High throughput synthesis of peptide α-thioesters through the use of "volatilizable" support
High throughput synthesis of peptide α-thioesters through the use of "volatilizable" support
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DOI：
10.1021/cc800076b
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发表时间：
2008-09-01
影响因子：
--
通讯作者：
Houghten, Richard A.
中科院分区：
文献类型：
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作者：
Li, Yangmei;Yu, Yongping;Houghten, Richard A.
天然化学结扎促进了中小型蛋白质和环肽的全合成，从而为有机化学工具打开了蛋白质世界的大门。1天然化学结扎依赖于两步的结合。在第一步中，c端肽α-硫酯与n端半胱氨酸肽反应。第二步涉及快速的分子内s -到n -移位，在连接位点形成酰胺键。最近，通过使用辅助硫醇，连接方法的范围从n端半胱氨酸扩展到非半胱氨酸残基，从而增加了该方法的适用性。2 c端肽α-硫酯是所有这些方法的关键中间体。对c端肽α-硫酯的需求刺激了我们实验室对这类肽的简单有效的合成方法的开发。目前已经报道了几种固相合成肽α硫酯的方法。先前的研究报道了利用Boc和Fmoc化学合成肽α-硫酯的策略。对于Boc固相化学，在合成肽之前，必须先通过将3-巯基丙酸偶联到MBHA上，将对甲基苯并胺（MBHA）树脂转化为硫醇连接树脂。对于Fmoc化学，肽α-硫酯通常通过使用“安全捕获”磺胺树脂来获取。在这种方法中，磺胺必须通过烷基化活化，然后用过量的巯基亲核试剂将完全保护的肽从树脂中分离出来。然后用浓三氟乙酸溶液去保护完全保护的肽硫酯。其他方法，如主酰胺连接剂（BAL）策略依赖于通过还原胺化将第一个氨基酸酯锚定在醛功能化树脂上。5 .在n端拉长肽序列后，必须去除c端酯保护基团以释放羧基，然后与氨基酸硫酯偶联，然后从固体载体上切割。尽管针对不同类型的树脂固体载体开发了不同的合成方法，但目前可用的固相合成肽α-硫酯的方法既不像目前合成肽酸和肽酰胺的技术那么简单也不高效。此外，还没有特定的树脂用于肽α-硫酯的固相合成。因此,
Native chemical ligation has facilitated the total synthesis of small-and medium-sized proteins and cyclic peptides and has thus opened the world of proteins to the tools of organic chemistry. 1 Native chemical ligation relies on the combination of two steps. In the first step, a C-terminal peptide α-thioester is reacted with an N-terminal cysteine peptide. The second step involves a rapid intramolecular S-to N-shift forming an amide bond at the ligation site. Recently, the scope of ligation methods has expanded from N-terminal cysteine to noncysteine residues by employing auxiliary thiols, thus increasing the applicability of the approach. 2 C-terminal peptide α-thioesters are key intermediates in all of these methodologies. This need for C-terminal peptide α-thioesters has stimulated the development in our laboratory of simple and efficient synthetic methods for this class of peptides.Currently there are several reported methods for the solid-phase synthesis of peptide αthioesters. Previous studies report strategies for the synthesis of peptide α-thioesters using both Boc and Fmoc cheminstry. For Boc solid-phase chemisty p-methylbenzhydrylamine (MBHA) resin must first be converted to a mercaptan linker resin by coupling 3-mercaptopropionic acid to MBHA prior to the peptide synthesis. 3 For Fmoc chemistry, peptide α-thioesters are commonly accessed by utilizing a “safety-catch” sulfonamide resin. 4 In this method the sulfonamide must be activated by alkylation before the fully protected peptide is cleaved from the resin with an excess of a thiol nucleophile. The fully protected peptide thioester is then deprotected with concentrated trifluoroacetic acid in solution. Other approaches such as the backbone amide linker (BAL) strategy rely on anchoring the first amino acid ester on an aldehyde-functionalized resin by reductive amination. 5 After elongating the peptide sequence at the N-terminal, the C-terminal ester-protected group must be removed to release the carboxyl group and then coupled with the amino acid thioester, prior to cleavage from the solid support. Though there are different synthetic methods developed for different types of resin solid supports, the methods available thus far for the solid-phase synthesis of peptide α-thioesters are neither as simple nor efficient as the current techniques for the synthesis of peptide acids and peptide amides. Furthermore, there exists no specific resin for the solid-phase synthesis of peptide α-thioesters. Therefore the