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.

中文翻译：

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同位素标记的 L-苯丙氨酸和 L-酪氨酸的合成

介绍了稳定同位素取代的 L-苯丙氨酸的合成路线，它允许在任何位置或位置组合引入 13C、15N 和氘标记。为了标记芳环，已经开发了一种苯甲酸乙酯（或苯甲腈）的合成路线，基于 1,6-二取代的己三烯系统的电环闭环，通过消除一个（氨基）取代基进行原位芳构化. 已经制备了几种重要的（高度同位素富集的）合成子，即苯甲腈、苯甲醛、苯甲酸乙酯和二苯氧基乙酸乙酯。标记的 L-苯丙氨酸是由两种芳香族前体合成的，首先转化为苯丙酮酸钠，随后通过酶促还原胺化反应将该中间体转化为 L-α-氨基酸。以这种方式，以 10 克规模和高对映体纯度 (≥ 99% ee) 获得高度富集的苯丙氨酸。该方法已通过 [1'-13C]-L-Phe 和 [2-D]-L-Phe 的合成得到验证。此外，还描述了从同位素富集的前体苯甲腈和苯甲酸乙酯开始将同位素引入 L-酪氨酸的两种方法。