Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6.
J Am Chem Soc. 2010 Mar 10;132(9):2889-91. doi: 10.1021/ja910544p.
There has been enormous interest in both naturally occurring and synthetic cyclic peptides as scaffolds that preorganize a given amino acid sequence into a rigid conformation. Such molecules have been employed as nanomaterials, imaging agents, and therapeutics. Unfortunately, the laboratory synthesis of cyclic peptides directly from linear precursors is afflicted by several thermodynamic and kinetic challenges, resulting in low chemical yields and poor chemo- and stereoselectivities. Here we report that amphoteric amino aldehydes can be used for efficient syntheses of cyclic peptides in high yields and selectivities starting from alpha-amino acids or linear peptides. The cyclizations effectively operate at unusually high molar concentrations (0.2 M), while side processes such as epimerization and cyclodimerization are not observed. The products are equipped with sites that allow for a highly specific, late-stage structural modification. The overall efficiency of the macrocyclization is due to the coexistence of nucleophilic and electrophilic reaction centers in amphoteric amino aldehydes.
人们对天然存在和合成的环状肽作为支架非常感兴趣，因为它们可以将给定的氨基酸序列预组织成刚性构象。这些分子已被用作纳米材料、成像剂和治疗剂。不幸的是，直接从线性前体合成环状肽受到几个热力学和动力学挑战的困扰，导致化学产率低、化学和立体选择性差。在这里，我们报告两性氨基酸醛可用于从α-氨基酸或线性肽高效合成高产率和高选择性的环状肽。环化反应在非常高的摩尔浓度（0.2 M）下有效进行，而不会观察到消旋化和环二聚化等副反应。产物具有允许高度特异性的后期结构修饰的位点。由于两性氨基酸醛中存在亲核和亲电反应中心，因此大环化的整体效率很高。
