V. Bavetsias, A. Jackman, R. Kimbell
Jan 5, 1996
Citations
0
Influential Citations
26
Citations
Journal
Journal of Medicinal Chemistry
Abstract
The syntheses of γ-linked l-d, d-d, and d-l dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) are described. The general methodology for the synthesis of these molecules involved the preparation of the dipeptide derivatives employing solution phase peptide synthesis followed by condensation of the dipeptide free bases with the appropriate pteroic acid analogue via diethyl cyanophosphoridate (DEPC) activation. In the final step, tert-butyl esters were removed by trifluoroacetic acid (TFA) hydrolysis. Z-l-Glu-OBut-γ-d-Ala-OBut, for example, was prepared from α-tert-butyl N-(benzyloxycarbonyl)-l-glutamate and tert-butyl d-alaninate via isobutyl-mixed anhydride coupling. The Z-group was removed by catalytic hydrogenolysis and the resulting dipeptide free base condensed with 2-desamino-2-methyl-N10-propargyl-5,8-dideazapteroic acid via DEPC coupling. Finally, tert-butyl esters were removed by TFA hydrolysis to give ICI 198583-γ-d-Ala. The compounds were tested as inhib...