A) Synthesis of intermediate (IX): The reaction of alpha-pinene (I) with paraformaldehyde at 180 C gives 10-hydroxymethyl-2-pinene (II), which by reaction with dihydropyran and p-toluenesulfonic acid in dichloromethane is converted to the tetrahydropyranyl ether (III) The reaction of (III) with diborane in THF affords 10-(tetra-hydropyran-2yloxymethyl)pinan-3-ol (IV), which is oxidized with CrO3 - MnSO4 - H2SO4 in ether to the ketone (V). The stereoselective reduction of (V) with NaBH4 in methanol gives the alcohol (VI), which is mesylated with methanesulfonyl chloride and triethylamine in dichloromethane to the mesyl ester (VII). The reaction of (VII) with sodium azide in HMPT yields the azide (VIII), which by reduction with LiAlH4 in refluxing ethyl ether affords 10-tetrahydropyran-2-yloxymethyl)pinan-3-ylamine (IX).

1) The condensation of (IX) with 2-cyclopentyl-2-(pivaloyloxy)acetyl chloride (X) in dichloromethane gives the amide (XI), which is deprotected with p-toluenesulfonie acid in methanol to yield N-(10-hydroxymethylpinan-3-yl)-2-cyclopentyl-2-(pivaloyloxy)acetamide (XII). The oxidation of (XII) with SO3 - pyridine in DMSO affords the aldehyde (XIII), which is submitted to a Wittig condensation with 4-carboxybutyltriphenylphosphonium bromide (XIV) by means ot NaH in DMSO to give the heptenoic acid derivative (XV). The deprotection of (XV) with NaOH yields the racemic mixture (at the 1,5-hydroxy substituent) (XVI), which is finally resolved into its two diastereomers by methylation with diazomethane, column chromatography (silica gel hexane) and hydrolysis with NaOH in methanol.

2) Amine (IX) is acylated with trifluoroacetic anhydride and pyridine in dichloromethane to the amide (XVII), which is hydrolyzed with p-toluenesulfonic acid in methanol yielding the alcohol (XVIII). The oxidation of (XVIII) with anhydrous H2SO4 - pyridine in DMSO triethylamine affords the aldehyde (XIX), which is submitted to a Wittig condensation with 4-carboxybutyltriphenylphosphonium bromide by means of NaH in DMSO giving the heptenoic acid (XX). Methylation of (XX) with diazomethane affords the corresponding methyl ester (XXI), which is deprotected with NaOH yielding the amino ester (XXII). The acylation of (XXII) with the acyl chloride (X) gives the protected amido ester (XXIII), which by partial hydrolysis with NaOH affords the racemic mixture (XVI), already obtained.

A) Synthesis of intermediate (IX): The reaction of alpha-pinene (I) with paraformaldehyde at 180 C gives 10-hydroxymethyl-2-pinene (II), which by reaction with dihydropyran and p-toluenesulfonic acid in dichloromethane is converted to the tetrahydropyranyl ether (III) The reaction of (III) with diborane in THF affords 10-(tetra-hydropyran-2yloxymethyl)pinan-3-ol (IV), which is oxidized with CrO3 - MnSO4 - H2SO4 in ether to the ketone (V). The stereoselective reduction of (V) with NaBH4 in methanol gives the alcohol (VI), which is mesylated with methanesulfonyl chloride and triethylamine in dichloromethane to the mesyl ester (VII). The reaction of (VII) with sodium azide in HMPT yields the azide (VIII), which by reduction with LiAlH4 in refluxing ethyl ether affords 10-tetrahydropyran-2-yloxymethyl)pinan-3-ylamine (IX).

1) The condensation of (IX) with 2-cyclopentyl-2-(pivaloyloxy)acetyl chloride (X) in dichloromethane gives the amide (XI), which is deprotected with p-toluenesulfonie acid in methanol to yield N-(10-hydroxymethylpinan-3-yl)-2-cyclopentyl-2-(pivaloyloxy)acetamide (XII). The oxidation of (XII) with SO3 - pyridine in DMSO affords the aldehyde (XIII), which is submitted to a Wittig condensation with 4-carboxybutyltriphenylphosphonium bromide (XIV) by means ot NaH in DMSO to give the heptenoic acid derivative (XV). The deprotection of (XV) with NaOH yields the racemic mixture (at the 1,5-hydroxy substituent) (XVI), which is finally resolved into its two diastereomers by methylation with diazomethane, column chromatography (silica gel hexane) and hydrolysis with NaOH in methanol.

2) Amine (IX) is acylated with trifluoroacetic anhydride and pyridine in dichloromethane to the amide (XVII), which is hydrolyzed with p-toluenesulfonic acid in methanol yielding the alcohol (XVIII). The oxidation of (XVIII) with anhydrous H2SO4 - pyridine in DMSO triethylamine affords the aldehyde (XIX), which is submitted to a Wittig condensation with 4-carboxybutyltriphenylphosphonium bromide by means of NaH in DMSO giving the heptenoic acid (XX). Methylation of (XX) with diazomethane affords the corresponding methyl ester (XXI), which is deprotected with NaOH yielding the amino ester (XXII). The acylation of (XXII) with the acyl chloride (X) gives the protected amido ester (XXIII), which by partial hydrolysis with NaOH affords the racemic mixture (XVI), already obtained.