N-terminal peptide aldehydes as electrophiles in combinatorial solid phasesynthesis of novel peptide isosteres

N-Terminal peptide aldehydes were synthesized on a solid support and utiliz ed as electrophiles in nucleophilic reactions in order to furnish novel and diverse peptide isosteres. The aldehyde moiety of the peptide was synthesi zed by coupling a protected aldehyde building block to the peptide and depr otecting it quantitatively in less than 3 min. It was found that protection of the two succeeding amide nitrogens was necessary in order to avoid reac tion between the aldehyde and backbone amides. The N-terminal peptide aldeh ydes were successfully reacted in the following way: (a) reductive aminatio n with a large variety of amines, leading to N-alkyl-gamma -aminobutyric pe ptide isosteres positioned centrally in the peptide; (b) reductive aminatio n with amino esters, leading to N-terminal 2,5-diketopiperazine peptides; ( c) Horner-Wadsworth-Emmons olefination, leading to unsaturated peptide isos teres positioned centrally in the peptide; and (d) Pictet-Spengler condensa tions, leading to tetrahydro-beta -carbolines either positioned centrally i n a peptide or fused with a diketopiperazine ring in the N-terminus of the peptide.