An efficient stereoselective synthesis of 6-α-aminoestradiol: Preparation of estradiol fluorescent probes

• Published in: Steroids 1997-06, Vol.62 (6), p.462-467
• Main Authors: Adamczyk, Maciej, Mattingly, Phillip G., Reddy, Rajarathnam E.
• Format: Article
• Language: English
• Subjects: 6-α-aminoestradiol; Biological and medical sciences; Crystallography, X-Ray; Estradiol - analogs & derivatives; Estradiol - chemical synthesis; Estradiol - chemistry; Fluorescent Dyes - chemical synthesis; fluorescent probe for estrogen-binding protein; Hormones. Endocrine system; Medical sciences; Models, Chemical; Models, Molecular; Pharmacology. Drug treatments; Spectrophotometry, Infrared; Stereoisomerism; β-estradiol
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/S0039-128X(97)00015-9

6-Oxoestradiol ( 2) was protected as its bis[(2-trimethylsilylethoxy)methyl] ether ( 4) and converted to the corresponding oxime ( 4). The oxime ( 4) on reduction with zinc in ethanol afforded the bis-SEM ether of 6-α-aminoestradiol ( 5) in 96% epimeric excess. Subsequently, 5 was hydrolyzed with HF to 6-α-aminoestradiol ( 6) in good yield. The absolute stereochemistry of the amino group in 6 was established by NMR and confirmed by X-ray crystallography on the corresponding 4-bromobenzamide derivative ( 9). Treatment of amine ( 6) with 6-(t-butoxycarbonylamino)hexanoic acid succinimidyl ester ( 10) followed by hydrolysis produced the amine ( 12) with a C-6 linker. The fluorescent probes ( 7 and 13) were prepared from 6 and 12 respectively, in 54–60% yield and >99% purity.