Compounds with chiral phosphorus atom centers are playing increasingly important roles in the development of pharmaceutical drug candidates, agrochemicals, and chiral ligands in catalysis. In our search for specific cholinesterase inhibitors for the treatment of Alzheimer’s Disease, we have been investigating a chiral organophosphorus scaffold—the alkyl 2-(dimethylamino)ethyl phenyl phosphate. A variety of methods are currently available to determine the enantiomeric excess (ee) of chiral organophosphorus compounds, including chiral high-performance liquid chromatography and vibrational circular dichroism; however, these are often time-consuming methods due to condition optimization and also limited due to instrumentation availability. Herein, we describe the use of 1H in the presence of the lanthanide shift reagent, Eu(hfc)3 (Europium tris[3-(heptafluoropropylhydroxymethylene)-d-camphorate]) to assay the ee’s for these phosphate triesters. Previous studies employing this reagent focused on the alpha-carbon protons of the phosphate triesters to display enantiotopic behavior. However, in the fore-mentioned phosphate triesters, the terminal methyl group of the alkyl substituent was observed to have the most highly chemically shift-affected signal and proved to be most useful in the determination of ee. We hypothesize that this contrasting behavior from earlier reports is due to the Lewis-basic nitrogen atom coordinating to the Lewis-acidic europium atom center. To further probe this effect, we have synthesized a series of racemic chiral phosphate triesters with various alkyl chain lengths and heteroatom-containing substituents. Our results show a trend where more Eu(hfc)3 is needed to determine the ee for analogs of the alkyl 2-(dimethylamino)ethyl phenyl scaffold with longer alkyl chain lengths: ethyl (6 mg), butyl (10 mg), and hexyl (25 mg). In addition, the 2-(trimethylammonium)ethyl series required much less shift reagent to determine ee (6 mg for both butyl and hexyl) than the 2-(dimethylamino)ethyl analogs, indicating that charge may also play a large role in affecting how each enantiomer are magnetically influenced in the ligand-Lewis acid complex. In summary, this work describes a convenient method to rapidly determine the ee’s of P-chiral compounds using Eu(hfc)3, in which protons most affected are those most distal to the phosphate moiety.

Enantiopurity determination of alkyl P-chiral compounds with Eu(hfc)3: The terminal methyl group signal is most enantiotopically affected

2019 Spring National Meeting

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