Spiroborate Ester-Mediated Asymmetric Synthesis of β-Hydroxy Ethers and Its Conversion to Highly Enantiopure β-Amino Ethers

Borane-mediated reduction of aryl and alkyl ketones with α-aryl- and α-pyridyloxy groups affords β-hydroxy ethers in high enantiomeric purity (up to 99% ee) and in good yield, using as catalyst 10 mol % of spiroborate ester 1 derived from (S)-diphenylprolinol. Representative β-hydroxy ethers are successfully converted to β-amino ethers, with minor epimerization, by phthalimide substitution under Mitsunobu’s conditions followed by hydrazinolysis to obtain primary amino ethers or by imide reduction with borane to afford β-2,3-dihydro-1H-isoindol ethers. Nonracemic Mexiletine and nAChR analogues with potential biological activity are also synthesized in excellent yield by mesylation of key β-hydroxy pyridylethers and substitution with five-, six-, and seven-membered ring heterocyclic amines.