Methyl hypofluorite in the synthesis of 16-methoxyestradiol stereoisomers

Stephanie D. Jonson, D. André D'Avignon, John A. Katzenellenbogen, Michael J. Welch

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The unusual 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 con- firmed the stereochemistry of the 16- and 17- positions. 16α-Methoxyestradiol-17β and 16β-methoxyestradiol-17β, each with the preferred β orientation for the 17-alcohol, were determined to have relative binding affinities of 1.5% and 2.3%, respectively. The stereoisomer with the unfavored α orientation at the 17-position, 16α-methoxyestradiol- 17α, 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.

Original languageEnglish (US)
Pages (from-to)470-478
Number of pages9
JournalSteroids
Volume63
Issue number9
DOIs
StatePublished - Sep 1 1998
Externally publishedYes

Keywords

  • 16-methoxyestradiol
  • HMQC-TOCSY
  • Methyl hypofiuorite
  • NOESY

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