| Abstract | The unequivocal synthesis of pteroyl-γ-l-glutamates has been achieved.
The synthesis of -γ-glutamyl peptides, by "classical" methods, followed by coupling to a pteroic acid (2) derivative and by deprotection, was adopted as the general scheme. Attempts to repeat a previously published synthesis of γ-glutanyl peptides (Route 1) were abandoned when the dipeptide derivative (61) could not be crystallised.
Crystalline and readily purified intermediates, including several which had not been previously prepared, were obtained during work on the novel synthesis (Route 2) of a pteroyl triglutamate derivative (99).
Picolyl and 4-nitrobenzyl esters were used for carboxy-terminal protection and the peptide chain was built from an amino-terminal residue. Unfortunately, the pteroyl derivative (99) could not be deprotected and the route was abandoned; although it still provides a feasible synthesis of γ-glutamyl peptides.
Chain elongation from an amino-terminal residue, allowing purification by salt formation at the γ-carboxy-terminal, was retained as a feature of subsequent schemes (Routes 3 and 4). The tertiary-butyl ester was employed for carboxy-terminal protection, to simplify final deprotection. Route 3 provided the fully-protected pteroyl tri-penta- and heptaglutamates (109), (110) and (111), which were fully characterised for the first time, although their synthesis by a different route had been previously reported.
The use of protection by salt formation, at the γ-carboxy terminal, allowed the rapid synthesis (Route 4) of the pteroyl triglutamate derivative (114), which was readily deprotected to yield analytically pure pteroyl-γ-l-glutamyl-γ-l-glutamyl-L-glutamic acid.
Very close attention was paid to the purity of the pteroic acid used in this work, so that, no doubt as a consequence, the pteroyl derivatives obtained were readily crystalline and easily purified. Previously, other workers have encountered severe purification difficulties when preparing similar compounds. |
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