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

被引:45
作者
Groth, T [1 ]
Meldal, M [1 ]
机构
[1] Carlsberg Lab, Dept Chem, Ctr Solid Phase Organ Combinatorial Chem, DK-2500 Copenhagen, Denmark
来源
JOURNAL OF COMBINATORIAL CHEMISTRY | 2001年 / 3卷 / 01期
关键词
D O I
10.1021/cc000058+
中图分类号
O69 [应用化学];
学科分类号
081704 ;
摘要
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.
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页码:45 / 63
页数:19
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