Screening of Optically Active Nickel Initiators for Enantioasymmetric Polymerization of γ-Benzyl Glutamate-N-Carboxyanhydride

Abstract

The incorporation of only L-amino acids into DNAencoded proteins imparts a great biological significance to the chirality of amino acids. This importance also translates to compounds synthesized from amino acid components. As with all chiral materials, it is typically more difficult to synthesize amino acids as pure enantiomers rather than as racemic mixtures. One method of utilizing the racemate is to kinetically resolve it into optically pure product and unreacted enantiomer.1 We have explored the polymerization of R-amino acid-Ncarboxyanhydrides (NCAs) to form block copolypeptides for applications as biomedical materials.2 In such materials, the absolute configuration of the amino acid monomers is crucial for both structural development and biological activity.3 To utilize synthetic, racemic amino acids in these materials, we pursued the use of optically active initiators to develop enantioasymmetric polymerizations. We now report the use of chiral pyridinyl oxazoline ligands in nickel initiators to enantioasymmetrically polymerize γ-benzyl-glutamate NCA. Enantioasymmetric ring-opening polymerizations have been developed for many chiral cyclic monomers such as epoxides and episulfides.4 There also have been attempts to prepare optically active polypeptides from racemic NCA mixtures. Interest in this area has arisen from the pharmaceutical value of the optically active products as well as possible relevance to the origins of handedness in biological macromolecules.5 Some of the different chiral initiators used to induce asymmetry in NCA polymerizations include optically active amines6 and polypeptides,7 organoaluminum complexes,8 and chiral nickel carboxylates.9 These initiators generally displayed moderate-to-poor efficiencies and gave complex polymerizations whose propagation steps were poorly understood. All systems gave broad molecular weight distributions and poor control of polymer molecular weights and displayed reasonable enantioselectivities only at very low conversions of monomer. We have developed nickel initiators that allow the controlled polymerization of NCAs.2 Using this methodology, polypeptides can be prepared with defined chain lengths and with narrow molecular weight distributions. A key feature of this system is that all polymer formation occurs with identical nickel-containing reactive species. The straightforward nature of this system provides a superior starting point for the development of an enantioasymmetric polymerization system compared to previous methods used to polymerize NCAs. In particular, asymmetric initiators can be prepared by direct substitution of the achiral 2′,2′bipyridyl (bpy) ligand in our nickel system with a suitable optically active ligand (Figure 1). The choice of a suitable chiral ligand required some consideration. Most common chiral ligands are bidentate, since the chelate structure provides both a rigid environment as well as asymmetry around the metal.1 A large number of chiral chelating ligands are based on bisarylphosphines,10 which unfortunately form ineffective initiators when complexed with nickel due to their poor donating ability, as we have previously shown for PPh3. For this reason, we focused our attention on N-donor ligands that are similar in character to bpy, which forms a very efficient initiator.11 We initially explored diimine and bisoxazoline ligands (e.g., 1-4) (Figure 2), which have been used extensively in metalmediated asymmetric aziridinations,12 Diels-Alder reactions,13 and olefin polymerizations.14 These ligands were found to bind only weakly to zerovalent nickel and were thus also generally ineffective in generating active NCA polymerization initiators. To increase coordinating ability, we decided to study hybrid ligands consisting of pyridine coupled with either a chiral imine or oxazoline group (Figure 3). To test the efficiency of such ligands, we prepared achiral 5 and evaluated its ability to form an active initiator. When 5 was mixed with Ni(COD)2 in tetrahydrofuran (THF), a stable blue complex, 5Ni(COD), was formed. This compound displayed NCA polymerization activity that was virtually identical to that of bpyNiFigure 1. Strategy for formation of chiral nickel NCA polymerization initiators.