Pharmacological modulation of the nuclear estrogen receptor (ER) is important for the treatment of ER-positive breast cancer and hormone related osteoporosis. Selective ER modulators such as tamoxifen and raloxifene exhibit tissue-dependent inhibition, while the downregulator fulvestrant is considered a pure antiestrogen. These drugs were discovered to exhibit cross-reactivity with G protein-coupled estrogen receptor (GPER) and may be responsible for off-target effects. The ER binding affinities of phenolic oxabicyclic compounds have been reported previously; recently a compound designated AB-1 was identified through computational and biomolecular screening as the first ER-selective ligand that does not bind GPER. Further study of structure activity relationships and development of analogues with increased selectivity and affinity for ER proteins requires efficient synthesis of this scaffold. The precursor 1,1-dicarbonylcyclohex-3-ene was constructed by Diels-Alder cycloaddition with in-situ generation of the dienophile from formaldehyde and 1,3-dicarbonyl compounds catalyzed by zinc(II)chloride in the presence of diene. The carbonyl functionalities were converted to hydroxyl groups by either lithium aluminum hydride or Grignard addition. The subsequent Prins cyclization with substituted benzaldehydes gave acceptable yields of the desired scaffolds. Competing intramolecular ether formation of oxabicyclo[2.2.2]octane was identified as a side reaction that reduced the yield of the desired products. Comparing a series of Lewis acid catalysts gave the best results with hafnium(IV)triflate. We also investigated a two-step process in which the diols were converted into the spirocyclic acetal, followed by Prins cyclization. The optimization of these steps enabled improved overall yields and provided access to a series of novel structural analogues. Continuing studies will evaluate the binding affinities towards nuclear ER isoforms, and their biological activity associated with modulation of transcriptional and signaling processes will be accessed. Promising leads identified in these investigations may have potential for the development of new ER-targeted therapeutics.

Efficient syntheses of phenolic oxabicyclo[3.3.1]non-7-ene scaffolds for optimization of selectivity towards estrogen receptor targets

2019 Fall National Meeting

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