Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Biopolymers. 2011;96(5):578-85. doi: 10.1002/bip.21591.
We demonstrate the first solid-phase synthesis of highly functionalized bis-peptides. Bis-peptides are ladder oligomers composed of stereochemically pure, cyclic bis-amino acids joined by substituted diketopiperazine linkages. They have a shape-programmable backbone that is controlled by controlling the stereochemistry and sequence of the monomers within each oligomer. Functionalized bis-peptides are assembled using a new amide bond forming reaction (acyl-transfer coupling) that we have previously developed and a novel activation strategy that allows the sequential formation of penta- and hexa-substituted diketopiperazines from extremely hindered N-alkyl-alpha,alpha-disubstituted amino acids. We present mechanistic evidence that acyl-transfer coupling is competitive with direct acylation in the formation of hindered amide bonds. We also detail the synthesis of four functionalized bis-peptides, and that by combining bis-peptides with amino acids through diketopiperazine linkages, bis-peptides can mimic the display of residues i, i+4, i+7 of an alpha-helical peptide.
我们展示了高度官能化的双肽的首例固相合成。双肽是由立体纯的、环状双氨基酸通过取代的二酮哌嗪键连接而成的梯状寡聚物。它们的骨架形状可编程，通过控制每个寡聚物中单体的立体化学和序列来控制。我们使用以前开发的新酰胺键形成反应（酰基转移偶联）和一种新的活化策略来组装官能化的双肽，该策略允许从非常受阻的 N-烷基-α，α-二取代氨基酸中顺序形成五取代和六取代的二酮哌嗪。我们提出了酰基转移偶联与受阻酰胺键形成中的直接酰化竞争的机制证据。我们还详细介绍了四种官能化双肽的合成，并且通过通过二酮哌嗪键将双肽与氨基酸结合，可以模拟α-螺旋肽的残基 i、i+4、i+7 的显示。
