Triblock Peptide and Peptide Thioester Synthesis With Reactivity-Differentiated Sulfonamides and Peptidyl Thioacids
Triblock Peptide and Peptide Thioester Synthesis With Reactivity-Differentiated Sulfonamides and Peptidyl Thioacids
复制标题
DOI：
10.1002/anie.200903050
复制
发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Sharma, Indrajeet
中科院分区：
文献类型：
--
作者：
Crich, David;Sharma, Indrajeet
作为一种转变性的新范式的规范，肯特的概念[1]的天然化学连接，使嵌段合成肽已大大扩展和优化，因为它在1994年推出。[2]这些改进中的大量已经解决了肽基硫酯合成方法的开发和由N-末端2-巯基乙胺（通常为半胱氨酸）的机械要求所造成的限制。[3]然而，也许最重要的修饰是由肯特和同事[4]引入噻唑烷基团，作为与天然化学连接本身相容的N-末端半胱氨酸部分的保护手段，并允许将三个或更多个肽连接成单个实体。我们的实验室一直在开发一种替代方法的嵌段合成肽，其中C-末端肽基硫代酸与缺电子的N-末端磺酰胺反应产生天然酰胺键。[5]该反应的机理不限于使用任何特定的氨基酸，其涉及缺电子磺酰胺上的硫代羧酸酯的亲核芳族取代，得到高度反应性的硫酯，并且在失去二氧化硫后，得到胺，最终得到酰胺产物（方案1）。该方法的一种变体使用游离胺和缺电子芳基卤，如桑格或Mukaiyama试剂，代替磺酰胺作为缩合剂。[6]美国
As is the norm for a transformational new paradigm, Kent’s concept [1] of native chemical ligation enabling the block synthesis of peptides has been considerably extended and optimized since its introduction in 1994.[2] A significant number of these improvements have addressed the development of methods for peptidyl thioester synthesis and the limitations posed by the mechanistic requirement of a N-terminal 2-mercaptoethylamine, typically cysteine.[3] Perhaps the most important modification, however, was the introduction by Kent and co-workers [4] of the thiazolidine group as a means of protection for N-terminal cysteine moieties compatible with the native chemical ligation itself, and permitting the ligation of three or more peptides into a single entity. Our laboratory has been engaged in the development of an alternative method of block synthesis for peptides in which a C-terminal peptidyl thioacid reacts with an electron-deficient N-terminal sulfonamide to yield a native amide bond.[5] The mechanism of this reaction, which is not limited to the use of any particular amino acid, involves nucleophilic aromatic substitution by the thiocarboxylate on the electron deficient sulfonamide to give a highly reactive thioester and, after loss of sulfur dioxide, an amine leading ultimately to the amide product (Scheme 1). A variant on the method employs a free amine and an electron deficient aryl halide, such as the Sanger or Mukaiyama reagents, as the condensing agent in place of the sulfonamide.[6]