N-Terminal Peptide Aldehydes as Electrophiles in Combinatorial Solid Phase Synthesis of Novel Peptide Isosteres

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Abstract
N-Terminal peptide aldehydes were synthesized on a solid support and utilized as electrophiles in nucleophilic reactions in order to furnish novel and diverse peptide isosteres. The aldehyde moiety of the peptide was synthesized by coupling a protected aldehyde building block to the peptide and deprotecting it quantitatively in less than 3 min. It was found that protection of the two succeeding amide nitrogens was necessary in order to avoid reaction between the aldehyde and backbone amides. The N-terminal peptide aldehydes were successfully reacted in the following way: (a) reductive amination with a large variety of amines, leading to N-alkyl-γ-aminobutyric peptide isosteres positioned centrally in the peptide; (b) reductive amination with amino esters, leading to N-terminal 2,5-diketopiperazine peptides; (c) Horner−Wadsworth−Emmons olefination, leading to unsaturated peptide isosteres positioned centrally in the peptide; and (d) Pictet−Spengler condensations, leading to tetrahydro-β-carbolines either positioned centrally in a peptide or fused with a diketopiperazine ring in the N-terminus of the peptide.