93789-69-6Relevant articles and documents
Synthesis and structure elucidation of potential 6-oxygenatedated metabolites of (22R)-6*9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxypregn-4 -ene-3,20-dione, and related glucocorticosteroids
Thalen, Arne,Wickstroem, Lars-Inge
, p. 16 - 23 (2000)
(22R)-6α,9α-Difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxypregn- 4-ene-3,20-dione (rofleponide) is a synthetic glucocorticosteroid with high affinity for the rat thymus glucocorticoid receptor and a very high biotransformation rate demonstrated through incubation with a human liver S9 subcellular fraction. Because oxidation in the 6-position is an important metabolic pathway of glucocorticosteroids, the potential 6β-hydroxy and 6-oxo metabolites of rofleponide were synthesized to be used as reference compounds. Three alternative routes were used to reach the 6-hydroxy compound: (a) a one-step procedure involving allylic oxidation of rofleponide by selenium dioxide, (b) selenium dioxide oxidation of the corresponding 1,4-diene followed by selective 1,2-hydrogenation using Wilkinson's catalyst, and (c) autoxidation of a 3-methoxypregna-3,5-diene derivative. All three routes proceeded stereospecifically. Routes (a) and (c) gave approximately the same overall yield of the 6β-hydroxy epimer, whereas the overall yield from route (b) was much lower, primarily because of incomplete 1,2-hydrogenation. The 6-oxo compound was prepared through Pfitzner/Moffat oxidation of the 6-hydroxy compound. The stereochemistry of the 6-hydroxy substituent is discussed on the basis of 1H-NMR spectroscopy and supplementary 2D NOESY experiments. Copyright (C) 2000 Elsevier Science Inc.
