Groth T, Meldal M
Center for Solid Phase Organic Combinatorial Chemistry, Department of Chemistry, Carlsberg Laboratory, Gamle Carlsberg Vej 10, DK-2500 Valby, Denmark.
J Comb Chem. 2001 Jan-Feb;3(1):45-63. doi: 10.1021/cc000058+.
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.
N-末端肽醛在固相载体上合成，并用作亲核反应中的亲电试剂，以提供新颖多样的肽类似物。肽的醛部分通过将受保护的醛构建块偶联到肽上并在不到3分钟内定量脱保护来合成。发现保护两个连续的酰胺氮是必要的，以避免醛与主链酰胺之间的反应。N-末端肽醛以以下方式成功反应：(a) 与多种胺进行还原胺化反应，生成位于肽中央的N-烷基-γ-氨基丁酸肽类似物；(b) 与氨基酯进行还原胺化反应，生成N-末端2,5-二酮哌嗪肽；(c) 霍纳-沃兹沃思-埃蒙斯烯化反应，生成位于肽中央的不饱和肽类似物；(d) 皮克特-施彭格勒缩合反应，生成位于肽中央的四氢-β-咔啉或与肽N-末端的二酮哌嗪环稠合的四氢-β-咔啉。
