A Vaulted Biaryl Phosphoric Acid-Catalyzed Reduction of alpha-Imino Esters: The Highly Enantioselective Preparation of alpha-Amino Esters

Link: JACS ASAP

Guilong Li, Yuxue Liang, and Jon C. Antilla*

Department of Chemistry, University of South Florida, 4202 East Fowler Avenue CHE205A, Tampa, Florida 33620

This is a new organocatalytic method for enantioselective reduction of acyclic alpha-imino esters to form the corresponding alpha-amino esters (and subsequently alpha-amino acids). The method employed sterically hindrance chiral biaryl phosphoric acid as a ligand and Hantzsche ester as hydrogen source in a transfer hydrogenation process. Several biaryl phosphoric acids were initally considered.

In the initial studies, imino esters 2a-c were screened in the reaction using using phosphoric acid (PA) 1e to investigate the effect of solvents and it was found that non-polar, non-coordinating solvents such as benzene and toluene gave the best results, especially with imino ester 2a-b while ester 2c did not work too well presumably due to its steric hindrance.

Next, all PAs in Figure 1 were screened using 2a as a test substrate and PA 1e was found to be the most optimal acid for the reaction.

Generality of the reaction was established in the following table, where several alpha-imino esters were subjected to the optimal reaction conditions. In all cases, the reactions proceeded in excellent yields to give products in excellent ees.

In general, the imino esters were pre-formed before subjecting to the reactions. When the imino esters were formed in situ before the reductions, yields were lower (10-20%). However, in the cases of the alkyl-substituted imino esters (Table 3, entries 9-11), yields were found to be good to excellent, indicating that this reduction could be performed with an alpha-imino ester generated in situ in one pot.