Large-Scale Synthesis of the Glycine Schiff Base Ni(II) Complex Derived from (<i>S</i>)- and (<i>R</i>)-<i>N</i>-(2-Benzoyl-4-chlorophenyl)-1-[(3,4-dichlorophenyl)methyl]-2-pyrrolidinecarboxamide
Todd T. Romoff, Bernardo G. Ignacio, Noel Mansour, Andrew B. Palmer, Christopher J. Creighton, Hidenori Abe, Hiroki Moriwaki, Jianlin Han, Hiroyuki Konno, Vadim A. Soloshonok
Abstract
Non-natural, tailor-made amino acids are of crucial importance to the synthesis of bioactive peptides and new chemical entities. Innovative methodology is always needed for the preparation of enantiomerically pure amino acids that does not rely on tedious resolution procedures. We report here the multikilogram scale synthesis of the chiral nucleophilic glycine equivalent Ni(II) complexes (S)-19 and (R)-19 derived from (S)- and (R)-N-(2-benzoyl-4-chlorophenyl)-1-[(3,4-dichlorophenyl)methyl]-2-pyrrolidinecarboxamide. Replacement of the traditional carbonate bases with the soluble organic base DBU for synthesis resulted in improved process efficiency, safety, and yield. The issue of partial racemization of the proline moiety is critically addressed, and enantiomeric purities in excess of 99.5% ee are routinely achieved in this manufacture.