Backbone amide linker (BAL) strategy for Nα-9-fluorenylmethoxycarbonyl (Fmoc) solid-phase synthesis of unprotected peptide p-nitroanilides and thioesters
Backbone amide linker (BAL) strategy for Nα-9-fluorenylmethoxycarbonyl (Fmoc) solid-phase synthesis of unprotected peptide p-nitroanilides and thioesters
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DOI：
10.1021/jo990629o
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发表时间：
1999-11-26
影响因子：
3.6
通讯作者：
Barany, G
中科院分区：
文献类型：
--
作者：
Alsina, J;Yokum, TS;Barany, G
已经设计了一种新的和通用的骨架酰胺连接体（BAL）策略，用于与N-α-9-芴基甲氧羰基（Fmoc）固相合成方案一起制备含有受阻、非反应性和/或敏感部分的C-末端修饰的肽。该策略包括ii）通过锚定倒数第二个残基开始肽合成，其羧基通过骨架氮正交保护，（ii）继续用标准方案在C -> N方向上延长肽链，（iii）选择性正交除去羧基保护基，（iv）固相活化侧羧基并与所需的C-末端残基偶联，和（v）最终裂解/脱保护以将游离肽产物释放到溶液中。为了说明这种方法，已经制备了几种模型肽对硝基苯胺和硫酯，具有优异的产率和纯度，具有最小的外消旋。这样的化合物非常难以通过标准Fmoc化学制备，包括最初设想的BAL策略。
A novel and general backbone amide linker (BAL) strategy has been devised for preparation of C-terminal modified peptides containing hindered, unreactive, and/or sensitive moieties, in concert with N-alpha-9-fluorenylmethoxycarbonyl (Fmoc) solid-phase synthesis protocols. This strategy comprises ii) start of peptide synthesis by anchoring the penultimate residue, with its carboxyl group orthogonally protected, through the backbone nitrogen,(ii) continuation with standard protocols for peptide chain elongation in the C --> N direction, (iii) selective orthogonal removal of the carboxyl protecting group, (iv) solid-phase activation of the pendant carboxyl and coupling with the desired C-terminal residue, and (v) final cleavage/deprotection to release the free peptide product into solution. To illustrate this approach, several model peptide p-nitroanilides and thioesters have been prepared in excellent yields and purities, with minimal racemization. Such compounds are very difficult to prepare by standard Fmoc chemistry, including the BAL strategy as originally envisaged.