Synthesis of selectively multi-labelled histidines with stable isotopes and chiral synthesis of L-histidine from L-aspartic acid

Abstract

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.).