Convenient synthesis of N-methylamino acids compatible with Fmoc solid-phase peptide synthesis
Convenient synthesis of N-methylamino acids compatible with Fmoc solid-phase peptide synthesis
复制标题
DOI：
10.1021/jo050477z
复制
发表时间：
2005-06-24
影响因子：
3.6
通讯作者：
Kessler, H
中科院分区：
文献类型：
--
作者：
Biron, E;Kessler, H
含有N-α-甲基氨基酸的肽显示出令人感兴趣的治疗特性，并且越来越多地被认为是潜在有用的治疗剂。不幸的是，它们的合成受到许多N-甲基氨基酸的高价格和不可获得性的阻碍。本发明描述了一种有效和实用的制备N-α-甲基-N-α-（邻硝基苯磺酰基）-α-氨基酸的方法，无需大量纯化。该方法是基于众所周知的N-α-芳基磺酰氨基酯的N-烷基化反应，通过使用硫酸二甲酯和DBU作为碱对其进行改进。通过使用S（N）2-型皂化与碘化锂有效地实现酯裂解，避免用氢氧化锂水解观察到的外消旋化。合成的N-α-甲基氨基酸与Fmoc固相肽合成的相容性通过使用正常偶联条件有效制备N-甲基二肽来证明。所述方法允许在非常短的时间内制备N-α-甲基氨基酸，并使用Fmoc固相肽合成快速合成N-甲基肽。
N-alpha-Methylamino acid containing peptides exhibit interesting therapeutic profiles and are increasingly recognized as potentially useful therapeutics. Unfortunately, their synthesis is hampered by the high price and unavaibility of many No-methylamino acids. An efficient and practical preparation of N-alpha-methyl-N-alpha-(o-nitrobenzenesulfonyl)-alpha-amino acids without extensive purification is described. The procedure is based on the well-known N-alkylation of N-alpha-arylsulfonylamino esters which was improved by using dimethyl sulfate and DBU as base. Ester cleavage is efficiently achieved by using an S(N)2-type saponification with lithium iodide, avoiding racemization observed with lithium hydroxide hydrolysis. Compatibility of the synthesized N-alpha-methylamino acids with Fmoc solid-phase peptide synthesis is demonstrated by using normal coupling conditions to efficiently prepare N-methyl dipeptides. The described procedure allows the preparation of N-alpha-methylamino acids in a very short period of time and a rapid synthesis of N-methyl peptides using Fmoc solid-phase peptide synthesis.