Ethyl Nitroacetate in Aza-Henry Addition on Trifluoromethyl Aldimines: A Solvent-Free Procedure To Obtain Chiral Trifluoromethyl α,ß-Diamino Esters.

A self-catalyzed aza-Henry addition of ethyl nitroacetate on N-alkyl trifluoromethyl aldimines was reported to synthesize ß-amino α-nitro trifluoromethyl esters, precursors of α,ß-diamino acid derivatives. In the presence of a resident chiral center on the imine nitrogen, the use of a suitable Lewis acid leads to a good stereofacial control, always resulting from a nucleophilic unlike attack. By starting from optically pure N-protected trifluoromethyl aldimines or directly from N-α-amino ester trifluoromethyl aldimines, small ψ[CH(CF3)NH]-peptidomimetic backbones can be achieved in which a new primary amine function represents a possible center for synthetic extension. Finally, a very interesting, and never observed before, palladium-catalyzed syn ß-elimination occurred, leading to the selective nitro group reduction reaction on the syn-α-amino ester functionalized aza-Henry adducts and obtaining more stable optically pure trifluoromethyl conjugated imines.

New Synthesis of Trifluoromethyl Aldimines Containing L-α-Amino Ester Moieties and Their Use in Mannich-Type Reactions.

L-α-amino esters were considered valuable chiral starting materials in the condensation reaction with trifluoroacetaldehyde (fluoral) ethyl hemiacetal to obtain new functionalized trifluoromethyl aldimines. Starting from these latter compounds, isovaleraldehyde was used in proline-catalyzed Mannich-type addition reactions to give trifluoromethyl syn- or anti-γ-amino alcohols bearing the L-α-amino ester function, simply by changing the reaction temperature.

Stereoselective ZrCl4-Catalyzed Mannich-type Reaction of ß-Keto Esters with Chiral Trifluoromethyl Aldimines.

A method for the synthesis of fluorinated ß'-amino ß-dicarbonyl compounds using a Zr-catalyzed Mannich-type reaction has been developed, starting from N-protected trifluoromethyl aldimines and cyclic or acyclic ß-keto esters bearing different ester residues. The in situ generated metallic complex reacted with optically pure trifluoromethyl aldimine derived from (R)-α-methylbenzylamine, giving a highly diastereoselective asymmetric Mannich-type addition with formation of a chiral quaternary center. The absolute configuration at the new chiral centers was assigned through two-dimensional nuclear Overhauser effect spectroscopic analysis coupled with computational studies.