AmericanChemicalSociety.com

The modified PHOX ligand synthesis continues to be highly dependent on the identity and nature of the substituent, so a single synthesis path has not been achieved. Thus far on the project we have synthesized seven new 5’-substituted PHOX ligands, two new 4’-substituted ligands, and have made several improvements in methodology. We have been able to replace some of the ortho-lithiation reactions with Pd or Cu cross-coupling procedures.

Hammett analysis of the 13C NMR shifts correlates best with sigma para (rather than sigma meta or sigma para plus) for both the 4’- and 5’-substituted ligands. We had thought the 5’- would correlate better with sigma meta, but this suggests a more general electronic donation / withdrawal effect. We are continuing with additional analysis to understand this observation.

To study the new ligands in asymmetric reactions, we surveyed a number of solvents and nucleophiles to look for reactions that gave a range of enantiomeric ratio data for the various ligands with either 1,3-diphenylallyl acetate or 1,3-diphenylallyl ethyl carbonate. We monitored the results by chiral HPLC and typically ran the reactions in triplicate to look for consistency. For the test reaction, we have settled on the amination of the carbonate substrate with benzylamine in ethyl acetate as the solvent (slightly more reproducible and consistent than THF or methylene chloride). Interestingly, we did find that in a few cases, the reactions failed to go to completion. When these reactions were analyzed, the enantioselectivity was much higher than the corresponding cases where the reactions did go to completion. We are currently investigating the possibility of some type of kinetic resolution, product isomerization, or other process that would give these disparate results.

We have studied approximately half of the ligand substituents thus far and the 5’-substituted ligands generally show a slightly lower levels of enantioselectivity than the 4’-isomers. We are continuing to study these reactions currently and will conduct the Hammett analysis and look for correlations with the NMR data.