A viable synthesis of N-methyl cysteine
A viable synthesis of N-methyl cysteine
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DOI：
10.1002/bip.20889
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发表时间：
2008-01-01
期刊：
影响因子：
2.9
通讯作者：
Hondal, Robert J.
中科院分区：
文献类型：
--
作者：
Ruggles, Erik L.;Flemer, Stevenson, Jr.;Hondal, Robert J.
虽然存在许多用于生产N-甲基氨基酸衍生物的方法，但是用于生产N-甲基半胱氨酸（MeCys）衍生物的方法是次优的，因为它们具有低收率或在合成方案期间导致显著的巯基脱保护。本文重点介绍了MeCys的生成及其随后在Fmoc固相肽合成中用于生成含N-甲基胱氨酸的肽的用途。比较和对比了在酸不稳定或酸稳定巯基保护基团存在下半胱氨酸氨基甲基化的各种方法。MeCys的生产最好通过形成经由Fmoc-Cys（StBu）-OH环化获得的恶唑烷酮前体来实现。恶唑烷酮开环后，亚胺离子还原生成Fmoc-MeCys（StBu）-OH，总产率为91 M。该方法的关键是使用电子中性的Cys-衍生物，因为其他极性Cys-衍生物使用恶唑烷酮方法得到差的结果。随后，Fmoc-MeCys（StBu）-OH结构单元用于在对应于谷氧还蛋白和硫氧还蛋白还原酶的活性位点的两个肽片段中用MeCys残基替换Cys残基。这里使用的实施例强调了MeCys（StBu）衍生物的使用，其允许容易的树脂上转化为MeCys（5-Npys）残基，其随后可用于分子内二硫键形成，伴随着肽在固体载体上的裂解。(C)2007 Wiley Periodicals，Inc.
While a number of methods exist for the production of N-methyl amino acid derivatives, the methods for the production of N-methyl cysteine (MeCys) derivatives are suboptimal as they either have low yields or lead to significant sulfhydryl deprotection during the synthetic protocol. This article focuses on the generation of MeCys and its subsequent use in Fmoc solid-phase peptide synthesis for the generation of N-methyl cystine containing peptides. Various methods for amino methylation of cysteine, in the presence of acid labile or acid stable sulfhydryl protecting groups, are compared and contrasted. Production of MeCys is best attained through formation of an oxazolidinone precursor obtained via cyclization of Fmoc-Cys(StBu)-OH. Following oxazolidinone ring opening, iminium ion reduction generates Fmoc-MeCys(StBu)-OH with an overall yield of 91 M. The key to this procedure is using an electronically neutral Cys-derivative, as other polar Cys-derivatives gave poor results using the oxazolidinone procedure. Subsequently, the Fmoc-MeCys(StBu)-OH building block was used to replace a Cys residue with a MeCys residue in two peptide fragments that correspond to the active sites of glutaredoxin and thioredoxin reductase. The examples used here highlight the use of a MeCys(StBu) derivative, which allows for facile on-resin conversion to a MeCys(5-Npys) residue that can be subsequently used for intramolecular disulfide bond formation with concomitant cleavage of the peptide the solid support. (C) 2007 Wiley Periodicals, Inc.