Synthesis of the Folylpolyglutamate Synthetase Inhibitor Nα-Pteroyl-Lornithine and its Nδ-Benzoyl and Nδ-Hemiphthaloyl Derivatives, and an Improved Synthesis of Nα-( 4-Amino-4-deoxypteroy1)-Nδ-hemiphthaloyl-Lornithine

Abstract

N10-Formylpteroic acid may be prepared from folic acid by sequentially heating with formic acid and cleaving the glutamate side chain with carboxypeptidase G1. Condensation of the product with the Nα,O bis( trimethylsilyl) derivative of Nδ-(tert-butyloxycarbonyl)-L-ornithine via a modification of the carboxyliccarbonic anhydride peptide synthesis, followed by stepwise removal of the N10-formyl group with NaOH and of the Nδ-tert-butyloxycarbonyl group with trifluoroacetic acid affords Nα-pteroyl-L-ornithine. A similar sequence, starting from methyl Nδ-benzoyl-L-ornithinate and methyl Nδ-phthaloyl-L-ornithinate and using gentle treatment with sodium hydroxide in DMSO to selectively remove the methyl ester and N10-formyl groups while hydrolyzing only one of the phthaloyl amide bonds, gives the hitherto undescribed compounds Nδ-benzoyl- and Nδ-hemiphthaloyl-Nα-pteroyl-L-ornithine, respectively. An improved synthesis of Nδ-hemiphthaloyl- Nα-(4-amino-4-deoxypteroyl)-L-ornithine, based on the same chemistry but using 4-amino-4-deoxyN10- formylpteroic acid and methyl Nδ-phthaloyl-L-ornithinate, is also described.