DESIGN AND OPTIMIZATION OF NEW PHOSPHINE OXAZOLINE LIGANDS VIA HIGH-THROUGHPUT CATALYST SCREENING

This paper uses the phosphine oxazoline ligands 1 and an allylation tr ansformation (reaction 1) to illustrate the value of divergent ligand syntheses and high-throughput screening in catalyst discovery and opti mization. Thus, a diverse set of Ligands 1 (Table 1) was prepared via a divergent synthesis involving the pivotal intermediate, phosphine-su bstituted amino alcohol 7 (Scheme 1). Single-crystal X-ray crystallogr aphic data was obtained for a nickel complex 8 (Figure 3) of the pheny l-substituted ligand ii. This analysis illustrated some structural fea tures of the ligand systems 1 that may be conducive to asymmetric cata lysis. High-throughput screens were then used to correlate the ligand 1 R-substituents with asymmetric induction in the allylation reaction 1, and it emerged that the pseudo-spherical adamantyl substituent was superior to other R-substituents. Other parameters in the catalyst sys tems were also varied, sometimes in ''two-dimensional'' screens. No pr onounced solvent effects were identified. Abstraction of chloride was shown to be detrimental, whereas addition of chloride provided no adva ntages. One of the most critical of all the variables probed was, rath er surprisingly, the effect of ligand-to-metal ratio; enantioselectivi ties dropped sharply and eventually reversed when this ratio was incre ased above 1:1. These observations were rationalized in terms of a che lated complex A and a nonchelated one B (Scheme 3). The implications o f these results for high-throughput screening of catalyst systems in g eneral, and for Ligands 1 in particular, are discussed.