The required phosphonate reagent (IV) was prepared by two alternative methods. Bromination of benzylacetone (I) in cold methanol afforded 1-bromo-4-phenyl-2-butanone (II). Subsequent displacement of the bromide ion of (II) with NaI in acetone led to the iodo ketone (III). The desired phosphonate (IV) was then obtained by the Arbuzov reaction of (III) with trimethyl phosphite. Alternatively, alkylation of the dianion of dimethyl 2-oxopropyl phosphonate (V) with benzyl bromide led to phosphonate (IV).

The title compound was prepared starting from the known bicyclic lactone (VI). Oxidation of the primary alcohol function of (VI) to the corresponding aldehyde (VII) was accomplished by either following the Pfitzner-Moffat method or by means of Dess-Martin perodinane reagent. Aldehyde (VII) was then converted to enone (IX) by Wittig reaction with the phosphonium salt (VIII) or, in a related method, by Wadsworth-Emmons condensation of (VII) with phosphonate (IV). Stereoselective reduction of enone (IX) with either L-selectride or (-)-B-chlorodiisopinocampheylborane produced the (15S)-allylic alcohol (X) as the major diastereoisomer, which was isolated by flash chromatography. Then, catalytic hydrogenation of the double bond of (X) gave the saturated alcohol (XI). Reduction of the lactone function employing DIBAL led to the protected lactol (XII). Subsequent removal of the phenylbenzoyl group of (XII) with K2CO3 in methanol furnished dihydroxy lactol (XIII). In a variation of this sequence, the phenylbenzoyl group of (XI) was first removed by methanolysis, and the resultant dihydroxy lactone (XIV) was then reduced with DIBAL to lactol (XIII).

A closely related strategy using tetrahydropyranyl protection has been reported. Protection of the allylic alcohol (X) with dihydropyran in the presence of p-toluenesulfonic acid yielded the tetrahydropyranyl ether (XVII). Catalytic hydrogenation of (XVII) gave rise to (XVIII), which was further reduced to lactol (XIX) employing DIBAL in cold toluene. After methanolysis of the phenylbenzoyl group of (XIX), the resultant lactol (XX) was subjected to Wittig condensation with the phosphonium reagent (XV), yielding olefin (XXI). After conversion of acid (XXI) to the corresponding isopropyl ester(XXII), the tetrahydropyranyl group was removed by means of pyridinium tosylate in MeOH.

The title compound was prepared starting from the known bicyclic lactone (VI). Oxidation of the primary alcohol function of (VI) to the corresponding aldehyde (VII) was accomplished by either following the Pfitzner-Moffat method or by means of Dess-Martin perodinane reagent. Aldehyde (VII) was then converted to enone (IX) by Wittig reaction with the phosphonium salt (VIII) or, in a related method, by Wadsworth-Emmons condensation of (VII) with phosphonate (IV). Stereoselective reduction of enone (IX) with either L-selectride or (-)-B-chlorodiisopinocampheylborane produced the (15S)-allylic alcohol (X) as the major diastereoisomer, which was isolated by flash chromatography. Then, catalytic hydrogenation of the double bond of (X) gave the saturated alcohol (XI). Reduction of the lactone function employing DIBAL led to the protected lactol (XII). Subsequent removal of the phenylbenzoyl group of (XII) with K2CO3 in methanol furnished dihydroxy lactol (XIII). In a variation of this sequence, the phenylbenzoyl group of (XI) was first removed by methanolysis, and the resultant dihydroxy lactone (XIV) was then reduced with DIBAL to lactol (XIII).

Wittig condensation of lactol (XIII) with (carboxybutyl)triphenylphosphonium bromide (XV) in the presence of potassium tert-butoxide produced the Z-olefin (XVI). Conversion of carboxylic acid (XVI) to the title isopropyl ester was then accomplished by alkylation with 2-iodopropane in the presence of DBU.

In an alternative method, the aldehyde lactone (XXIII) was subjected to Wadsworth-Emmons reaction with phosphonate (IV) to afford enone (XXIV). Stereoselective ketone reduction, followed by catalytic hydrogenation of the resultant allylic alcohol (XXV), provided (XXVI). Both the benzoate ester and the lactone groups of (XXIV) were hydrolyzed by KOH, yielding trihydroxy acid (XXVII), which was further cyclized to lactone (XIV) in boiling toluene. The hydroxyl groups of (XIV) were then protected with ethyl vinyl ether in the presence of trichloroacetic acid to produce the bis-acetal (XXVIII). Reduction of the lactone function of (XXVIII) to the corresponding lactol (XXIX), followed by Wittig reaction with the phosphorane generated from phosphonium salt (XV) and potassium t-butoxide, furnished olefin (XXX). After acidic hydrolysis of the acetal protecting groups of (XXX), the carboxylate function was converted to the corresponding isopropyl ester by treatment with 2-iodopropane and cesium carbonate.

The required phosphonate reagent (IV) was prepared by two alternative methods. Bromination of benzylacetone (I) in cold methanol afforded 1-bromo-4-phenyl-2-butanone (II). Subsequent displacement of the bromide ion of (II) with NaI in acetone led to the iodo ketone (III). The desired phosphonate (IV) was then obtained by the Arbuzov reaction of (III) with trimethyl phosphite. Alternatively, alkylation of the dianion of dimethyl 2-oxopropyl phosphonate (V) with benzyl bromide led to phosphonate (IV).

The title compound was prepared starting from the known bicyclic lactone (VI). Oxidation of the primary alcohol function of (VI) to the corresponding aldehyde (VII) was accomplished by either following the Pfitzner-Moffat method or by means of Dess-Martin perodinane reagent. Aldehyde (VII) was then converted to enone (IX) by Wittig reaction with the phosphonium salt (VIII) or, in a related method, by Wadsworth-Emmons condensation of (VII) with phosphonate (IV). Stereoselective reduction of enone (IX) with either L-selectride or (-)-B-chlorodiisopinocampheylborane produced the (15S)-allylic alcohol (X) as the major diastereoisomer, which was isolated by flash chromatography. Then, catalytic hydrogenation of the double bond of (X) gave the saturated alcohol (XI). Reduction of the lactone function employing DIBAL led to the protected lactol (XII). Subsequent removal of the phenylbenzoyl group of (XII) with K2CO3 in methanol furnished dihydroxy lactol (XIII). In a variation of this sequence, the phenylbenzoyl group of (XI) was first removed by methanolysis, and the resultant dihydroxy lactone (XIV) was then reduced with DIBAL to lactol (XIII).

Wittig condensation of lactol (XIII) with (carboxybutyl)triphenylphosphonium bromide (XV) in the presence of potassium tert-butoxide produced the Z-olefin (XVI). Conversion of carboxylic acid (XVI) to the title isopropyl ester was then accomplished by alkylation with 2-iodopropane in the presence of DBU.