Chiral amplification and the catalytic process in the enantioselective conjugate addition of chiral alkoxydimethylcuprate to (E)-cyclopentadec-2-en-l-one

Abstract

The stoichiometric conjugate addition with 60% enantiomeric excess (e.e.), of a chiral alkoxydimethylcuprate prepared from an 80:20 mixture of (1R,2R,3S,4S)-3-[(1-methylpyrrol-2-yl)methylamino]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol [endo-(+)-MPATH-3] and its enantiomer [endo-(–)-MPATH], to (E)-cyclopentadec-2-en-1 -one 1 produced (R)-(–)-muscone 2 in 76 %e.e. and 82% chemical yield. This chiral amplification can be explained by considering that the reaction proceeds via a homochiral dimeric cluster of the chiral alkoxydimethylcuprate. The catalytic conjugate addition was realized by adding methyllithium and the enone alternately to a toluene solution of the chiral alkoxydimethylcuprate prepared from a catalytic amount of the chiral ligand and copper(I) salt. (R)-(–)-Muscone with 99% optical purity was obtained in 85% chemical yield by the use of 0.36 equiv. of endo-(+)-MPATH and 0.33 equiv of copper(I) iodide. This methodology provides not only the highest enantioselectivity, but also useful information on the structure and mechanism of the conjugate addition of the organocuprate prepared from the copper(I) salt and alkyllithium.