The large amount of waste derived from coupling reagents is a serious drawback of peptide synthesis from a green chemistry viewpoint. To overcome this issue, we report an electrochemical peptide ...synthesis in a biphasic system. Anodic oxidation of triphenylphosphine (Ph
3
P) generates a phosphine radical cation, which serves as the coupling reagent to activate carboxylic acids, and produces triphenylphosphine oxide (Ph
3
P&z.dbd;O) as a stoichiometric byproduct. In combination with a soluble tag-assisted liquid-phase peptide synthesis, the selective recovery of desired peptides and Ph
3
P&z.dbd;O was achieved. Given that methods to reduce Ph
3
P&z.dbd;O to Ph
3
P have been reported, Ph
3
P&z.dbd;O could be a recyclable byproduct unlike byproducts from typical coupling reagents. Moreover, a commercial peptide active pharmaceutical ingredient (API), leuprorelin, was successfully synthesized without the use of traditional coupling reagents.
The large amount of waste derived from coupling reagents is a serious drawback of peptide synthesis from a green chemistry viewpoint.
Both naturally occurring and artificial cyclic peptides are in high demand for a wide range of therapeutic applications due to the improvement of their enzymatic stability, cell permeability, and ...pharmacological activity compared to their linear counterparts. Among the simplest yet challenging cyclizations is the head‐to‐tail fashion, where linear peptides are cyclized via C‐ and N‐termini, since most current peptide synthesis has been dominated by the use of C‐terminal protecting supports. Herein, we demonstrate that a soluble‐tag‐assisted liquid‐phase peptide synthesis in combination with a backbone amide linker strategy is applicable to the head‐to‐tail cyclization. The use of an amide “N‐tag” instead of the general terminal C‐tag enables an effective head‐to‐tail cyclization on‐support. The key for successful cyclization is a tagging position that enables the center of the peptide to be grabbed.
Cyclic peptides are in high demand for a wide range of therapeutic applications. Among the simplest yet challenging cyclizations is the head‐to‐tail fashion via the C‐ and N‐termini, as most current peptide syntheses use C‐terminal protecting supports. Herein, we demonstrate that a soluble‐tag‐assisted liquid‐phase peptide synthesis in combination with a backbone amide linker strategy is applicable to the head‐to‐tail cyclization.
Soluble epoxide hydrolase (EC 3.3.2.10) is a key enzyme in the regulation of inflammation and metabolism, whereas, the role of its N-terminal phosphatase activity (N-phos) has been poorly understood ...because of a lack of selective inhibitors. Here we report 4-aminobenzoic (Ki 15.3 µm) and 3-amino-4-hydroxy benzoic acid (Ki 11.7 µm) as selective competitive inhibitors of N-phos.
Oxidative biaryl coupling of aryls with different electronic features generally fails. However, this has not been systematically studied via theoretical analysis, and thus, the crucial factor ...governing coupling efficiency remains unclear. Herein, we propose that the “oxidation potential gap (ΔEox)” is a key parameter in predicting the efficiency of an intramolecular oxidative coupling reaction, with ΔEox defined as a difference in the oxidation potentials of the relevant aromatic rings. Our experimental and computational analyses revealed that the efficiency of an aromatic intramolecular coupling reaction correlates with the activation energy (ΔE≠) of C−C bond formation of the radical cation intermediates. Furthermore, ΔE≠ correlates with ΔEox. Therefore, we demonstrate the tuning of ΔEox by attaching cleavable extra electron‐donating/‐withdrawing groups, enabling the rational synthesis of a phenanthridone skeleton using aromatic rings with an electronic gap.
Experimental and computational studies have revealed that the efficiency of intramolecular oxidative cross‐coupling reactions is governed by the SOMO–HOMO gap of the coupling partners, and that the reaction efficiency can be predicted by the oxidation potential gap (ΔEox). Furthermore, tuning of the ΔEox value by the addition of cleavable electron‐donating or ‐withdrawing groups enabled the electrochemical synthesis of phenanthridone skeletons.
Redox‐induced regioselective C(sp3)‐H C‐glycosidation for unactivated prolinols was achieved by controlling the anomeric reactivity of electrochemically generated iminium cations. A mechanistic study ...revealed that the intermediate was pooled as covalent azaribose or iminium cation species in situ, and the electrophilicity of intermediates can be adjusted by changing coexisting acids. We found that the armed/disarmed analogy concept of traditional glycochemistry can be adapted to our C‐glycosidation reaction. Finally, we invented a logical synthetic methodology, named “reactivity switching” concept, and synthesized a series of imino‐C‐nucleosides (C‐azanucleosides) based on this methodology.
Electrochemical C‐glycoside formation was achieved by a “reactivity switching” methodology, which is an expansion of the traditional armed/disarmed concept. Logical reactivity design was enabled by considering electron density, pKa, and resulting anomeric leaving ability of acetate moiety of in situ generated glycoside donors. Finally, we synthesized various imino‐C‐nucleosides (C‐azanucleosides).
Anodic formation of N,O-acetals using amides or carbamates as starting materials, commonly referred to as Shono oxidation, has been an iconic reaction in the field of synthetic organic ...electrochemistry. However, it is, in principle, not stereoselective and the commonly used neighboring-carbonyl-group participation is not usually effective. Herein, we demonstrate that the use of alkylidene protective groups is extremely effective in controlling the stereoselectivity. Although the detailed mechanism remains an open question, under our reaction conditions, the conformation restriction effect is dominant rather than the steric hindrance effect.
Herein, we report that the 2,7-dimethoxynaphthyl (2,7-DMN) group is a novel electroauxiliary that is readily installed at the N-α position of a carbamate through Friedel–Crafts-type arylation. The ...resulting N-α C–C bond is easily cleaved through low-potential electrochemical oxidation to give the corresponding iminium cation.
Although radical ion chain pathways have long been recognized in the field of synthetic organic chemistry and are expected to be operative in various reactions, it is somewhat complicated to verify ...their involvement, since counting the number of electrons is not straightforward. Herein, a series of bis‐styrenes is designed and synthesized to investigate electron transfer events by using radical cation 4+2 cycloadditions as probes. It is demonstrated that the intramolecular single electron transfer seems to be ineffective, while the intermolecular variants are highly effective. Therefore, a truly catalytic amount of electricity is enough for full conversions, confirming that chain pathways were definitely involved.
A series of bis‐styrenes are designed and synthesized to investigate electron transfer events by using radical cation 4+2 cycloadditions as probes. It is demonstrated that the intramolecular single electron transfer seems to be ineffective, while the intermolecular variants are highly effective. A truly catalytic amount of electricity is enough for full conversions, confirming that chain pathways are definitely involved.
The frass of several herbivorous insect species has been utilised as natural medicines in Asia; however, the metabolite makeup and pharmaceutical activities of insect frass have yet to be ...investigated. Oligophagous Papilionidae insects utilise specific kinds of plants, and it has been suggested that the biochemicals from the plants may be metabolised by cytochrome P450 (CYP) in Papilionidae insects. In this study, we extracted the components of the frass of Papilio machaon larvae reared on Angelica keiskei, Oenanthe javanica or Foeniculum vulgare and examined the biological activity of each component. Then, we explored the expression of CYP genes in the midgut of P. machaon larvae and predicted the characteristics of their metabolic system. The components that were extracted using hexane, chloroform or methanol were biochemically different between larval frass and the host plants on which the larvae had fed. Furthermore, a fraction obtained from the chloroform extract from frass of A. keiskei-fed larvae specifically inhibited the cell proliferation of the human colon cancer cell line HCT116, whereas fractions obtained from the chloroform extracts of O. javanica- or F. vulgare-fed larval frass did not affect HCT116 cell viability. The metabolites from the chloroform extract from frass of A. keiskei-fed larvae prevented cell proliferation and induced apoptosis in HCT116 cells. Next, we explored the metabolic enzyme candidates in A. keiskei-fed larvae by RNA-seq analysis. We found that the A. keiskei-fed larval midgut might have different characteristics from the O. javanica- or F. vulgare-fed larval metabolic systems, and we found that the CYP6B2 transcript was highly expressed in the A. keiskei-fed larval midgut. These findings indicate that P. machaon metabolites might be useful as pharmaceutical agents against human colon cancer subtypes. Importantly, our findings show that it might be possible to use insect metabolic enzymes for the chemical structural conversion of plant-derived compounds with complex structures.
Herein, we report a practical method for de novo preparation of imino‐d‐ribitol and C‐azanucleosides. The diastereopure Imino‐d‐ribitol was synthesized on a multigram scale by simple manipulation, ...and late‐stage anomeric derivatization by regio‐ and diastereoselective electrochemical C(sp3)−H activation enabled the efficient synthesis of the corresponding C‐azanucleosides with high β‐selectivity.
Completely stereoselective synthesis of C‐azanucleosides was achieved. Assistance of the sterically hindered pentylidene acetal worked well under electrochemical conditions, and redox‐induced N‐α hydroxylation and continuous C‐glycosidation gave desired C‐azanucleosides with high β‐selectivity (>98 %).
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