Histidine-containing peptides are valuable therapeutic agents for a treatment of neurodegenerative diseases. However, the synthesis of histidine-containing peptides is not trivial due to the potential of imidazole sidechain of histidine to act as a nucleophile if unprotected. A peptide ligation method utilizing the imidazole sidechain of histidine has been developed. The key imidazolate intermediate that acts as an internal acyl transfer catalyst during ligation is generated by deprotonation. Transesterification with amino acids or peptides tethered with C-terminal thioester followed by N→N acyl shifts led to the final ligated products. A range of histidine-containing dipeptides could be synthesized in moderate to good yields via this method without protecting the imidazole sidechain. The protocol was further extended to tripeptide synthesis via a long-range N→N acyl transfer, and tetrapeptide synthesis.
Cross-metathesis (CM) has recently emerged as a viable strategy for protein modification. Here, efficient protein CM has been demonstrated through biomimetic chemical access to Se-allyl-selenocysteine (Seac), a metathesis-reactive amino acid substrate, via dehydroalanine. On-protein reaction kinetics reveal a rapid reaction with rate constants of Seac-mediated-CM comparable or superior to off-protein rates of many current bioconjugations. This use of Se-relayed Seac CM on proteins has now enabled reactions with substrates (allyl GlcNAc, N-allyl acetamide) that were previously not possible for the corresponding sulfur analogue. This CM strategy was applied to histone proteins to install a mimic of acetylated lysine (KAc, an epigenetic marker). The resulting synthetic H3 was successfully recognized by antibody that binds natural H3-K9Ac. Moreover, Cope-type selenoxide elimination allowed this putative marker (and function) to be chemically expunged, regenerating an H3 that can be rewritten to complete a chemically enabled "write (CM)–erase (ox)–rewrite (CM)" cycle.
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Abstract The Brønsted acidity of graphene oxide (GO) materials has shown promising activity in organic synthesis. However, roles and functionality of Lewis acid sites remain elusive. Herein, we reported a carbocatalytic approach utilizing both Brønsted and Lewis acid sites in GOs as heterogeneous promoters in a series of multicomponent synthesis of triazoloquinazolinone compounds. The GOs possessing the highest degree of oxidation, also having the highest amounts of Lewis acid sites, enable optimal yields (up to 95%) under mild and non-toxic reaction conditions (85 °C in EtOH). The results of FT-IR spectroscopy, temperature-programed decomposition mass spectrometry, and X-ray photoelectron spectroscopy identified that the apparent Lewis acidity via basal plane epoxide ring opening, on top of the saturated Brønsted acidic carboxylic groups, is responsible for the enhanced carbocatalytic activities involving Knoevenagel condensation pathway. Recycled GO can be effectively regenerated to reach 97% activity of fresh GO, supporting the recognition of GO as pseudocatalyst in organic synthesis.
Abstract A method involving tandem activation of γ‐thiolactone by silver‐DABCO pair has been developed to enable successful amidation of homocysteine thiolactone by various amino acid residues and dipeptides with yields up to 95%. The introduction of thiol functionality to peptides directly using cysteine or homocysteine would require the protection of the reactive sulfhydryl groups and deprotection at a later stage of the synthesis. The γ‐thiolactone chemistry presented herein shows that it could serve as a masked and activatable reaction handle to prepare a range of thiol‐containing peptides in a more atom‐economical way. The resulting thiol‐containing peptides could facilitate late‐stage functionalization and structural diversification of functional or bioactive peptides. The silver(I) ion was found to be essential for the activation of the γ‐thiolactone, poor reactions were observed otherwise. A tentative mechanism for the silver‐DABCO promoted γ‐thiolactone aminolysis was proposed and supported by the evidence from thermal desorption electrospray ionization mass spectrometry.
Heavy-metal pollution is a serious environmental problem. The development of an adsorbent with the ability to bind a diverse range of toxic metal ions would make the water purification process more economically efficient. Various polysulfide materials have been reported to capture mercury efficiently, but there have been relatively few studies on the potential of these materials to bind other toxic metals at the same time. In this work, bipyridine-containing polysulfides have been synthesized for the first time by inverse vulcanization between elemental sulfur and a dioleyl bipyridine (DOBP) derivative. The incorporation of the bipyridine motif into polysulfide copolymer was verified through characterization via NMR, Fourier transform infrared (FT-IR), and Raman spectroscopy techniques. In addition, a facile and inexpensive method for creating microporous structures in polysulfide materials has been developed using sodium bicarbonate as the CO2-foaming agent. The developed foaming protocol provided a weakly basic solution during the salt-leaching step that caused partial ester hydrolysis of the DOBP component in poly(S40-r-DOBP60) and conveniently installed additional alcohol and carboxylic acid groups in the polysulfide, confirmed by the presence of a broad O–H stretch in the corresponding FT-IR spectra. The metal adsorption experiment of bicarbonate-foamed poly(S40-r-DOBP60) with a multielement solution indicated 82–100% removal of 11 toxic metal ions including Cr3+, Mn2+, Ni2+, Cu2+, Ag+, Cd2+, In3+, Ba2+, Hg2+, Pb2+, and Bi3+ using a single adsorbent. The broad-spectrum metal ion capture exhibited by the foamed bipyridine-containing polysulfide was attributed to the fact that this material has the widest variety (six types) of functional groups among the three adsorbents tested. This work has demonstrated that by incorporating various types of ligands into molecular designs of the alkene cross-linker, the potential of the polysulfide materials in heavy-metal removal could be expanded.
Olefin metathesis has emerged as a powerful tool in organic synthesis. The activating effect of an allylic hydroxy group in metathesis has been known for more than 10 years, and many organic chemists have taken advantage of this positive influence for efficient synthesis of natural products. Recently, the discovery of the rate enhancement by allyl sulfides in aqueous cross-metathesis has allowed the first examples of such a reaction on proteins. This led to a new benchmark in substrate complexity for cross-metathesis and expanded the potential of olefin metathesis for other applications in chemical biology. The enhanced reactivity of allyl sulfide, along with earlier reports of a similar effect by allylic hydroxy groups, suggests that allyl chalcogens generally play an important role in modulating the rate of olefin metathesis. In this review, we discuss the effect of allylic chalcogens in olefin metathesis and highlight its most recent applications in synthetic chemistry and protein modifications.
Cesium carbonate promoted direct amidation of unactivated esters with amino alcohols was developed without the use of transition-metal catalysts and coupling reagents. This method enabled the synthesis of several serine-containing oligopeptides and benzamide derivatives with yields up to 90%. The methodology proceeds under mild reaction conditions and exhibits no racemization for most naturally occurring amino acid substrates. The reaction demonstrates good compatibility with primary alkyl and benzyl esters and broad tolerance for a range of amino acid substrates with nonpolar and protected side chains. The hydroxy group on the amine nucleophile was found to be critical for the reaction to be successful. A likely mechanism involving cesium coordination to the substrates enabling the subsequent proximity-driven acyl transfer was proposed. The practicality of this approach was demonstrated in the preparation of a biologically active nicotinamide derivative in a reasonable yield.
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