Synthesis of 4-formyl estrone using a positional protecting group and its conversion to other C-4-substituted estrogens.
4-Formyl estrone was synthesized in overall good yield in three steps starting from estrone. This was achieved by conducting an electrophilic aromatic substitution reaction using formaldehyde, triethylamine, and MgCl2 on 2-tert-butyl estrone, which was readily prepared in 96% yield from estrone using tert-butyl alcohol and BF3OEt2. The tert-butyl group acted as a positional protecting group to prevent reaction at the 2-position. The tert-butyl group was readily removed in good yield using AlCl3 in dichloromethane/CH3NO2. To our knowledge, this represents the first use of a positional protecting group for the synthesis of a C-4-modified estrogen. 4-Formyl estrone was used as a common precursor to obtain a variety of other C-4 modified estrogens in very high yields such as 4-methylestrone and 4-hydroxymethylestrone as well as the novel estrogen 4-carboxyestrone. The syntheses of 4-formyl, -methyl-, and -hydroxymethyl estrone represent dramatic improvements over previously reported syntheses of these compounds.
Liu
Yong
Y
Department of Chemistry, University of Waterloo, Waterloo, ON, Canada.
Kim
Byoungmoo
B
Taylor
Scott D
SD
D004967:Estrogens / Q000138:chemical synthesis* / Q000737:chemistry; D004970:Estrone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D008968:Molecular Conformation; D013237:Stereoisomerism
D004967:Estrogens; D004970:Estrone