5,6,11,12-Tetrahydrochrysenes: Synthesis of Rigid Stilbene Systems Designed To Be Fluorescent Ligands for the Estrogen Receptor

Kwang Jin Hwang, James P. O'Neil, John A. Katzenellenbogen

Research output: Contribution to journalArticlepeer-review

Abstract

We have prepared a series of tetrahydrochrysenes as fluorescent ligands for the estrogen receptor. The stilbene chromophore in this tetracyclic system is held rigid and is adorned with an electron-donating hydroxyl group at C-8 that corresponds to the phenolic hydroxyl of estrogens and an electron acceptor at C-2 to give a donor-acceptor fluorophore. Additional substituents at C-5 and C-11 provide additional bulk that improves receptor binding affinity without distorting the planar conjugated system. The tetrahydrochrysene core was prepared by an acyloin condensation of α-alkyl m-methoxyhydrocinnamate esters, followed by a double dehydrative cyclization. The cis and trans isomers of the alkyl substituted systems could be separated and their stereochemistry ascertained by X-ray crystallographic analysis; the trans isomer has the higher receptor binding affinity, and the derivative with ethyl substituents at C-5 and C-11 has the best affinity. The donor-acceptor systems were prepared by functional group manipulations on one of the aromatic methoxy groups: conversion to the trifluoromethanesulfonate was followed by a palladium-mediated carbonylation to give the acetyl derivative and methoxycarbonylation to give the ester. The ester was further elaborated to the amide and nitrile. The nitro compound was prepared by nitration of protio system, itself prepared by hydrogenolysis of the trifluoromethanesulfonate. As will be described later, these tetrahydrochrysenes provide a favorable combination of estrogen receptor binding affinity and long wavelength, high quantum yield fluorescence to make them useful as fluorescent ligands for the estrogen receptor.

Original languageEnglish (US)
Pages (from-to)1262-1271
Number of pages10
JournalJournal of Organic Chemistry
Volume57
Issue number4
DOIs
StatePublished - Feb 1 1992

ASJC Scopus subject areas

  • Organic Chemistry

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