Design and Optimization of New Phosphine Oxazoline Ligands via High-Throughput Catalyst Screening
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This paper uses the phosphine oxazoline ligands 1 and an allylation transformation (reaction 1) to illustrate the value of divergent ligand syntheses and high-throughput screening in catalyst discovery and optimization. Thus, a diverse set of ligands 1 (Table 1) was prepared via a divergent synthesis involving the pivotal intermediate, phosphine-substituted amino alcohol 7 (Scheme 1). Single-crystal X-my crystallographic data was obtained for a nickel complex 8 (Figure 3) of the phenyl-substituted ligand 1i. This analysis illustrated some structural features of the ligand systems 1 that may be conducive to asymmetric catalysis. 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 systems were also varied, sometimes in 'two-dimensional' screens. No pronounced solvent effects were identified. Abstraction of chloride was shown to be detrimental, whereas addition of chloride provided no advantages. One of the most critical of all the variables probed was, rather surprisingly, the effect of ligand-to-metal ratio; enantioselectivities dropped sharply and eventually reversed when this ratio was increased above 1:1. These observations were rationalized in terms of a chelated complex A and a nonchelated one B (Scheme 3). The implications of these results for high-throughput screening of catalyst systems in general, and for ligands 1 in particular, are discussed.
author list (cited authors)
Porte, A. M., Reibenspies, J., & Burgess, K.