The title compound was synthesized by coupling two structural moieties. The C/D ring fragment (XII) was prepared as shown in Scheme 28478101a. Indane derivative (I) was protected as the acetate ester (II) and subsequently alkylated at the alpha position of the sulfone group with the chiral tosylate (III) to afford (IV). Reductive cleavage of the sulfone group of (IV) by means of sodium amalgam yielded diol (V), which was protected as the acetonide (VI) using 2,2-dimethoxypropane and p-toluenesulfonic acid. Reprotection of the free hydroxyl group of (VI) as the acetate ester (VII), followed by ketal hydrolysis with iodine in MeOH, produced diol (VIII). This was then silylated with tert-butyldimethylsilyl triflate, giving bis-silyl ether (IX). The acetyl group of (IX) was reductively cleaved with LiAlH4, and the resulting alcohol (X) was oxidized to the corresponding ketone (XI) employing N-methylmorpholine-N-oxide in the presence of tetra-n-propylammonium perruthenate (TPAP). Then, Wittig reaction of ketone (XI) with (bromomethylene)triphenylphosphorane furnished the required bromo olefin (XII).

The A ring fragment (XXV) was synthesized as follows. Ring opening of epoxide (XIII) with 1,3-propanediol (XIV) in the presence of potassium tert-butoxide afforded the hydroxy ether (XV). The primary alcohol group of (XV) was then esterified with pivaloyl chloride (XVI) in the presence of pyridine to give (XVII). After hydrogenolysis of the benzyl ethers of (XVII), the 1,2-diol moiety was protected as the corresponding acetonide (XVIII) by means of 2,2-dimethoxypropane. Swern oxidation of the free alcohol group of (XVIII) generated aldehyde (XIX), and subsequent addition of vinylmagnesium bromide to (XIX) provided the allylic alcohol (XX) as a diastereomeric mixture. After protection of the hydroxyl group of (XX) as the pivalate ester, acid hydrolysis of the acetonide furnished diol (XXI). This was then converted to epoxide (XXII) under Mitsunobu conditions. Addition of lithium trimethylsilylacetylide (XXIII) to the epoxide (XXII) and then hydrolysis of the pivalate esters yielded (XXIV). This compound was protected as the tris(tert-butyldimethylsilyl) ether, and the diastereomeric mixture was separated by flash chromatography to provide intermediate (XXV).

Coupling of the A-ring fragment (XXV) and the C/D-ring fragment (XII) to give adduct (XXVI) was carried out in the presence of tris(dibenzylideneacetone) (chloroform)dipalladium and triphenylphosphine. The silyl protecting groups were finally removed by treatment with tetrabutylammonium fluoride.

The title compound was synthesized by coupling two structural moieties. The C/D ring fragment (XII) was prepared as shown in Scheme 28478101a. Indane derivative (I) was protected as the acetate ester (II) and subsequently alkylated at the alpha position of the sulfone group with the chiral tosylate (III) to afford (IV). Reductive cleavage of the sulfone group of (IV) by means of sodium amalgam yielded diol (V), which was protected as the acetonide (VI) using 2,2-dimethoxypropane and p-toluenesulfonic acid. Reprotection of the free hydroxyl group of (VI) as the acetate ester (VII), followed by ketal hydrolysis with iodine in MeOH, produced diol (VIII). This was then silylated with tert-butyldimethylsilyl triflate, giving bis-silyl ether (IX). The acetyl group of (IX) was reductively cleaved with LiAlH4, and the resulting alcohol (X) was oxidized to the corresponding ketone (XI) employing N-methylmorpholine-N-oxide in the presence of tetra-n-propylammonium perruthenate (TPAP). Then, Wittig reaction of ketone (XI) with (bromomethylene)triphenylphosphorane furnished the required bromo olefin (XII).

The A ring fragment (XXV) was synthesized as follows. Ring opening of epoxide (XIII) with 1,3-propanediol (XIV) in the presence of potassium tert-butoxide afforded the hydroxy ether (XV). The primary alcohol group of (XV) was then esterified with pivaloyl chloride (XVI) in the presence of pyridine to give (XVII). After hydrogenolysis of the benzyl ethers of (XVII), the 1,2-diol moiety was protected as the corresponding acetonide (XVIII) by means of 2,2-dimethoxypropane. Swern oxidation of the free alcohol group of (XVIII) generated aldehyde (XIX), and subsequent addition of vinylmagnesium bromide to (XIX) provided the allylic alcohol (XX) as a diastereomeric mixture. After protection of the hydroxyl group of (XX) as the pivalate ester, acid hydrolysis of the acetonide furnished diol (XXI). This was then converted to epoxide (XXII) under Mitsunobu conditions. Addition of lithium trimethylsilylacetylide (XXIII) to the epoxide (XXII) and then hydrolysis of the pivalate esters yielded (XXIV). This compound was protected as the tris(tert-butyldimethylsilyl) ether, and the diastereomeric mixture was separated by flash chromatography to provide intermediate (XXV).

Coupling of the A-ring fragment (XXV) and the C/D-ring fragment (XII) to give adduct (XXVI) was carried out in the presence of tris(dibenzylideneacetone) (chloroform)dipalladium and triphenylphosphine. The silyl protecting groups were finally removed by treatment with tetrabutylammonium fluoride.