LongLarf

Bio‐orthogonal modification of dehydroalanine residues in peptides and proteins is achieved by photoredox catalysis with a newly designed water‐soluble Ir^III complex in aqueous media and a variety of zinc benzylsulfinates as reagents.

Abstract

Dehydroalanine (Dha) residues are attractive noncanonical amino acids that occur naturally in ribosomally synthesised and post‐translationally modified peptides (RiPPs). Dha residues are attractive targets for selective late‐stage modification of these complex biomolecules. In this work, we show the selective photocatalytic modification of dehydroalanine residues in the antimicrobial peptide nisin and in the proteins small ubiquitin‐like modifier (SUMO) and superfolder green fluorescent protein (sfGFP). For this purpose, a new water‐soluble iridium(III) photoredox catalyst was used. The design and synthesis of this new photocatalyst, [Ir(dF(CF₃)ppy)₂(dNMe₃bpy)]Cl₃, is presented. In contrast to commonly used iridium photocatalysts, this complex is highly water soluble and allows peptides and proteins to be modified in water and aqueous solvents under physiologically relevant conditions, with short reaction times and with low reagent and catalyst loadings. This work suggests that photoredox catalysis using this newly designed catalyst is a promising strategy to modify dehydroalanine‐containing natural products and thus could have great potential for novel bioconjugation strategies.

Publication date: 13 May 2021

Source: Chem, Volume 7, Issue 5

Author(s): Yujie Wang, Mingyang Wang, Yibiao Li, Qiang Liu

Piezoelectricity has been used to generate trifluoromethyl (CF₃) radicals for the mechanochemical C−H trifluoromethylation of aromatic compounds (see scheme). As compared to conventional solution‐based approaches, this mechanoredox C−H trifluoromethylation enabled cleaner and more sustainable access to a wide range of trifluoromethylated N‐heterocycles and peptides, which are important structural motifs in modern drug discovery.

Abstract

The application of piezoelectricity for the generation of trifluoromethyl (CF₃) radicals is reported together with the development of a method for the mechanochemical C−H trifluoromethylation of aromatic compounds. As compared to conventional solution‐based approaches, this mechanoredox C−H trifluoromethylation enables cleaner and more sustainable access to a wide range of trifluoromethylated N‐heterocycles and peptides, which are important structural motifs in modern drug discovery. This study thus represents an important milestone for future applications of mechanoredox systems to medicinal and pharmaceutical science.

We demonstrated a Glaser‐like coupling reaction by atom manipulation. The intramolecular reaction was performed within a single molecule, facilitated by the design of the precursor molecule. By using high‐resolution atomic force microscopy, we revealed precursors, intermediates, and products. Resolving and manipulating the positions of individual hydrogen atoms in intermediates provided information about the reaction pathway.

Abstract

Glaser‐like coupling of terminal alkynes by thermal activation is extensively used in on‐surface chemistry. Here we demonstrate an intramolecular version of this reaction performed by atom manipulation. We used voltage pulses from the tip to trigger a Glaser‐like coupling between terminal alkyne carbons within a custom‐synthesized precursor molecule adsorbed on bilayer NaCl on Cu(111). Different conformations of the precursor molecule and the product were characterized by molecular structure elucidation with atomic force microscopy and orbital density mapping with scanning tunneling microscopy, accompanied by density functional theory calculations. We revealed partially dehydrogenated intermediates, providing insight into the reaction pathway.

Of the more than 100 casbane diterpenes known to date, only the eponymous parent hydrocarbon casbene itself has ever been targeted by chemical synthesis. Outlined herein is a conceptually new approach that brings not a single but a variety of casbane derivatives into reach, especially the more highly oxygenated and arguably more relevant members of this family. The key design elements are a catalyst controlled intramolecular cyclopropanation with or without subsequent equilibration, chain extension of the resulting stereoisomeric cyclopropane building blocks via chemoselective hydroboration/cross coupling, and the efficient closure of the strained macrobicyclic framework by ring closing alkyne metathesis. Of arguably highest relevance is the fact that a hydroxy‐directed catalytic trans ‐hydrostannation allows for late‐stage diversity. These virtues are manifested in concise total syntheses of depressin, yuexiandajisu A, and ent ‐pekinenin C; the latter turned out to be identical with euphorhylonal A, which had obviously been misassigned in the literature.

In this review, we summarise progress in benzofuran and benzothiophene C−H functionalisations over the past five years, including 1) alkylations, 2) arylations and heteroarylations, 3) carboxylations, carbamoylations and C‐heteroatom bond formations and 4) cyclisations.

Abstract

Benzofurans and benzothiophenes are important pharmaceutical motifs, appearing in a broad range of small molecule therapeutic classes. Often overlooked by synthetic methodologists in favour reactions of the analogous indole bicyclic system, there is nevertheless a plurality of approaches to effecting benzofuran and benzothiophene C−H functionalisations. In this review, we summarise progress in this area over the past five years, including 1) alkylations, 2) arylations and heteroarylations, 3) carboxylations, carbamoylations, and C‐heteroatom bond formations and 4) cyclisations.

Regeneratable: The first example of a sustainable catalytic synthesis of diethyl carbonate (DEC) from CO₂ and alkoxysilane substrate with Zr(OEt)₄ catalysts is reported. That the disiloxane byproduct was regenerable offers a new promising direction for the development of waste‐free synthesis of DEC.

Abstract

New sustainable approaches should be developed to overcome equilibrium limitation of dialkyl carbonate synthesis from CO₂ and alcohols. Using tetraethyl orthosilicate (TEOS) and CO₂ with Zr catalysts, we report the first example of sustainable catalytic synthesis of diethyl carbonate (DEC). The disiloxane byproduct can be reverted to TEOS. Under the same conditions, DEC can be synthesized using a wide range of alkoxysilane substrates by investigating the effects of the number of ethoxy substituent in alkoxysilane substrates, alkyl chain, and unsaturated moiety on the fundamental property of this reaction. Mechanistic insights obtained by kinetic studies, labeling experiments, and spectroscopic investigations reveal that DEC is generated via nucleophilic ethoxylation of a CO₂‐inserted Zr catalyst and catalyst regeneration by TEOS. The unprecedented transformation offers a new approach toward a cleaner route for DEC synthesis using recyclable alkoxysilane.

Waste Recycling: Our current dependence on rapidly depleting resources and the growing accumulation of chemical waste have become a grave concern to our society. This has sparked interest in the contemporary catalysis community to develop green technologies for the chemical conversion of waste products to valuable feedstocks enabling the circular economy. This article reviews the applications of homogeneous (de)hydrogenative catalysis for the conversion of chemical waste products – CO₂, N₂O, plastics, and glycerol to useful chemical feedstocks.

Abstract

Increasing production and usage of several consumer products and energy sources have resulted in the accumulation of a substantial amount of waste products that are toxic and/or difficult to biodegrade, thus creating a severe threat to our planet. With the recently advocated concepts of circular chemistry, an attractive approach to tackle the challenge of chemical waste reduction is to utilize these waste products as feedstocks for the production of useful chemicals. Catalytic (de)hydrogenation is an atom‐economic, green and sustainable approach in organic synthesis, and several new environmentally benign transformations have been reported using this strategy in the past decade, especially using well‐defined transition metal complexes as catalysts. These discoveries have demonstrated the impact and untapped potential of homogeneous (de)hydrogenative catalysis for the purpose of converting chemical wastes into useful resources. Four types of chemical waste that have been (extensively) studied in recent years for their chemical transformations using homogeneous catalytic (de)hydrogenation are CO₂, N₂O, plastics, and glycerol. This review article highlights how these chemical wastes can be converted to useful feedstocks using (de)hydrogenative catalysis mediated by well‐defined transition metal complexes and summarizes various types of homogeneous catalysts discovered for this purpose in recent years. Moreover, with examples of hydrogenative depolymerization of plastic waste and the production of virgin plastic via dehydrogenative pathways, we emphasize the potential applications of (de)hydrogenation reactions to facilitate closed‐loop production cycles enabling a circular economy.

The reactivity of NaBH₄ was controlled by atmospheric CO₂, thus suppressing direct reduction of aldehydes to alcohols. High selectivities towards reductive amination alkylation reactions indicate the in‐situ formation of less reducing NaBH(OCHO)₃. This protocol provides a surrogate for conventional reducing reagents in reductive amination reactions.

We report the use of CO₂ to curb the reactivity of NaBH₄ enabling its use in reductive amination reactions. CO₂ readily reacts with NaBH₄ to decrease its capacity to reduce aldehydes to alcohols while remaining able to reduce imines and iminium ions for desired alkylation reactions. The formation of NaBH(OCHO)₃ as a reducing reagent was critical to achieve the desired selectivity. A general protocol was established for C–N bond formation reactions and replacing NaBH₄ with NaBD₄ allowed for reductive amination with concomitant deuteration to be carried out.

Abstract

Aryl phosphorus compounds have found versatile applications in materials, medicinal and synthetic chemistry. As a powerful tool, aryne chemistry has been widely utilized in constructing aryl C−P bonds under mild conditions; this has enabled facile access to a variety of structurally diverse aryl–phosphorus compounds with good efficiency. The present review aims to offer a comprehensive overview of the chemistry between arynes and organophosphorus compounds, with emphasis placed on reactivity modes and mechanistic aspects. According to the valency of phosphorus atoms, this paper is divided into two main sections, reactions of arynes with organophosphorus(III) compounds and those with organophosphorus(V) compounds.

Abstract

Herein, we disclose a ruthenium‐catalyzed regioselective β‐C(sp ³)−H bond functionalization on the piperazine core using aldehydes as alkylating agents. The present transformation appears to go through the dehydrogenation of the piperazine to propagate to enamine in situ, followed by nucleophilic addition to the aldehyde and hydrogenation to result in the regioselective β‐C(sp ³)−H alkylation. A variety of aromatic, heteroaromatic, aliphatic aldehydes were employed for the C‐3 alkylation of N‐alkyl‐N′‐p‐nitrophenyl substituted piperazines.

A mild, deoxygenative fluorination approach was developed using only oxalyl chloride and potassium fluoride to access a broad variety of fluorinated phosphorus(V) compounds in neutral, cationic, or anionic forms. The method circumvents working with both pyrophoric starting materials and hazardous fluorinating reagents, making fluorinated group 15 heteroatoms in organic frameworks more accessible.

Abstract

Fluorinated organophosphorus(V) compounds are a very versatile class of compounds, but the synthetic methods available to make them bear the disadvantages of 1) occasional handling of toxic or pyrophoric P^III starting materials and 2) a dependence on hazardous fluorinating reagents such as XeF₂. Herein, we present a simple solution and introduce a deoxygenative fluorination (DOF) approach that utilizes easy‐to‐handle phosphine oxides as starting materials and effectively replaces harsh fluorinating reagents by a combination of oxalyl chloride and potassium fluoride. The reaction has proven to be general, as R₃PF₂, R₂PF₃, and RPF₄ compounds (as well as various cations and anions derived from these) are accessible in good yields and on up to a multi‐gram scale. DFT calculations were used to bolster our observations. Notably, the discovery of this new method led to a convenient synthesis of 1) new difluorophosphonium ions, 2) hexafluorophosphate salts, and 3) fluorinated antimony‐ and arsenic‐ compounds.