N-Terminal peptide aldehydes as electrophiles in combinatorial solid phase synthesis of novel peptide isosteres.
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-gamma-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-beta-carbolines either positioned centrally in a peptide or fused with a diketopiperazine ring in the N-terminus of the peptide.
Groth
T
T
Center for Solid Phase Organic Combinatorial Chemistry, Department of Chemistry, Carlsberg Laboratory, Gamle Carlsberg Vej 10, DK-2500 Valby, Denmark.
Meldal
M
M
D000447:Aldehydes / Q000138:chemical synthesis* / Q000737:chemistry; D000478:Alkylation; D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D007202:Indicators and Reagents; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry
D000447:Aldehydes; D002243:Carbolines; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D010455:Peptides; D010879:Piperazines