Enantio- and diastereoselective addition of cyclohexylMeldrum's acid to β- and α,β-disubstituted nitroalkenesvia N-sulfinyl urea catalysis

Abstract

Using N-sulfinyl urea catalysis, a method has been developed for the asymmetric synthesis of biologically important γ-amino acids with a high level of efficiency, practicality and unprecedented control of multiple stereocenters. This method is based upon the highly enantio- and diastereoselective addition of cyclohexyl Meldrum's acid as an easily deprotectable monocarboxylic acid equivalent. The addition to both β-substituted and α,β-disubstituted nitroalkenes using N-sulfinyl urea organocatalyst 8 is described. The utility of this new method toward drug production is demonstrated by the mole scale preparation of a key precursor to the commercial drug Lyrica using catalyst 8 at only 0.2 mol% loading. Moreover, α,β-disubstituted nitroalkene addition products were efficiently converted to γ-amino acid derivatives without epimerization of either stereocenter.