Palladium-catalyzed coupling of 2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (I) with 2-methyl-3-butyn-2-ol (II) provided adduct (III). Subsequent cleavage of the propargyl alcohol of (III) with KOH in toluene gave the free acetylene (IV). Lithiation of (IV), followed by quenching with ethyl chloroformate, yielded the aryl propiolic ester (V). Conjugate addition to (V) of the in situ-generated lithium dimethylcuprate gave the Z-crotonate (VI), which was further reduced to the allylic alcohol (VII) using DIBAL. Enantioselective Simmons-Smith cyclopropanation in the presence of (+)-diethyl tartrate produced the cyclopropyl alcohols (VIII) in 80% e.e. favoring the (-)-enantiomer. This mixture was converted to the diastereomeric camphenoate esters, which were separated by preparative chromatography. The desired major isomer (IX) was then hydrolyzed to give the enantiomerically pure alcohol (X), and then oxidized to aldehyde (XI) using N-methylmorpholine-N-oxide and tetrapropylammonium perruthenate.

Palladium-catalyzed coupling of 2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (I) with 2-methyl-3-butyn-2-ol (II) provided adduct (III). Subsequent cleavage of the propargyl alcohol of (III) with KOH in toluene gave the free acetylene (IV). Lithiation of (IV), followed by quenching with ethyl chloroformate, yielded the aryl propiolic ester (V). Conjugate addition to (V) of the in situ-generated lithium dimethylcuprate gave the Z-crotonate (VI), which was further reduced to the allylic alcohol (VII) using DIBAL. Enantioselective Simmons-Smith cyclopropanation in the presence of (+)-diethyl tartrate produced the cyclopropyl alcohols (VIII) in 80% e.e. favoring the (-)-enantiomer. This mixture was converted to the diastereomeric camphenoate esters, which were separated by preparative chromatography. The desired major isomer (IX) was then hydrolyzed to give the enantiomerically pure alcohol (X), and then oxidized to aldehyde (XI) using N-methylmorpholine-N-oxide and tetrapropylammonium perruthenate.

Palladium-catalyzed coupling of 2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (I) with 2-methyl-3-butyn-2-ol (II) provided adduct (III). Subsequent cleavage of the propargyl alcohol of (III) with KOH in toluene gave the free acetylene (IV). Lithiation of (IV), followed by quenching with ethyl chloroformate, yielded the aryl propiolic ester (V). Conjugate addition to (V) of the in situ-generated lithium dimethylcuprate gave the Z-crotonate (VI), which was further reduced to the allylic alcohol (VII) using DIBAL. Enantioselective Simmons-Smith cyclopropanation in the presence of (+)-diethyl tartrate produced the cyclopropyl alcohols (VIII) in 80% e.e. favoring the (-)-enantiomer. This mixture was converted to the diastereomeric camphenoate esters, which were separated by preparative chromatography. The desired major isomer (IX) was then hydrolyzed to give the enantiomerically pure alcohol (X), and then oxidized to aldehyde (XI) using N-methylmorpholine-N-oxide and tetrapropylammonium perruthenate.

Horner-Emmons condensation of aldehyde (XI) with phosphonate (XII) produced the diene ester (XIII). Finally, ethyl ester hydrolysis of (XIII) gave rise to the title carboxylic acid.