79950-77-9Relevant articles and documents
Design and synthesis of histidine analogues of folic acid and methotrexate as potential folylpolyglutamate synthetase inhibitors
Mao, Zhenmin,Pan, Jianping,Kalman, Thomas I.
, p. 4340 - 4344 (1996)
Folylpolyglutamate synthetase (FPGS) is responsible for the conversion of naturally occurring folates and antifolates to their poly-γ-glutamyl derivatives, which are the forms required for intracellular retention of folates and are also the preferred subs
Further Studies on the Protection of Histidine Side Chains in Peptide Synthesis: The Use of the ?-Benzyloxymethyl Group
Brown, Tom,Jones, John H.,Richards, John D.
, p. 1553 - 1562 (2007/10/02)
Further studies on the use in peptide synthesis of N(?)-phenacyl protection for histidine side chains have shown that whilst this prevents the side chain-induced racemization which can occur if there is a lone pair of electrons available at the ?-nitrogen, there are concomitant drawbacks.As an alternative approach to the racemisation problem, the effect of halogenation of the heterocyclic ring carbons (to diminish the availability of the ?-nitrogen lone pair) has been investigated.This gives derivatives which are convenient in both classical and solid-phase applications, the halogen modifying groups being removed at the last stage by catalytic hydrogenolysis over a rhodium catalyst.Racemization is suppressed as expected, but it is not eleminated completely: direct blockade of the ?-nitrogen appears to be indispensable for its complete prohibition.Protection of the ?-nitrogen with a benzyloxymethyl group has now been found to be much more satisfactory than the use of the phenacyl group for this purpose.A ?-benzyloxymethyl substituent not only prohibits side chain-induced racemisation but also gives derivatives with convenient physical properties which can be incorporated into well estblished classical and solid-phase strategies without the need for any novel or additional operations or changes in protocol.The protecting group is stable to basic conditions, to trifluoroacetic acid, and to aqueous solutions of carboxylic acids, but is cleaved cleanly and rapidly by hydrogen bromide in trifluoroacetic acid or by catalytic hydrogenolysis.N(α)-t-Butoxycarbonyl-N(?)-benzyloxymethyl-L-histidine has been prepared in good yield by a simple procedure from an easily accessible intermediate and isolated as a crystalline solid; its use has been demonstrated by a number of exercises including a solid-phase synthesis of 5-isoleucine-angiotensin II and a classical synthesis of trihistidine.
