- Improved synthetic routes to the selenocysteine derivatives useful for Boc-based peptide synthesis with benzylic protection on the selenium atom
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Selenocysteine (Sec) derivatives, i.e., Boc-Sec(MBn)-OH (1) and Boc-Sec(MPM)-OH (2), which are useful for chemical synthesis of selenopeptides, were obtained from L-serine in five steps with total yields of 73% and 74%, respectively. The enantiomeric excesses were confirmed to be >99% e.e. by optical resolution using a chiral column on HPLC. On the other hand, for the case of a Fmoc-protected Sec derivative, i.e., Fmoc-Sec(MPM)-OH, similar reactions resulted in low yields and partial racemization taking place. [PRESENTED EQUATION]
- Shimodaira, Shingo,Iwaoka, Michio
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p. 260 - 271
(2017/03/09)
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- A comprehensive one-pot synthesis of protected cysteine and selenocysteine SPPS derivatives
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A proof-of-principle methodology is presented in which all commercially-available cysteine (Cys) and selenocysteine (Sec) solid phase peptide synthesis (SPPS) derivatives are synthesized in high yield from easily prepared protected dichalcogenide precursors. A Zn-mediated biphasic reduction process applied to a series of four bis-Nα-protected dichalcogenide compounds allows facile conversion to their corresponding thiol and selenol intermediates followed by insitu S- or Se-alkylation with various electrophiles to directly access twenty one known Cys and Sec SPPS derivatives. Most of these derivatives were able to be precipitated in crude form out of petroleum ether in sufficient purity for direct use as peptide building blocks. Subsequent incorporation of these derivatives into peptide models nicely illustrates their viability and applicability toward SPPS.
- Flemer, Stevenson
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p. 1257 - 1264
(2015/04/14)
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- Investigation of peptide thioester formation via N→Se acyl transfer
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Native chemical ligation is widely used for the convergent synthesis of proteins. The peptide thioesters required for this process can be challenging to produce, particularly when using Fmoc-based solid-phase peptide synthesis. We have previously reported a route to peptide thioesters, following Fmoc solid-phase peptide synthesis, via an N→S acyl shift that is initiated by the presence of a C-terminal cysteine residue, under mildly acidic conditions. Under typical reaction conditions, we occasionally observed significant thioester hydrolysis as a consequence of long reaction times (~48h) and sought to accelerate the reaction. Here, we present a faster route to peptide thioesters, by replacing the C-terminal cysteine residue with selenocysteine and initiating thioester formation via an N→Se acyl shift. This modification allows thioester formation to take place at lower temperatures and on shorter time scales. We also demonstrate how application of this strategy also accelerates peptide cyclization, when a linear precursor is furnished with an N-terminal cysteine and C-terminal selenocysteine.
- Adams, Anna L.,Macmillan, Derek
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- The use of 2,2′-dithiobis(5-nitropyridine) (DTNP) for deprotection and diselenide formation in protected selenocysteine-containing peptides
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In contrast to the large number of sidechain protecting groups available for cysteine derivatives in solid phase peptide synthesis, there is a striking paucity of analogous selenocysteine Se-protecting groups in the literature. However, the growing interest in selenocysteine-containing peptides and proteins requires a corresponding increase in availability of synthetic routes into these target molecules. It therefore becomes important to design new sidechain protection strategies for selenocysteine as well as multiple and novel deprotection chemistry for their removal. In this paper, we outline the synthesis of two new Fmoc selenocysteine derivatives [Fmoc-Sec(Meb) and Fmoc-Sec(Bzl)] to accompany the commercially available Fmoc-Sec(Mob) derivative and incorporate them into two model peptides. Sec-deprotection assays were carried out on these peptides using 2,2′-dithiobis(5-nitropyridine) (DTNP) conditions previously described by our group. The deprotective methodology was further evaluated as to its suitability towards mediating concurrent diselenide formation in oxytocin-templated target peptides. Sec(Mob) and Sec(Meb) were found to be extremely labile to the DTNP conditions whether in the presence or absence of thioanisole, whereas Sec(Bzl) was robust to DTNP in the absence of thioanisole but quite labile in its presence. In multiple Sec-containing model peptides, it was shown that bis-Sec(Mob)-containing systems spontaneously cyclize to the diselenide using 1eq DTNP, whereas bis-Sec(Meb) and Sec(Bzl) models required additional manipulation to induce cyclization.
- Schroll, Alayne L.,Hondal, Robert J.,Flemer, Stevenson
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experimental part
p. 155 - 162
(2012/05/20)
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- Preparation of the β3-homoselenocysteine derivatives Fmoc-β3hSec(PMB)-OH and Boc-β3hSec(PMB)-OH for solution and solid-phase-peptide synthesis and selenoligation
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The title compounds, 4 and 7, have been prepared from the corresponding α-amino acid derivative selenocystine (1) by the following sequence of steps: cleavage of the Se-Se bond with NaBH4, p-methoxybenzyl (PMB) protection of the SeH group, Fmoc or Boc protection at the N-atom and Arndt-Eistert homologation (Schemes 1 and 2). A β3-heptapeptide 8 with an N-terminal β3-hSec(PMB) residue was synthesized on Rink amide AM resin and deprotected ('in air') to give the corresponding diselenide 9, which, in turn, was coupled with a β3-tetrapeptide thiol ester 10 by a seleno-ligation. The product β3- undecapeptide was identified as its diselenide and its mixed selenosulfide with thiophenol (Scheme 3). The differences between α- and β-Sec derivatives are discussed.
- Floegel, Oliver,Casi, Giulio,Hilvert, Donald,Seebach, Dieter
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p. 1651 - 1666
(2008/02/13)
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- Synthesis of a selenocysteine-containing peptide by native chemical ligation
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(equation presented) A new method for the synthesis of selenocysteine derivatives and selenocysteine-containing peptides is described. Fmoc-Se-p-methoxybenzylselenocysteine (1) was prepared and used for solid-phase synthesis of peptides with an N-terminal unprotected selenocysteine. Subsequent native chemical ligation with a peptide thioester provided a 17-mer that corresponds to the C-terminus of ribonucleotide reductase with selenocysteine in place of cysteine.
- Gieselman, Matt D.,Xie, Lili,Van Der Donk, Wilfred A.
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p. 1331 - 1334
(2007/10/03)
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- Synthetic study of selenocystine-containing peptides
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N-9-Fluorenylmethoxycarbonyl-Se-4-methoxybenzylselenocysteine [Fmoc-Sec(MBzl)-OH] was synthesized from selenocystine and successfully applied to Fmoc-based solid-phase peptide synthesis. The stability and the deprotection conditions of the Se-MBzl group were examined. The diselenide bond of a peptide was directly and effectively established between Sec(MBzl) residues by treatment with iodine or the dimethyl sulfoxide-trifluoroacetic acid system. Reduction kinetics of diselenide and disulfide in model peptides by reduced glutathione were also studied comparatively.
- Koide,Itoh,Otaka,Yasui,Kuroda,Esaki,Soda,Fujii
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p. 502 - 506
(2007/10/02)
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