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Amphiphilic hypervalent iodine reagents enable the alkynylation of cysteine residues in peptides with lipophilic groups in water. The reaction proceeds in neutral standard buffers with high efficiency for a broad range of peptides and one protein. The thioalkynes can be converted into cleavable thioesters under acidic conditions.

Abstract

We report the functionalization of cysteine residues with lipophilic alkynes bearing a silyl group or an alkyl chain using amphiphilic ethynylbenziodoxolone reagents (EBXs). The reactions were carried out in buffer (pH 6 to 9), without organic co-solvent or removal of oxygen, either at 37 °C or room temperature. The transformation led to a significant increase of peptide lipophilicity and worked for aromatic thiols, homocysteine, cysteine, and peptides containing 4 to 18 amino acids. His₆-Cys-Ubiquitin was also alkynylated under physiological conditions. Under acidic conditions, the thioalkynes were converted into thioesters, which could be cleaved in the presence of hydroxylamine.

Computational investigations indicate that the use of N,N-dimethylhydroxylamine as organocatalyst enhances the rate of Morita-Baylis-Hillman reaction by lowering the activation energy of the rate-controlling aldol step. The rate enhancement is understood to originate from the a-effect of oxygen on nitrogen in hydroxylamine, which enhances the nucleophilicity of the nitrogen and results in its more effective conjugate addition to the enone to form an advanced and, thus, reactive enolate to participate in the aldol process. The activation energy of the aldol reaction is therefore reduced.

Synlett
DOI: 10.1055/a-1492-4943

Nowadays, hypervalent iodine chemistry has remarkably advanced in parallel with the emergence of novel hypervalent iodine reagents. Hypervalent iodine reagents, due to their outstanding characteristics including rich reactivities, excellent chemoselectivity, stability, and environmental friendliness, are becoming more and more popular in the synthetic organic chemistry. In this Account, a number of recent elegant research works and our perspective on the future of hypervalent iodine chemistry is presented.1 Introduction2 Recent Advances and Discussion2.1 Novel Reactivities of Hypervalent Iodine Reagents2.2 Atom-Economical Reactions Promoted by Hypervalent Iodine Reagents2.3 Other Applications of Hypervalent Iodine Reagents2.4 The Applications of DFT Calculations in Elucidating Reaction Mechanism Involving Hypervalent Iodine Reagents3 Outlook and Conclusion
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Nature Communications, Published online: 24 May 2021; doi:10.1038/s41467-021-23371-x

Transition metal-catalyzed C−H cyclization for medium-ring synthesis has been limited to reactive C−H bonds, the activation of unreactive C−H bonds still remains a challenge. Here the authors show the direct construction of 7-membered rings via Ni−Al co-catalyzed unreactive C−H cyclization of benzoimidazoles with alkenes, providing a series of tricyclic imidazoles.

An efficient synthesis of some functionalized saturated azaheterocycles has been accomplished by controlled functionalization through ozonolysis and cyclization with reductive amination of various readily available cycloalkenes.

Abstract

An improved, efficient synthesis of some functionalized saturated azaheterocycles has been accomplished by controlled functionalization of various readily available cyclic compounds containing ring C=C bond. The stereocontrolled synthetic concept was based on the oxidative ring cleavage of various unsaturated scaffolds across ozonolysis followed by ring closing with double reductive amination with primary alkylamines or fluorinated alkylamines. The protocol provided versatile azaheterocyclic derivatives with a piperidine or azepane framework.

Nature Chemistry, Published online: 24 May 2021; doi:10.1038/s41557-021-00683-5

A chiral (η3-allyl)iridium(iii) complex has previously been used to catalyse enantioselective allylic substitution reactions in the polar domain. Now, it has been shown that the visible-light excitation of this iridium complex unlocks an otherwise inaccessible radical-based pathway to achieve enantioselective alkyl–alkyl cross-coupling reactions between allylic alcohols and radical precursors.

Nature Chemistry, Published online: 24 May 2021; doi:10.1038/s41557-021-00698-y

Many C–C bond activation methods involve strain-releasing cleavage of small rings to compensate for unfavourable kinetics and thermodynamics. Now, the 1,2-positional interchange of vicinal C–C and C–Pd bonds has been reported, giving access to quaternary carbon–palladium bonds. This dyotropic rearrangement has been used for the enantioselective synthesis of functionalized fluorinated cyclopentanes.

Abstract

Transition-metal-catalyzed reactions of N-tosylhydrazones provide a convenient access to various molecules by novel carbon-carbon or carbon-heteroatom bond formations via carbene-type intermediates. The present review highlights recent developments in the field emphasize of the employment of different transition metals as catalysts, synthetic applications, mechanistic studies and use in domino and multicomponent reactions.

The hunt is still on for the most powerful neutral superbase. The steadily growing scope of applications has resulted in a renaissance of highly electron-rich phosphorus-containing Lewis and Brønsted bases. Strongly π-donating substituents at the center of basicity can be employed to increase the proton affinity and the σ-donation ability. This minireview highlights recently published achievements focusing especially on the past five years.

Abstract

The renaissance of Brønsted superbases is primarily based on their pronounced capacity for a large variety of chemical transformations under mild reaction conditions. Four major set screws are available for the selective tuning of the basicity: the nature of the basic center (N, P, …), the degree of electron donation by substituents to the central atom, the possibility of charge delocalization, and the energy gain by hydrogen bonding. Within the past decades, a plethora of neutral electron-rich phosphine and phosphazene bases have appeared in the literature. Their outstanding properties and advantages over inorganic or charged bases have now made them indispensable as auxiliary bases in deprotonation processes. Herein, an update of the chemistry of basic phosphines and phosphazenes is given. In addition, due to widespread interest, their use in catalysis or as ligands in coordination chemistry is highlighted.

Pre-formed oxidative addition complexes (OACs) are utilized to selectively arylate p-aminophenylalanine (pAF) in the presence of native functional groups, except cysteine. In phosphate buffer pH 7.5, OACs derived from electron-poor arenes provide full conversion in as little as 2 hours at micromolar concentration. A complimentary procedure using the weak base 1,5-diazabicyclo(4.3.0)non-5-ene (DBN) is also presented enabling arylation with electron-rich substrates with up to 97 % conversion.

Abstract

The selective N-arylation of p-aminophenylalanine in polypeptides with pre-formed palladium oxidative addition complexes is described. The depressed pKa of the aniline NH₂ group enables chemoselective C−N bond formation on peptides containing multiple other aliphatic amino groups at lysines or the N-terminus via Curtin–Hammett control under mild conditions. Using palladium complexes derived from electron-poor aryl halides, p-aminophenylalanine is fully arylated in aqueous buffer in as little as one hour at micromolar concentrations. A complementary protocol using the non-nucleophilic, organic base 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), expands the substrate scope to tolerate electron-rich functional groups provides up to 97 % conversion. These procedures enable the chemoselective conjugation of functionally diverse small molecule pharmaceuticals to p-aminophenylalanine containing derivatives of cell-penetrating peptides.

Abstract

Over the last several years, radical-mediated decarboxylative cross-coupling reactions employing alkyl carboxylic acids have emerged as a powerful tool for the regiospecific construction of carbon−carbon bonds. Under thermal or photocatalytic conditions, a wide variety of C(sp ³)-carboxylic acids and their redox-active esters undergo decarboxylative C−C bond formation with suitable reactant partners, leading to complex chemical scaffolds with wide-ranging applications. This synthetic strategy has several advantages over the more conventional organometallic reagents, including abundant starting material availability and high functional group tolerance associated with the mild reaction conditions. This review article highlights recent developments in the functionalization of α-heteroatom-substituted carboxylic acids as well as the more challenging unactivated acids, with representative examples discussed against the backdrop of insightful comments on reaction mechanisms. In addition, examples of the synthesis of natural products, drug molecules, and the late-stage modification of bioactive molecules employing this non-traditional C−C bond formation strategy are included. This review has been categorized into three main sections that are organized around the type of C−C bond being forged: C(sp ³)−C(sp ²), C(sp ³)−C(sp ³), and C(sp ³)−C(sp). Further, the reactions of carboxylic acids and their redox-active esters have been organized separately in each section.

The functionalization of methane, ethane, and other alkanes derived from fossil fuels is a central goal in the chemical enterprise. Recently, a photocatalytic system comprising [Ce^IVCl₅(OR)]^2– [Ce^IV, cerium(IV); OR, –OCH₃ or –OCCl₂CH₃] was disclosed. The system was reportedly capable of alkane activation by alkoxy radicals (RO•) formed by Ce^IV–OR bond photolysis. In this work, we present evidence that the reported carbon-hydrogen (C–H) activation of alkanes is instead mediated by the photocatalyst [NEt₄]₂[CeCl₆] (NEt₄⁺, tetraethylammonium), and RO• are not intermediates. Spectroscopic analyses and kinetics were investigated for C–H activation to identify chlorine radical (Cl•) generation as the rate-limiting step. Density functional theory calculations support the formation of [Cl•][alcohol] adducts when alcohols are present, which can manifest a masked RO• character. This result serves as an important cautionary note for interpretation of radical trapping experiments.

Nature, Published online: 20 May 2021; doi:10.1038/s41586-021-03637-6

A radical approach for the selective C–H borylation of azines

Abstract

A Pd-catalyzed cascade cyclization for the construction of fused dihydrocyclohepta[de]naphthalene skeletons was developed. The skeleton was assembled from 3-iodo-4H-chromen-4-one, norbornene and 8-bromo-1-naphthoic acid. Unlike the classic Catellani reaction, which involves the removal of norbornene, in the present system, norbornene acts as a building block for the construction of rigid nonplanar molecular architectures rather than as an ortho-directing transient mediator. This synthesis involves the formation of three C−C bonds via a one-pot process, and it is compatible of a series of substituents.

E factor under scrutiny: Do you know which is the impact on the overall process of the organocatalyst synthesis? Within the framework of the green chemistry principles, this Review analyses the synthetic routes towards some of the most important organocatalyst scaffolds. The introduction of a new chemistry metric, the E _G factor, will provide an idea of the actual impact of the catalyst synthesis within the overall organocatalytic process.

Abstract

Can green chemistry be the right reading key to let organocatalyst design take a step forward towards sustainable catalysis? What if the intriguing chemistry promoted by more engineered organocatalysts was carried on by using renewable and naturally occurring molecular scaffolds, or at least synthetic catalysts more respectful towards the principles of green chemistry? Within the frame of these questions, this Review will tackle the most commonly occurring organic chiral catalysts from the perspective of their synthesis rather than their employment in chemical methodologies or processes. A classification of the catalyst scaffolds based on their E factor will be provided, and the global E factor (E _G factor) will be proposed as a new green chemistry metric to consider, also, the synthetic route to the catalyst within a given organocatalytic process.

Phosphine-catalyzed tandem Michael addition/intramolecular Wittig reactions have been developed for the synthesis of chiral 2,5-dihydro-1 H -pyrrole and tetrahydropyridine derivatives. These processes have been rendered catalytic in phosphine, thanks to the in situ reduction of phosphine oxide by phenylsilane. Furthermore, catalytic and asymmetric P(III)/P(V) processes were implemented using enantiopure chiral phosphines.

Breeding methanol: Hydrogenation of CO₂ to methanol with a manganese-based catalytic system was studied using alcohols as co-reagents. Experimentally derived mechanistic insight led to the choice of suitable Lewis acid co-catalysts to unlock the limiting resting state by transferring the formate ligand into a formate ester. This allowed to develop the conditions where the product methanol acts as the co-reagent and solvent (ROH=MeOH). The resulting reaction system corresponds to a base-metal catalyzed liquid phase process for “breeding” methanol via CO₂ hydrogenation.

Abstract

The hydrogenation of CO₂ to methanol was achieved using a catalytic system comprising metal complexes of the form [Mn(CO)₂[N(C₂H₄PR₂)] (R= ⁱ Pr/Ph, [HN(C₂H₄PPh₂)₂]=MACHO−Ph) together with Lewis acid additives. Mechanistic studies suggest initial CO₂ insertion into a Mn−H bond leads to a formate complex as resting state. By systematically balancing the interaction between the acidic additive and the catalyst, the formate ligand could be removed through esterification to unleash the full catalytic potential. The reaction conditions were optimized on basis of the partial reaction order of relevant compounds. The combination of MACHO−Ph and Ti(O ⁱ Pr)₄ was identified as the most active system with a TON of 160 (p(CO₂)=5 bar, p(H₂)=160 bar, T=150 °C). Using methanol as solvent and co-reagent allows the catalytic conversion of CO₂/H₂ in a liquid phase process comprising only the substrates and products.

Publication date: 13 May 2021

Source: Chem, Volume 7, Issue 5

Author(s): Shou-Kun Zhang, Antonio Del Vecchio, Rositha Kuniyil, Antonis M. Messinis, Zhipeng Lin, Lutz Ackermann

Nature, Published online: 12 May 2021; doi:10.1038/s41586-021-03448-9

Nitrogen is ‘deleted’ from secondary amines using anomeric amide reagents, which react with the amine to form an isodiazene, after which nitrogen gas is released and the resulting carbon radicals combine to form a carbon–carbon bond.