SYNTHESIS OF SELECTIVELY MULTILABELLED 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-N-15]diamino acid 4 was achieved by hydrogen exchange to give DL-[3,3,5,5-H-2(4),5-N-15]diamino acid 5. The imidazole ring was constructed by heating of compound 5 with (NaSCN)-N-15 in D2O to give labelled 2'-mercapto-DL-histidine 6, which was oxidized at C-2' to give the desired L-[3,3,5'-H-2(3),1',3'-N-15(2)]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-degrees-C, and subsequent enzymic resolution gave L- [3,3-H-2(2),1',3'-N-15(2)] histidine L-8. A similar sequence of reactions carried out on the diamino acid 5 with (KSCN)-C-13-N-15 gave DL-[2'-C-13,3,3,5'-H-2(3),1',3'-N-15(2)]histidine 7-C-13. Deuteriation at C-2 and C-2' of 7-C-13 with DCI-D2O (pD 5.0) at 180-degrees-C and subsequent back-exchange of deuterium at C-2' with water (pH 7.0) at 120-degrees-C gave DL- [2'-C-13,2,3,3,5'-H-2(4), 1',3'-N-15(2)]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.).