Methyl hypofluorite in the synthesis of 16-methoxyestradiol stereoisomers.
The usual chemistry of methyl hypofluorite provides a previously unexplored route for functionalizing the 16-position of estradiol. Three isomers of 16-methoxyestradiol were prepared via two synthetic routes, each using methyl hypofluorite. The estrogen receptor binding affinity of these compounds was determined to evaluate their potential as positron emission tomographic (PET) imaging agents targeting estrogen receptor-positive breast cancer. Radiolabeled methyl hypofluorite ([11C]CH3OF) would allow the rapid preparation of novel carbon-11 PET imaging agents. The 17-trimethylsilyl enol ethers of 3-benzyloxy and 3-trifloxyestrone were prepared as substrates to react with methyl hypofluorite. Conditions for the reaction of methyl hypofluorite with simple substrates were optimized to provide reasonable reaction yields with the steroidal substrates. Following introduction of the methoxy substituent at the 16-position, reduction and deprotection conditions were manipulated to yield the various methoxyestradiol isomers. Two-dimensional NMR techniques (HMQC and HMQC-TOCSY) were instrumental in the characterization of the methoxyestradiol isomers. NOESY experiments confirmed the stereochemistry of the 16- and 17-positions. 16 alpha-Methoxyestradiol-17 beta and 16 beta-methoxyestradiol-17 beta each with the preferred beta orientation for the 17-alcohol, were determined to have relative binding affinities of 1.5% and 2.3%, respectively. The stereoisomer with the unfavored alpha orientation at the 17-position, 16 alpha-methoxyestradiol-17 alpha, exhibited only a 0.5% relative binding affinity for the estrogen receptor. The biological evaluation of these compounds was not pursued further because of their low binding affinities.
Jonson
S D
SD
Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
d'Avignon
D A
DA
Katzenellenbogen
J A
JA
Welch
M J
MJ
D004952:Esters / Q000737:chemistry*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000378:metabolism; D013237:Stereoisomerism; D014055:Tomography, Emission-Computed
C115608:16-methoxyestradiol; D004952:Esters; D006845:Hydrocarbons, Fluorinated; D007202:Indicators and Reagents; D011960:Receptors, Estrogen; C115607:methyl hypofluorite; D004958:Estradiol