Novel and efficient synthesis of estriol and its 16-glucuronide via 2,4,16α-tribromoestrone

A novel synthesis of estra-1,3,5(10)-triene-3,16α, 17β-triol (5), sodium 3,17β-dihydroxyestra-1,3,5(10)-trien-16α-yl-β-D-glucopyranosuronate (12b) and sodium 3-hydroxyestra-1,3,5(10)-trien-17β-yl-β-D-glucopyranosuronate (10b) is described. 2,4,16α-Tribromo-3-hydroxyestra-1,3,5(10)-trien-17-one (2a) was efficiently synthesized in one step with quantitative yield by bromination of 3-hydroxyestra-1,3,5(10)-trien-17-one (1) with cupric bromide. Treatment of (2a) with NaOH in aqueous pyridine under the controlled conditions gave the 16α-hydroxy-17-ketone (4a) without ketol rearrangement. The ketol (4a) was converted in quantitative yield into the triol (5)via a sodium borohydride reduction in the presence of palladium chloride. Reaction of (4a) with methyl 1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranosuronate using silver carbonate as a catalyst yielded the 16-monoglucuronide acetate methyl ester (11). The reductive removal of the bromines of (11) with sodium borohydride followed by NaOH hydrolysis gave the glucuronide (12b). A direct glucuronidation of 2,4-dibromoestra-1,3,5(10)-triene-3,17β-diol (8) and a subsequent hydrolysis of the 17-glucuronide (9) gave the glucuronide (10b).