111093-94-8Relevant articles and documents
An analogue of the antioestrogen tamoxifen of sufficient rigidity to exist as distinct enantiomers: Synthesis and conformtional dynamics studies
McCague
, p. 97 - 110 (2007/10/02)
The conformationally constrained tamoxifen analogue 1-methyl-8-phenyl-9-[4-[2-(dimethylamino)ethoxy]phenyl]-6,7 dihydro-5H-benzocycloheptene has been synthesised. A key synthetic step is a novel method for introduction of a methyl group into the aromatic ring of benzosuberone by enolate oxygen directed lithiation. Conformational studies were carried out on the methoxy precursor of the above compound. Dynamic 1H NMR revealed a free energy barrier to racemisation of enantiomeric atropisomers, ΔG[ = 20 (±1) kcal mol-1. It could be separated by chromatography at -5°C on (+)-poly(triphenylmethylmethacryate) into enantiomers which racemised with t( 1/2 ) 1.8 h at -5.2°C corresponding to Δ[ = 20.9 kcal mol-1. The difficulties in designing analogues having a greater degree of conformational constraint are discussed.