Studies on the synthesis of cyanomethyleneamino pseudopeptides

Various cyanomethyleneamino pseudodipeptides were easily prepared in high yield by the Lewis acid catalyzed addition of trimethylsilyl cyanide to unstable aldimine intermediates, obtained from the reaction of N-protected α-amino aldehydes with C-protected amino acids. The two possible (R)-and (S)-epimers at the peptide bond surrogate chiral center were obtained. In this thermodynamically controlled synthesis, the absolute configurations of the α-amino aldehyde and the amino acid proved to be the main factors determining its stereoselectivity. The new N-Boc- and N-Z-protected pseudodipeptides were deblocked under standard conditions. In spite of the lability of the new peptide bond surrogate ψ[CH(CN)NH] in basic medium, high yields of C-deprotected pseudodipeptides were obtained by controlling the saponification conditions of the methyl esters. The use of free α-amino acids in the modified Strecker synthesis reported here can be employed as an alternative for the synthesis of C-deprotected cyanomethyleneamino pseudopeptides. The N- or C-elongation of these pseudodipeptides via the DCC method led to the corresponding ψ[CH(CN)NH] pseudotripeptides in high yield. © 1993 American Chemical Society