Base-catalyzed hydrogen-deuterium exchange with a partial retention of configuration in enolate-forming carbon acids

Various N-acylated and N-alkylated derivatives of L and D,L-phenylalanine dimethylamide were synthesized. These substrates were allowed to react with potassium tert-butoxide in tert-butyl alcohol-O-d at various temperatures. The H-D exchange at the alpha position was followed by mass spectrometric isotopic intensity analysis. The racemization was monitored using two methods: polarimetry and NMR. The NMR method employed a chiral lanthanide shift reagent, [Eu(facam)3, or tris-[3-(trifluoromethylhydroxymethylene)d-camphorato]Eu(III). This reagent induces different chemical shifts for enanthiotopic protons in the substrate and allows for optical purity determination via integration. The substrates studied are all derivatives of phenylalanine dimethylamide, PN, and differ in the R group attached to the amino nitrogen. The N-acylated derivatives are PPN (R = pivalyl), BPN (R = benzoyl), tBPN(R = tert-butyloxycarbonyl), DAPN(R = perdeuterioacetyl), and FPN (R = formyl). The N-alkylated substrates are PN (R = H), DPN (R = benzhydryl), and TPN (R = trityl). It was observed that PPN (R = pivalyl), undergoes H-D exchange at the alpha position with a small but significant retention of configuration in the system studied at 300C. However, the phenomenon disappears when 18-crown-6 is added to the base system. This crown ether is known to effectively chelate potassium ions in its cavity. PPN also exhibits a partial retention with exchange when the base is the sodium analog. An explanation for this phenomenon is offered by invoking a carbanion intermediate that is asymmetrically ion paired with K