New Development in Syntheses of Steroid

Stereoselective Syntheses of Steroid CD-Ring and Side Chain

Abstract

Four synthetic routes to steroid CD-ring synthons possessing various side chains, and two methods for stereospecific introduction of steroid side chains at C (20) are presented. In the first approach, (-) - (R) - [3 (R) -hydroxy-5-methyl-1 (Z) -hexenyl] - (7aR) -methyl-4-hydroinden-5-one (4) and (+) - (1R) -acetyl- (7aR) -methyl-4-hydroinden-5-one (32) were synthesized by highly enantioselective double Michael addition of a chiral alkenyl copper-phosphine complex to 2-methyl-2-cyclopentenone in which C (23R) -allylic alcohol moiety served to control the cis stereochemistry at C (17) and C (13) as a key reaction. In the second approach, (±) -De-AB-cholestan-9-one (50) was synthesized by highly stereoselective double Claisen rearrangements of allylic alcohol 54, the first one to introduce the acyl chain at C (14) and the second to introduce the chain at C (13) with the right trans stereochemistry between 18-methyl and C (14) hydrogen, as well as the geometry of the [17 (20) E] -olefin. The C-ring was constructed by the cyclization of acyl carbanion and the side chain was introduced by the alkylation of the secondary tosylate 51 with acyl carbanion 70. (±) -De-AB-cholest-8 (14), 22-diene-9-one (74) and its optically active form were synthesized, in the third and fourth approaches, by double Claisen rearrangements of (±) -triol 78 and the palladium-catalyzed cyclization of (+) -1, 3-diene monoepoxide 122, respectively. In both approaches, the cis relative stereochemistry between 18-methyl and side chain at C (17) was introduced by the product development controlled methylation of 2-butenyl-3-alkylvalerolactone. In the syntheses of side chains, the 20 (R) -and 20 (S) -configurations were introduced by the alkylation of 20-tosyloxy steroids with the protected cyanohydrin 131 and by the palladium-catalyzed 1, 4-addition of nucleophiles to 15, 16-epoxy-E-17 (20) -alkylidene steroids.