Efficient discovery of chiral catalysts for asymmetric reactions by modular ligand design, solid-phase synthesis, and high-throughput determination of enantiomeric excess

We have designed a new class of chiral modular ligands for use as asymmetric catalysts. Our ligands consist of an N-acylethylenediamine core for binding transition metals and attached amino acids for a source of chirality. We developed a solution-phase and a solid-phase procedure for the synthesis of chiral N-acylethylenediamine ligands. We initially tested purified ligands as chiral catalysts for the addition of dialkylzinc reagents to aldehydes. Three sites of diversity on the ligands were optimized to enhance the enantioselectivity of the catalysts using an iterative procedure. A valine-based ligand emerged that promoted the addition of Me2Zn to 2-naphthaldehyde, benzaldehyde, and 4-chlorobenzaldehyde to give the corresponding alcohol products in 86%, 84%, and 81% ee, respectively. The same ligand also catalyzed the addition of Et2Zn to 4-chlorobenzaldehyde in 90% ee. The crude valine-based ligand obtained via a solid-phase synthesis catalyzed the addition of Me2Zn to benzaldehyde in an identical 84% ee compared to the purified ligand.;We further expanded the synthetic usefulness of chiral N-acylethylenediamine ligands by applying them as catalysts for the addition of vinylzinc reagents to aldehydes to give chiral allylic alcohols. The ligands were synthesized using parallel solid-phase methods. We optimized three diversity sites using a positional scanning approach. The optimized dipeptide structure was found to promote the formation of 10 different (E)-allylic alcohols with enantioselectivities ranging from 90% to 95% ee. This ligand was effective for both aromatic and alpha-branched aldehydes, and vinylzinc reagents derived from both bulky and straight chain terminal alkynes.;We have developed a high-throughput e&barbelow;nzymatic m&barbelow;ethod for d&barbelow;etermining e&barbelow;nantiomeric e&barbelow;xcess (EMDee) of methyl p-tolyl sulfoxide. The two enantiomers of the sulfoxide have very different inhibition constants for the horse liver alcohol dehydrogenase catalyzed oxidation of ethanol to acetaldehyde. Therefore, the initial rate of ethanol oxidation in the presence of the sulfoxide is correlated with the sulfoxide ee. We screened crude samples of sulfoxides obtained from the asymmetric oxidation of methyl p-tolyl sulfide by cumyl hydroperoxide in the presence of chiral tartrate ester complexes with Ti(O-i-Pr)4. We found that most EMDee determinations where within +/-10% ee of the HPLC measurement for the same sample.