Asymmetric synthesis of an optically active 1-benzylindane derivative as a selective agonist for estrogen receptor beta

Abstract

1-(3-Fluoro-4-hydroxybenzyl)-5-hydroxy-2,3-dihydro-1H-indene-1-carbonitrile rac-1a is a potent and highly selective agonist for estrogen receptor β that shows potential as a therapeutic agent for obesity and depression in postmenopausal women. To assess the more precise pharmacological actions of rac-1a, a stable and large-scale supply of optically active (R)-1a is required. In this study, our objective was to synthesize (R)-1a by developing a rapid and more efficient asymmetric synthetic pathway. The rapid supply of (R)-1a was accomplished by diastereomeric resolution of the easily obtainable racemic precursor 1-(3-fluoro-4-methoxybenzyl)-5-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid rac-3a using a chiral oxazolidinone auxiliary. Despite the need to discard the unwanted enantiomer, this approach enabled stable gram-scale supply of (R)-1a by a short process that minimized purification by column chromatography. Furthermore, by exploring more efficient synthetic methods, we synthesized chiral precursor (R)-3a by asymmetric desymmetrization of 1,3-diol 5, which is an important reaction in asymmetric synthesis.