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

Summary N 10 -Formylpteroic acid may be prepared from folic acid by sequentially heating with formic acid and cleaving the glutamate side chain with carboxypeptidase G 1 . Condensation of the product with the N α ,O bis( trimethylsilyl) derivative of N δ -(tert-butyloxycarbonyl)-L-ornithine via a modification of the carboxyliccarbonic anhydride peptide synthesis, followed by stepwise removal of the N 10 -formyl group with NaOH and of the N δ -tert-butyloxycarbonyl group with trifluoroacetic acid affords N α -pteroyl-L-ornithine. A similar sequence, starting from methyl N δ -benzoyl-L-ornithinate and methyl N δ -phthaloyl-L-ornithinate and using gentle treatment with sodium hydroxide in DMSO to selectively remove the methyl ester and N 10 -formyl groups while hydrolyzing only one of the phthaloyl amide bonds, gives the hitherto undescribed compounds N δ -benzoyl- and N δ -hemiphthaloyl-N α -pteroyl-L-ornithine, respectively. An improved synthesis of N δ -hemiphthaloyl- N α -(4-amino-4-deoxypteroyl)-L-ornithine, based on the same chemistry but using 4-amino-4-deoxyN 10 - formylpteroic acid and methyl N δ -phthaloyl-L-ornithinate, is also described.