A reinvestigation of the D-homoannular rearrangement and subsequent degradation pathways of (11β,16α)-9-fluoro-11,16,17,21-tetrahydroxypregna- 1,4-diene-3,20-dione (triamcinolone)

Article abstract of DOI:10.1016/0039-128X(94)90028-0

The commercial anti-inflammatory drug triamcinolone has been shown to rearrange by similar, but distinct pathways when exposed to certain trace metal ions or to dilute aqueous base. In the presence of aqueous base, the 16-hydroxy-20-keto system undergoes reverse aldol cleavage of the 16,17- bond, followed by aldol cyclization linking C-16 to C-20. This base-catalyzed rearrangement gives a 16β,17α-dihydroxy product and a corresponding 16α,17α-dihydroxy product in roughly 4 to 1 ratio. Metal-catalyzed rearrangement provides the 16α,17α-dihydroxy product with extremely high stereoselectivity. Mechanistic models are proposed that help explain the ratio of products isolated from each route. The studies presented suggest that similar forms of rearrangement could be of preparative value in syntheses requiring specific stereochemistry of appropriately substituted bicyclic α,β-dihydroxyketones. Under more rigorous conditions of aqueous base treatment these rearrangement products undergo further decomposition with loss of formaldehyde from the hydroxymethyl group, followed by β- elimination of water. Reaction of the β-elimination product with formaldehyde results in the formation of a dimeric species linked by a methylene group.