1-ethoxyethylidene, a new group for the stepwise SPPS of aminooxyacetic acid containing peptides
1-ethoxyethylidene, a new group for the stepwise SPPS of aminooxyacetic acid containing peptides
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DOI：
10.1021/jo701628k
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发表时间：
2008-02-01
影响因子：
3.6
通讯作者：
Dumy, Pascal
中科院分区：
文献类型：
--
作者：
Foillard, Stephanie;Rasmussen, Martin Ohsten;Dumy, Pascal
十多年来，肟醚连接已被证明是制备各种肽偶联物的最有效技术之一。然而，尽管有许多报道，含氨基肽的制备仍然受到NH-O功能的n -过酰化的阻碍，无论是在其结合过程中还是通过肽链延伸。这限制了在最后一个酰化步骤引入受保护的nh - o功能，并阻止了使用标准固相肽合成（SPPS）程序来制备更复杂的氨基肽。我们研究了含有N- boc或N，N'-bis- boc保护的氨基乙酸（Aoa）的修饰fmoc -赖氨酸在肽链延伸过程中的偶联，发现它们都不足够。为了克服这一限制，我们建议用1-乙氧基乙基（Eei）保护Aoa片段，以提供2-（1-乙氧基乙基乙氧基氨基）乙酸构建块。我们发现Eei基团与标准的SPPS条件完全兼容，并且可以安全地将氨基功能多次结合到生长的肽中。由于eei保护的Aoa在肽合成中保持了与正常氨基酸一样的柔韧性，它可能成为直接制备氨基肽的规则。
[GRAPHICS]For more than a decade, the oxime ether ligation has proven to be one of the most efficient technique for the preparation of various peptide conjugates. However, despite numerous reports, the preparation of aminooxy-containing peptides is still hampered by N-overacylation of the NH-O function either during its incorporation or through the peptide-chain elongation. This restricts the introduction of protected-NH-O function at the last acylation step and prevents the use of standard solid-phase peptide synthesis (SPPS) procedures for the preparation of more complex aminooxy-peptides. We have studied the coupling of modified Fmoc-lysine containing either N-Boc- or N,N'-bis-Boc-protected aminooxyacetic acids (Aoa) during the elongation of the peptide chain and found that none of them is adequate. To circumvent this limitation, we propose to protect the Aoa moiety with a 1-ethoxyethylidene group (Eei) to provide 2-(1-ethoxyethylideneaminooxy)acetic acid building block. We showed that the Eei group is fully compatible with standard SPPS conditions and safely allows the multiple incorporation of the aminooxy functionality into the growing peptide. Since Eei-protected Aoa remains as flexible as normal amino acids in peptide synthesis, it may become the rule for the straightforward preparation of aminooxy peptides.