Gavrilyuk Julia I, Evindar Ghotas, Chen Jin Yu, Batey Robert A
Davenport Chemical Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, Canada M5S 3H6.
J Comb Chem. 2007 Jul-Aug;9(4):644-51. doi: 10.1021/cc060119p. Epub 2007 Jun 20.
A method for the synthesis of polypeptides modified with a tetrazole ring at the N-terminus is described. Reaction of the N-terminal amino group of solid-supported peptides with arylisothiocyanates generates thiourea intermediates, which upon treatment with Mukaiyama's reagent (2-chloro-1-methylpyridinium iodide) generate electrophilic carbodiimide functionality. Trapping by the azide anion and electrocyclization of the intermediate imidoylazide generates an aryl-substituted 5-aminotetrazole at the N-terminus of the peptide. To prevent competitive cyclization of a neighboring amide N-H into the carbodiimide, there should not be a free N-H at the [X-1] position relative to the activated carbodiimide. Protection of the N-H group at this position or incorporation of a secondary amino acid is thus required for optimal tetrazole formation. Cleavage from the resin releases the hybrid molecules incorporating a 5-aminotetrazole ring conjugated onto a peptidic fragment.
描述了一种在N端合成用四唑环修饰的多肽的方法。固相支持肽的N端氨基与芳基异硫氰酸酯反应生成硫脲中间体，该中间体在用向山试剂（2-氯-1-甲基碘化吡啶）处理后生成亲电碳二亚胺官能团。叠氮阴离子捕获中间体亚胺酰叠氮并进行电环化反应，在肽的N端生成芳基取代的5-氨基四唑。为防止相邻酰胺N-H与碳二亚胺发生竞争性环化反应，相对于活化的碳二亚胺，在[X-1]位置不应有游离的N-H。因此，为了实现最佳的四唑形成，需要保护该位置的N-H基团或引入仲氨基酸。从树脂上裂解下来后，释放出结合有与肽片段共轭的5-氨基四唑环的杂合分子。
