Asymmetric synthesis of (R)-(–)- and (S)-(+)-muscone by enantioselective conjugate addition of chiral dimethylcuprate to (E)-cyclopentadec-2-en-1-one

Abstract

A variety of optically active secondary amino alcohols have been prepared from camphor and screened as chiral non-transferable cuprate ligands in conjugate addition reactions. The reactions of (E)-cyclopentadec-2-en-1-one with chiral dimethylcuprates derived from the ligand in toluene afforded muscone in enantiomeric excesses as high as 26–89%. The stereochemistry of the product correlates with the configuration of the chiral ligand used. Thus the conjugate addition using the ligand prepared from exo-3-monosubstituted-amino-exo-2-hydroxybornane gave (S)-(+)-muscone, while with endo-ligand, (R)-(–)-muscone was obtained in higher enantioselectivity. Muscone of essentially 100% optical purity was obtained by the addition of small amounts of THF (tetrahydro-furan)(2–10 equiv.) to the toluene solution of the chiral cuprate reagent prepared from (1R,2R,3S,4S)-3-[(1-methylpyrrol-2-yl)methylamino]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol 23(endo-MPATH). The effect of the stoichiometry of the chiral ligand and the cuprate reagent on the chemical yield and enantioselectivity was briefly investigated.