A viable synthesis of N-methyl cysteine.
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%. 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 from the solid support. (c) 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 61-68, 2008. This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com.
Ruggles
Erik L
EL
Department of Biochemistry, Given Laboratory, Burlington, VT 05405, USA.
Flemer
Stevenson
S
Hondal
Robert J
RJ
D000595:Amino Acid Sequence; D003500:Cyclization; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D008745:Methylation; D008969:Molecular Sequence Data; D023303:Oxazolidinones / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry*
D023303:Oxazolidinones; D010456:Peptides, Cyclic; D003545:Cysteine; C017507:mecysteine