Asymmetric synthesis of novel highly sterically constrained (2 S,3 S)-3-methyl-3-trifluoromethyl- and (2 S,3 S,4 R)-3-trifluoromethyl-4-methylpyroglutamic acids

Abstract

Asymmetric synthesis of the novel highly sterically constrained (2 S,3 S)-3-methyl-3-trifluoromethyl- and (2 S,3 S,4 R)-3-trifluoromethyl-4-methylpyroglutamic acids has been developed via diastereoselective Michael addition reactions between a Ni(II) complex of the chiral non-racemic Schiff base of glycine with ( S)- o-[ N-( N-benzylprolyl)amino]benzophenone (BPB) and the corresponding trifluoromethyl-containing crotonates. Of particular synthetic interest is the reaction of the glycine Ni-complex with ethyl 3-trifluoromethyl crotonate featuring excellent diastereoselectivity (>98% de) as a result of complete stereochemical discrimination between the methyl and trifluoromethyl groups. A mechanistic rationale for the observed kinetically controlled stereochemical outcome is discussed.