Synthesis of selectively multi-labelled histidines with stable isotopes and chiral synthesis of L-histidine from L-aspartic acid
An efficient and concise synthesis of three types of multi-labelled histidines with stable isotopes to be used for investigating pharmacokinetics and enzymic reaction mechanisms in vivo is described. Selective deuteriation at C-3 and C-5 of DL-[5-15N]diamino acid 4 was achieved by hydrogen exchange to give DL-[3,3,5,5-2H4,5-15N]diamino acid 5. The imidazole ring was constructed by heating of compound 5 with NaSC15N in D2O to give labelled 2′-mercapto-DL-histidine 6, which was oxidized at C-2′ to give the desired L-[3,3,5′-2H3,1′,3′-15N2] histidine L-7 after enzymic resolution. To replace deuterium at C-5′ with hydrogen, the labelled histidine 7 was heated in water (pH 5.0) at 180 °C, and subsequent enzymic resolution gave L-[3,3-2H2,1′,3′-15N2]histidine L-8. A similar sequence of reactions carried out on the diamino acid 5 with KS13C15N gave DL-[2′-13C,3,3,5′-2H3,1′,3′-15N2]histidine 7-13C. Deuteriation at C-2 and C-2′ of 7-13C with DCl–D2O (pD 5.0) at 180 °C and subsequent back-exchange of deuterium at C-2′ with water (pH 7.0) at 120 °C gave DL-[2′-13C,2,3,3,5′-2H4,1′,3′-15N2]histidine 10. Synthesis of optically pure L-histidine starting from L-aspartic acid is also described. The optical purity of the synthesized L-histidine was estimated to be 93.8%(e.e.).