Synthesis and structure elucidation of potential 6-oxygenated metabolites of (22R)-6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione, and related glucocorticosteroids

(22R)-6 alpha,9 alpha-Difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propy lmethylenedioxypregn-4-ene-3,20-dione (rofleponide) is a synthetic glucocor ticosteroid with high affinity for the rat thymus glucocorticoid receptor a nd 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 6 beta-hydroxy and 6-oxo metabolites of rofleponide were synthesized to be us ed as reference compounds. Three alternative routes were used to reach the ti-hydroxy compound: (a) a one-step procedure involving allylic oxidation o f rofleponide by selenium dioxide, (b) selenium dioxide oxidation of the co rresponding 1,4-diene followed by selective 1,2-hydrogenation using Wilkins on's catalyst, and re) autoxidation of a 3-methoxypregna-3,5-diene derivati ve. All three routes proceeded stereospecifically. Routes (a) and (c) gave approximately the same overall yield of the 6 beta-hydroxy epimer, whereas the overall yield from route (b) was much lower, primarily because of incom plete 1,2-hydrogenation. The 6-oxo compound was prepared through Pfitzner/M offat oxidation of the 6-hydroxy compound. The stereochemistry of the 6-hyd roxy substituent is discussed on the basis of H-1-NMR spectroscopy and supp lementary 2D NOESY experiments. (C) 2000 Elsevier Science Inc. All rights r eserved.