Aminonitriles and aminothioamides related to natural amino acids.

Abstract

N-p-Methoxybenzyloxycarbonyl and N-tert.-butyloxycarbonyl amino acid amides related to a series of natural amino acids were dehydrated to the corresponding Meoz- and Boc-alpha-aminonitriles. Deprotection of the latter derivatives afforded alpha-aminonitriles related to alanine, tyrosine, phenylalanine, dihydrophenylalanine, histidine, Dopa, ornithine, asparagine and glutamine. Thioamidation with H2S/NH3 or H2S/NEt3 in general converted the protected amino nitriles to Meoz- and Boc-alpha-aminothioamides. When deprotected these furnished the alpha-aminothioamides corresponding to alanine, tyrosine, phenylalanine, dihydrophenylalanine and histidine. For dehydration and thioamidation of histidine and Dopa, N alpha-Boc-im trityl-histidine and N-Boc-O, O'-diacetyldihydroxyphenylalanine were useful. Dopa was obtained as the free and Boc-thiohydrazide. Also prepared were N alpha,omega-diMeoz-ornithine DCHA, Meoz-2,5-dihydrophenylalanine DCHA and N,O-diMeoz-tyrosine as starting materials and N,O-dicarbobenzyloxycarbonyltyrosinamide, N,O-diZ-tyrosine nitrile and Z-beta-cyano-beta-alaninamide as model compounds. During deprotection of Meoz-alanine thioamide, transfer of an anisyl group from the N-Meoz protecting group to sulfur took place as a side reaction that yielded alanine p-methoxybenzyl beta-imidothiolic ester. This study provides two new series of amino acid analogs with potential antimetabolite activity. Also suitable for incorporation into peptide analogs, these afford approaches to relating structure and conformation to activity in biologically active peptides.