The reaction of phenol (I) with ethyl bromoacetate (II) by means of NaH in dimethoxyethane gives ethyl phenoxyacetate (III), which is condensed with dimethyl methylphosphonate (IV) by means of n-butyllithium in THF to afford dimethyl 2-oxo-3-phenoxypropylphosphonate (V). The Wittig condensation of (V) with (2'alpha-hydroxy-4'alpha-p-phenylbenzoyloxy-5'beta-ormylcyclopent-1'alpha-yl)acetic acid 1,2'-lactone (VI) by means of NaH in dimethoxyethane yields the ketonic lactone (VII), which is reduced with aluminum isopropoxide in refluxing toluene to give the hydroxy lactone (VIII). The hydrolysis of the protecting group of (VIII) with K2CO3 in methanol yields the dihydroxy lactone (IX), which is then protected with dihydropyran affording the bis(tetrahydropyranyloxy) compound (X). The reduction of the lactone group of (X) with diisobutylaluminum hydride in toluene yields the protected hemiacetal (XI), which is condensed with 4-pentinoic acid (XII) by means of LiCH3 in HMPT affording 6,9alpha-dihy-droxy-11alpha,15alpha-bistetrahydropyranyloxy-16-phenoxy-17,18,19,20-tetranorprost-4-yn-13-trans-enoic acid methyl ester (XIII) resulting from the methylation with CH2N2 of the acid intermediate.

The acetylation of (XIII) with acetic anhydride and triethylamine in methylene chloride yields the diacetoxy-bistetra-hydropyranyloxy acetylenic compound (XlV), which by a treatment with Cu2Br2-LiCH3 in ether is converted into 16-phenoxy-9alpha-acetoxy-11alpha,15alpha-bistetrahydropyranyloxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid methyl ester (XV). Elimination of the tetrahydropyranyl groups with acetic acid in water gives the corresponding dihydroxy compound (XVI), which is fully deprotected with K2CO3 in methanol yielding 9alpha,11alpha,15alpha-trihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid (XVII). The methylation of (XVII) with diazomethane affords the corresponding methyl ester (XVIII), which by treatment with tert-butyldimethylsilyl chloride (XIX) in DMF is converted into the corresponding 11,15-bis(silyloxy) compound (XX). The oxidation of (XX) with CrO3 - pyridine in CH2Cl2 affords 9-oxo-16-phenoxy-11alpha,15alpha-bis(tert-butyldimethylsilyloxy)-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid methyl ester (XXI), which is deprotected with aqueous acetic acid giving the free keto ester (XXII). Finally, this ester is hydrolyzed by treatment with pancreatic lipase.

The reaction of phenol (I) with ethyl bromoacetate (II) by means of NaH in dimethoxyethane gives ethyl phenoxyacetate (III), which is condensed with dimethyl methylphosphonate (IV) by means of n-butyllithium in THF to afford dimethyl 2-oxo-3-phenoxypropylphosphonate (V). The Wittig condensation of (V) with (2'alpha-hydroxy-4'alpha-p-phenylbenzoyloxy-5'beta-ormylcyclopent-1'alpha-yl)acetic acid 1,2'-lactone (VI) by means of NaH in dimethoxyethane yields the ketonic lactone (VII), which is reduced with aluminum isopropoxide in refluxing toluene to give the hydroxy lactone (VIII). The hydrolysis of the protecting group of (VIII) with K2CO3 in methanol yields the dihydroxy lactone (IX), which is then protected with dihydropyran affording the bis(tetrahydropyranyloxy) compound (X). The reduction of the lactone group of (X) with diisobutylaluminum hydride in toluene yields the protected hemiacetal (XI), which is condensed with 4-pentinoic acid (XII) by means of LiCH3 in HMPT affording 6,9alpha-dihy-droxy-11alpha,15alpha-bistetrahydropyranyloxy-16-phenoxy-17,18,19,20-tetranorprost-4-yn-13-trans-enoic acid methyl ester (XIII) resulting from the methylation with CH2N2 of the acid intermediate.

The acetylation of (XIII) with acetic anhydride and triethylamine in methylene chloride yields the diacetoxy-bistetra-hydropyranyloxy acetylenic compound (XlV), which by a treatment with Cu2Br2-LiCH3 in ether is converted into 16-phenoxy-9alpha-acetoxy-11alpha,15alpha-bistetrahydropyranyloxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid methyl ester (XV). Elimination of the tetrahydropyranyl groups with acetic acid in water gives the corresponding dihydroxy compound (XVI), which is fully deprotected with K2CO3 in methanol yielding 9alpha,11alpha,15alpha-trihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid (XVII). The methylation of (XVII) with diazomethane affords the corresponding methyl ester (XVIII), which by treatment with tert-butyldimethylsilyl chloride (XIX) in DMF is converted into the corresponding 11,15-bis(silyloxy) compound (XX). The oxidation of (XX) with CrO3 - pyridine in CH2Cl2 affords 9-oxo-16-phenoxy-11alpha,15alpha-bis(tert-butyldimethylsilyloxy)-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid methyl ester (XXI), which is deprotected with aqueous acetic acid giving the free keto ester (XXII). Finally, this ester is hydrolyzed by treatment with pancreatic lipase.

The reaction of phenol (I) with ethyl bromoacetate (II) by means of NaH in dimethoxyethane gives ethyl phenoxyacetate (III), which is condensed with dimethyl methylphosphonate (IV) by means of n-butyllithium in THF to afford dimethyl 2-oxo-3-phenoxypropylphosphonate (V). The Wittig condensation of (V) with (2'alpha-hydroxy-4'alpha-p-phenylbenzoyloxy-5'beta-ormylcyclopent-1'alpha-yl)acetic acid 1,2'-lactone (VI) by means of NaH in dimethoxyethane yields the ketonic lactone (VII), which is reduced with aluminum isopropoxide in refluxing toluene to give the hydroxy lactone (VIII). The hydrolysis of the protecting group of (VIII) with K2CO3 in methanol yields the dihydroxy lactone (IX), which is then protected with dihydropyran affording the bis(tetrahydropyranyloxy) compound (X). The reduction of the lactone group of (X) with diisobutylaluminum hydride in toluene yields the protected hemiacetal (XI), which is condensed with 4-pentinoic acid (XII) by means of LiCH3 in HMPT affording 6,9alpha-dihy-droxy-11alpha,15alpha-bistetrahydropyranyloxy-16-phenoxy-17,18,19,20-tetranorprost-4-yn-13-trans-enoic acid methyl ester (XIII) resulting from the methylation with CH2N2 of the acid intermediate.

The acetylation of (XIII) with acetic anhydride and triethylamine in methylene chloride yields the diacetoxy-bistetra-hydropyranyloxy acetylenic compound (XlV), which by a treatment with Cu2Br2-LiCH3 in ether is converted into 16-phenoxy-9alpha-acetoxy-11alpha,15alpha-bistetrahydropyranyloxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid methyl ester (XV). Elimination of the tetrahydropyranyl groups with acetic acid in water gives the corresponding dihydroxy compound (XVI), which is fully deprotected with K2CO3 in methanol yielding 9alpha,11alpha,15alpha-trihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid (XVII). The methylation of (XVII) with diazomethane affords the corresponding methyl ester (XVIII), which by treatment with tert-butyldimethylsilyl chloride (XIX) in DMF is converted into the corresponding 11,15-bis(silyloxy) compound (XX). The oxidation of (XX) with CrO3 - pyridine in CH2Cl2 affords 9-oxo-16-phenoxy-11alpha,15alpha-bis(tert-butyldimethylsilyloxy)-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid methyl ester (XXI), which is deprotected with aqueous acetic acid giving the free keto ester (XXII). Finally, this ester is hydrolyzed by treatment with pancreatic lipase.