A REINVESTIGATION OF THE D-HOMOANNULAR REARRANGEMENT AND SUBSEQUENT DEGRADATION PATHWAYS OF 1,16,17,21-TETRAHYDROXYPREGNA-1,4-DIENE-3,20-DIONE (TRIAMCINOLONE)

The commercial anti-inflammatory drug triamcinolone has been shown to rearrange by similar, but distinct pathways when exposed to certain tr ace metal ions or to dilute aqueous base. In the presence of aqueous b ase, 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. T his base-catalyzed rearrangement gives a 16 beta,17 alpha-dihydroxy pr oduct and a corresponding 16 alpha,17 alpha-dihydroxy product in rough ly 4 to 1 ratio. Metal-catalyzed rearrangement provides the 16 alpha,1 7 alpha-dihydroxy product with exremely high stereoselectivity. Mechan istic models are propsed that help explain the ratio of products isola ted 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 alpha,b eta-dihydroxyketones. Under more vigorous conditions of aqueous base t reatment these rearrangement products undergo further decomposition wi th loss of formaldehyde from the hydroxymethyl group, followed by beta -elimination of water. Reaction of the beta-elimination product with f ormaldehyde results in the formation of a dimeric species linked by a methylene group.