH OR radical where X', R' and Rub are as NH-N b defined above, followed if required by the removal of any protecting group present; or, if required a compound of formula I in which Y is -CHIHUAHUAS-where Z is hydrogen, is reduced to give, after the protecting groups are removed, a compound of formula I in which Y is -CH2-CH2-; or, if required, subjecting to nucleophilic addition the free carbonyl on the chain of a compound of formula I in which Y is -CH2-CH2- or -CHIHUAHUAS- and Z is as defined above, and R3 and R4 together form an ox group to afford, upon removal of any protecting groups, a compound of formula I in which Y is -CH2-CH2- or -CHIHUAHUAS- and Z is as defined above, and one of R3 and R4 is hydroxy while the other is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenol or aryl-Cl-C6-alkyl and, if required, preparing the ether derivative from a compound of formula I in which Y is -CH2-CH2- or -CHIHUAHUAS- wherein Z is as defined above, one of R3 and R4 is hydroxy while the other is hydrogen, C -Colloquial, C2-ClO-alkenyl, C2-C10-alkynYl, phenol or aryl-Cl-C6-alkyl, and any other hydroxyl groups present are protected to give after removal of any protecting groups a compound of formula I in which Y is -CH2-CH2- or -CHIHUAHUAS-where Z is as defined above and one of R3 and R4 is Cl-C6-alkoxy or aureole-Cl-C6-alkoxy while the other is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenol or aryl-Cl-C6-alkyl; or, if required, converting a compound of formula I into another or -to the lactose or pharmaceutically or veterinarily acceptable salt or, if required, converting a salt of a compound of formula I to -the free compound or, if required, separating a mixture owe ~84~i7 isometric compounds of formula I into individual isomers.
Protecting groups for the hydroxyl functions are ether or ester residues readily converted to hydroxyl groups under mild conditions, for instance acid hydrolysis. Preferred groups include sill ethers: for instance trialkylsilyl ethers like trim ethyl, dimethyl-tert.-butyl, dim ethyl isopropyl, or climethylethyLsilyl ether; and also acutely and enol ether rest idles: for instance, tetrahydropyranyl ether, -tetrahydrofuranyl ether, dioxanyl ether, oxathianyl ether, I
Oak Oak where Ask is cl-C6-alkyl.

Kitten protecting groups are preferably petal and thioketal OR
residues: I era groups in which X', R' and Rub are as defined above.
Alkylation of a compound II with a compound III is carried out by using at least a 1.1 molar equivalent excess of III per mole of II. The reaction may be run in any inert solvent e.g. in a linear or cyclic ether like deathly ether, tetrahydrofuran, Dixon or dimethoxyethane; in an aliphatic or aromatic hydrocarbon like Nixon, Newton, Bunyan or Tulane; in a halogenated hydrocarbon like dichloromethane or carbon twitter-chloride, as well as in mixtures of these solvents.
Especially when E in compound III is (C6H5)3P-, dimethylsulfoxide, hexamethylphosphoramide, and other aprotic solvents are particularly useful.
Dimethylsulfoxide gives the dimethylsulfinyl carbanion upon reaction with an alkali hydrides which in turn can generate carbanions with formula III
from the corresponding phosphoranes and phosphonates; this solvent is thus particularly preferred, since carbanions III can then be generated in situ.
For the alkylations described above, the reaction temperature may range from the freezing point to the boiling pullout of water, although room temperature is particularly preferred.
Reaction of a compound II with a compound III gives a mixture of geometric isomers, in that the new exocyclic double bond formed in the reaction may be is or trans. If desired, the individual geometric isomers may be separated by fractional crystallization from a suitable solvent or by chromatography, either thin layer, column or liquid-liquid at low, medium or high pressure. Silica gel or magnesium silicate may be used as support with a solvent like cyclohexane, Nixon, Bunsen, ethylene chloride, ethyl ether, isopropyl ether, ethyl acetate or methyl acetate as the mobile phase.
When necessary, the ether protecting groups may be removed from -the hydroxyl functions with mild acid hydrolysis, for instance with moo- or polycarboxylic acids like acetic, formic, citric, oxalic, or tartaric in a solvent lice water, acetone, tetrahydrofuran, dimethoxyethane or a low molecular weight alcohol, or with a sulfonic acid like p-toluenesulfonic in a low molecular weight alcohol like an hydrous ethanol or methanol, or with a polystyrene-sulfonic resin. For example, a 0.1-0.25N polycarboxylic acid (like oxalic or citric is used with a suitable low-boiling solvent miscible with water and readily removable under vacuum a-t -the end of the reaction.
Sill ether residues may be selectively removed in the presence of other protecting groups with F ions in solvents like tetrahydrofuran and dimethylformamide.
Ester protecting groups may be removed by following typical saponification procedures.
Petal and thioketal protecting groups for kittens are generally removed as are acutely or thioacetal groups, with mild acid hydrolysis as described above.
Thioketals and thioacetals may be selectively removed in the pro-since of other protecting groups with, for instance, mercuric chloride in aqueous acetone or acetonitrile, or a mixture of them, in the presence of an alkaline earth carbonate like that of calcium or magnesium.
The optional reduction of a compound I in which Y is -CHIHUAHUAS-wherein Z is hydrogen, to afford, after any protecting groups are removed, a compound I in which Y is -CH2-CH2- is preferably run in liquid ammonia, with or without a co-solvent (for instance, an aliphatic alcohol like left.-buttonhole or a 2-Cl-C~-alkylpropan-2~ol, or a cyclic ether like tetrahydrofuran _ 9 _ or Dixon), with an excess of an alkali or alkaline earth metal like Lithuania, sodium, potassium or calcium. At the end of the reaction, a weak acid like arnmonium chloride or sulfate or an aliphatic alcohol like ethanol or propanol is used as a pro-tons source. The reaction temperature may range from -70 C
to -that of the solvent a-t rollicks.
Nucleophilic addition to -the free carbony:l group on the o chain in a compound I in which Y is -CH2-CH2- or -CHIHUAHUAS-, Z is as defined above, and R3 and R4 together form an ox group gives a secondary or tertiary alcohol, depending on the nucleophile.
A secondary alcohol is preferably prepared with an alkali or alkaline earth (like sodium, lithium, calcium or magnesium) bordered or with zinc bordered to give, after any protecting groups are removed, a compound I in which Y is -CH2-CH2- or -CHIHUAHUAS-, z is as defined above, and one of R3 and R4 is hydrogen and the other is hydroxy. 0.5-6 moles of reducing agent are used per mole of the carbonyl derivative I, in an aqueous or an hydrous solvent for instance, a linear or cyclic ether like ethyl ether, tetrahydrofuran, dimethoxyethane or Dixon, an aliphatic or aromatic hydrocarbon like Newton or Bunsen, a halogenated hydrocarbon like ethylene chloride, or a hydroxyl-containing solvent like methyl, ethyl or isopropyl alcohol, as well as mixtures of these. The reaction temperature may range from -40 C to the boiling point of -the solvent, but is preferably between -25 C and ~25 C.
A tertiary alcohol is prepared by reaction with an organometallic derivative to give, after any protecting groups are removed, a compound I
in which Y is -CH2-CH2- or -CHIHUAHUAS-, Z is as defined above, and one of R3 and R4 is Of C6 Y ' 2 10 Y 2 10 1 6 alkyd while the other is hydroxy. The organome-tallic may be a magnesium derivative like RlOMgHal (in which Rio is Cl-C6-alkyl, C2-C10-alkenyl, phenol or aryl-Cl-C6-alkyl and Hal is halogen, preferably chlorine or bromide), a lithium curate like RloCuLi (Rio as above), an organoli-thiwm derivative like RloI.i (Rio as above), or an alkali or alkaline earth ace-tylide (Rll-C--C-) M (in which n is 1 or 2, Roll is hydrogen, Stewart or branched I.. I.

Cl-C8-alkyl, aryl-Cl-C6-alkyl, or aureole, particularly phenol, and M is an alkali or alkaline earth metal). The reaction between -the carbonyl compound and one ox these org~nometalllc derivatives is preferably run with 1.05 moles (or slightly more) of reagent per mole of compound, in an anhy~rous solvent:
for instance, an aprotic solvent like dimethylsulfoxi.de or heY.clrneth~lphos-formed, a linear or cyclic ether like ethyl ether, tetrahydrofuran, anisole, Dixon or dime-thoxyethane, or an a:liphatic or aromatic hydrocarbon like Newton Nixon, Bunsen or -Tulane. The reaction temperature may range from approximately -70 C to the boiling point of the solvent, but is preferably between -60 C and 20 C.
Whether it is a secondary or tertiary alcohol, the product of this nucleophilic addition is a mixture of the epimeric S and R alcohols. The individual S ( Cud 1 ) and R I R ) alcohols (in which R12 is hydrogen, C -C -alkyd, C2-C10-alkenyl, C2-C10-alkynyl, phenol or aryl-Cl-C6-alkyl) may be separated as desired using the fractional crystallization and cremate-graph techniques described above.
The optional preparation of ethers from -these secondary and tertiary alcohols to give, after any protecting groups are removed, compounds with formula I in which Y is -CH2-CH2- or -CHIHUAHUAS-, Z is as defined above, and one of R3 and I is Cl-C6-alkoxy or aryl-Cl-C6-alkoxy while -the other is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenol or aryl-Cl-C6-alkyd, may be effected by reaction with an optionally aryl-substituted dia~.oalkane in the presence of a catalyst like fluoroboric acid or boron trifluoride in an organic solvent like dichloromethane. Alternatively, it may be done by reaction of the hydroxyl group (either free or as its salt) with an alkyd or arylalkyl halide in the presence of a base like silver oxide, in a solvent like dimethylsulfoxide or dime-thylformamide.
The following reactions are all run using standard procedures:
optional transformation of a compound with formula I into another, optional lactose or salt preparation, preparation of the free compound I from its salt/ and separation of individual isomers from a mixture.
For example, a compound with formula I in which R3 and Al are both hydrogen may be prepared from one in which one of R3 and R4 is hydrogen while the other is hydroxy by preparing the tessellate from -the alcohol, for instance by -treatment with tussle chloride Lo the presence of base, and reducing the tessellate with Nub or NaB(CN)H3 in water, aqueous alcohol or dime-thylEorln-aside or with Lyle in an an hydrous solvent like ethyl ether or tetrahydro-Furman, a-t a temperature raying from room temperature to the boiling puerility of the solvent. Analogously, a compound with formula I in which Al and R2 are both hydrogen may be prepared from one in which one of Al and R2 is hydrogen while the other is hydroxy, and a compound I in which D is -SHEA- may be pro-pared from one in which D is SHEA.
A compound with formula I in which R3 and R4 together form an ox group may be prepared from one in which one of R3 and R4 is hydrogen while the other is hydroxy by selective oxidation with excess activated Noah in an inert, preferably chlorinated solvent like ethylene chloride or chloroform at room temperature or, alternatively, with 1.1-1.2 molar equivalents of dichlorodicyanobenzoquinone in an inert solvent like Dixon, Bunsen or a mixture at a temperature ranging from 40 C to the boiling point of the solvent.
In an analogous fashion a compound with formula I in which Al and R2 -together form an ox group may be prepared from one in which one of Al and R2 is hydrogen while the other is hydroxy, and a compound I in which D
is KIWI may be prepared from one in which D is SHEA.
When only one of several secondary alcohol functions is to be oxidized, the others must be protected as described above the protecting groups are then removed at the end of the reaction.
A compound with formula I in which one of Al and I is Cluck-alkoxy or aryl-Cl-C6-alkoxy may be prepared from one in which one of Al and R2 is hydroxy through etherification analogous -to that described for a compound with formula I in which one of R3 and R4 is hydroxy. Again, when only one of several secondary alcohol functions is -to react, -the others must be protected; the protecting groups are then removed at the end of the reaction.

A compound with formula I in which R is a carboxylic ester group (for instance, a Cl-C12-alkoxycarbonyl) may be prepared from one in which R
is a free carboxylic group by following standard procedures, for qxampl~
reaction with an appropriate alcohol, like a cl-C12-aliphatic alcohol, in the presence of an acid catalyst, like p--toluenesulEonic acid, or alterna -lively, treatment with a diazoa:Lkane.
The optional conversion of a compound with formula I in which R is an esterified carboxyl group (i.e., a Cl-C12-alkoxycarbonyl) -to one in which R is a free carboxyl group may be effected using standard saponification procedures: treatment with an alkali or alkaline earth hydroxide in water or aqueous alcohol, followed by acidification.
The optional preparation of a compound with formula I in which R
is -SHARI" (R"=hydroxy) from one in which R is a free or es-terified carboxyl group may be effected by reduction of the ester with Lyle in ethyl ether or tetrahydrofuran at reflex.
The optional conversion of a compound with formula I in which R is a free earboxyl group to one in which R is CON R era and Rub as defined above) may be effected by treatment with an amine HER Rub in the presence of a condensing agent, for instance a carbodiimide like dieyclohexylcarbodiimide.
A compound with formula I in which R is a earboxylic ester may be converted into one in which R is -CON / R by -treatment with an amine HER Rub in a suit-able organic solvent at reflex for 2-3 hours.

The optional preparation of a compound with formula I in which R is N-N
a -C ¦¦ radical from one in which R is a free carboxyl group may be NH-N
effected by forming first the corresponding acid halide (preferably chloride, perhaps with thinly or oxalyl chloride in refluxing dichloroe-thane or Dixon), then the aside derivative (for example, with ammonia), followed by dehydration to -the nitrite (for instance with p-toluenesulfonyl chloride in pardon at 90-100 C) and finally reaction of -the nitrite with sodium aside and ammonium chloride in dimethylformamide at a temperature ranging from room temperature to 100 C. This reaction of -the carboxyl group to give -ON or N-N
I is preferably run on the starting material.
\ NH-N

I? - 13 -1' I"

lt7 The optional conversion of a compound with formula I in which R is a free or esterified carboxyl group into one in which R is -KIWI may be effected using standard procedures, for instance the preparation of the corn responding chloride from -the acid or ester and subsequent RoSenmund reaction as described in Org. Reactions).
A compound with phenol I in which R is -COREY (R' as defined above) may be prepared from one in which R is a free or eastward carboxyl group by reacting the hydrochloride of the carboximide ester (prepared with standard methods) with a suitable alcohol, according -to the procedure described in J. Amer. Chum. Seiko), for example.

Acetalization, for example the optional preparation of a compound OR
with formula I in which R is -OH era (where X' is oxygen and R' and Rub are as defined above) is effected by reaction o-f the alluded with an alcohol or ylycol in the presence of a catalyst like p-toluenesulfonic acid or a sulfonic resin in a solvent which allows the removal of the water formed by azeotropic distillation, by an exchange reaction with acetone-dioxolane in which acetone is removed as it forms, or by reaction with an ortho-ester in which the alcohol is distilled away as it forms. The acutely may also be prepared from the corresponding thioacetal by reaction with a suitable alcohol or glycol in the presence of a mercuric salt (preferably HgC12) as an exchange catalyst and an alkaline earth carbonate, in an inert solvent.

Thioacetalization; for example the optional preparation of a come OR
pound with formula I in which R is -OH era (where X' is sulfur and R' and Rub are as defined above) from one in which R is -COO, is preferably effected by reaction with a moo- or dimercaptan like methylmercaptan, e-thylmercap-tan, dithioethyleneglycol or dithiopropyleneglycol in the presence of a catalyst like boron trifluoride ether ate in an inert solvent, preferably a halogenated or aromatic hydrocarbon (ethylene chloride, chloroform, Bunsen, Tulane).
The corresponding petals and thioketals may be prepared from kittens by following the procedure described above for acetals and trio-ace-tals.
Lactose and salt preparation from a compound with formula I, as I - I -well as preparation of compound I from its salt, are performed using standard procedures.
Individual isomers are separated from mixtures of lsomeric come pounds I using standard -techniques like Tractional crystallization and chromatography.
Compounds with formula III in which E is (R O)2P-~(O~- (R as defined above) are prepared by reacting a compound VII
R O \ O
/ P-CH2-(CH2)m D (Shim VII
Roe in which R , ml, D, my and R"' are as defined above, with at least one molar equivalent of one of the following bases: an alkali or alkaline earth hydrides like sodium, potassium, lithium or calcium hydrides an alkali or alkaline earth alcohol ate like sodium or potassium tert.-bu-tylate, an alkali or alkaline earth aside like sodium aside, or an alkali or alkaline earth salt of a carboxyamide, like N-sodioacetamide and N-sodiosuccinimide.
Compounds with formula III in which E is (C6H5)3P- are prepared by reacting a compound with formula VIII
Hal-cH2-(cH2)m D (Shim VIII
in which ml, D, my and R"' are as defined above and Hal is halogen, with 1.1-1.3 molar equivalents of triphenylphosphine in an organic solvent like Bunsen, acetonitrile or deathly ether and then treating the product pros--phoneme salt with an equivalent quantity of an inorganic base like Noah, KOCH, Nikko or Nikko Compounds with formula VII are prepared using standard methods, for example those described by Corey et at. in J. Amer. Chum. Seiko) and 88,5654(1966). Compound VIII is also prepared following standard procedures.
Compounds with formula II are new compounds covered by this invent lion, as are procedures for -their preparation.
Compounds with formula II in which Y is -CH2-CH2-, or -SWISS-, Z
as defined above, are prepared in a procedure involving:

(a ) reaction of a compound with formula XI
G \
( I ) p (SHEA 2 ) q H H XI

wherein p, q, Al and R'2 are as defined above and G is a protected carbonyl group or a group I OX' wherein G' is a sill ether or acutely ether residue, with a compound of formula V
I
E~CH-C-(CH2) X (C 2) 7 V

wherein E, Z, ml, R5, R6, X, my and R7 are as defined above, to afford a compound of formula XII
G

/ \
( OH 2 ) P ( OH 2 ) H H
XII
I

lo l I lo R5, R6, X, no and R7 are as defined above;
(b ) optional conversion of a compound with formula XII into a compound of formula XIII
/ G
(Swoop (SUE) El H
I =R~3 R5 XIII

Al y'-C-(CH2)n I (Sheehan 7 R~4 R6 1 2 3' 4, no, R5, R6, X, no and R7 are as defined above, and Y' is -CH2-CH2- or -CHIHUAHUAS-, Z as defined above;
(c ) removal of -the protecting group in G to afford a cornpownd of formula XIV
G"

I p 2 q H H
¦ XIV

1 R YUCCA ) -C-X-(CH ) -R
R~4 R6 1 2 ' 3' 4, no, R5, R6, X, no and R7 are as defined above and G" is SHEA OH or KIWI;
(d ) optional oxidation of a compound of formula XIV wherein G"
is cry and the other hydroxy groups, if present, are protected as report-Ed above.
The reaction between a compound with formula XI and one with formula V is run in the same way as that reported above for the reaction between compounds II and compounds III.
The optional conversion of a compound with formula XII into one with formula XIII is effected with reactions analogous -to those described above for the preparation of one compound with formula I from another: for example, nucleophilic addition to the carbonyl on the chain, etherifica-lion of the product alcohols and hydrogenation.
As stated above, when G is a group ~CH~MOG', the protecting group G' may be a sill ether residue (for instance, a trialkylsilyl ether like trim ethyl, dime-thyl~tert.-butyl, dimethylisopropyl, or dimethylethylsilyl ether, but preferably dimethyl-tert.-butyl) or an acutely ether residue (for instance, tetrahydropyranyl ether, tetrahydrofuranyl ether, dioxanyl ether, oxa-thianyl ether, but preferably tetrahydropyranyl).
The protecting group G' in a compound with formula XIII is removed as described previously: that is, selectively, with F for a sill ether and with acid hydrolysis for an acutely ether. When a protecting group G' must be removed in the presence of other labile ether groups, these latter should be acutely ethers when -OX' is a sill ether or sill ethers when -OX' is an acutely ether.
hen G is a protected carbonyl group it is preferably protected as acutely or -thioace-tal, for example a dimethoxyacetal, a diethoxyaceta:l, a dimethylthioacetal, a diethylthioacetal, preferably a dimethoxyacetal, or as Cal -O-petal, or -thioketal, for example a ethylenedioxyke-tal SHEA 0 , a propylene-dithioketal (SHEA) S a propylenedioxyketal (OH ) O , a ethylenedi-thio-petal OH -S preferably a e-thylenedioxyke-tal.
The removal of said protecting groups in a compound of formula XIII
as well as the optional protection of the free hydroxy groups in a compound of formula XIV, e.g. as acutely ethers or sill ethers, may be effected as previously reported.
The optional oxidation of a compound of formula XIV wherein G" is hydroxy, may be effected using standard oxidation procedures for secondary alcohols: for example treatment of the alcohol in an organic solvent like acetone with a solution of chronic android in sulfuric acid, following normal procedures.
Compounds with formula XI are prepared with a procedure involving:
(a ) conversion of a compound XXIA or XXIB
OH G"' / \
Jo (SHEA) SHEA) q H H
(SHEA) (Schick XXIA ¦ XXIB

H H

\ I OH
o in which p and q are as defined above and G"' is a protected carbonyl group as reported above, into a compound XXII

I.

b. , -- 18 --(Shop (Schick H H
XXII

in which p, q, end G are as defined above;
(b ) reaction of compound XXII with a compound OKRA in which R is a Cl-C6-alkyl or aryl-Cl-C6~alkyl to give a compound with formula XXIII
G

"2 p _ 2 q H H
< ¦ XXIII

o COREY

in which p, q, G and R13 are as defined above;
(c ) reduction of -the product compound XXIII to a compound with formula XXIV
G
I P (SHEA) H H
\ ¦ XXIV

H OH COREY

in which Go p, q and R13 are as defined above;
(d ) optional separation of compound XXIV into -the individual optical antipodes;
(e ) optional conversion of compound XXIV into a compound with formula XXV

I, i - 19 ", ( OH 2 ) ~1~1 xxv OH H COREY

in which G, p, q and R13 are as defined above;
(f ) transformation of a compound XXIV or XXV into a compound with formula XXVI

/ G C
( OH 2 ) P H 2 ) H H
¦ XXVI

R' ' COO

wherein G, p, q, Al and R'2 are as defined above.
A compound of formula XXII wherein G is a group SHAG', in which G' is as defined above may be prepared from one of formula XXIA by known methods, e.g. by reaction in the presence of base, with a sill halide, a Solon or a sill trifluoroacetamide or, for example, by reaction with a vinyl ether X~=~G where X" is -O-, -S- or -(SHEA) (r=0~1), according to known procedures.
A compound of formula XXII, in which G is a protected carbonyl, may be prepared from one of formula XXIB by oxidation in pardon with an excess of the pyridine-chromic android complex, or by oxidation according to Moffat-t in a mixture of Bunsen and dimethylsulphoxide with duskily-hexylcarbodiimide in the presence of pyridinium trifluoroacetate.
the reaction between a compound with formula XXII and OKRA
try as defined above, but preferably methyl) is run in the presence of I
moles of a base like sodium methoxide, sodium ethoxide, sodium or potash-I'm hydrides or potassium ter-t.-butoxide, with an excess of 6-12 moles of .
my. - 20 -carbonic duster per mole of kitten, neat or in an inert solvent in an ox-gent and water free atmosphere The -temperature may range from approximately 0 -80 C (preferably 60-~0 C) for a period between 10 minutes and 1 hour.
The yield varies from 5% to 90%, depending on the -temperature, the reaction -time and the concentration.
A compound with formula XXIII may be reduced with an alkali or alkaline earth bordered in aqueous solution, preferably a-t a pi between 5.3 and 7.2, or at -20 C with ethanolic Nub in ethylene chloride/ethanol.
Generally, the reduction is complete in 30 minutes and the excess reagent is quenched by adding a readily reducible species, like acetone, and a proton donor, like acetic acid.
The individual optical antipodes of a compound with formula XXIV, in which G is as defined above, may be separated by saponifying the ester using standard procedures, forming a salt of -the product acid with an optical-lye active base like quinine, chinconine, ephedrine, l-phenyl-l-amino-ethane, dihydroabietylamine, amphetamine or arginine, and separating the resulting diastereomeric salts by fractional crystallization, for example. The optically active acid is then recovered by conversion to the sodium salt and subsequent acidification of its aqueous solution to a pi which does not interfere with the protecting group in G.
Optionally the hydrolysis of the protecting groups may precede the optical resolution: -the protecting groups are then restored at the end of the separation process.
The optically active free acid prepared in this way is then con-vented to an optically active ester XXIV using standard procedures, for instance treatment with a suitable di.azoalkane.
If desired, using an identical procedure, a rhizomic mixture of come pounds XXV may be separated into individual optical antipodes.
Alternatively, compounds XXIV and XXV wherein G is a protected carbonyl group may be resolved into their optical antipodes deprotecting the carbonyl group in G, reacting -this with an optically active primary amine, for example arginine, Lawson, ala nine, 1-phenyl-1-ethyl-ami.ne, l-phenyl-l-119~3417 propyl-amine and similar, to give the corresponding optically active diastereoisomeric Showoff bases; these may be separated by known methods, e.g.
by fractionate crystallization or by HP~C, the amino group may be hydrolyzed to KIWI in a known manner then the separated optically active keto-esters may be transformed into the optical antipodes XXIV and XXV by ketalization or acetalization in a conventional way.
The optional conversion of a compound with formula XXIV to one with formula XXV may be done on either a rhizomic mixture or the individual isomers separated as described above. In this transformation, the configure-lion of the free hydroxyl on the cyclopentane ring is inverted. The prove-dune involves esterification of the hydroxyl, for example by treatment with 2-4 molar equivalents of triphenylphosphine and 2-4 molar equivalents of a carboxylic acid like acetic, benzoic or p-phenylbenzoic, or with 2-4 molar equivalents of ethyl azo-bis-carboxylate in an inert solvent like an aroma-tic hydrocarbon, perhaps halogenated, like Bunsen or chlorobenzene, or a cyclic ether like tetrahydrofuran, and subsequent selective saponification of the ester function formed in this way, for example by transesterification in an inert alcohol R130H in the presence of an alkali carbonate, preferably K2C03 .
A compound with formula XXVI is prepared from a compound XXIV or XXV using known methods. For example, the free hydroxyl group in compound XXIV or XXV may be converted to a Cl-C6-a]koxy, an aryl-Cl-C6-alkoxy or a labile ether like a sill or acutely ether using the ether preparation techniques already described for the analogous reactions of compounds with formula I.
The free hydroxyl group in a compound with formula XXIV or XXV may be oxidized to an ox group, and the product kitten may be converted to a petal or thioketal according to the procedure described above for compounds with formula I to afford a tertiary alcohol.
A hydrogen atom may replace the free hydroxyl group in a compound with formula XXIV or XXV, for example, by treatment with a sulfonic acid chloride like p-toluenesulfonyl, methanesulfonyl or benzenesulfonyl chloride I.' arid subsequent reduction of the product sulfonate, for instills with Lyle in standard methods. In this case the carboxylic ester group (-COORS) is reduced at the same time -to the primary alcohol (-SHEA), which may -then be oxidized -to the alluded with Mets reagent.
A product compound with formula XXVII
/ G

H H

in which one of Al and R"2 is hydrogen, Of Colloquial, C2-C10-alkenyl, aureole or aryl-Cl-C6-alkyl while the other is hydroxy, Cl-C6-alkoxy, aryl-Cl-C6-alkoxy or a labile ether group, or Al and R"2 together form a kitten pro-tooting group may be converted to the corresponding compound with formula XXVI by reduction following standard procedures, for example, with dyes-butylaluminum hydrides or lithium diisobutylaluminum hydrides When a compound XXVII is reduced with Lyle following standard procedures, -the product is the corresponding primary alcohol which may also be prepared from -the free acid by standard reduction with BH3 in tetrahydro-Furman. The free acid is prepared by saponification of -the ester. This prim many alcohol may then be oxidized to the alluded, with Moffat-t's reagent, for example, as mentioned previously.
Compounds with formula XXIA and ZEBU are prepared with known methods. For example, a compound XXIA in which pal is prepared by selective reduction of bicycle [3.3.0] octane-3,7-dione (J Amer. Chum So., 82,6347(1960)) or by reduction of bicycle [3.3.0] octane-3,7-dione-monoketal (J. Comma)), followed by removal of the kettle from -the carbonyl function. In both cases, the product hydroxy kitten XXI with pal is a mixture of -the endo-hydroxy and exo-hydroxy derivatives, with approxi-mutely 80~ endow The two isomers may readily be separated, using -the cores-pounding rhizomic silyloxy derivative, by fractional crystallization or chromatography, as described several -times above.
A compound with formula XXI in which pal and q=2 is prepared frown bicycle [4.3.0] non-7-en-3-one XXVIIX

-o XXVIIt which has a is junction between the two rings, in a procedure involving the protection of the kitten as a petal or thioketal (as described above), stand-end hydroboration of the double bond, and subsequent removal of -the kitten protecting group as described above.
Compound XXVIII may be synthesized, for example, as described by J. P. Vital in "5tereochimie et Selectivity Reactionelle en Serve Bicycle [n.3.0] alcanique", presented at the University de Sciences et Techniques duo Languedocr Academic de Montpelier, n diehard C.N.R.S.~.O. 11257(1975).
A compound with formula XXIA in which pal and q=2 (prepared, for example, as described above) may be converted to other XXI derivatives by successive ketalization or thioketalization, oxidation, Bayer-Willinger and formulation of the product using methods analogous to those reported above.
A compound of formula XXIB wherein p is zero and q is 1 or p is 1 and q is zero may be prepared from the bromidrine 5-exo-bromo-6-endo-hydroxy-bicycle [3.2.0] hootenanny [J. Chum. So., Perking 1, 1767 (1965)] by known methods: for example said bromidrine may be converted into its acutely, thioacetal, petal or thioketal, then dehalogenated to the compound XXIB using the known methods of organic chemistry such as, for example, the reduction with chromium (II) salts, the catalytic hydrogenation in the presence of Pd/CaCO3 or Pd/C and in the presence of anhalohydric acid acceptor, or the reduction with tributyl tin hydrides A compound of formula XXIB wherein p is 2 and q is 1 or q is 2 and p is 1, may be prepared, e.g., from a compound of formula XXVIII by a process comprising: reducing -the carbonyl group to alcohol, e.g. with Lyle in ethyl ether, protecting the alcoholic group, e.g. as tetrahydropyranylether to 3L~984~

or sill ether, hydroborating, by conventional methods, the olefinic double bond, oxidizing, Deb locking the protected hydroxy group, following the acetalization or ketalization.
A compound of formula XXIB wherein p=q=2 may be prepared by know methods e.g. from 2-hydroxy-perhydro-azulen-6-one which in -turn may be ox-twined as described by D. K. Bonnier and K. Ankara Ram. in In. J. of Chum. vol. X, page 1 (lg72).
The compound of formula XXVIII may be used as starting material also for the preparation of the compounds of formula XI wherein G is a group SHAG' wherein G' is the residue of a sill ether and wherein, when one of Al and R'2 is hydrogen and the other is hydroxy, the latter is preferably protected as acutely ether or as ester, following the reaction scheme reported below:

~C2C33 ~C~2C33 O OH
(XXVIII) (XXIX) (XXX) OX' OX' Octal O-AcetalO-Acetal (XXXI) (XXXIIa : GO (XXXIIIa : GO
(XXXIIb : G'=silyl- (XXXIIIb : G'=silyl-ether residue) ether residue) The compound XXVIII, by known methods, e.g. those previously reported, is converted into the kowtow ester XXIX which is reduced to the ~-hydroxy ester XXX wherein the hydroxy group is protected as acutely ether;
the obtained compound XXXI is then submitted, in a conventional manner, to the hydrobora-tion at the olefinic double bond to give the alcohols XXXIIa and XXXIIIa which are then resolved by chromatography or by fractionate crystallization, converted into -the corresponding sill ethers XXXIIb and XXXIIIb and finally transformed into -the compounds of formula XI by reduce lion with dlisobutylaluminium hydrides in Tulane according -to known methods.
The compounds of formula I show the same pharmacological activities as -the natural pros-tacyclin, or PGI2 but, as compared with PGI2, the come pounds covered by this invention have a particular advantage in their greater stability in the range of pi between zero and 11, in particular, at physiologic phi this leads to longer lasting and more constant biological activity. The source of this greater stability is -the different chemical structure of these compounds as compared to natural prostacyclin. Since there is an oxygen heteroatom in the 2-oxa-bicyclo ~3.3.0] octane system, natural prostacyclin is an exocyclic enol ether and so is extremely acid sensitive. The product of reaction with acid, 6-keto-PGF , shows almost lo none of the biological activity characteristic of natural prostacyclin. On the other hand, the compounds covered by this invention have no oxygen in the bicyclic system and so are not enol ethers. Since -they are not highly labile as are the natural derivatives, they may be administered by mouth.
In addition, compounds of formula I in which there is a hindering group, such as a Cl-C6-alkyl group or an electron receptor group, e.g.
fluorine, near the hydroxyl in position 15 (R3 or R4 = hydroxy) are more resistant to enzyme-induced (for instance, 15-PG-dehydrogenase) metabolic degradation than natural prostacyclin.
The pharmacological actions of natural prostacyclin are known.
Thus, for example, when inhaled in asthmatic patients, pros-tacyclin prevents specifically induced (e.g. by nebulized water or by effort) bronchoconstric-lion [S. Bunk et at, J. Rest Medical Science, 6, 256 (1978)]; when infused in man, it shows hypotensive and vasodilator activity and also shows blood platelet anti-aggregant and disaggregant proper-ties [Suckle et at, Harm.
Rest Comma 10, 545 (1978)~; prostacyclin also possess uterus stimulant action in the monkey and in woman; furthermore, pros-tacyclin exhibits luteolytic activity in test animals and is able -to protect the gastric mucous membrane from ulcers induced by non-s-teroidal antiinflammatory substances, e.g.

acutely salicylic acid (AS) and indomethacin, in test animals. e.g. the rat.
In natural prostacyclin these activities are combined with a marked chemical instability which is unsuitable for pharmaceutical use. As already reported, the compounds of formula I have pharmacological actions similar to those of natural prostacyclin but the undesired comics instability of PGI2, is absent in the compounds of the invention.
In comparison with PGI2, for equally active antiaggregant doses, the in vitro luteoly-tic activity in -the hamster is eight times greater for __ _ 5c,13t-lla,15S-dihydroxy-9a-deoxy-9a,7a-homo-dimetthylene-1~-phenoxy-17,18, 19,20-tetranor, prostacycla-5,13-dienoic acid.
As -to their prostacyclin- and prostaglandin-like activity the come pounds covered by this invention may be used in human and veterinary medicine when natural prostacyclin and prostaglandins are indicated there-poetical.
For instance, these compounds are useful in -treating asthma because of their pronounced bronchodilatory effect. In this application, they may be administered by various routes:

go -orally in tablets, capsules, pills, or liquids like drops or syrups; rectally in suppositories, intravenously, in~ramuscul-arty or subcutaneously; by inhalation as aerosols or vaporizer solutions; or by insufflation as powders. Doses of approYlmate~
lye 0.01-4mg/ky may be given from 1 to times daily, but the exact dose depends on -the age, weight and condition of -the patient as well as -the administration method.
For anti-asthmatic applications the compounds covered by this invention may be combined with other anti-asthmatic:
simpaticomimetics like isoproterenol, ephedrine, etc.; xanthine derivatives like theophillin and aminophillin; and corticoster-oils like prednisolone and ACT
In addition the compounds covered by this invention exhibit oxytocic activity and so may be used in place of oxytoc-in to induce labor or expel a dead fetus, both in human and veterinary obstetrics. For this application, the compounds are given intravenously at a dose of approximately O.Ol~g/kg/minute until the end of labor, or by mouth.
The compounds covered by this invention are also luteolytic and so are useful in fertility control, with the advantage -that they stimulate the smooth muscles much less and so are free of the side effects of natural prostaglandins like vomiting and diarrhea.
Further, these compounds are anti-ulcerogenic and thus may be used to reduce and control excessive gastric secretion in mammals. In this way they minimize or eliminate -the form-anion of gastrointestinal ulcers and accelerate the cure of any ulcers already present in the gastrointestinal tract. They are administered in this case by intravenous infusion or by intro-venous, subcutaneous or intramuscular injection; doses for I
., Jo Lo intravenous infusion range from Old to 500 ~g/kilo/minute.
The total daily dose for both injection and infusion is on -the order of 0.1-20mg/kg depending on the age, weight an condition of the patient or animal and on the administration method.
Louvre, like natural pros~acyclines, the most import lent pharmacological property of the compounds covered by this invention is their platelet anti-aggregant activity, that is, the capacity -to inhibit platelet aggregation, to decrease adhesion to prevent clot formation and to dissolve recently-formed clots. This platelet anti-aggregant activity is also associated with a relaxing of the coronary arteries. For these reasons, these compounds are useful in preventing and treating myocardial infarctions and, in general, in treating and preventing thermoses, in treating conditions like author-sclerosis, arteriosclerosis and, more generally, dihyperlipi-Delia.
Normal administration methods are used in this Apple cation: that is, intravenous, subcutaneous, intramuscular, etc.
In emergency situations intravenous administration is preferred, in doses ranging from 0.005 to 20 mg/kg/day, again depending on the age, weight and condition of the patient and on the ad mini-striation method.
As mentioned above, the compounds covered by this invention are useful in human and veterinary therapy, with several administration methods. They may be given orally in tablets, capsules, drops or syrups; rectally in suppositories;
parenterally, in solutions or suspensions gives subcutaneously or intramuscularly; intravenously, as preferred in emergencies;
by inhalation in aerosols or vaporizer solutions; in sterile grafts for prolonged action; or endovaginally, for instance in -;, ho vaginal suppositories.
Pharmaceutical and veterinary composition of -the compounds covered by this invention may be prepared convention-ally using common carriers and/or delineates. For example, sterile and isotonic aqueous solutions are preferrer or intravenous injection or infusion. Sterile aqueous solutions or suspensions in aqueous or non aqueous medium are used for subcutaneous or intramuscular injections. A sterile compress or a silicon rubber capsule containing or impregnated with the active ingredient may be used for sterile grafts.
Conventional carriers and delineates include water, gelatin, lactose, dextrose, sucrose, minutely, sorbitol, cellulose, talc, Starkey acid, calcium and magnesium Stewart, glycols, starch, gum Arabic gum adragant, alginic acid, align-ales, lecithin, polysorbates, vegetable oils, etc.
The compounds may be given with a vaporizer using an aqueous suspension or solution of them, preferably in their salt forms, for instance the sodium salt. Or the compounds may be suspended or dissolved in one of -the common liquefied propel-tents like dichlorodifluoromethane or dichlorotetra-fluoroethane and given with a pressurized container like an aerosol bomb. When the compound is not soluble in the propel-tent, a co-solvent must be added to the pharmaceutical formulation for instance, ethanol, dipropyleneglycol and/or a tensioactive substance. In the following examples, TOP, DMtB, DICK, THY, DMSO, DIVA and DMF refer respectively to tetrahydro-perineal, dimethyl-tert-butyl, 1,4-diox-2-enyl, tetrahydro~uran, dimethylsulphoxide, diisobutylaluminiumhydride and dim ethyl-formamide.
The following examples illustrate but do not in any I

way limit the present invention.
Example 1 lug of sodium bordered (0.029 molt is added with stirring to a solution of 11.6g of bicyclo[3.3.0]octane~3,7-drone (8.4xlO Molly) in loom of ethylene chloride end loom ox ethanol. After 45 minutes at this temperature, the excess fee-gent is decomposed by slowly adding 20ml of acetone. The mix-lure is then neutralized with 1.4ml of acetic acid, and vapor-axed under vacuum to afford a residue which is taken up in water and methane chloride. The organic phase is evaporated to dry-news and filtered on silica gel (70:30 hexane:ethyl ether as fluent) to afford 9.lg of 7~-hydroxy-bicyclo~3.3.0]octan-3-one.
A solution of this compound (Molly) in 27ml of an hydrous dimethylformamide is treated with 12.8g of dim ethyl-tert-butylsilyl chloride and 8.85g of imidazole. The resulting mixture is heated to 60C for 5 hours, cooled, diluted with two volumes of water and extracted with ethyl ether (3x40ml and 2x20ml). The combined organic extract is washed with 5% Nikko and then water until neutral and evaporate to dryness to give 15.8g of crude product (95% yield). Purification on silica gel affords 2.85g of 7-exo-hydroxy-bicyclo[3.3.0]octan-3-one-dimethyl-tert-butylsilyl ether and 11.8g of 7-endo-hydroxy-bicyclo[3.3.0]octan-3-one-7-dimethyl-tert-butylsillye ether.
A solution of the latter (11.8g, 4.63xlO molt in 295ml of methyl carbonate (Mohawk) is stirred with the exclusion of water in an inert atmosphere and treated cautiously with 6.95g of 80% sodium hydrides When hydrogen evolution ceases, the reaction mixture is heated at 75-80 for forty minutes.
After cooling, the mixture is diluted with two volumes of ethyl ether and cautiously treated with 13g of glacial acetic acid.
The organic phase is then separated with pi 5.2-5.5 buffer and the aqueous layer is extracted with ethyl ether. The combined organic extract is dried over Nazi and evaporated to dryness to give 12.82g of d,l-7-endo-hydroxy-bicyclo[3.3.0]octan-3-one-2 carboxymethyl-ester-7-dimethyl--tert-bu-tylsilyl ether ~85% of the 14.49g theoretical yield which after purification on silica gel (45g/g, with 97-3 hexane:ethyl ether as fluent) affords 10.81g of the pure product;~max=254m~"~=7,000.
Starting with the ego isomer, the same procedure affordsd,1-7-exo-hydroxy-bicyclo[3.3.0]octan-3-one-2-carbboxy-methylester-7-dimethyl-tert-butyl silylether;~max=254m~ =6,500.
Example 2 A solution of 7.5g of d,1-7-endo-hydroxy-bicyclo [3.3.0]-octan-3-one-2-carboxymethylester-7-dimethyyl-tert-butyl silylether (DMtB-silylether) in 75ml of dichloromethane and 75ml of ethanol is cooled to -20C and treated with stirring with O.9g of sodium bordered. After stirring for 15 minutes, the excess reagent is destroyed by adding 12ml of acetone. The mixture is 20 brought to 0C, 20ml of 20% KH2PO4 is added, the solvent is evaporated under vacuum and the residue is extracted several times with ethyl ether. The combined organic extract is washed with 5ml of water and evaporated to dryness to afford a residue which is crystallized from Nixon to give 4.8g of dunned-dihydroxy-bicyclo[3.3.0]-octane -2-exo-carboxymethylester-7-DMtB-silylether, m.p.=~8-70C. The mother liquor is adsorbed on 25g of silica gel; elusion with 90:10 n-heptane:ethyl ether gives another 2g of product pure enough to be used as is.
A solution of 6g of d,1-3,7-endo-dihydroxy-bicyclo 30[3.3.0]-octane-2-exo-carboxymethylester-7-DMtB-sillylether in ;~!

loom of 80:20 methanol water is treated with 2g of potassium hydroxide and heated to rollicks for 3Q minutes. after concentra-lion under vacuum, the mixture is acidified to pi 5.1 and extracted with ethyl acetate. Evaporation of the organic layer gives 5.1g of d,l-3,7-endo-dihydroxy-2-carbo~y-bicyclo-[3.3.0]-octane-7-DMtB silylether. A solution of this compound in 150ml of acetonitrile is then treated with 2.81g of d-~)-ephedrine.
4 hours at room temperature afford yo-yo of a salt which is crystallized twice from acetonitrile to give 1.85g of (+)-3,7-endo-dihydroxy-2-exo-carboxy-bicyclo[3.3.0]-octanee-7-DMtB-sily-lether-d(+~-ephedrine salt. All the mother liquors are collect-Ed and evaporated to dryness to give a residue which is dissolve Ed in water and treated with 0.68g of sodium hydroxide in water.
The d-(+)-ephedrine is recovered in a Bunsen extraction, and the sodium salt solution it acidified to phi and extracted with ethyl acetate. The organic phase is evaporated to dryness to give a residue which is treated with 2.2g of 1-ephedrine to afford after several crystallization 2.3g of end-dihydroxy-2-exo-carboxy-bicyclo~3.3.0]octane-7-DMttB-silylether -1-ephedrine salt.
Example 3 -A solution of 6.28g of d,l-3,7-endo-dihydroxy-bicyclo-~3.3.0]octane-7-DMtB-silylether-2-exo-carboxymethyLester in 30ml of an hydrous ethylene chloride is treated with 2.19g of 2,3-dihydropyran and 39mg of p-toluenesulfonic acid. After 3 hours at room temperature, the reaction mixture is washed with I
Nikko (2x5ml). Evaporation of the organic phase to dryness gives 8g ofd,l-3,7-endo-dihydroxy-bicyclo-[3.3.0]octane-7-DMttub-silylether-3-THP-ether-2-carboxy~ethyl ester, which is then dried by being taken up in an hydrous Bunsen (2xl5ml) and Lo '7 evaporated to dryness. This product in 30ml of an hydrous ethyl ether is added drops, in 15 minutes, to a stirred suspension of 0.6g of Lyle in 40ml ox an hydrous ethyl ether. Stirring is continued for 30 minutes before the excess reagent is destroyed by the cautious addition of 5ml of acetone followed by water-saturated ethyl ether. 10g of an hydrous sodium sulfate is then added. Filtration of the organic solution and evaporation to dryness afford 7.2~ of d,l-3,7-endo-dihydroxy-2-exo-hydroxymeth yl-bicyclo[3.3.0]octane-7-DMtB-silylether-3-T~P-etthen.
The following compounds are prepared in this way from optically active starting materials:
nat-3,7-endo-dihydroxy-2-exo-hydroxymethyl-bicycloowe]-octane-7-DMtB-silylether~3 THP-ether;
ent-3,7-endo-dihydroxy-2-exo-dihydroxymethyl-bicycclue]-octane-7-DMtB-silylether 3-THP-ether.
If Dixon is used instead of 2,3-dihydropyran, the corresponding 3(2'-DIOX)-ethers are obtained.
example 4 A solution of 3.8g of d,1-3,7-endo-dihydroxy-bicyclo-[3.3.0]octane-2-exo-carboxymethylester-7-DMtB-silyylether in 40ml of Bunsen is treated first with 3.66g of benzoic acid and 7.9g of triphenylphosphine, and then, with stirring, with 5.30g of ethyl azo-bis-carboxylate in 15ml of Bunsen. After 40 minutes of stirring, the organic phase is washed with ON sulfuric (2x20ml), and then sodium carbonate (3xl5ml) and finally water until neutral. Evaporation to dryness affords a mixture of d,l-3-exo-7-endo-dihydroxy-bicyclo[3.3.0]-octane-22-exo-carboxymethylester-7-DMtB-silylether-3-benzoate and dunned-hydroxy-bicyclo[3.3.0]oct-3-ene-2-exo-carboxymethyylester-7-DMtB-silylether.

'7 The crude reaction product it dissolved in an hydrous methanol, stirred for 3 hours, and treated with 0.5g of an hydrous potassium carbonate. Evaporation to dryness affords a residue which is taken up in ethyl acetate and saturated KH2PO4. The organic phase is washed until neutral and vapor-axed to dryness. The residue is adsorbed on silica gel and eluded with hexane and hexane:ethyl ether to give:
a) long of d,l-7-endo-hydroxy-bicyclo[3.3.0]oct-3-ene-2-carboxymethylester-7-DMtB-silylether, which is dissolved in methanol, treated with 0.3g of 5% Pod on Cook and hydrogenated at room temperature and pressure to give dunned hydroxy-bicyclo[3.3.0]octane-2-carboxymethylester-7-DMtB-ssilylether;
b) 2.01g ofd,l-3-exo-7-endo-dihydroxy-bicyclo[3.3.0]octane-2--carboxymethylester-7-DMtB-silylether, which is saponified as described in Example 2 with 5% potassium carbonate in 80:20 methanol water to give d,l-3-exo-7-endo-dihydroxy-bicyclo[3.300]~
octane-2-exo-carboxy acid-7-DMtB-silylether. This is then separated into individual optical antipodes with (+) and (-) amphetamine.
Reaction with ethereal dia~omethane converts -I-exo-7-endo-dihydroxy-bicyclo[3.3.0]octane-2-exo-caaerobics acid-7-DMtB-silylether into the methyl ester derivative. Subsequent reaction with 2,3-dihydropyran followed by reduction with Lyle in ethyl ether gives (~)-3-exo~7-endo-2-exo~hydroxy-methyl-bicyclo[3.3.0~octane-3-THP-ether-7-DMtB-sillylether.
The (--) enantiomers and the rhizomic mixture are prey pared analogously.
Example 5 5g of d,l-7-endo-hydroxy-bicyclo[3.3.0]octane-DMtB-silylether 3-exo-carboxymethylester in loom of aqueous methanol '7 is saponified with 2g of KOCH, at reflex. After the methanol is removed under vacuum, the aqueous solution of the potassium salt is extracted to remove neutral impurities, acidified, and extracted with ethyl ether. The latter extracts are combined and evaporated to dryness to give 4.5g of the do acid which is then separated into optical antipodes with (-I) and (-) ephedrine.
1.32g of (-)-7-endo-hydroxy-bicyclo[3.3.0]octane-7-DMtB-silylether-2-exo-carboxy acid is then dissolved in 20ml of THY and treated with 10ml of lo BH3 in THY. After 4 hours at room temperature, the excess reagent is destroyed by the cautious addition of 20ml of 1.5N Noah. The THY is then removed under vacuum and the aqueous phase is extracted with ethyl ether.
The combined organic extract is washed until neutral and evaporated to dryness to afford l.Q2g of (-)-7-endo-hydroxy-2-exo-hydro.Yymethyl-bicyclo[3.3.0]octane-7-DMtB-sillylether.
The (~) isomer and the rhizomic mixture are prepared analogously.
example 6 2.7g of d,1-7-endo-hydroxy-2-exo-hydroxymethyl-bicyclo[3.3.0]octane-7-DMtB-silylether in 20ml of ethylene chloride is treated with 0.95g of 2,3-dihydropyran and 20mg of p-toluenesulfonic acid for 3 hours at room temperature. After being washed with 7% aqueous Nikko and then water, the organic phase is evaporated to dryness to give crude d,1-7-endo-hydroxy-2-exo-tetrahydropyranyloxymethyl-bicyclo[3.3.Q]octtane-7-DMtB-silylether. This is dissolved in 15ml of THY and treated with 4.5g of tetrabu-tylammonium fluoride for 10 hours, with stirring.
The reaction mixture is then concentrated under vacuum, adsorbed on silica gel and eluded with benzene:ethyl ether to give 2.lg ofd,l-7-endo-hydroxy-2-exo-THP-oxymethyl-bicyclo-[3..3.0]octane.

A solution of this product in 25ml of acetone is cooled to -20C - -8 C with stirring and treated with 4.2ml of I Jones' reagent (Crow in aqueous sulfuric acid) over a period of 15 minutes, until a slight pink color persists. After an adcli-tonal 14-20 minutes of stirring, 1.5ml of isopropanol is added drops and the resulting green solution is diluted with 6 vowels of Bunsen. The organic phase is washed with 20%
(NH4)2SO4 until neutral], and the combined aqueous phase is no-extracted with Bunsen The combined Bunsen extract is dried and evaporated to dryness to afford 1.82g of d,1-2-exo-THP-oxy-methyl-bicyclo[3.3.0]octan-7-one.
The net- and enact- isomers are prepared analogously.
Example 7 With external cooling and stirring to keep the react lion temperature near 20-22C, a solution of 6.57g of potassium tert-butylate in 65ml of DMSO is added drops to 6.76g of 4-carboxybutyl-triphenyl-phosphonium bromide in 40ml of DMSO.
After the addition, the mixture is diluted with an equal volume of water, acidified to pi 5 and extracted with ethyl ether.
The aqueous phases are discarded, and the combined organic ox-tract is re-extracted several times with 0.5N Noah. The alkaline aqueous phases are acidified to pi and re-extracted with 50:50 ethyl ether:pentane. This combined organic extract is brought to small volume, treated with ethereal diazomethane until a yellow coloration persists, and then evaporated to dryness.
The residue is then dissolved in 50ml of acetone, treated with 20ml of ON aqueous oxalic acid, and held at 40-45C for 8 hours.
After the acetone is removed under vacuum, the aqueous phase is extracted with ethyl acetate, and the combined organic extract is evaporated to dryness. Purification of the resulting residue on silica gel with ethyl ether as fluent gives a mix-lure ofd,1-5-cis,trans-[2'-exo-hydroxymethyl-bicyclo[3.3..0]oct-7'-enyl]-pentenoic acid methyl ester (1.75g). The individual isomers may be separated with high pressure liquid-liquid chromatography to the 5-trans-d,l and the suicidal isomers;
the latter is named 5-cis-~(20-~12)-octanor-12-hydroxymethyl-9a-deoxy-9a-methylene-prostacycl-5-enoic acid methyl ester.
If the 4-carboxybutyltriphenylphosphonium bromide in the above procedure is replaced by one of the following Witting reagents (3-carboxypropyltriphenylphosphonium bromide, 5-carboxy-pentyltriphenylphosphonium bromide, 4-carboxy-2-oxa-butyl-triphenylphosphonium bromide), the methyl esters of the follow-in acids are prepared:
d,1-5-cis-~(20-~12)-octanor-2-nor-12~-hydroxyme-thhyl-9a-deoxy-9a-methylene-prostacycl-5-enoic acid;
d,1-5-cis-~(2n~12)-octanor-2a-homo-12~-hydroxymethhyl-9a-deoxy-9a-methylene-prostacycl-5-enoic acid;
d,1-5-cis-~(20-~12)-octanor-3-oxa-12~-hydroxymethyyl-9a-deoxy-9a-methylene-prostacycl-5-enoic acid;
as well as their trueness isomers and the individual net- and enact- antipodes.
example 8 A stirred solution of 7.16g of 5-cis-~(20-~12)-octanor-12~-hydroxymethyl-9a-deoxy-9a-methylene-prostacycllink acid methyl ester in 80ml of 75:25 benzene:dimethylsulfoxide is treated with 8.9g of dicyclohexylcarbodiimide and then with 14.2ml of a pyridinium trifluoroacetate solution (prepared by adding 25ml of 75:25 benzene:DMSO to lml of trifluoroacetic acid and 2ml of pardon). After four hours of stirring, the reaction mixture is diluted with loom of Bunsen and 3g of oxalic acid t I' in water is added drops. The dicyclohexylurea is removed by filtration, the organic phase is separated and washed with water (Sx6ml). Reduction in volume jives a Bunyan solution of the formula derivative which is added all at once to a solution of (2-oxo-heptyl)dimethyl phosphonate sodium salt. The latter is prepared by adding drops 7.58g of (2-oxo-heptyl)-dimethyl phosphonate in 40ml of an hydrous Bunsen to a stirred solution of 1.02g of sodium hydrides (80% mineral oil dispersion) in an inert gas atmosphere, continuing stirring until Ho evolution ceases. After the addition of the formal derivative to this sodium phosphonate salt, stirring is continued for 20 minutes.
The reaction my xture is then neutralized with saturated monosodium phosphate solution. The organic phase is separated, reduced to small volume, adsorbed on silica gel and eluded with cyclohexane: ethyl ether to give 6.4g of cisterns-deoxy-9a-methylene-15-oxo-prostacycla-5,13-dienoicc acid methyl ester.
Using an analogous 12~-hydroxymethyl derivative from example 7 gives the methyl esters of the following acids:
20 5-cis-13-trans-9a-deoxy-9a-methylene-15-oxo-2-nor--prostacycla-5, dunk acid;
5-cis-13-trans-9a-deoxy-9a-methylene-15-oxo-2a-hommo-prostacycla-dunk acid;
Swiss-trans-9a-deoxy~9a-methylene-15-oxo-3-oxa-prostacyyokel-dunk acid;
as well as their trueness geometric isomers, in the net-, enact-and do forms.
Example g A stirred and cooled ~5-8C) solution of 1.35g of 2-exo-hydroxymethyl-7-endo-hydroxy-bicyclo [3.3.0]octane-DMtB-I
silylether in 5ml of pardon is treated wit to 0.82g of bouncily chloride. After 8 hours at room temperature, ON H2S04 is added and the mixture is extracted with ethyl ether to give 2-exo-benzoyloxymethyl-7-endo-hydroxy-bicyclo [3.3.0]octane-7-DMt~-silylether. This silylether group is removed by reflex in 20ml of acetone with 8ml of ON oxalic acid. The acetone is removed under vacuum and the residue is extracted with ethyl ether -to afford, after purification on silica gel, l.llg of 2-exo-benzoyl~
oxymethyl-7-endo-hydroxy-bicyclo[3.3.0]-octane. This is disk solved in pardon and then added to a solution of lug of Crow in loll of pardon. After 6 hours at room temperature, this mixture is diluted with 20ml of Bunsen and filtered. The lit-irate is evaporated under vacuum and the residue is taken up in ON sulfuric acid and Bunsen. After being washed with ON H2SO4 and water until neutral, the organic extract is evaporated to dryness to afford 0.98g of 2-exo-benzoyloxymethyl-bicyclo[3.3.0]-octan-7-one. A solution of this compound in 5ml of an hydrous THY is then added to a solution of (2-oxo-S-trimethoxy-pentyl)-dim ethyl phosphonate sodium salt, prepared by adding drops a suspension of 0.23g of 80% sodium hydrides in HO to a solution of 2.12g of (2-oxo-5-trimethoxy-pentyl)-dimethyl phosphonate in 6ml of an hydrous THY. After 10 hours of stirring, the mixture is neutralized with 15% KH2PO4, the THY is evaporated under vacuum and the residue is extracted with ethyl ether. The combined extract is concentrated in volume, adsorbed on silica gel and eluded with hexane:ether to afford lug of bouncily-oxymethyl-bicyclo[3.3.0]oct-7-enyl-1,1,1-trimetho~~y-pent-5-en-4-one, or12~-benzoyloxymethyl-w(20-~12)-octanor-4-oxo-9a-deepoxy-9a-methylene-prostacycl-S-enoic acid-orthomethylester, as a mixture of the Swiss and trueness olefins which are then separate Lo I" 7 Ed by high pressure liquid-liquid chromatography.
Subsequent treatment with aqueous methanol and H2SO4 gives -the corresponding methyl ester derivatives. Reaction of 0.3g of methyl ester with 0.25ml of 1,3-ethanedithiol in ethylene chloride and a catalytic amount of BF3-etheLate for 15 minutes at 0C then affords 12~-benzoyloxymethyl-~(20-~12)-octanor-4,4-ethylenendithio-9a-deoxy-9a-me-thylenee-prostacycl-5-enoic acid methyl ester.
Example 10 0.8g of 12~-benzoyloxymethyl-~(20-~12)-oc-tanor-4-oxo-9a-deoxy-9a-methylene-prostacycl-5-enoic acid methyl ester in loll of methanol is selectively de-benzoylated upon treatment with stirring with 0.15g of an hydrous K2CO3. After the solvent is evaporated, the residue is taken up in 15% aqueous KH2PO4 and ethylene chloride to afford upon evaporation of the organic phase12~-hydroxymethyl-~(20-~12)-octanor-4-oxo-9a-deoxyyo-yo-methylene-prostacycl-5-enoic acid methyl ester A solution of this compound in loll of SCHICK and loll of ethanol cooled to -20C is treated with 90mg of Nub and stirred for two hours.
Excess reagent is then destroyed with 15~ aqueous acetic acid, the solvent is evaporated and the residue is adsorbed on silica gel. Elusion with ethyl ether affords 0.21g of 12~-hydroxy-methyl-~(20-~12)-octanor-4S-hydroxy-9a-deoxy-9a-meethylene-prostacycl-5-enoic acid methyl ester and 0.13g of the 4R-hydroxy isomer.
The individual products are then saponified with 20 aqueous methanol and 19~ potassium carbonate to afford, after acidification and extraction with ethyl acetate, 0.18g of 12 ~-hydroxymethyl-~(20-~12)-oc-tanor-4S-hydroxy-9a-dDixie-methylene-prostacycl-5-enoic acid-1,4-~-lactone and O.llg of the I I`

'7 OR isomer. Oxidation of these following the procedure in example 8 gives the formula derivatives.
Example 11 0.28g of 4,4~ethylenetithio-12~-benzoyloxymethyl-~
(20-~12)-octanor-9a-deoxy-9a-methylene-prostacycl--5-enoic acid methyl ester is selectively de-benzoylated upon methanolysis with K2CO3 in an hydrous methanol to jive the corresponding 12~-hydroxymethyl derivative. This is then oxidized to the alluded according to the procedure in example 8 to give the 12e-formyl derivative.
Reaction of 0.12g of this compound in Bunsen with the phosphonate prepared from 0.177g of (2-oxo-3,3-dimethyl-heptyl)-dimethyl phosphonate and 20mg of 80% Nay, as described in example 8, gives 5,13t-16,16-dimethyl-4,4-dithioethylene-dioxy-15-oxo-9a-deoxy-9a-methylene-prostacycla-5,1dunk acid methyl ester.
In an analogous fashion, using (4-cyclohexyl-2-oxo-butyl)-dimethyl phosphonate as the phosphonate and the US-lactose from example 10 as the alluded affords 5,13t-4S-hydroxy-15-oxo-9a-deoxy-9a-methylene-17-cyclohexyll-18,19,20-trinor-prostacycla-5,13-dlenoic acid-1,4-~-lactone. Or, with (3-phenoxy-2-oxo-propyl~-dimethyl phosphonate, 5,13t-45-hydroxy-15-oxo-9a-deoxy-9a-methylene-17,18,19,20-tetranor--phonics-prostacycla-5,13-dienoic acid-1,4-~-lactone is prepared.
Example 12 Using (2-oxo-3S-methyl-haptyl)-dimethyl phosphonate and (2~oxo-3S-fluoro-heptyl)-dimethyl phosphonate as the phase founts and 12~-formyl-~(20~12)-octanor-4R-hydro~y-9a Dixie-m.ethylene-prostacycl-5-enoic acid-1,4-~-lactone as the alluded, the procedures of examples 8 and 11 afford:

5,13t-4R-hydroxy-15-oxo-9a-deoxy-9a-methylene-16S--methyl-prostacycla-5,13-dienoic Acadia atone;
5,13t-4R-hydroxy-15-oxo-9a-deoxy-9a-me-thylene-l~SSyria-prostacycla-5,13-dienoic acid 1,4-~-lactone.
Example 13 A solution of 0.7g of 5c,13t-15-oxo-9a-deoxy-9a-me-thy-lene-prostacycla-5,13-dienoic acid methyl ester in 7ml of ethylene chloride and 7ml of ethanol cooled to -20C is treated with 38mg of sodium bordered. After 20 minutes of stirring, the reaction is quenched with 2ml of acetone and 2.5ml of 20%
aqueous Nope. The mixture is then reduced in volume under vocal and extracted with ethylene chloride. The combined organic extract is evaporated to dryness to give a residue which is purified on silica gel with ethyl ether as fluent to afford 0.32g of 5c,13t-15S-hydroxy-9a-deoxy-9a methylene-prostacycla-dunk acid methyl ester and 0.26g of the 15R isomer.
This same procedure for reducing the 15-oxo derive-lives from examples 8, 11 and 12 affords the methyl esters of the following acids:
5cis,13-trans-9a-deoxy-9a-methylene-15S-hydroxy-2--nor-prosta-cycla-5,13-dienoic acid;
5cis,13trans-9a-deoxy-9a-methylene-15S-hydroxy-2a--homo-prosta-cycla-5,13-dienoic acid;
5cis,13trans-9a-deoxy-9a-methylene-15S-hydroxy-3-ooxa-prosta-cycla-5,13-dienoic acid;
5cis,13trans-9a-deoxy-9a-methylene-4,4-diethioethyylenedioxy-15S-hydroxy-prostacycla-5,13-dienoic acid;
and the l,4-lactones of the following acids:
5c,13t-9a-deoxy-9a-methylene-4S,15S-dihydroxy-17-ccyclohexyl-lg, 19,20-~-trinor-pros-tacycla-5,13-dienoic acid to . , 5c,13t~9a-deoxy-9a-methylene-4S,15S-dihydroxy-16-pphonics, 19,20-~-tetranor-prostacycla-5,13-dienoic acid 5c,13t9a-deoxy-9a-methylene-4R,15S-dihydroxy-16S-methyl--prostacycla-5,13-dienoic acid;
5c,13t-9a-deoxy-9a-methylene-4R,15S-dihydroxy-16S--flyer-prostacycla-5,13-dienoic acid;
as well as their trueness geometric isomers, in the net-, enact-and do forms.
Example 14 A solution of 0.35g of 5c,13t-15-oxo-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid methyl ester in loll of 2:1 ethyl ether Tulane is cooled to -30C and treated with stirring with 5ml of 5% methyl magnesium iodide in ethyl ether.
after 4 hours of stirring, the mixture is brought to 0C and quenched with 20~ aqueous ammonium chloride. The organic phase is washed with water, sodium bicarbonate and water, dried over McCoy, treated with O.lml of pardon, and evaporated under vacuum to give a mixture of the 15S and 15R alcohols. Swooper-lion on silica gel with 80:20 ethyl ether isopropyl ether as fluent affords Old of 5c,13t-15S-hydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid methyl ester and Old of the 15R
isomer.
Example 15 With the same substrate but an hydrous THY as solvent, reaction with 8ml of 0.3M ethanol magnesium bromide in THY gives, after chromatography on silica gel, 5c,13t-15-ethynyl-15S-hydroxy 9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid rnethylester and its 15R isomer.
With 0.3M vinyl magnesium bromide, 5c,13t-15-vinyl-15S-hydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dieenoic acid methyl ester and its 15R isomer are prepared.

Example 16 A solution of 0.26g of 5c,13t-9a deoxy-9a-methylene-4R,15S-dihydroxy-16S-methyl-prostacycla-5,13-c1iennote Acadia lactose in ethylene chloride is cooled to -10-8C and -treated - aye -,.~. of with stirring with 0.3ml of boron trifluoride ether ate (1.2xlO Mix an hydrous ethylene chloride) and then 5% dismay-than in ethylene chloride until a yellow color persists. The solution is washed with 5% aqueous Nikko and then water until neutral, evaporated to dryness, and purified on silica gel (3g) to give 0.21g of Sc,13t-9a-deoxy-9a-methylene-4R,15S-dihydroxy-16S-methyl-prostacycla-5,13-dienoic acid-1,4-~-lactone-15-methy-tether.
Example 17 A solution of 0.74g of d,1-2-exo-hydroxymethyl-3-exo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo[3.3.0]octane in 15ml of an hydrous ethylene chloride is added all at once to a solution of 3.1g of Collins reagent (~5H5N2)2.CrO3 in 4~ml of an hydrous ethylene chloride, with stirring and cooling to 0-5C. Filter-in earth is added after 15 minutes of stirring and the mixture is filtered to give a clear solution of the corresponding d,1-2-exo-formyl derivative. After the solvent is evaporated under vacuum, the residue is taken up in an hydrous Bunsen and added to a solution of sodium dimethyl-(2~oxo-octyl)-phosphonate.
This latter is prepared by adding 0.59g of (2-oxo-octyl)-dimethyl phosphonate in loll of Bunsen drops to a suspension of 0.07g of 80% Nay in 20ml of Bunsen and stirring the resulting mixture for approximately 1 hour/ until hydrogen evolution ceases. Stir-ring is continued for 20 minutes after the alluded is added to the phosphonate carbanion solution. The organic phase is then neutralized with excess 25% aqueous Nope and separated. After drying, it is evaporated to dryness to give a residue which is purified on silica gel (cyclohexane:ethyl ether as fluent) to afford 0.81g of d,1-2-exo-[3'-oxo-non-1'-trans-1'-enyl]-3-exo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo 3.3.0 octane.

I, A

Example _18 A solution of 1.05g of d,1-2-exo-hydroxyme Thailand-THP-oxy-7-endo-DMtB-silyloxy-bicyclo[3.3.0]octane in 8ml of 75:25 benzene:DMSO is treated with 0.89g of dicyclohexylcarbodi-imide and then, with stirring, with 1.42ml of a pyridinium trifluoroacetate solution. Peter 3 hours of stirring, 20ml of Bunsen are added and excess carbodiimide is quenched with 0.13g of oxalic acid in 3.8ml of water. The Bunsen phase is separate Ed washed until neutral, and concentrated under vacuum to give a solution of 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo[3.3.0]octane.
The d,l-,nat- and enantio-formyl derivatives are pro-pared using this procedure. In the same way, if 7-exo-hydroxy-bicyclo[3.3.0]octan-3-one-7-dimethyl-tert-butylsillyl-ether is used in the procedures of examples 1, 2 and I 2-exo-formyl-3-endo-THP-oxy-7-exo-DMtB-siloxy-bicyclo[3.3.0]octanno is obtained.
Example 19 A solution of 322mg of (2-oxo-heptyl)-dimethyl pros-fount in 5ml of Bunsen is added to a suspension of 43.5mg of 80% Nay in loll of Bunsen, and the resulting mixture is stirred until hydrogen evolution ceases. In the dark, 258mg of finely divided N-bromosuccinimide are added and stirring is continued for another 5 minutes. 0.37g of 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo[3.3.0]octane in 5ml of Bunsen is then added and the resulting mixture is stirred for another 15 minutes, after which the reaction mixture is part-toned between Bunsen and 15~ Nipped. The organic phase is dried, concentrated to small volume, adsorbed on silica gel and eluded with $0:20 cyclohexane:ethyl ether to afford 0.42g of 30 2-exo-[2'-bromo-3'-oxo-oct-1'-enyl]-3-endo-THP-oxyy-7~endo-DMtB-~(, 3L'7 silyloxy bicycle 3.o]octane(~max=25lm~ Sue If (2-oxo-3R-fluoro-heptyl)-dime-thyl phosphona-te is used, -the corresponding 2-exo-~2'-bromo-3'-oxo-41R-fluorO-oc-t-l'--trans-enyl]-derivative is obtained.
Example 20 A solution of 0.3g of [2-oxo-4(2')-te-trahydrofuryl-butyl]-dimethyl phosphonate is added drops to a stirred suspension of 36mg of 80% sodium hydrides in 5ml of Bunsen.
Stirring is continued until hydrogen evolution ceases, and then a solution of 0.37g of 2-exo-formyl-3-endo-THP-oxy-7-exo-DMtB-silyloxy-bicyclo[3.3.0]octane is added. After another 20 minutes of stirring, the mixture is taken up in Bunsen and 20%
aqueous monosodium phosphate. The organic phase is separated, concentrated to small volume, adsorbed on silica gel and eluded with benzene:ethyl ether to give 0.35g of 2-exo-[3'-oxo-5'(2")-tetrahydrofuryl-pent-l'-trans-enyl[-3-endo-THP-oxyy-7-exo-DMtB-silyloxy-bicyclo[3~3~o]octane(~max=229m~,~=8, Example 21 If 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo[3.3.0]octane was the 2-exo-formyl-7-exo-bicyclo derive-live used in the procedure described in example 20, and if tune following phosphates were used:
(2-oxo-heptyl)-dimethyl phosphonate;
(2-oxo-octyl)-dimethyl phosphonate;
(2-oxo-3S-methyl-heptyl)-dimethyl phosphonate;
(2-oxo-4-cyclohexyl-butyl)-dimethyl phosphonate;
(2-oxo-4-phenyl-butyl)-dimethyl phosphonate;
(2-oxo-3-m-trifluoromethylphenoxy-propyl)dimethyl phosphonate;
(2-oxo-3-methyl-3-butoxy-hutyl)-dimethyl phosphonate;
then the following compounds were prepared:

I;; - 47 -. ,. Jo Lo 7

3-endo-THp-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo-ooct-1'-trans-l'-enyl)-bicyclo[3.3.0]octane;
3-endo-THP-oxy-7-exc~-DMtB-silyloxy-2-exo~(3'-oxo--non trays-l'-enyl)bicyclo [3.3.0]octane;
3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo-44'S-me thyl-oc-t-l'-trans-l'-enyl)bicyclo [3.3.0~octane;
3-endo-THP-oxy 7-exo-DMtB-silyloxy-2-exo-(3'-oxo-5'-cyclo-hexyl-pent-l'-translll-enyl)bicyclo [3.3.0]octane;
3-endo-T~P-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo-5'-phenyl-peen -1'-trans-1'-enyl)-bicyclo[3.3.0]octane;
3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo-44'-m-tri-fluo~romethylphenoxy-but-1'-trans-1'-enyl)-bicycloo[3.3.0]octane;
3-endo-THP-oxy-7-exo-DMtB-silyloxy-2~exo-(3'-oxo-44'i-methyl-4'-butoxy-pent-l'-trans-l'-enyl)-bicyclo[3.3.Q]octanee.
sample 22 A solution of 0.3g of d,l-2-exo-(2'-bromo-3l-oxo-4lR-fluoro-oct-l'-trans-l-enyl)-3-endo-THP-oxy-7-endo--DMtB-silyloxy-bicyclo[3.3.0]octane in loll of an hydrous ether is added drop-wise in 15 minutes to a Old solution of zinc bordered in ethyl ether (loll). After stirring for two hours, the reaction mixture is quenched with saturated sodium chloride and ON
sulfuric acid. The ether layer is separated and washed with water, 5~6 Noah, and then water. Evaporation to dryness affords a mixture of the 3'S and OR hydroxy alcohols which are separated by liquid-liquid chromatography with isopropyl ether as solvent to give O.llg of d,l-2-exo-(2'-bromo-3'S-hydroxy-4'R
fluoro-oct-l'-trans-llenyl) 3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicycle 3.3.0 octane and Old of the OR epimer.
Example 23 A solution of 0.3g of 2-exo-[3'-oxo-5' ~2")-tetrahydro-or 48 Lo furyl-pen-t~ trueness enyl]-3-endo-THP-oxy-7-exo-DM-tB-silyloxy-bicyclo[3.3.0]octane in 3ml of ethylene chloride and 3ml o ethanol is cooled to -10-15C and then treated with 25mg of Nub. After 30 minutes o E stirring, the reaction mixture is quenched with 1.5ml ox acetone and 3ml of saturated Nope, evaporated under vacuum, and then extracted with ethylene sheller de. The organic phase is dried over Nazi and evaporated to dryness to give a residue which is purified on silica gel (hexane:ethyl ether as fluent) to afford Old of excuse-hydroxy-5'(2" ~-tetrahydrofuryl-pent-1'-trans-1'-enyl]-3-endo-THP-oxy-7-exo-DMtB-silyloxy-bicyclo [3.3.0]octane and O.llg of the OR isomer.
sample 24 By following the procedure of examples 22 and 23 using one of the unstriated kittens prepared as in examples 19, 20 and 21, the following compounds were prepared:
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(2'-brommo-3'S-hydroxy-oxt-l'-trans-l'enyl) bicycle [3.3.0]octane;
endTHP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hydroxy-ocCal trans-l'-enyl)bicyclo[3.300]0ctane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hyddroxy-non-l'-octal! -trays' l'-enyl)-bicyclo [3.3.0]octane;
end-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hydroxy-nnon-l'-trans-l'-enyl)-bicyclo [3.3.0]octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hyddroxy-cyclo-hexyl-pent-l'-trans-l'enyl)-bicyclo [3.3.0]octane;
3-endo-THP-oxy-7-endo-DMtB-Sily]oxy-2-exo-(3lS-hyddroxy-5 phenyl-pent-l'-trans-l'-enyl~ -bicycle [3.3.0]octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'S-hydroxy-4'-m-30 trifluoromethylphenoxy-but-1'-trans-1'-enyl)-bicycclue]-octane;
3-endo-THP-oxy-7-endo-DM-tB-silyloxy-2-exo-(3'S-hyyclroxy~
methyl-4'-butoxy-pent-1'-trans-1'-enyl)-bicyclo~3.oaken;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(2l-brommo-3'R-hydroxy-oct-ll-trans-ll-enyl)-bicyclo [3.3.0]octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-Z-exo-(3'R-hyddroxy-oct-l'-trans-l'-enyl)-bicyclo[3.3.0]octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hyddrowsy-methyl-oct-l'-trans-l'-enyl)-bicyclo~3.3.0]octane;;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hyddroxy-non-l'-trans-l'-enyl)-bicyclo [3.3.0]octane;
3-endo-THP-oxy-7 endo-DMtB-silyloxy-2-exo- (3'R-hydroxy-5'-cyclo-hexyl-pent-l'-trans-l'-enyl)-bicyclo[3.3.0]octane;;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hyddroxy-5~-phenyl-pent-l'- trans-l'-enyl)-bicyclo [3.3.0]octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hyddroxy-4'-m-trifluoromethylphenoxy-but-l'-trans-l'-enyl)-biccycle [3.3.0]-octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'4-hyddroxy-4'-methyl-4'-butoxy-pent-1'-trans-1'-enyl)-bicyclo[3..3.0]octane.
Example 25 A solution of 1.17g of 2-exo-(3'S-hydroxy-oct-l`-trans-l'-enyl)-3~endo-THP-oxy-7-endo-DMtB-silyloxyy-bicyclo[3.3.0]-octane in 12ml of an hydrous ethylene chloride is -treated with 120mg of 2,3-dihydropyran and 5mg of p-toluenesulfonic acid.
Aster 4 hours at room temperature, the organic phase is washed successively with 5?6 Nikko and water and then evaporated to dryness to give 1.45g of crude 2-exo-(3'S-THP-oxy-oct-l'-trans-l'~enyl)-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicycclue]-octane. This product is dissolved in 12ml of IF and treated ,. .

with 2g of tetrabutylammonium fluoride. The resulting mixture is stirred for 12 hours at room temperature and concentrated to small volume to give a residue which is purified on silica gel (ethyl ether as fluent) -to afford 920mg of 2-exo-(3'S-hydroxy-oct-l'-trans-l'-enyl)-3-endo-7-endo-dihydroxy-bicyyclo~3.3.0J-octane-3,3'-bis-T~P-ether.
Example 26 Using the procedure of example 25 with compounds pro-pared according to examples 22, 23 and 24, the following bicyclo~3.3.n]octane-3,3'-bis-THP-ether derivatives were pro-pared:
2-exo-(2'-bromo-3'S-hydroxy-4'-fluoro-oct-1'-transsunnily-endo-7-endo-dihydroxy;
2-exo-(2'-bromo-3'R-hydroxy-4'R-fluoro-oct-l'-tranns-l'-enyl)-3-endo-7-endo-dihydroxy;
2-exo-~3'S-hydroxy-5' (2")-tetrahydro:Euryl-pent-l'-trans-l'-enyl)-3-endo-7-exo-dihydroxy;
2-e xo-(3'R-hydroxy-5' (twitter drofuryl-pent-l'-trans-l'-enyl)-3-endo-7-exo-dihydroxy;
2-exo-(2'-bromo-3'S-hydroxy-oct-l'-trans-l'-enyl)--3-endo-7-endo-dihydroxy;
2-exo-(2'-bromo-3'R-hydroxy-oct-l'-trans-l'-enyl)--3-endo-7-endo-dihydroxy;
2-exo-(3'S-hydroxy-oct-l'-trans-l'-enyl)-3-endo-7--endo-dihydroxy;
2-exo-(3'R-hydroxy-oct-l'-trans-l'-enyl)-3-endo-7-endo-dihyydroxy;
2-exo-(3'S-hydroxy-4'S-methyl-oct--l'-trans-l'-enyyl)-3-endo-7-endo-dihydroxy;
2-exo-(3'R-hydroxy-4'S-methyl-oct-l'-trans-l'-enyl)-3-endo--7-endo-dihydroxy;
2-exo-(3'S-hydroxy-non-l'-trans~l'-enyl)-3-endo-7--endo-dihydroxy;

-2-exo-(3'R-hydroxy non-l'-trans-l'-enyl)-3-endo-7-endo-dihydroxy;
2-exo-(3'S~hydroxy-5'-cyclohexyl-pent-l'~trans~l'---enyl)-3-endo-7-endo-dihydroxy;

- aye -..~
.,~

2-exo-(3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-enylLund-endo-dihydroxy;
2-exo-(3'R-hydroxy-5'-phenyl-pent-1'-trans-1'-enylLund-endo-dihydroxy;
2-exo-(3'S-hydroxy-4'-m-trifluorome-thylphenoxy -but-l'-trans-1'-enyl)-3-endo-7-endo-dihydroxy;
2-e~o-(3'R-hydroxy-4'-m~trifluoromethylphenoxy-butt-l'trans-1'-enyl)-3-endo-7-endo-dihydroxy;
2-exo-(3'S-hydroxy-4'-methyl-4'-butoxy-pent-1'-traans-1'-enyl)-3-endo-7-endo-dihydroxy;
2-exo-(3'R-hydroxy-4'-methyl-4'-butoxy-pent-1'-traans-1'-enyl)-3-endo-7-endo-dihydroxy.
Example 27 Successive portions of a solution of 0.4g of chronic android are added with stirring to 4ml of pardon. Once the complex is formed/ this mixture is treated with 0.36g of 2-exo-(3'S-hydroxy-5'(2")-tetrahydrofuryl-pent-1'-trans--1'-enyl)-3-endo-7-exo-dihydroxy-bicyclo[3.3.0]octane-3,3'-biss-THP-ether in 4ml of pardon. The reaction mixture is held overnight at room temperature, diluted with 3 volumes of Bunsen, and filtered.
The filtrate is then evaporated to give a residue which is part-toned between Bunsen and ON sulfuric acid. The aqueous portion is re-extracted with Bunsen, washed successively with water, Nikko and water, and evaporated to dryness to give 0.31g of2-exo-(3'S-hydroxy-5'(2"-tetrahydrofuryl-pent-1'-ttrueness'-enyl)-3-endo-hydxoxy-bicyclo[3.3.0]octan-7-one-3,33'-bis-THP-ether.
Example 28 A stirred and cooled (-10-6C) solution of 0.8g of 2~exo-(3'S-hydroxy-oct~ trans-l'-enyl)-3-endo-7-endo-dihydroxy-I-` Gil '7 bicyclo[3.3.Q]octane-3, 3'-bis-THP-ether in 20ml of acetone is -treated with l.~ml of Jones' reagent in 15 minutes. After an-other 15 minutes of stirring, 80ml of Bunsen is added. The organic phase is separated, washed with 15% aqueous (N~[4)2SO4 until neutral, dried and evaporated to dryness to afraid yo-yo of2-exo-(3'S-hydroxy-oct-l'-trans-l'-enyl)-endo-hydrfoxy-bicyclo[3.3.0]octan-7-one-3, 3'-bis-tetrahydropyranylether.
Example 29 Using either of the oxidation procedures described in examples 27 and 28 on the trios of example 26, the following 3-endo-hydroxy-bicyclo~3.3.0]octan-7-one-3,3'-bis--THP-ethers are prepared:
2-exo-(2'-bromo-3'S-hydroxy-4'R-fluoro-oct-l'-tranns-l'-enyl);
2-exo-(2'-bromo-3'R-hydroxy-4'R-fluoro-oct-l'-tranns-l'-enyl);
2-exo- (3'S-hydroxy-5' (2")-tetrahydrofuryl-pent-1'-trans-1'-enyl);
2-exo- (3' R-hydroxy-5' (2'l)-te trahydrofuryl-pent-1'--trans-1'-enyl);
2-exo- (2'-bromo-3'S-hydroxy-oct-l'-trans-l'-enyl);
2-exo-(2'-bromo-3'R-hydroxy-oct-l'-trans-l'-enyl);;
2-e Jo- (3'S-hydroxy-oct-l'- trans-l'-enyl);
2-exo-(3'R-hydro.xy-oct-l'-trans-l'-e.nyl);
2~exo-(3'S-hydroxy-4'S-methyl-oct-l'-trans-l'-enyll);
2-exo-(3lR-hydroxy-4'S-methyl-oct-l'-trans-l'-enyll);
2-exo-(3'S-hydroxy-non-l'-trans-l'-enyl);
2-exo-(3'R-hydroxy-non-l'-trans-l'-enyl);
2-exo-(3'S-hydroxy-5'-cyclohexyl-pent-1'-trans-1'-enyyule;
2-exo-(3' R-hydroxy-5'-cyclohexyl-pent-1'- trans-1'-enyl);
2-exo-(3'S-hydroxy-5'-phenyl-pent-1'-trans--1'-enyye);
2-exo-(3'R-hydroxy-5'-phenyl-pent-1'-trans-1'-enyllo;
2-exo-(3'S-hydroxy-4'-m-trifluoromethylphenoxy-but-1'-trwryness'-enyl);
2-exo-(3'R-hydroxy-4'-m-trifluoromethylphenoxy-butt-1'-trans-1'-enyl);

Al I

enyl);
2-exo~(3'S-hydroxy-4'-methyl~4'-bu-toxy-pent-1'-trrans-1'-enyl);
2-exo-(3'R-hydroxy-4'-methyl-4'-bUtoxy-pent-l'-traans-l'-enyl);
Example 30 A solution of 2.lg of d,1-2-exo-(3'-oxo-non-1'-trans-l'-enyl)-3-exo-THP-oxy-7-endo-DMtB-silyloxy-bicycllo [3.3.0]-octane (prepared according to example 17) is reduced at -15C
in ethylene chloride ethanol with 0.17g of Nub, following the procedure of example 23, to afford 2.Olg of d,l-2-exo-(3'(S,R)-hydroxy-non-1'-trans-1'-enyl)-3-exo-THP-oxy-7-endoo-DMtB-silyl-oxy-bicyclo[3.3~0]octane. Without separating the 3'S and OR
alcohols, this product is reacted in 30ml of ethylene chloride with 0.4g of 2,3-dihydropyran in the presence of 25mg of twill enesulfonic acid to give the corresponding d,l-exo-(3l(S,R)-hydroxy-non-l'-trans-l'-enyl)-3-exo-hydroxy-7-endoo-DMtB-silyloxy-bicyclo[3.3.0]octane-3,3'-bis-THP-ether. With no fur-then purification, this product is treated with 2.5 molar equivalents of tetrabutyl ammonium fluoride in THY to remove the sill ether.
The product d,1-2--exo-(3'(S,R)-hydroxy-non-l'-trans-l'-enyl)-3-exo-7-endo-dihydroxy-bicyclo[3.3.0]octane--3,3'-bis-THP-ether (1.660g) is then oxidized with pardon - chronic ashy-drive to give 1.25g of d,l-2-exo-(3'(S,R)-hydroxy-non-l'-trans-l'-enyl)-3-exo-hydroxy-bicyclo L3.3.0]oc-tan-7 one-3,3'-bis-THP~
ether.
Example 31 A solution of (2-oxo-5,5,5-trimethoxy-pentyl)-dim ethyl phosphonate in loll of THY is added drops to a stirred suspension of 68mg of Nay (80~) in loll of an hydrous THY.
Stirring is continued until hydrogen evolution ceases, and then I

a solution of 0.67g of d,1-2-exo-(3'(S,R)-hydroxy-non-l'-trans-l'-enyl)~3-exo-hydroxy-bicyclo[3.3.0]octan-7-one-33,3'-bis-THP-ether in 5ml of THE is added. After 6 hours of stirring at 40-45C, 20ml of 20% Myopia is added and the THY is removed under vacuum. The residue is extracted with ethyl ether, and the organic extract is dried over Nazi and evaporated. Adsorption of the residue on silica gel and elusion with cyclohexane:e-thyl ether afford 0.76g of d,1-5t,13t-4-oxo-11~,15(S,R)-dihydroxy-20-methyl-9a-deoxy-9a-methylene-prostacycla-5,13-diennote acid-trimethylorthoester-11,15-bis-THP-ether.
A solution of this product in 15ml of an hydrous moth-anon is treated with 6mg of p-toluenesulfonic acid for 5 hours at room temperature. O.lml of pardon is added, the solution is evaporated to dryness, and the residue is purified on silica gel (isopropyl ether ethyl ether as fluent) to afford 0.20g of d,1-5t,13t-4 oxo-11~,15S-dihydroxy-20-methyl-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid-trimethylorthoester and 0.21g of the 15R epimer.
Example 32 Following the procedure of example 31 with a bicycle-[3.3.0]octan-7-one prepared as in examples 27, 28 and 29, the following trimethylorthoesters were prepared:
5,13t-4-oxo-11~,15S-dihydroxy-9a-deoxy 9a-methylene-prosta-cycla-5,13-dienoic acid;
5,13t-5-oxo-11~,15S-dihydroxy-9a-deoxy-9a-methylenne-20-methyl-prostacycla-5,13-dienoic acid;
5,13t-4-oxo-11~,15S-dihydroxy-9a-deoxy-9a-methylenNoah')-tetrahydrofuryl-18,19,20-trinor-prostacycla-5~13-ddunk acid;
5,13t-4--oxo-11~,15S-dihydroxy-9a-deoxy-9a-methyleenwomb-triflurormethylphenoxy-17,18,19,20-tetranor-prostaacycla 5,13-'I

dunk acid;
as well as their 15R epimers.
Each of the ortho-esters of examples 31 and 32 is -then converted to its methyl ester by refluxing it in methanol (15ml/g) with 2ml of 0.2N oxalic acid and recovering the product by evaporating the methanol and extracting with ethyl ether.
Subsequent saponification with 2% KHC03 in 80~ aqueous methanol gives the free acid.
Example 33 A solution of 0.45g of tweaks ,15S-dihydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid-trimethyl-orthoester (A =244~,~=9,850) in 6ml of methanol and 1.2ml of 0.2N oxalic acid is reflexed for two hours. Evaporation of the methanol under vacuum and extraction with ethyl ether give 0.42g of the corresponding methyl ester.
A solution of this product in 6ml of an hydrous ethyl ether is added drops to a stirred Old solution of zinc bordered (loll) in 10 minutes. After 1 hour of stirring at room temperature, the reaction is quenched with ON sulfuric acid.
The organic phase is separated, washed until neutral, and evaporated to dryness to give 0.4g of 5,13t-4(S,R),11~,15S-trihydroxy-9a-deoxy-9a-methylene-prostacycla-5,13--dunk acid methyl ester. Chromatographic separation on silica gel (ethyl ether ethyl acetate as fluent) affords O.llg of 5,13-t-4S,11~,15S-trihydroxy-9a-deox~-9a-methylene-prostacycla-5,13--dunk acid methyl ester and 0.14g of the 4R-epimer methyl ester.
A solution of the latter compound in 5ml of methanol is treated with 0.05g of lithium hydrate and 0.3ml of H20 and then stirred a-t room temperature for 6 hours. Removal of the methanol under vacuum, acidification of pi 5.6 and rapid i - 56 -. ., I,.

'7 extraction with ethyl acetate afford Tracy-trihydroxy-9a-deoxy-9a-methylene-prostacycla-5,13--dunk acid.
Treatment of a stirred ethyl acetate solution of this compound with 0.5 parts of a polystyrenesulfonic resin (hydrogen ion form) gives try ,15S-trihydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid-1,4-~-lactone quantitatively.
The US epimer-~-lactone was prepared analogously.
Example 34 A solution of 0.8g of 5,13t-4-oxo-11~,15S-dihydroxy-20-methyl-9a-deoxy-9a-methylene-prostacycla-5,13-ddunk acid-trimethylorthoester-11,15-bis-THP-ether in 20ml of ethylene chloride ethanol is cooled to -20C and treated with 50mg of Nub. After 30 minutes of stirring, the reaction is quenched with 2ml o-f acetone and 5ml of saturated monosodium phosphate.
Evaporation of the ethylene chloride and ethanol under vacuum and repeated extraction with ethyl ether afford, after the come brined organic extract is dried and evaporated, 0.75g of 5,13-t-

4(S,R),11~,15S-trihydroxy-20-methyl-9a-deoxy-9a-meethylene-prostacycla-5,13-dienoic acid-trimethylorthoester-11,15-bis-THP-ether.
This crude product is dissolved in 2.2ml of methane-sulfonyl chloride. The reaction mixture is held overnight at room temperature and then partitioned between iced ON sulfuric acid and ethyl ether. The combined organic extract is washed with brine, dried and evaporated at low temperature to give

5,13t-4(S,R),11~,15S-trihydroxy-20-methyl-9a-deoxyy-9a-methylene-prostacycla-5,13-dienoic acid-trimethyl~orthoester-4-mesylate-11,15-bis-THP-ether.
With no further purification, this product is dissolve Ed in an hydrous ethyl ether and treated with 50mg of lithium I

aluminum hydrlde in ethyl ether. After stirring for 2 hours at room temperature and 1 hour at reflex, -the reaction mixture is quenched with 2ml of ethyl acetate and then wet ethyl ether.
Drying over Nazi and evaporating the ethyl ether give 0.5g of crude 5,13t~ ,]5S-dihydroxy-20-methyl-9a-deoxy-9a-methylene-pros-tacycla-5,13-dienoic acid-trirnethyl-orthoester-11,15-bis-THP-ether.
After treatment at reflex with 12ml of methanol and 4ml of 0.3N aqueous oxalic acid, standard work-up gives 0.2g of 5,13t-11~,15(S)-dihydroxy-20-methyl-9a-deoxy-9a-meethylene-prostacycla-5,13-dienoic acid methyl ester. Liquid-liquid chromatography shows that the product is mainly trays (85%), with 15% of the is isomer.
Example 35 In an inert gas atmosphere, a stirred suspension of 0.4g of Nay (75% mineral oil dispersion) in 13.5ml of DMSO is heated to 60-65C for 4 hours. The mixture is then cooled to room temperature and held at 20-22C while 2.6g of 4-carboxy-butyl-triphenyl phosphonium bromide in 6ml of DMSO and 0.85g of 2-exo-(3'S-hydroxy-non-l'-trans-l'-enyl~-3-endo-hyydroxy-bicyclo[3.3.0]octan-7-one~3,3'-bis-THP-ether are added success lively. After stirring for 3 hours, the mixture is diluted with 35ml of water and the aqueous phase is extracted with ethyl ether (5xl2ml) and ethyl ether:benzene (7xl2ml). The combined organic extract is re-extracted with 0.5N Noah (3xl5ml) and then water until neutral, and then discarded. The combined aqueous alkaline extract is acidified to pi 5.3 and extracted with 1:1 ethyl ether:pentane. Washing until neutral, drying over Nazi and removing the solvent afford 0.86g of 5,13t-11~,15S-dihydroxy-9a-deo~y-9a-methylene-20-methyl-prostacyyokel-.,~.

'7 dunk acid 11,15-bis-THP-ether. This product is then ester-fled by treatment with diazomethane, and the perineal protecting groups are removed, as follows:
The methyl ester is dissolved in an hydrous methanol and treated with a solution of 10 molar equivalents of p-toluenesulfonic acid. After 4 hours, the p-toluenesulfonic acid is neutralized with pardon and the mixture is evaporated to dryness. Purification on silica gel affords 5,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacyyokel-dunk acid methyl ester, which is then separated into the individual 5c,13t and 5t,13t isomers by liquid-liquid cremate-graph.
Example 36 -With stirring and external cooling to keep the react lion temperature at 20-22C, a solution of freshly sublimed potassium tert-~utylate in 12ml of an hydrous DMSO is treated successively with 1.8g of 4-carboxybutyl-triphenyl phosphonium bromide in 10ml of DMSO and 0.65g of 2-exo-(2'-bromo-3'S-hydroxy-oct-l'-trans-l'-enyl)-3-endo-hydroxy-bicycclue]-octane 7-one-3,3'-bis-THP-ether in 5ml of DMSO. After stirring for 8 hours at room temperature, the mixture is diluted with an equal volume of water, acidified to pi 5 and extracted with 1:1 ethyl ether:pentane. The acidic aqueous phase is discarded, and the combined organic extract is extracted with 0.8N Noah ~5x20ml) and then water until neutral. Chile this organic phase is discarded, the aqueous alkaline extract is acidified to pi 5 and extracted with 1:1 ethyl ether:pentane. The combined extract is dried over Nazi, filtered and treated with ethereal diazomethane until a yellow coloration persists. Evaporation to dryness gives crude 11~,15S-dihydroxy-9a-deoxy-9a-methylene-of - 59 -prostacycl-5-en-13-ynoic acid methylester-11,15-bis-THP-ether.
Removal of the perineal protecting group followed by liquid-liquid chromatography gives 5c~11~,15S-dihydro~xy-9a-~eoxy~9a~
methylene-pro.stacycl~5-en-13-ynoic acid methyl ester, plus the it geometric isomer.
Example 37 When the bicyclo[3.3.0]octan-7-one-3,3'-bis-THP-ethers prepared according to examples 27,28,29 and 30 were used in the procedure of examples 35 and 36, the methyl esters of the following acids were obtained:
5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-proostacycla-5,13-dunk acid;
5c-11~,15S-dihydroxy-9a-deoxy-9a-methylene-16R-fluurea-prostacycl-5-en-13-ynoic acid;
5c-11~,15S-dihydroxy-9a-deoxy-9a-~Rthylene-16S-fluurea-prostacycl-5-en-13-ynoic acid;
5c-11~,15S-dihydroxy-9a-deoxy-9a~methylene-17(2')--twitter-hydrofuryl-1~,19,20-trinor-prostacycl-5-en-13-ynoito acid;
5c-11~,15S-dihydroxy~9a~deoxy~9a-methylene~prostaccyclone-yank acid;
5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-proostacycla-5~13-dunk acid;
5c,13t-llN,15S-dihydroxy-9a-deoxy-9a-methylene-16SSmoothly prostacycla-5,13-dienoic acid;
5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-20--methyl prostacycla-5,13-dienoic acid;
5c~13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-17--phenol 18,19,20~trinor-pros-tacycla~5,13-dienoic acid;
5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-16--m-CF3~
phenoxy~l7,1~,19,20~tetranor-prostacycla-5,13-diennote acid;

~`~ - 60 -Jo 5c,13t~ ,15S-dihydroxy-9a-deoxy-9a-methylene-16-methyl-16--butoxy-18,19,20-trinor-prostacycla-5,13-dienolc acid;
as well as their trueness geometric isomers, plus the 15 epimers of both.
These were then saponified to give the free acids.
Example 38 A solution of 0.45g of 2-exo-(3'S-hydroxy-oct-l'-trans-1'-enyl)-3-endo-hydroxy-bicyclo~3.3.030ctan--7-one-3,3'-bis-THP~ether in ethyl acetate is hydrogenated at ambient temperature and pressure in the presence of Old of 5% Pod/
Cook, until 1.01 equivalents of hydrogen are absorbed.
Filtration and evaporation to dryness give 0.42g of 2-exo-~3'S-hydroxy-octan-l'-yl)-3-endo-hydroxy-bicyclo[33.3.0]-octan-7-one-3,3'-bis-THP-ether. Treatment of this with the Witting reagent prepared from 4-carboxy-butyl phosphonium bromide according to examples 35, 36 and 37 affords a product which is esterified with diazomethane and depyranylized to give 0.12g of 11~,15S-dihydroxy-9a-deoxy-9a-methylene-prostacycllink acid methyl ester The Swiss and trueness geometric isomers are spear-axed by liquid-liquid chromatography.
Example 39 _ .
Using (3-carboxy-propyl)-phosphonium bromide in the procedure of examples 37 and 38 instead of (4-carboxy-butyl)-phosphonium bromide gave the following acids:
5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-2-nnor-prosta-cycla-5,13-dienoic;
5c-11~,15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-pprostacycl~5-enoic;
5c-11~,15S-dihydroxy-9a-deox~-9a-methylene-2-nor-pprostacycl-5-en-13-ynoic acid.

~9~'7 Example 40 -By using (5~carboxy-pentyl)-phosphonium bromide in -the procedure of examples 37 and 38, 5c,13t~ ,15S-dihydroxy pa-deoxy-9a-methylene~2ahomo-pros-tacycla-5,13-dienoito acid and I
13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-20-me--Thelma-prostacycla-5,13-dienoic acid were prepared.
Example 41 A solution of 0.37g of 5c,13-t-11~,15S-dihydroxy-9a-deoxy-9a~methylene- prostacycla-5,13-dienoic acid methyl ester in loll of Bunsen is heated to 50C with 250mg of 2,3-dichloro-5,6-dicyano-benzoquinone for 8 hours. The precipitate is removed by filtration, and the Bunsen solution is purified on a short alumina column to give 0.29g of 5c,13t-11~-hydroxy-15-oxo-9a-deoxy 9a-methylene-prostacycla-5,13-dienoic acid methyl ester.
solution of this product in ethyl ether:toluene is cooled to -20C and treated with 1.2ml of lo methyl magnesium bromide in ethyl ether. After 2.5 hours at -20C, the reaction is quenched with NH4C1 solution. The organic phase is separated, reduced in volume and purified on silica gel (ethyl ether ethyl acetate as eluentl to give Old of 5c,13t-11~,15S-dihydroxy-15 methyl-9a-deoxy-9a-methylene-prostacycla-5,13-diennote acid methyl ester and 0.072g of the 15R hydroxy epimer.
Example 42 A solution of 2.2g of 3-endo-hydroxy-bicyclo[3.3.0]-octan-7-one in loom of an hydrous Bunsen is treated with 4ml of ethylene glycol and 0.2g of p-toluenesulfonic acid MindWrite and reflexed for 12 hours-while the water which forms during the reaction is collected. 0.25ml of pardon is then added and the mixture is cooled. The organic phase is washed with water, Nikko ,,. I

'7 and then water, and evaporated to dryness to give 2.32g of 3-endo-hydroxy-bicyclo [3.3.0]octan-7-one-7,7-e thylenedioxide.
A solution of this product in 40ml of ace-tone is cooled to -5C and treated at this temperature with ~.lml of Jones' reagent. After 20 minutes at -5C, excess oxidant is quenched with 4ml of isopropyl alcohol. 150ml of Bunsen is added, and the Bunsen phase is washed successively with 20%
(NH4)2SO4, water, 5% Nikko and water. Evaporation to dryness gives 2.1g ofd,l-bicyclo[3.3.0]octan-3,7-dione-2-carboxymethyl--ester-7,7-ethylenedioxide.
According to the procedure of example 2, a solution of this product in 20ml of SCHICK and 20ml of ethanol is reduced with Nub at -20QC to give 1.72g of d,l-3-endo-hydroxy-bicyclo-[3.3.0]octan-7-one-2-exo-carboxymethylester-7,7-etthylenedioxide.
A solution of 1.57g of this compolmd in 3ml of dip methylformamide is treated with 1.3g of dimethyl-tert-butyl-sill chloride and 0.885g of imidazol, and then held at 0C for 5 hours. After cooling, water is added and the usual work-up affords 2.3g of d,l-3-endo-hydroxy-bicyclo[3.3.0]octan-7-one-2-exo-carboxymethylester-7, 7-ethylenedioxide-3-dimethyl-tert-butylsilylether. Subsequent reduction with Lyle in an hydrous ethyl ether, as described in example 3, gives d,1-3-endo-hydroxy-2-exo-hydroxymethyl-7,7-ethylene-dioxy-bicyclo[3.33.0]octan-7-one-3-dimethyl-tert-butyl sill ether quantitatively.
Example 43 By using dithioethylene glycol in the procedure of example 42 instead of ethylene glycol, the corresponding 7,7-ethylenedithio analogies were prepared.
Example 44 1.8g of d,l-3-endo-hydroxy-2-exo-hydroxymethyl-7,7-ethylenedioxy-bicyclo [3.3.0]octan-7-one-3-dime thyl~tert-butyl - I -or .'`~., !

lo 7 sill ether is oxidized according to the procedure of example 18 to give the corresponding formula derivative. This is -then reacted with (2-oxo-heptyl)-dimethyl phosphonate as in example 20 to give 1.23g of d,l-3-endo-hydroxy--2-exo-(3'-oxo-oct-1'-trans-l'-enyl)-7,7-ethylenedioxy-bicyclo [3.3.0~octan-7-one-3-dimethyl-tert-butyl silylether (maxim =8980). According to the procedure in example 22, this is reduced with zinc bordered in ether to give 1.22g of d,l-3-endo-hydroxy-2-exo-(3'(S,Rl-hydroxy-oct-l'-trans-1'-enyl)-7,7-ethylennedioxy-bicyclo-~3.3.0]octan-7~one-3-dimethyl-tert-butyl silylether.
A solution of this compound in 25ml of methanol is treated with loll of lo H2SO4 at reflex for 50 minutes. The methanol is evaporated under vacuum, the residue is extracted with ethyl ether, and the organic phase is evaporated -to dryness to afford 0.72g of crude d,l-3-endo-hydroxy-2-exo-(3'(S,R)-hydroxy-oct-l'-trans-l'-enyl)-bicyclo[3.3.0]oatan--7-one. The individual isomers are separated by chromatography on silica gel with hexane:ethyl ether as fluent and then converted to the tetrahydropyranyl ethers by treatment with 2,3-dihydropyran in ethylene chloride as in example 25. In this fashion, a compound identical in all respects to 2-exo-(3'S-hydroxy-oct-l'-trans-1'-enyl)-3-endo-hydroxy-bicyclo[3.3.0~octan-7-one-3,33'-bis-tetra-hydropyranylether prepared as in example 28 is prepared from the 3'-S-hydroxy isomer.
Similarly, with the procedure of examples 42 and 44, all the compounds prepared as in examples 27, 28 and 29 were obtained.
Example 45 Saponification of 4.8g of d,1-3-endo-hydroxy-2-exo-carboxymethylester-7,7-ethylenedioxy-bicyclo ~3.3.0]octan-7-one -- I --3L~1 7 with loom of 2.5~ potassium carbonate in 80:20 methanol water at reflex for 40 minutes and subsequent work-up as described in example 2 gave 4.02g of d,l-3-endo-hydroxy-2-exo-carboxy-bicyclo-[3.3.0]octan-7-one-7,7-ethylenedioxide. This compound is disk solved in 80ml of an hydrous tetrahydrofuran, cooled to -10~, and treated drops with 2.lg of triethylamine in 12ml of an hydrous tetrahydrofuran and then 2.2g of ethyl chlorocarbonate in 12ml of an hydrous tetrahydrofuran, while keeping the tempera-lure at -10C. After 1 hour of stirring at -10C, 1.4g of sodium aside in 12ml of water is added slowly and stirring is continued for another 25 minutes. me reaction mixture is then concentrated under vacuum and diluted with water. The 2-exo-carboxy-aæide is isolated rapidly by filtration and dried under vacuum.
A solution of 4.01g of this compound in 8ml of pardon is treated with 4ml of acetic android and held at 5-8C for 24 hours. The reaction mixture is then partitioned between ice water, ethyl ether and ON sulfuric acid. The organic layer is separated, washed until neutral, dried and evaporated to dryness to give 4.1g of 3-endo-hydroxy-2-exo-carboxya~ide-bicyclo[3.3.0]-octan-7-one-3-acetate-7,7-ethylene-dioxide.
This product is suspended in acetic acid (50ml) and water (8ml), and the mixture is heated to 40C. When hydrogen evolution is noted, it is heaved to 60-70C for 2 hours, after which the excess acetic acid is removed by steam distillation.
After cooling, the mixture is extracted with ethyl ether ethyl acetate and the aqueous phase is brought to pi 9 with sodium hydrate. me alkaline phase is washed with saturated salt sol-union and evaporated to dryness to give 1.92g of 3-endo-hydroxy-2-exo-amino-bicyclo[3.3.Q]octan-7-one-3-acetate. reaction of this with the mixed android from ethoxycarboyl chloride and 2S-hydroxy-heptanoic acid-2-acetate affords 3-endo-hydroxy-2-exo-(2ls-acetoxy-heptanoyl-amide)-bicyclo[3.3~o]occtan-7-one-3 acetate. A solution of this compound in an hydrous dim ethyl-sulfoxide is then reacted with the slide obtained from 4-carboxy-butyl-triphenyl phosphonium bromide to give, after saponifica-lion, 5t-llc~,15S-dihydroxy-9a-deo xy-9a-methylene-12-aza-13-o pros tacycl-5-enoic acid.
In an analogous fashion the wrap analog was prepared from the 2'R-hydroxy-heptanoic acid.
Expel 46 Ethylene glycol (15ml) and p-toluensulfonic acid (0.9g) are added to a solution of 2-exo-bromo-3-endo-hydroxy-bicyclo-[3.2.Q]heptane-6-one in Bunyan and the mixture is reflexed for 12 hours, withdrawing water which forms during the reaction, then the mixture is added by pardon (0.6ml) and cooled at room temperature.
The organic phase is washed with water, 2.5% aqueous Nikko and water, dried. Bunsen (loom) is partially removed in vacuum, then the mixture is -treated with tribu-tyltin-hydride (41g) in No atmosphere at 55 for 8 hours. After cooling at room temperature the organic phase is washed with saturated aqueous Nope, dried and evaporated to dryness. Purification of the resulting residue on Sue (240g) with benzene-ethylether as fluent affords 14.9g of 3-endo-hydroxy-bicyclo [eighteen-

6-one-6,6-ethylene dioxide.
Example 47 .
A stirred solution of 3-endo-hydroxy-bicyclo[3.2.0]-heptane-6-one-6,6-ethylendioxide ~12.75g) in Bunsen (340ml) and DMSO (112ml) was treated with dicyclohexylcarbodiimide (46.35g) r -- I --. Jo g to pardon t5.9g) and trifluoroacetic acid (5.4g). After 6 hours, the mixture is diluted with Bunsen (600ml) and water (50ml), filtered from dicyclohexylurea and the organic phase is washed with water, dried on McCoy and evaporated to dryness affording bicyclo[3.2.0]heptane-3,6-dione-5,6-diethylenedioxwide.
A solution of this crude product in dime-thylcarbonate (70ml) is added to a suspension of sodium hydrides (80% in mineral oil, 4g). The mixture is stirred until Ho development ceases at room temperature then it is warmed for 40 minutes at 75-80.
After cooling, the reaction mixture is diluted with Bunsen (350ml) and acetic acid (8.4g), washed with water, dried and evaporated to dryness affording a mixture (1:1) of do bicyclo[3.2.0]heptane-3,6-dione-2-carboxy methylester-6,6-ethyl-en dioxide (pickle) and d,l-bicyclo[3.2.0]heptane-3,6-dione-4-carboxymethylester-6,6-ethylene dioxide (pluck) which are separated by means of chromatography on Sophie , Fe free) using hexane-ethylether as eluents.
Example 48 Using in the procedure of -the example 47g 14.85 of 3-endo-hydroxy-bicyclo[4.3.0]nonane-7-one-7,7-ethyleen dioxide the oxidation process affords 13.9g of bicyclo[4.3.0]nonane-3,7-dione-7,7-ethylendioxide giving the carbomethoxylation process 4.2g ofdl-bicyclo[4.3.0]nonane-3,7-dione-2-carboxymethyleester-

7,7-ethylenedioxide (pluck) and 4.8g of dl-bicyclo[4.3.0]-nonane-3,7-dione-4-carboxymethylester-7,7 ethylendioxide also named asdl-bicyclo[4.3.0]nonane-3,8-dione-2-carbo~ymethyleester-

8,8-ethylenedioxide (p=2,-q=1).
Example 49 A stirred solution of bicyclo[4.3.0]nonane-7-en-3-one ,'.~.

(90 g) in dim ethyl carbonate (350 ml) is added to a suspension of sodium hydrides (80% dispersion in mineral oil, 42 g) in dimethylcarbonate (550 ml). After ceasing the hydrogen evil-lion, the mixture is heated for 4.5 hours at 75-80, cooled at rut., diluted with Bunsen (2.71) and washed with 25% aqueous Nope solution, evaporated to dryness affording bicycle 14.3.0]-nonane~7-ene-3-one-2-carboxymethylester (91 g) (Max 252 my ~=8.200).
A solution of this compound in ethylene chloride (1.21) and ethanol (1.21) is cooled at -20 and, under stirring, treated with Nub ~14.4 g).
The mixture is stirred for 30 minutes, again at -20, then it is treated with acetic acid (23 ml), warmed at room them-portray, and the solvents are evaporated in vacuum.
The residue is partitioned between ethyl acetate and water, the organic phase is dried and evaporated in vacuum affordingdl-bicyclo~4.3.0]nonane-7-ene-3-endo-hydroxy-2-exoo-carboxymethylester (64 g) which is dissolved in dry tetrahydro-Furman (THY) and treated with 2,3-dihydropyrane (33 g) and p-toluensulphonic acid (0.63 g) for 3 hours at rut.. Pardon (0.4 g) is added to the reaction mixture and then, after cool-in at 0 C, under stirring a solution of 1.2 M BH3 in THY is also added during 45 minutes. The stirring goes on for 1 hour at 0C then water is added to destroy residual hydrides Vender vigorous stirring, with external cooling at -5+0, the formed borne is oxidized by the slow concurrent addition 110 ml of EM
sodium hydroxide and 110 ml of 30% hydrogen peroxide maintain-in the internal temperature at 20-25. The oxidation mixture is diluted with Bunsen (2 1) and the layers are separated. The aqueous layer it extracted with Bunsen (2x50). The organic layers are combined washed successively with 1% sodium carbon-..~ . .

38~'7 ate, saturated sodium sulfite and saturated sodium chloride and dried on McCoy. Evaporation of the solvents affords a crude mixture of 7 and 8 hydroxy compounds which are separated by means of Sue (300g) column chromatography, ethyl ether as fluent, obtaining respectively:

dl-bicyclo[4.3.0]nonane-3-endo, 7c,-dihydroxy-2-exo-carboxymethyl-ester-3-THP-ether (24g) and dl-bicyclo[4.3.0]nonane-3-endo, 8 -dihydroxy-2-exo-carboxymethylester-3-TIIP-ether (27g).
A solution of the 7~-hydroxy alcohol (24g) in dry DMF
(30ml) is treated with dimethyl-ter-butyl-silyl chloride (15.8g) and imidazole (8.85g) and then it is heated for 5 hours at 60, cooled at room temperature, diluted with water (9Oml) and then extracted with ethyl ether.
Lowe organic layers are collected, washed with water and evaporated to dryness affording dl-bicyclo [4.3.0]nonane-3-endow I -dihydroxy-2-exo-carboxymethylester-3-THP-ether -7-DMs silylether. To a stirred solution of this compound in dry Tulane (220ml) cooled at -70, a solution of 1.4M DIVA in Tulane is added over a period of 45 minutes, maintaining the temperature between -70-~-60. The stirring is continued for 2 hours, the residual hydrides is destroyed by addition of 2 M
isopropyl alcohol in Tulane.
The reaction mixture is warmed at room temperature and successively 309~ aqueous NaH2P04(60ml)and Nosegay) are added. After filtration, the organic phase is washed with water and evaporated in vacuum affording dl-bicyclo[4.3.0]3-endo, 7~-dihydroxy-2-exo-formyl-3-THp-ether-7~DMg-silyleether (p=2,q=1).
Using in this procedure the 8~-hydroxy compound, we have obtain-Ed dl-bicyclo[4.3.0lnonane-3-endo,8~;-dihydroxy-2-exoo-carboxymethyl-Jo -- 69 i, .

I

ester-3-THP-ether-8-DMB-silylether and dl-bicyclo[4.3.0]nonane-3-enao, I -dihydroxy-2-exo-forn~1-3-THP-ether, 8-DMB-silylether.
Example 50 A solution of (2-oxo-heptyl)dimethylphosphonate (0.33g) in dry Bunsen (5ml) is added -to a stirred suspension of Nazi (80% dispersion in mineral oil, 43.5mg) in dry Bunsen (loll).
After 1 hour N-Br-succinimide (2~0 my) is added and then, after 5 minutes, a solution of bicyclo[4.3.0]nonane-3-endo,8~-dihy-droxy-2-exo-formyl-3-THP-ether, 8-DMB-silylether (0.4g) in Tulane (5ml).
The stirring is continued for lo minutes, then -the reaction mixture is washed with aqueous 15% Nope, dried and evaporated in vacuum to give 2-exo[2'-bromo-3'-oxo-oct-1'-trans-enyl[-3-endo-THP-oxy-8~;-DMB-silyloxy-bicyclo[4.3..0]nonane,)~max 251m~ =8.900.
Example 51 A solution of (3-phenoxy-2-oxo-propyl)dimethylphos-fount (2.85g) in Bunsen (loll) is added to a stirred suspense ion of Nay (owe mineral oil dispersion, 0.33g) in Bunsen (50ml).
The stirring is continued for 45 minutes, then a solution of 2-exo-formyl-3-endo-THP-oxy-7~ -DMB-silyloxy-bicyclo[4.3.0]nonane-(3.82g) in Tulane is added. After 20 minutes the organic phase is washed with aqueous 20% Nope and water, dried and vapor-axed to dryness affording after filtration on Swig), using benzene-ethyl ether as eluent,2-exo-[3'-oxo-4'-phenoxy-but-1'-trans-enyl] -3-endo-THP-oxy-7~ -DMB-silyloxy-bicyclo[4.3.0]nonane (3.97g). Using in -the procedure (5-cyclohexyl-2-oxo-butyl)-dim ethyl phosphonate and starting from the aldehydes of the example 49 we have obtained:

,.
., 2-exo[3'-oxo-5'-cyclohexyl-pen t-l~-trans-enyl]-3-endo-TH
7~-DMB-silyloxy-bicyclo[4.3.0]nonane~max Mohawk 2-exo[3~-oxo-5l-cyclohexyl-pent-l'-trans-enyl]-3-eendo-THp-ox~-8r Dims silyloxy-bicyclo 4.3.0 nonage Max Moe-Example 52 the DMB-silylether-O~,~-unsa-turated kittens, obtained in accordance with the procedure of the examples 50, aye are reduced to allylic alcohols and (b) the new hydroxy group is protected as THP-ether; successively (c) the DMs-silylether protecting group is selectively removed giving a secondary alcohol which (d) is oxidized to kitten; finally after removal (e) of all the remaining protective groups (f) the epimeric allylic alcohols are separated by HPLC-chromatography on Sue.

Working in a 2.10 molar scale, the following procedure is used:
reduction 1.10 2 mole (0.32g) of Nash is added to a stirred solution of a unsaturated ketone-DMB-silylether (2.10 m) in ethylene chloride-ethanol (1:1) (180ml) cooled at -10~-15.
After 30 minutes, the residual hydrides is destroyed by adding acetone (loll) and aqueous saturated Nope (25ml). The sol vents are removed in vacuum and the residue is partitioned between water and ethylene chloride. The organic layer is separated dried and evaporated to dryness affording a mixture of 3'S, OR allylic alcohols-silylethers (2.10 m).
by protection of allylic alcohols as THP-ethers: the crude mixture of 3'S, 3'R-allylic alcohols silylether (2.10 m) was treated with ethylene chloride (30ml) and to the stirred solution 2,3-dihydropyrane (2g) and p-toluensulphonic acid (0.038g) are added. The reaction is complete after 2 hours stopped by addition of pardon (0.5ml) and the sealants are Jo I

removed by evaporation in vacuum to give a crude mixture of 3'S, 3'R-THP-e-ther silylethers.
c) desilylation: a solution of the above obtained material in dry THY (80ml) is treated for 12 hours at rut with dry tetrabutylammonium fluoride (14g). After concentration in vacuum to small volume, the residue is absorbed on Sue (40g) and following elusion with ethyl ether affords the secondary alkalis, 3;R-THP-ethers (about 2.10 m).
d) oxidation: dieyelohexylearbodiimide (6.5g), pardon (lml) and trifler acetic acid (0.5ml) are added successively to a stirred solution in 75:25 benæene-DMSO (60ml) of the secondary alcohol-3'S,3'R-THP-ether. After 4.5 hours the reaction mixture is diluted with Bunsen (loom) and with a solution of oxalic acrid (3g) in water. Formed dicyelohexylurea is filtered, organic layer is washed until neutral, dried and evaporated to dryness.
elf) depyranylization and ehromatographie separation: a solution of the 3'S,3'R-THP-ether-ketones in methanol (30ml) is stirred at rut. for 3 hours with p-toluensulphonic acid (0.18g); after addition of pardon (0.5ml) it is evaporated -to dryness. The residue is dissolved in cyclohexane-ethyl acetate (aye) and injected in HPLC instrument to give the following veto alcohols:
2-exo[2'bromo-3'S-hydroxy-oet-ll-trans-enyl]-3-enddohydroxy-bicyclo[4.3.0]nonane-8-one 2-exo[2'bromo-3'R-hydroxy-oct-l'-trans-enyl]-3-enddo hydroxy-bieyelo[4.3.0]nonane-8-one 2-exo[3'S-hydroxy-4'-phenoxy-but-1'-trans-enyl]-3--end hydroxy-bieyelo~4.3.0]nonane-7-one 2-exo[3'R-hydroxy-4l-phenoxy-but-1'-trans-enyl]-3--end hydroxy-bieyelo[4.3.0]nonane-7-one ',~` .,~

2-exo[3'S-hydroxy-5-cyclohexyl-pent~l'-trans-enyl]-3-enno hydroxy-bicyclo[4.3.0]nonane-7-one 2-exo[3'R-hydroxy-5-cyclohexyl-pen-t-1'-trans~enyl]-3end-hydroxy~bicyclo[4.3.0]nonane-7-one 2exo~3'S-hydroxy-5-cyclohexyl-pent-1'-trans-enyl[-3end hydroxy-bicyclo[4.3.0]nonane-8-one 2-exo[3'R-hydroxy-5-cyclohexyl-pent-1'-trans-enyl]end hydroxy-bicyclo[4.3.0]nonane-8-one.
Example 53 Under a No atmosphere, a suspension of Nay (80% disk pension in mineral oil, yo-yo) in dry DUO (70ml~ is stirred for 4 hours at 65. After cooling at 25-30, dry 4-carboxy-butyl~
triphenyl phosphonium bromide (13g) is added to it, obtaining a doe;? red solution of the slide.
After addition of a solution of 2-exo[2'bromo-3'S-hydroxy-oct-l'-trans-enyl]-3-endo hydroxy-bicyclo[4.3.û]nonane-owing) in dry DMSO (6ml), the reaction mixture is stirred for 1 hour at 28 and then for 4 hours at 40; afterwards it is cooled at rut., diluted with water (80ml), acidified up to pi 4.5 by adding ON H2SO4 and extracted with ethyl ether (4x50ml, 2x25). The aqueous layer is discarded, the organic phases are combined washed with water (this washing is discarded), then with N Noah (5xlOml) and water until neutral. The combined alkaline extracts are acidified up to pi 5 and extracted with ethyl ether to give 5(~,E)-llc~,15S dihydroxy-9a-deoxy-9a,9b-dimethylene-prostacycla-5-en-13-ynoic acid (a mixture of 5 c-and 5 t-isomers). The individual geometric isomers are obtained after chromatographic separation on acidic SiO2(40g/each y of acid) using cyclohexane-ethyl acetate as eluents.
Example 54 ..~`~

Under a No atmosphere, to a stirred solution of potassium--ter-butoxide (3.36g), freshly sublimated, in dry DMSO
(36 ml) it is added 6.5g of 4~carboxy-bu-tyl-triphenyl-phos-phoneme bromide to give a deep red solution of the slide. after addition of a solution of 2-exo~3'R-hydroxy-4'-phenoxy-but-1'-trans-enyl]3~endo hydroxy-bicyclo[4.3.0]nonane-7-one (0.8g) in dry DMSO (3ml), the reaction mixture is stirred for 5 hours at 42, cooled diluted with water (50ml) acidified up to phi and extracted with ethyl ether (4xlOml). The aqueous phase is disk carded the combined ethereal extracts are washed with water (loll, this washing is discarded), and with 0.5N NaOH(4x6ml) and water until neutral. The combined alkaline extracts are acidified up to pi 5 and extracted with ethyl ether. The organic phases are combined dried and evaporated to dryness to give:
5(Z,E),13t-11~,15R-dihydroxy-9a-deoxy-7a homo-9a-methylene-16-phenoxy-17,18,19,20-tetranor-prostacycla-5,13-diennote acid (a mixture of 5c and 5t-geometrical isomers`.
The individual geometric isomers are obtained after chromatographic separation on acidic SiO2(40g/each g of acid) using cyclohexane-ethyl acetate as eluents.
Example _ Using the veto alcohols of the example 52 in the procedure of the examples 53,54 we have prepared the following prostacyclanoic acids:
5c-11~,15S-dihydroxy-9a-deoxy-9a,9b-dimethylene-prrostacycla-5-en-13-ynoic acid.
5c,13t-11~,15S-dihydroxy-9a-deoxy-7a homo-9a-methylene-16-phonics 17,18,19,20-tetranor-prostacycla-5,13-dienoic acid 5c,13t-11~,15S-dihydroxy-9a-deoxy-9a,9b-dimethylenne-17-cyclo-.,;.

'7 hexyl-18,19,20-trinor-prostacycla-5,13-dienoic acid 5c,13t-11~,15S-dihydroxy-9a-deoxy-7a homo-9a-me-thylene-17-cyclohexyl-18-lg,20-trinor-pros-tacycla-5~l3-dienooil acid 5t-11~,15S-dihydroxy~9a-deoxy-9a,9b-dimethylene-prros-tacycla-5-en-13-ynoic acid 5t,13t-11~,155-dihydroxy-9~-deoxy-7a homo-9a-methylene-16-phenoxy-17,18,19,20-tetranor-prostacycla-5,13-diennote acid 5t,13t-11~,15S-dihydroxy-9a-deoxy-9a,9b-dimethylenne-17-cyclo-hexyl-18,19,20-trinor-prostacycla-5,13-dienoic acid 5t,13t-11~,15S-dihydroxy-9a-deoxy-7a homo-9a-methylene-17-cyclo-hexyl-18,19,20-trinor-prostacycla-5,13-dienoic acid.
Example 56 Using the procedure of the example 46, 30g of 2-ace-toxyperhydroazulen-6-one, also named as 3-endo-hydroxy-bicyclo-[5.3.0]decane-8-one acetate (obtained in accordance with DO
Banerjee et at. Indian J. Chum. 10,1,1972) is transformed into its ethylendioxide (29.lg). Then the compound is saponified by treatment with 2% K2CO3 in aqueous methanol to give end-hydroxy-bicyclo[5.3.0]decane-8-one-8,8-ethylenediooxide and oxidized using the procedure of the example 47 and treated with dimethylcarbonate (see the procedure of example 47 -to obtain dl-bicyclo[5.3.0]decane-3,8-dione-2-carboxymethyleester-8,8-ethylene dioxide, 21.2g,~max 254nm;~--7.000.
Example 57 The bicyclo-~-keto-ester-ethylene dioxides obtained in the examples 47, 48 and 56 are reduced with the following procedure:
NaBH4(0.9g) is added portions to a stirred solution of the bicyclo-~-keto ester-ethylenedioxides (2~5.10 my in 1:1 ethylene chloride ethanol (150ml), cooled at -20. After go '7 additional stirring for 30 minutes at -20, the residual hydrides is destroyed by adding acetone (12ml). Roy reaction mixture is warmed at room -temperature treated with aqueous 20% KH2PO4 and after removal of solvents, and dilution with water (20ml) it is extracted with ethylene chloride. The organic phases are combined, washed until neutral with water, dried and evaporated to dryness. The residue is equilibrated by treatment with absolute methanol (20ml) and sodium methoxide (0.54g), for 12 hours at rut.; acetic acid (0.59g) addition followed by evaporation of solvents and extraction with ethylene chloride gives about 0.22.10 m of the following bicyclo-~-hydroxy ester-ethylene dioxides.
dl~3-endohydroxy-bicyclo[3.2.0]heptane-6-one-2-exo-carboxymmoth-ylester-6,6-ethylene dioxide dl-3-endohydroxy-bicyclo[3.2.0]heptane-6-one-4-exo-carboxy--methylester-6 r 6-ethylene dioxide, also named as: dl-3-endo hydroxy-bicyclo[3.2.0]heptane-7-one-2-exo-carboxymmethylester-7,7-ethylene dioxide dl-3-endo hydroxy-bicyclo[4.3.0]nonane-7-one-2-exo-carboxy-methylester-7r7-ethylene dioxide dl-3-endo hydroxy-bicyclo[4.3.0]nonane-8-one-2-exo-carboxy-methylester-8,8-ethylene dioxide dl-3-endo hydroxy-bicyclo[5~3.0]decane-8-one-2-exo-carboxy-methylester-8,8-ethylene dioxide.
In the following, a solution of 2.10 m of each of these compounds in dry ethylene chloride, 25ml, is reacted with 2,3-dihydropyran (2g) and p-toluensulphonic acid (38mg, 2.10 m) for 2 hours at rut. The reaction is stopped by adding pardon (O.lml) and the mixture is evaporated to dryness in vacuum affording the corresponding 3-THP-e-thers which are .. ...
Jo I, used without any further purification.
Example 58 The 3-endo-hydroxy-2-exo-carboxymethylesters and -their 3-THP-ethers, obtained with the procedure of -the example 57 are reduced to give the corresponding 2-exo-hydroxymethyl derivatives with following procedure: a solution of 2.10 em of the kowtow-ester (both alcohol and 3-THP ether) in dry ethyl ether (25ml) is added drops to a stirred suspension of Lyle (0.4) in dry ethyl ether (50ml). After additional stirring for 30 minutes the residual hydrides is destroyed by adding acetone (5ml~ and ethyl-ether saturated with water. Dry MgSO4,12g, is added to, then the organic phase is filtered and evaporated to dryness.
We obtain the following 3-endohydroxy-2-exo-hydroxy-methyl:
bicyclo[3.2.0]heptane-6-one-6,6-ethylenedioxide bicyclo[3.2.0]heptane-7-one-7,7-ethylenedioxide bicycle [4.3.0]nonane-7-one-7,7-ethylenedioxide bicyclo[4.3.0~nonane~8-one-8,$-ethylenedioxide bicyclo[5.3.0]decane-8-one-8,8-ethylenedioxide and their 3-endo-hydroxy-THP-ethers both rhizomic and optical active form (net, en) when optical active material, coming from optical resolution successively described, is used in the reductive process.
Example 59 -Free kitten is obtained by treatment of a solution of endhydroxy-2-exo-hydroxymethyl-bicyclo[5.3.0]decane-88-one-8, 8-e-thylenedioxide (5g, 2010 m) in methanol (20ml) and water (2ml) with p-toluensulphonic acid (0~3g) for 2 hours at reflex temperature. the solvents are evaporated in vacuum and the residue is filtered through a short column o-f Sue.

Jo Working in accordance with the procedure of the example 54, a solution of the so obtained 3-endo-hydroxy-2-exo-hydroxymethyl-bicyclo[5.3.0]8-one(4.7g) in dry DMSO (17ml) is reacted with the slide formed from potassium ter-butoxide (27g), DMSO (280ml) and 3-carboxy-propyl-phosphoniur~romide for 5 hours at 40. The reaction mixture is diluted with water (300ml) and extracted with 80:20 ethylether-benzene to remove triphenyl-phosphoxide. These extracts are discarded an alkaline phases are acidified up to pi 5 and repeatedly extracted with ethyl ether (8x200) and with 3:1 ethylether-ethylacetate (5xlOO). The combined organic extracts are dried, concentrated to a small volume (loom) treated with ethereal diazomethane to achieve the methyl ester and then evaporated to dryness.
The crude material is chromatographed on Sue (loo) (ethyl acetate as fluent) to give 5 (ZOO) octanor-12~
hydroxymRthyl-ll~-hydroxy-9a-deoxy-7a~homo-9ar 9b-dimRkhylene-2-nor-prostacycla-5-enoic acid methyl ester (4.lg).
By treating this compound in dry DMF (12 ml)with dimethyl-ter-butyl-silyl-chloride (2.2g) and imidazole (1.55g) at 15 for I hours, followed from dilution with water (24ml) and extraction with ethyl ether and chromatographic purification on Swig, cyclohexane ethyl ether as fluent) we obtain its moo 12~-DMB silyloxy methyl-ether (4.31g 80%).
Treatment with pardon (loll), acetic android (5ml) at rut. for 12 hours and hydrolysis with aqueous methanol and p-toluensulphonic acid afford SUE (2C-~12)octanor 12~-hydroxy methyl hydroxy pa Dixie home Ahab dim ethylene 2 nor prostacycla-5-en-oic acid methylester-ll-acetate. Preparative chromatography (using a HPLC-instrumRnt and monitoring with refractive index) on Sue treated with 3% Agony (with ethylene-chloride-ethylacetate as fluent) affords the individual geometric 5 c and it isomers. In similar way, SUE)-octanor-12~-hydroxymethyl-11~-hydroxy-9a-deoxy-7a--whom-methylene-prostacycla-5-enoic acid methyl ester-11-ace-tate and their 5c and it individual geometric isomers are prepared when 3-endo-hydroxy-bicyclo[4.3.o]nonane-7-one-2-exo-caarboxymethyle ter-7,7-ethylenedioxide is used in side of the corresponding per-hydroazulene compound and the 4-carboxybutylphosphonium bromide is utilized in side of the 3-carboxypropyl-one.
Example 60 Starting from the 2-exo-hydroxymethyl-THP-ether come pounds of the example 58 and from 12~-hydroxymethyl-11-acetate of the example 59, we have obtained the corresponding aldehydes by the following oxidative procedure:
Successively, dicyclohexylcarbodiimide (0.64g), pardon (O.lml) trifluoroacetic acid (0.05ml) are added to a stirred solution of the hydroxymethyl compound (2.10 em) in 75:25 benaene-DMSO (6ml). After 4.5 hours, the reaction mixture is diluted with Bunsen (20ml) and water (loll) and stirred for 30 minutes again. Dicyclohexylurea is filtered off and the organic layer is washed with water until neutral and then concentrated up to 10 ml affording a solution in dry Bunsen of the following aldehydes:
3-endo-THP-oxy-2-exo-formyl-bicyclo[3.2.0]heptane--6-one-6,6 ethylene dioxide 3-endo-THP-oxy-2-exo-formyl-bicyclo[3.2.0]heptane--7-one-7,7-ethylene dioxide 3-endo-THP oxy-2-exo-formyl-bicyclo[4.3.0]nonane-7-one-7,7-ethylene dioxide 3-endo-THP-oxy-2 exo-formyl-bicycloL4.3O0]nonane-8-one-8,8-it ethylene dioxide 3-endo-THP-oxy-2-exo-foryml-bicyclo[5.3.0]decane-88-one-8,8-ethylene dioxide ~(20-~12)oc-tanor-12~-formyl-ll~-hydroxy-7-homo-9aa,9b-dimethyl2ne-2-nor-pros-tacycla-5-enoic acid me-thyles-ter-ll-aceta-te (EYE);
5c;5t).
~(20~12)octanor-12~-formyl~ -hydroxy-9a-deoxy-7a-homo~9a-methylene-prostacycla-5-enoic acid methylester-ll-acetate (socket).
These compounds are used in the following Witting-Homer reactions with any further purification.
Example 61 A solution of (2-oxo-heptyl)dimethylphosphonate (0.49g) in Bunsen (6ml) is added drops to a stirred suspension of Nay (80~ dispersion in mineral oil, 66mg, 2.2.10 m) in Bunsen (15ml). After an additional stirring for I we add a solution of 2.10 em of 5t-~(20-~12)octanor-12~-formyl-1~ -hydroxy-9a-deoxy-7a-homo~9a,9b-dimethylene-2-nor-prostacycla 5-enoic acid methyl-ester-ll-acetate in Bunsen (loll) -to it. After an additional hour the reaction is stopped by adding a solution of acetic acid (132mg) in Bunsen (5ml); the organic phase is washed with water until neutral, dried and evaporated to dryness.
The residue, 1.2g, is absorbed on Sue tog), following elusion with cyclohexane-ethylacetate gives 5t,13t-11~-hydroxy-15-oxo-9a-deoxy-7a-homo-9a,9b-dimethylene-2-nor-prrostacycla-5,13-dunk acid methyl ester-ll-acetate (0.76g),~ Max 228m~ ~=9.800.
The following ~,~ -unsaturated kittens are obtained when the other aldehydes of the example 60 are used in the above procedure:
5c,13t-1~-hydroxy-15-oxo-9a-deoxy-7a-homo-9a,9b-dimethylenee-2-`` - 80 1~9~ '7 nor prostacycla-5,13-dienoic acid-methylester-ll-acetate maxim and the mixture of their SUE) isomers 5t,13t-11~-hydroxy-15-oxo-9a-deoxy-7a-homo-ga-methhylene-prosta-cycla-5,13~dienoic acid methylester-ll-acetate (Max 229~m Jo =10.000) and its it and 5(Z,E)-isomers and the following 2-exo[3~-oxo-oct-l'~trans-enyl]3-endo-hydroXy-THP-ethers:bicyclo~3.2 0]heptane-6-one-6,6-ethylenedloxide bicyclo[3.2.0]heptane-7-one-7,7-ethylenedioxide bicyclo[4.3.0]nonane-7-one-7,7-ethylenedioxide bicyclo[4.3.0]nonane-8-one-8,8-ethylenedioxide bicyclo[5.3.0]decane-8-one-8,8-ethylenedioxide.
Example 62 Using in the procedure of the example 61, different dimethylphosphonates we have prepared the following unseater-axed kittens:
a) by reaction of 3-endo-THP-oxy-2-exo-formyl-bicyclo[3.2.0]-heptane-7-one-7,7-ethylenedioxide (2.10 em) with (2-oxo-3(S,R)-fluoro-heptyl)dimethylphosphonate (0.54g) we obtain 3-endo-THP-oxy-2-exo[3'-oxo-4'(R,S)fluoro-oct~ trans-enyl]bicyclo[3.2.0]-heptane-7-one-7,7-ethylenedioxide (0.72g)~max 229 nm,~=9.900[~]D=
SCHICK) b) by reaction of the heptane-6-one-6,6-ethylenedioxide alluded (2.10 em) with (2-oxo~octyl)dimethylphosphonate we obtain end-THP-ox~-2-exo[3'-oxo-non-1'-trans-enyl]bicyclo~3.2eighteen-one-6,6-ethylenedioxide~max 228 no ~9.300 c) by reaction with the heptane-7-one-7,7-ethylenedioxidealdehyde with (2-oxo-4-phenyl-butyl)dimethylphosphona-te (0.565g) we obtain 3-endo-THP-oxy-2-exo-[3'-oxo-5;-phenyl-pent-1'--trrans-enyl]-bicyclo[3~2.0]heptane-7-one-7,7-ethylenedioxide d) by reaction with the nonane-7-one-7,7-ethylenedioxide with ~9~t7 0.52g of (2--oxo-3S-methylheptyl)and with (2-oxo--3R-me-thyl-heptyl)dimethyl phosphonate we obtain respectively:
3-endo-THP-oxy-2-exo[3'-oxo-4'S-methyl-oct-l'-tranns-enyl]bicyclo~
[4.3.0]nonane-7-one-7,7-ethylenedioxide and 3-endo-THP-oxy-2-exo[3'-oxo-4'R-methyl-oct-1'-tranns-enyl]bicyclo-[4.3.0]nonane-7-one-7,7-ethylenedioxide.
Example 63 Pardon hydrobromideperbromide (C5H5N.HBr.Br2), 0.8g, is added to a stirred solution of 3-endo-THP-oxy-2-exo[3'-oxo-4'-(R,S)-fluoro-oct-l'-transenyl]bicyclo[3.2.0]heptanNina-ethylene dioxide in dry pardon (15ml). After additional stir-ring for 4 hours at rut., the precipitate is filtered off and the organic equate is partitioned among ice, ON H2SO4 and ethyl acetate. The organic layer is washed with cooled 0.5NH2SO4, brine, 1% sodium carbonate, water until neutral affording 0.71g of 2'bromo-4'(R,S)-fluoro compound, which is a mixture of 2 diastereoisomeric 4'S and OR derivatives. HPLC~chromatography on Sue with CH2C12-ethylether (85:15) affords the individual isomers:
0.22g of3-endo-THP-oxy-2-exo[2'bromo-3'-oxo-4'R-:Eluoro-ocCal transenyl]bicyclo[3.2.0]heptane-7-one-7,7-ethyleneedioxide~max 250nm ~=9.830 and 0.19g of the 4~s-fluoro isomer Max 251nm ~=9.750. Using in the above procedure different unstriated kittens, we obtain the followings:
3-endo-THP-oxy-2-exo[2'bromo-3'-oxo-non-1'-trans-eenyl]bicyclo-[3.2.0]heptane-6-one-6,6-ethylenedioxide and 3-endo-THP-oxy-2-exo[2'bromo-3'-oxo-oct-1'-trans-eenyl]bicyclo-[4.3.0]nonane-7-one-7,7-ethylenedioxide.
Example 64 on ethereal solution of 5% methyl magnesium iodide (5ml) I., is added to a stirred solution of 5t,13t-1~ -hydroxy-15-oxo-9a-deoxy-7a-homo-9a-methylene-prostacycla-5,13-dienoito acid methyl ester (0.4g) in 2:1 ethyl e-ther--toluene (12ml), cooled at -30. after stirring for additional 4 hours, the reaction mixture is warmed to 0 and the residual reagent is destroyed by adding of 20% aqueous N~4Cl. queue organic layer is separated, washed with water, dried and after addition of pardon (O.lml) is evaporated to dryness The residue dissolved in dry methanol (loll) is stirred with an hydrous K2C03(0.1g) for 2 hours.
The solution is filtered, evaporated in vacuum and the resulting crude material is partitioned between ethyl acetate 20% Nope.
The organic layer after the usual work-up is concentrated to small volume; the residue is absorbed on Swig). Elusion with 80:20 ethyl ether: isopropyl ether gives 5t,13t-11~,15S-dihydroxy-15-methyl-9a-deoxy-7a-homo-9a-methylene--prostacycla-5,13-With this procedure it is alsoobtained:5t,13t-11~,15S-dihydroxy-15-methyl-9a-deooxy-7a-homo-9a,9b-dimethylene-2-nor-prostacycla-5,13-dienoic acid-methylester and its 15R-epimer.
The free acids are obtained heating at the reflex temperature a solution of methyl esters in 80:20 methanol-water in the presence of 2% K2C03. The solvent is evaporated in vacuum and the residue is partitioned between ethyl ether and water. The organic layers are reextracted with 0.5% K2C03 and discarded. The combined alkaline phases are acidified up to pi 6 and extracted with ethyl ether. Combined organic phases are washed, dried on McCoy and evaporated to dryness -to give free acids.
Example 65 Using in the procedure of the example 64 ethanol magnesium bromide, vinyl magnesium bromide and ethyl magnesium bromide inside of the methyl magnesium iodide, the corresponding ethanol, 15-vinyl and 15-ethyl pros-tacycladienoic acids are obtained.
Example 66 Starting from the unsaturated kittens of the examples 61,62,63, secondary allylic alcohols are obtained using the following procedure: a solution of I unsaturated kitten ~2.10 m) in dry ethyl ether (20ml) is added to a stirred solution of 0.25M zinc bordered (48ml) in dry ethyl ether, drops in a period of 30 minutes. After an additional stirring for 2 hours, the residual hydrides is destroyed by adding saturated Nail. The organic layer is separated, washed until neutral, dried on Nazi and evaporated to dryness. Preparative HPLC-chromatography on Sue, using as fluent ethylene chloride/ethylacetate, affords:
5c,13t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a,9b-diimethylene-2-nor-prostacycla-5,13-dienoic acid methylester-ll-acetate and its SUE) and it geometric isomers.
5t,13t~,15S-dihydroxy-9a-deoxy-7a-homo-9a-me-thylene-prosstay cycla-5,13-dienoic acid methylester-ll-acetate and its SUE) and 5c-geometric isomers.
The following 2-exo[3'S-hydroxy-oct-l'-trans-enyl]3-endo-THP-oxy:
bicyclo[3.2.0]heptane-6-one-6,6-ethylenedioxide bicyclo[3~2.0]heptane-7-one-7,7-ethylenedioxide bicyclo[4.3.0]nonane-7-one-7~7-ethylenedioxide bicyclo[4.3.0]nonane-8-one-8,8-ethylenedioxide and the -following 3-endo-THP-oxy:
30 2-exo[2'bromo-3'S-hydroxy-4lR-fluoro-oct-l'-trans--enyl]bicyclo-r ~L9~3~3L'7 [3.2.0]heptane-7-one-7,7-ethylenedioxide 2-exo[2-bromo-3~s-hydroxy-4~s-fluoro-oct-l~-trans--enyl]bi [3.2.0]heptane-7-one-7,7-ethylenedioxide 2-exo[2'bromo-3'S-hydroxy-non-l'-trans-enyl]bicyclLowe .0]-heptane-6-one-6,6-ethylenedioxide 2-exo[3'S-hydroxy-non-l'-trans-enyl]bicyclo[3.2.0]heptenon-6,6-ethylenedioxide 2-exol3'S-hydroxy-5'-phenyl-pent-1'-trans-enyl]bicyclo[[3.2.0]-heptane-7-one-7,7-ethylenedioxide 2-exo[2'bromo-3'S-hydroxy-oct-l'-trans-enyl] bicycle]-nonane-7-one-7,7-ethylenedioxide 2-exo[3'S-hydroxy-4'S-methyl-oct-l'-trans-enyl]bicsuckle]-nonane-7-one-7,7-ethylenedioxide 2-exo[3'S-hydroxy-4'R-methyl-oct-l'-trans-enyl]bicyclo[[4.3.0]-nonane-7-one-7,7-ethylenedioxide 5c,13t-11~,15R-dihydroxy-9a-deoxy-7a-homo-9a,9b-diimethylene-2-nor-prostacycla-5,13-dienoic acid me thylester-ll-acetate and its 5 (ZOO) and it geometric isomers.
it,13t-11~,15R-dihydroxy-9a-deoxy-7a-homo-9a-methylenno-prostacycla-5,13-dienoic acid methylester-ll-acetate and its 5-(ZOO) and 5c-geometric isomers.
The following 2-exo[3'R-hydroxy-oct-l'-trans-enyl]3-end -THP-oxy:
bicycle [3.2.0]heptane-6-one-6,6-ethylenedioxide bicyclo[3.2.0]heptane-7-one-7,7-ethylenedioxide bicyclo[4.3.0]nonane-7-one-7,7-ethylenedioxide bicycle ~4.3.0]nonane-8-one-8,8-ethylenedioxide and the following 3-endo-THP-oxy:
2-exo[2'bromo-3'R-hydroxy-4' R-fluoro-oct-l'-trans-enyl]bicyclo-[3.2.0]heptane-7-one-7,7-ethylenedioxide lo 2-exo[2lbro~no-3lR-nydroxy-4ls-fluoro-oct-ll-transs-enyl]bi [3.2.0]heptane-7-one-7,7-ethylenedioxide 2-exo[2'bromo-3'R-hydroxy-non-l~trans-enyl]bicycloo[3~2.o]heptane 6-one-6,6-ethylenedioxide 2~exo[3'R-hydroxy-non-l~-trans-enyl]bicyclo[3.2 0]hep-tane-6-one-6,6-ethylenedioxide 2-exo[3'R-hydroxy-5'-phenyl-pent-1'-trans-enyl]bicsuckle]-heptane-7-one-7,7-ethylenedioxide 2-exo[2'bromo-3'R-hydroxy-oct-l'-trans-enyl]bicycllo[4.3.0]nonane-7-one-7,7-ethylenedioxide 2-exo[3'R-hydroxy-4'S-methyl-oct-l'-trans-enyl]bicsuckle]-nonane-7-one-7,7-ethylenedioxide 2-exo[3'R-hydroxy-4'R-methyl-oct~l'-trans-enyl]bicsuckle]-nonane-7-one-7,7-ethylenedioxide Example 67 The individual ll-acetate prostacycladienoic acid methyl-esters are converted both in their ll-hydroxy methyl esters by trays esterification in dry methanol with an hydrous K2C03 (0.5 mow equip) and in their ll-hydroxy free acid by treatment with K2C03 in 80~ aqueous methanol.
Example 68 Every one of the bicyclo-TI~P-oxy-ethylenedioxides obtained in the procedure of the example 66 is converted into the corresponding prostacyclenoic acids working up with the following procedure:
a solution of 1.10 em of the bicyclo-THP-oxy-ethylenedioxide in acetone (15ml) is reflexed with N aqueous oxalic acid (loll) for 8 hours. The acetone is evaporated in vacuum and the aqueous phase is extracted with ethyl ether. The combined extracts, after the usual work-up, are evaporated to dryness affording ~.~.;, - I -I

about 0.6-1.10 em owe the hydroxy kitten. A solution owe this compound in dry DMSO (2ml) is added to a solution of the slide obtained so on: in a No atmosphere potassium-tert-butoxide (1.35g) is added to dry DMSO (15ml), then -to it we added 4-carboxy-butyl-triphenyl-phosphoniumbromide (2.6g) -to obtain a deep-red solution of the slide. After addition of the kitten, the reaction mixture is warmed at 40-42 for 6 hours, cooled, diluted with water (20ml), acidified up to pi 5.1 and extracted with ethyl ether (5x25ml).
The aqueous phase is discarded, and the organic extracts are collected, washed with water (5ml; this washing is discarded) and extracted with SNOW Naomi ~6x6ml) and water until neutral. The combined alkaline extracts are combined, acidified to pi 5 and extracted with ethyl ether. The combined organic extracts are washed with water (2ml), dried on Nazi, and evaporated to dryness giving a mixture of the 5 Z and 5 E acids.
The individual geometric isomers are obtained a after ehromatographie separation on acidic Sophie , Fe free) using CH2C12-ethylace-tate as fluent (Sue 30g for each of 0.2g of the acid).
In this way we have prepared:
5t,13t-11~,15S-dihydroxy-9a-deoxy-9a-nor-methylenee-prostacycla-dunk acid 5t,13t-11~,15S-dihydroxy-9a-deoxy-9a-nor-methylenee-20 methyl-prostacycla-5, dunk acid 5t-11Cl,15S-dihydroxy-9a-deoxy-9a-nor-methylene-200-methyl-prosta-cycla-5-en-13-ynoic acid 5t,13t-11~j15S-dihydroxy-9a-deoxy-9a-methylene-7-nnorm ethylene prostaeycla-5,13-dienoic acid 5t,13t-11~,15S-dihydroxy-9a-deoxy 7a-homo-9a-methylene-pros-ta-I

cycla-5,13-dienoic acid 5t,13-t-].1~, 15S-dihydroxy-9a-deoxy-9a,9b-dimethylene-prostacycla-5,13-dienoic acid 5t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-mmethanes-fluoro-prostacycla 5-en~13-ynoic acid 5t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-mme-thylene-16R-:Eluoro-prostacycla-5-en-13-ynoic acid 5t,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nnorm ethylene 17-phenyl-18,19,20-trinor-prostacycla-5,13-dienoicc acid 5t,13t~ ,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylene-16S-methyl-prostacycla-5,13-dienoic acid 5t,13t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-me-thhylene-16R-methyl-prostacycla-5,13-dienoic acid 5t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylenee-prostacycla-5-en-13-ynoic acid 5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-nor-methylenee-prostacycla-dunk acid 5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-nor-methylenee-20-me-thyl-prostacycla-5,13-dienoic acid 5c-11~,15S-dihydroxy~9a-deoxy-9a-nor-methylene-20--me-thyl-prosa-cycla-5-en-13-ynoic acid 5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nnorm ethylene prostacycla-5,13-dienoic acid 5c,13t~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylene-prosttax cycla-5,13-dienoic acid 5c,13t-11~,15S-dihydroxy-9a-deoxy-9a,9b-dimethylenne-prostacycla-dunk acid 5c-1~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-methyleeons-Eluoro-prostacycla-5-en-13-ynoic acid 5c-1~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-methyleene-16R-fluoro-prostacycla-5-en-13-ynoic acid 5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nnorm ethylene 17-phenyl-18,19,20-trinor-prostacycla-5,13-dienoicc acid 5c,13t~,15S-dihydroxy-9a-deoxy-7a-~omo-9a-me-thylene-16S--methyl-pros-tacycla-5,13-dienoic acid 5c,13t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methyylene--16R-methyl-prostacycla-5,13-dienoic acid 5c-1~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylene-prosttacycla-5-en-13-ynoic acid and their 15R-isomers.
Example 69 Successively dicyclohexylcarbodiimide (0.32g) pardon-timely) and trifluoroacetic acid (0.022ml) are added -to a stirred solution of 5t,13t-11~,15S-dihydroxy-9a-deoxy-9a,7a-homo-dimethylene-15 methyl-prostacycla-5,13-dienoic acid methyl ester (0.39g) in 75:25 benzene-DMSO (6ml). After 5 hours the reaction mixture is diluted with Bunsen (20ml) and 1.2g of oxalic acid in water (loll). The stirring is continued for 20 minutes, the mixture is filtered and the organic phase is washed until neutral, dried and finally evaporated to dryness.
Chromatographic purification on Swig), ethyl ether as fluent gives 0.26g of 5tl13t-11-oxo-15S-hydroxy-9a-deoxy-7a-homo-9a-methylene-15-methyl-prostacycla-5,13-diionic acid methyl ester which is hydrolyzed with 2% aqueous K2C03 to give the free acid.
example 70 Sodium bordered (2.5g) in portions is added to a stirred solution of bicyclo[4.3.0]nonane-7-en-3-one(11.42g) in ethanol (80ml). After an additional stirring for 2 hours, acetic acid (5ml) is added and the mixture is evaporated to dryness.
The residue is partitioned between water and C~2C12, and the 341'7 organic layer is evaporated to dryness. A solution of the resulting bicyclo[4.3.0]nonane-7-en-3 hydroxy(llg) in dry DMF is heated successively with dimethyl-tert-butyl-silyl-chloride (15.6g) and imidazole (10.85g), warmed at 60D for 6 hours, cooled and diluted with water (66ml). After exhaustive extraction with ethyl ether and usual work-up we obtain bicycle-[4.3.0]nonane-7-ene-3-hydroxy-3-DMB-silyl-ether (l9.lg). Its solution in dry THY (loom) r cooled at 0C is treated (under stirring, in I atmosphere) with MBH3 solution in THY (75ml).
After 2 hours, maintaining the temperature at 25, we add N Noah (25ml) and 30% hydrogen peroxide (25ml). The mixture is heated at 60 for 2 hours, cooled and diluted with Bunsen (400ml). The organic layer is washed with 1% Nikko, saturated sodium sulfite, saturated Nail, dried and evaporated to dryness giving crude bicyclo[4.3.0]nonane-7(8)~-3-dihydroxy-3-DMB-silylether (20.3g). A solution of the resulting alcohol in 85/25 benzene-DMSO (150ml) is treated successively with dicy~lohexylcarbodiimide (16g) pardon (2ml) trifler acetic acid (lml), under stirring. After 5 hours, the mixture is diluted with Bunsen (400ml), water (50ml) with a solution of oxalic acid (6g) in water (75ml), and after additional stirring for 30 minutes is filtered. The organic phase is washed with water until neutral affording bicyclo[4.3.0]nonane-7(8)-one-3-hydroxy-DMB-silylether (18.25g) which is dissolved in methanol (60ml) and treated with 1.8g of p-toluensulphonic acid. After 12 hours, the mixture is treated with pardon (1.95ml) and evaporated to dryness. The residue is filtered on Sue (ethylether-ethylacetate as fluent) to give bicyclo[4.3.0]nonane-7(8)-one-3-hydroxy (log).
A solution of this compound in Bunsen (50ml) is .~,..

Lo reflexed in the presence of dry ethylene glycol (5.2g) and p-toluensulphonic acid (0-62g) withdrawing the water formed during the reaction. Aster 14 hours we add pardon (2ml) and the organic phase is cooled, washed with water, I Nikko and saturated Nail until neutral. Evaporation of solvents gives bicyclo[4.3.o]nonane-7(8)-one-3-hydroxy-7~7(g~8)-eethylene dioxide.
Example 7_ Saponification with I K2CO3 in 80~ aqueous methanol of -the dl-3-endo-hydroxy-bicyclo[4.3.0]nonane-8-one-8,8-diethylenedioxide-2-exo-carboxy-methylester (4.5g) gives the free acid (4.2g).
To a solution of the free acid (4.2g) in acetonitrile (120ml) it is added d(+)-ephedrine (2.3g); after 4 hours at rut.
egg of salt crystals giving after further crystallization from acetonitrile 2.15g of (~) bicyclo[4.3.0]nonane-8-one-8,8-ethylenedioxide-3-endo-hydroxy-2-exo-carboxylic acid do ephedrinium salt. All the liquor waters are combined, evaporated to dryness; the residue is dissolved in water and treated with N Noah up to alkaline pi (12-13). d(~)-Ephedrine is recovered by extraction with ether, then alkaline aqueous solution is acidified to pi 5 extracted with ethyl acetate and organic layer combined are evaporated to dryness. The residue is diluted in acetonitrile and the procedure is repeated using (-)ephedrine to give(-)bicyclo[4.3.0]nonane-8-one-8,8-ethylenedioxide--end-hydroxy-2-exo-carboxylic acid l(-)ephedrinium salt. Every one of the salts is separately dissolved in water/NaOH; the optically active base is recovered by extraction with ethyl ether, the alkaline aqueous phase is acidified up to pi 5-5,1 and extracted with ethyl-acetate affording on (~)bicyclo[4.3.0]nonane-8-one-8,8-ethylenedioxide-3-eendo-hydroxy--I
or,, Jo Lo 9~34~

-2-exo-carboxylic acid and (-)bicyclo[4.3.0]nonane-8-one-8,8-e-thylenedioxidee-3-endo-hydroxy-2-exo-carboxylic acid, which are converted in-to thy methyl ester with diazomethane treatment.
Example 72 A solution of 26g of dl-3-endo-hydroxy-bicyclo[4.3.0]-2-exo-carboxy-methylester-7-one-7,7-ethylenedioxidde in ace-tone (loom) is reflexed with ON H2S04 (20ml) for 4 hours.
Acetone is evaporated in vacuum and aqueous phase is extracted with ethyl-acetate. Combined organic extracts are washed until neutral, dried and evaporated to give 21.2g of do-3-endo-hydroxy-bicyclo[4.3.0]-2-exo-carboxymethyleester-7-one.
To a solution of the kitten in dry ace-tonitrile (250ml) it is added d-l-phenyl-l-ethyl-amine (12.1g) and solvent is slowly distilled off recovering 50ml in 30' minutes. The mixture is slowly cooled at rut. and then 12.12g of (+) 3-endo-hydroxy-7,7-(ll-phenyl-l'-ethylidenimino)-2-exo-carboxymethyleester-bicycler collected after filtration. The liquor waters are concentrated further -to give 6g of rhizomic material. Finally, a further concentration up to 80ml affords 11.42g of (-) end-hydroxy-7,7(1'-phenyl-l'ethylidenimino)-2-exo-carbboxy-methylester-bicycle].
Separately, the two Showoff bases are cleaved with 80:20 methanol ON H2S04 (200ml) at reflex temperature for 2 hours.
Solvent is evaporated in vacuum and aster extraction with ethyl acetate, the combined organic phases are washed until neutral, dried and evaporated in vacuum to give:
gig of (-I)3-endo-hydroxy-bicyclo~4.3.0]2-exo-carboxymethylesstern 7-one and 7.2g of (-) 3 -endo-hydroxy-bicyclo[4.3.0]2-exo-carboxymethylester-7-one, respectively.

~L~L9~ '7 Using this procedure, all the bicyclo-~hydroxy-carboxylic ester-ethylene dioxides ox the example 57 are submitted to optical resolution to give the following end-hydroxy alcohols:
(+)bicyclo[3.2.0]he~tane-6-one-2-exo- carboxymethylester (+)bicyclo[3.2.0]heptane-7-one-2-exo-carboxymethylLester (+)bicyclo[4.3.0]nonane-7-one-2-exo-carboxymethyleester (+)bicyclo[4.3.0]nonane-8-one-2-exo-carboxymethyleester (+)bicyclo[5.3.0]decane-8-one-2-exo-carboxymethyleester 10 (-)bicyclo[3.2.0]heptane-6-one-2-exo-carboxymethylfester (-)bicyclo[3.2.0]heptane-7-one-2-exo-carboxyme-thyLester (-)bicyclo[4.3.0]nonane-7-one-2-exo-carboxymethyleester (-)bicyclo[4.3.0]nonane-8-one-2-exo-carboxymethyleester (-)bicyclo[5.3.0]decane-8-one-2-exo-carboxymethyleester Using the procedure of the example 56; these kittens are converted into their ethylene dioxide derivatives.

s'; - 93 -

Claims (13)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing compounds having the following formula I

I

wherein R is (a) a free or esterified carboxy group; (b) -C(OR')3, where each R' group is independently C1-C6-alkyl or phenyl; (c) -CH2-R", where R"
is hydroxy or C2-C7-alkoxy; (d) where Ra and Rb are chosen inde-pendently from the group hydrogen, C1-C6-alkyl, C2-C6-alkanoyl and phenyl;
(e) -C=N; (f) a radical; (g) -CHO; or (h) a radical where each X' is independently -O- or -S- and the R' and R'b groups, whether the same or different, are C1-C6-alkyl or together form a straight or branched C2-C6-alkylene chain; D is: -CH2-, ?CH-OH, -CH=CH- (cis), -CH=CH-(trans), -C=C-, ?C=O, -O-, -S-, or ?N-Rc , where Rc may be hydrogen, C1-C6-alkyl or C2-C6-alkanoyl; one of R1 and R2 and, independently, one of R3 and R4 is hydrogen, C1-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-C1-C6-alkyl and the other is hydrogen, hydroxy, C1-C6-alkoxy or aryl-C1-C6-alkoxy, or, R1 and R2 and, independently, R3 and R4 together form an oxo group; each R5 and R6, whether the same or different, may be hydrogen, C1-C6-alkyl or halogen, or R5, R6 and the carbon atom to which they are bound form a ?C=CH2 or radicali Y is: -CH2-CH2-, -CH=CZ- (trans) or -CH=CZ- (Cis) where Z is hydrogen; X is: -(CH2)m - in which m3 is zero or 1, -CH=CH- (cis), -CH=CH- (trans), -O-, -S- or ,?N-Rc where Rc is as defined above; m1, m2, n1 and n2, whether the same or different, may be zero or an integer between 1 and 12 such that each sum m1 + m2 and n1 + n2 is less than or equal to 15; p and q are independently æero or an integer between 1 and 3 such that the sum p + q is an integer of 1 -to 6; R7 is an aryl group, either unsubstituted or subs-tituted with one or more of the following: halogen, halo-C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkoxy, phenyl; and the lactones derived from compounds of formula I and the phannaceutically or veterinarily acceptable salts thereof, which process comprises alkylation of compound II

II

wherein p, q, Y, n1, n2, X, R5, R6 and R7 are as defined above; one of R'1 and R'2 and, independently, one of R'3 and R'4 is hydrogen, C1-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-C1-C6-alkyl and the other is hydrogen, hydroxy, C1-C6-alkoxy, aryl-C1-C6-alkoxy or a protecting group bound to the bicyclic system or the side chain through an ether linkage, or R'1 and R'2 and, inclependently, R'3 and R'4 together form a protecting group for the ketone function, with a compound with formula III
E-CH-(CH2)m1 -D-(CH2)m2 -R" III
(-) wherein D, m1 and m2 are as defined above; E is a (C6H5)3P- or a (ReO)2p-(O)- group where each Re may independently be C1-C6-alkyl or phenyl;
R"' is (a") a carboxylic group, free, esterified or as its salt;
(b"') -C(OR')3, where R' is as defined above; (c") -CH2-RIV , where RIV is C2-C7-acyloxy or a protecting group bound to -CH2- through an ether linkage;

(d") , where Ra and Rb are as defined above; (e") -C=N; (f") a radical; (g") a radical where X', R' and R'b are as defined above, followed if required by the removal of any protecting group present; or, if required, a compound of formula I in which Y is -CH=CZ-where Z is hydrogen, is reduced to give, after the protecting groups are removed, a compound of formula I in which Y is -CH2-CH2-; or, if required, subjecting to nucleophilic addition the free carbonyl on the .omega. chain of a compound of formula I in which Y is -CH2-CH2- or -CH=CZ- and Z is as defined above, and R3 and R4 together form an oxo group to afford, upon removal of any protecting groups, a compound of formula I in which Y is -CH2-CH2- or -CH=CZ- and Z is as defined above, and one of R3 and R4 is hydroxy while the other is hydrogen, C1-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-C1-C6-alkyl and, if required, preparing the ether derivative from a compound of formula I in which Y is -CH2-CH2- or -CH=CZ- wherein Z is as defined above, one of R3 and R4 is hydroxy while -the other is hydrogen, C1-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-C1-C6-alkyl, and any other hydroxyl groups present are protected to give after removal of any protecting groups a compound of formula I in which Y is -CH2-CH2- or -CH=CZ- where Z is as defined above and one of R3 and R4 is C1-C6-alkoxy or aryl-C1-C6-alkoxy while the other is hydrogen, C1-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-C1-C6-alkyl; or, if required, converting a compound of formula I into another or to the lactone or pharmaceutically or veterinarily acceptable salt or, if required, converting a salt of a com-pound of formula I to the free compound or, if required, separating a mixture of isomeric compounds of formula I into individual isomers.

2. A process according to claim 1 wherein R"' is a carboxyl group, m1 is zero, m2 is 2, D or D' is -CH2-, ?C=O or ?CHOH in the S- or R-config-uration, p and q are both 1, R'1 is hydroxyl or protected hydroxyl, R'2 is hydrogen, Y is -CH2-CH2- or -CH=CH- (trans) one of R'3 and R'4 is hydroxyl or protected hydroxyl, n1 is zero, n2 is zero, 3 or 4, R5 is hydrogen or methyl, R6 is hydrogen, fluorine or methyl, X is -O- or -(CH2)m3 - wherein m3 is 1 and R7 is phenyl.

3. A process according to claim 2 wherein D or D' is -CH2-, R'3 is hydroxyl or protected hydroxyl and R'4 is hydrogen, Y is -CH=CH- (trans), n2 is zero, R5 and R6 are both hydrogen or are both methyl, X is -O- or is -(CH2)m3 - wherein m3 is 1 and R7 is phenyl or m-trifluoromethylphenyl.

4. A process according to claim 2 or 3 wherein D is and the process includes formation of a lactone of the obtained compound of formula I.

5. A process according to claim 1 wherein R''' is a carboxyl group, m is zero, D is -CH2-, m2 is 1 or 2, p is zero, 1 or 2, q is zero, 1 or 2, R'1 is hydroxyl or protected hydroxyl, R'2 is hydrogen, Y is -CH=CH- (trans), R'3 is hydroxyl or protected hydroxyl, R'4 is hydrogen or methyl, R5 is hydrogen, methyl or fluorine, R6 is hydrogen, methyl or fluorine, n1 is zero, n2 is zero or 3, X is -O- or is -(CH2)m3 - in which m3 is 1 and R7 is phenyl.

6. A process according to claim 5 wherein n2 is zero and R7 is phenyl.

7. A process according to claim 5 or 6 wherein R5 is hydrogen or methyl and R6 is hydrogen or methyl.

8. A process according to claim 5 or 6 wherein R5 is hydrogen or methyl and R6 is hydrogen or methyl, and m2 is 2.

9. A process according to claim 1 or 2 which includes the step of separating a mixture of compounds of formula I which are cis-trans isomers at the exocyclic double bond to obtain the individual cis- or trans-isomer.

10. A process according to claim 1 or 2 wherein a compound of formula II which is of cis or trans configuration at the exocyclic double bond is used to obtain a compound of formula I which is cis or trans, respectively.

11. A compound of formula I as defined in claim 1 or a pharmaceutically or veterinarily acceptable salt thereof, when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.

12. A process for the preparation of a compound of the general formula I

(I) wherein R1 represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms; Y represents -CH2-CH2- or trans -CH=CH-, one of R3 and R4 is hydrogen or methyl and the other is hydroxy; each of R5 and R6 whether the same or different may be hydrogen, methyl or fluorine; X is -(CH2)m- in which m is zero or 1, or -0-; n1 and n2, whether the same or different may be zero or an integer between 1 and 9 such that the sum n1 + n2 is less than or equal to 15, and R7 is a phenyl which may be substituted by 1 to 3 halogen atoms, a phenyl group, 1 to 3 alkyl groups having 1 to 4 carbon atoms, a halomethyl group, or alkoxy having 1 to 6 carbon atoms and the pharmaceutically acceptable salts thereof, which comprises reacting a compound of the general formula II

(II) wherein Y, n1, n2, X, R5, R6 and R7 are as defined above; R2 represents a free or functionally converted hydroxy group, with a Wittig reagent of the formula III

(III) and when required; subsequently in any order the isomers are separated, or protected hydroxy groups are liberated or a free carboxy group is esterified or an esterified carboxy group is hydrolysed or a carboxy group is converted into a salt.

13. A compound of formula I as defined in claim 12 or a pharmaceutically acceptable salt thereof, when prepared by a process according to claim 12 or an obvious chemical equivalent thereof.