Wiley InterScience Backfile Collection 1832-2000
Chemistry and Pharmacology
A synthetic route to stable-isotope-substituted L-phenylalanine is presented, which allows the introduction of 13C, 15N, and deuterium labels at any position or combination of positions. For labelling of the aromatic ring, a synthetic route to ethyl benzoate (or benzonitrile) has been developed, based on the electrocyclic ring-closure of a 1,6-disubstituted hexatriene system, with in situ aromatization by elimination of one (amino) substituent. Several important (highly isotopically enriched) synthons have been prepared, namely benzonitrile, benzaldehyde, ethyl benzoate, and ethyl diphenyloxyacetate. Labelled L-phenylalanines have been synthesized from both aromatic precursors by initial conversion into sodium phenylpyruvate and subsequent transformation of this intermediate into the L-α-amino acid by an enzymatic reductive amination reaction. In this manner, highly enriched phenylalanines are obtained on the 10-gram scale and with high enantiomeric purities (≥ 99% ee). The method has been validated by the synthesis of [1′-13C]-L-Phe and [2-D]-L-Phe. In addition, two methods are described for the introduction of isotopes into L-tyrosine starting from the isotopically enriched precursors benzonitrile and ethyl benzoate.
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