The design, synthesis, and application of new amino acid-based modular N-ethylenediamine ligands

Reactions that form optically active secondary alcohols are one of the most useful enantioselective transformations found in organic chemistry. Chiral secondary alcohols have many properties; they are important synthetic precursors and they are found in numerous naturally occurring and biologically active compounds. A new series of modular N-acylethylenediamine ligands that are derived from amino acids were prepared and tested for their ability to catalyze the asymmetric addition of alkylzinc reagents to aromatic and aliphatic aldehydes to provide secondary alcohols. The ligands contain a tertiary amine, an amino acid side chain, and a carbamate or amide functionality. One ligand, which was synthesized from isoleucine, catalyzed the addition of diethylzinc to cyclohexanecarboxaldehyde in 99% ee.; In order to expand the utility of the N-acylethylenediamine catalysts, their application to a variety of reactions is being explored, including the enantioselective dialkylzinc-promoted vinylation of aldehydes to yield chiral (E)-allylic alcohols. The chiral allylic alcohol motif is found in numerous naturally occurring products and chiral (E)-allylic alcohols are utilized extensively as key intermediates in the synthesis of a large assortment of biologically active targets. The alkenylation reaction was performed utilizing the Oppolzer methodology in conjunction with the new N-acylethylenediamine catalysts. The reaction conditions, including temperature, solvent, transmetalation conditions, and reaction time, were optimized. One ligand synthesized from isoleucine provided the allylic alcoho1 4,4-dimethyl-1-phenyl-pent-2-en-ol in 91% ee.; A solid-phase procedure has been developed for the synthesis of a second class of N-acylethylenediamine ligands. The ligands were obtained in good yield and purity, without the need for chromatography or other purification methods. Several new and previously reported ligands were prepared using this procedure. These compounds were examined as catalysts for the enantioselective addition alkylzinc reagents to aldehydes. In all cases, the crude ligands from the solid-phase syntheses catalyzed the reactions with similar yields and stereoselectivities when compared to ligands that had been purified by standard methods. A small library of dipeptide ligands was prepared utilizing the new solid-phase procedure and screened against the addition of alkenylzinc reagents to aldehydes. Two crude ligands gave the allylic alcohol 4,4-dimethyl-1-phenyl-pent-2-en-ol in 86% ee.