A stereoselective synthesis of 7 alpha-(3-carboxypropyl) estradiol from a noncontrolled substance.
Alkylation of 3,17 beta-bis(2-trimethylsilyl)ethoxymethyl-1,3,5(10) estratriene-6-one (2) with 5-bromo-1-pentene using NaHMDS in THF afforded 3,17 beta-bis(2-trimethylsilyl)ethoxymethyl-7-alpha-(4'pentenyl)-1,3,5(10) estratriene-6-one (3) in excellent stereoselectivity (> 95% epimeric excess). Functionalization of the side chain in compound 3 was accomplished via ozonolysis, oxidation and esterification to give 5 in 72% yield. The reduction of ester (5) using NaBH4 in MeOH afforded the corresponding 6 alpha-hydroxy compound (6) as a single isomer in 72% yield. The hydroxyl group in 6 was removed by converting to the corresponding xanthate (7) followed by reduction using n-Bu3SnH to afford 8 in good yield. Finally, the SEM protective groups in 8 were removed, after which the ester function was hydrolyzed with LiOH to give 7 alpha-(3'-carboxypropyl)estradiol (10), in 10.6% overall yield from 3.
Adamczyk
M
M
Division Organic Chemistry Research (9NM, AP20), Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
Johnson
D D
DD
Reddy
R E
RE
D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D004970:Estrone / Q000737:chemistry
C110494:7-(3'-carboxypropyl)estradiol; D004970:Estrone; D004958:Estradiol