A reinvestigation of the D-homoannular rearrangement and subsequent degradation pathways of (11 beta,16 alpha)-9-fluoro-11,16,17,21- 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 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 16 beta,17 alpha-dihydroxy product and a corresponding 16 alpha,17 alpha-dihydroxy product in roughly 4 to 1 ratio. Metal-catalyzed rearrangement provides the 16 alpha,17 alpha-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 alpha,beta-dihydroxyketones. Under more vigorous conditions of aqueous base treatment these rearrangement products undergo further decomposition with loss of formaldehyde from the hydroxymethyl group, followed by beta-elimination of water. Reaction of the beta-elimination product with formaldehyde results in the formation of a dimeric species linked by a methylene group.
Delaney
E J
EJ
Chemical Process Technology Department, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903.
Sherrill
R G
RG
Palaniswamy
V
V
Sedergran
T C
TC
Taylor
S P
SP
D002384:Catalysis; D008956:Models, Chemical; D015394:Molecular Structure; D012972:Sodium Hydroxide; D013237:Stereoisomerism; D014221:Triamcinolone / Q000737:chemistry*
D014221:Triamcinolone; D012972:Sodium Hydroxide