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An efficient and novel Ag^I-catalyzed methodology for the synthesis of multisubstituted 4-silyloxypyrrole-3-carboxylates with broad variability for the placement of substituents at the 2, 5-, and N-positions is presented. Convenient conversion of imino ethers to fully substituted pyrroles with uniformly high chemo- and regioselectivity was achieved. Mechanistic studies confirm a [3+2]-cycloaddition/C−O bond cleavage/ [1,5]-proton transfer cascade process.

Abstract

An unprecedented Ag^I-catalyzed efficient method for the coupling of imino ethers and enol diazoacetates through a [3+2]-cycloaddition/C−O bond cleavage/[1,5]-proton transfer cascade process is reported. The general class of imino ethers that includes oxazolines, benzoxazoles and benzimidates are applicable substrates for these reactions that provide direct access to fully substituted pyrroles with uniformly high chemo- and regioselectivity. High variability in substitution at the pyrrole 2-, 5- and N-positions characterizes this methodology that also presents an entry point for further pyrrole diversification via facile modification of resulting N-functional pyrroles.

A copper and pyrrolidine dual catalyst system enables the α‐alkylation of ketones to synthesize 1,4‐dicarbonyl compounds. The key intermediates are catalytically generated α‐tertiary alkyl radical species and enamines.

Abstract

Herein, we report an efficient method for the tertiary alkylation of a ketone by using an α‐bromocarbonyl compound as the tertiary alkyl source in a combined Cu‐organocatalyst system. This dual catalyst system enables the addition of a tertiary alkyl radical to an enamine. Mechanistic studies revealed that the catalytically generated enamine is a key intermediate in the catalytic cycle. The developed method can be used to synthesize substituted 1,4‐dicarbonyl compounds containing quaternary carbons bearing various alkyl chains.

Abstract

A transition-metal-free approach to synthesize unsymmetrical disulfides is reported that relies on a K₂CO₃-promoted one-pot reaction of thiosulfonates, thiourea and alkyl halides under mild conditions. The protocol tolerates a wide range of substrates, leading to various types of unsymmetrical disulfides in moderate to excellent yields. More importantly, the late-stage modification of natural products and drug molecules was also achieved.

Abstract

A palladium-catalysed tandem cyclisation reaction of amidoximes, isocyanides and amines to produce 5-aminoimidazoles was developed. Various 5-aminoimidazoles were prepared in good to excellent yields under mild conditions. This elegant domino process involves the effective cleavage of the N−O bond and the formation of new C−C and C−N bonds in a single operation.

A fast, easy‐to‐perform, mild and high‐yielding chemoselective amide‐forming ligation of acylsilanes with O‐diethylcarbamoyl‐derived hydroxylamines under aqueous conditions is reported. The reaction is mediated by citric acid and tolerates a wide range of reactive functional groups as demonstrated by the late‐stage modifications of a panel of drugs, peptides, natural products and biologically active molecules.

Abstract

We report the facile amide‐forming ligation of acylsilanes with hydroxylamines (ASHA ligation) under aqueous conditions. The ligation is fast, chemoselective, mild, high‐yielding and displays excellent functional‐group tolerance. Late‐stage modifications of an array of marketed drugs, peptides, natural products, and biologically active compounds showcase the robustness and functional‐group tolerance of the reaction. The key to the success of the reaction could be the possible formation of the strong Si−O bond via a Brook‐type rearrangement. Given its simplicity and efficiency, this ligation has the potential to unfold new applications in the areas of medicinal chemistry and chemical biology.

In this Review, we describe the most relevant advances towards translating the potential of transition metal catalysts to biological settings, including living cells or small‐animal models such as mice or zebrafish. We pay especial attention to the molecular and mechanistic aspects of the transformations.

Abstract

During the last decade, there has been a tremendous interest for developing non‐natural biocompatible transformations in biologically relevant media. Among the different encountered strategies, the use of transition metal complexes offers unique possibilities due to their high transformative power. However, translating the potential of metal catalysts to biological settings, including living cells or small‐animal models such as mice or zebrafish, poses numerous challenges associated to their biocompatibility, and their stability and reactivity in crowded aqueous environments. Herein, we describe the most relevant advances in this direction, with a particular emphasis on the systems’ structure, their mode of action and the mechanistic bases of each transformation. Thus, the key challenges from an organometallic perspective might be more easily identified.

The asymmetric synthesis of N‐substituted α‐amino esters has been achieved, in high yields and excellent enantioselectivities, employing sequence diverse metagenomic imine reductases (IREDs).

Abstract

N‐Substituted α‐amino esters are widely used as chiral intermediates in a range of pharmaceuticals. Here we report the enantioselective biocatalyic synthesis of N‐substituted α‐amino esters through the direct reductive coupling of α‐ketoesters and amines employing sequence diverse metagenomic imine reductases (IREDs). Both enantiomers of N‐substituted α‐amino esters were obtained with high conversion and excellent enantioselectivity under mild reaction conditions. In addition >20 different preparative scale transformations were performed highlighting the scalability of this system.

High value‐added conversion: From gas to nylon precursor. This 100 % atom economic and industrially relevant process is strongly influenced by the system polarity.

Abstract

The dicarbonylation of 1,3‐butadiene to adipic acid derivatives offers the potential for a more cost‐efficient and environmentally benign industrial process. However, the complex reaction network of regioisomeric carbonylation and isomerization pathways, make a selective and direct transformation particularly difficult. Here, we report surprising solvent effects on this palladium‐catalysed process in the presence of 1,2‐bis‐di‐tert‐butylphosphin‐oxylene (dtbpx) ligands, which allow adipate diester formation from 1,3‐butadiene, carbon monoxide, and methanol with 97 % selectivity and 100 % atom‐economy under scalable conditions. Under optimal conditions a variety of di‐ and triesters from 1,2‐ and 1,3‐dienes can be obtained in good to excellent yields.

Within the last decade, several of the most significant breakthroughs in the homogeneous electrochemical or photochemical reduction and hydrogenation of carbon dioxide have been driven by the introduction of amines or amine‐derived moieties in the reaction mixture. These amines play multiple roles, which are discussed herein to provide guidelines for the design of new catalysts with enhanced activity and selectivity.

Abstract

The selective and efficient reduction of carbon dioxide represents a key solution to producing non‐fossil‐fuel‐based feedstocks for the chemical industry, while alleviating the increasing atmospheric concentration of this greenhouse gas. A variety of catalytic methods for the CO₂ reduction reaction (CO₂RR) have been developed, including hydrogenations and electrochemical or photochemical reductions. For many of the most significant breakthroughs reported in the last decade, we realized that amines or closely related functional groups play a critical role for such transformations, and in several cases, are directly associated with the catalyst as a pendant group. Amines play multiple roles, such as CO₂ trapping agents, proton shuttles, electron donors, or facilitators of CO₂ reductions through formamide derivatives. In this Viewpoint, we compile some of these recent findings, and discuss their significance in a broader context in an attempt to provide guidelines for the design of new catalysts with enhanced activity and selectivity.

Late-stage modification is an indispensable approach for compound diversification in synthesis. Since enzymes offer particularly powerful means for mild, catalyst-controlled functionalisations, in recent years several novel biocatalytic methods have emerged enabling a broad array of orthogonal reactions. Herein, the wide range of late-stage biotransformations is reviewed and various enzyme classes along with topical examples are discussed.

Abstract

Enzyme catalysis is gaining increasing importance in synthetic chemistry. Nowadays, the growing number of biocatalysts accessible by means of bioinformatics and enzyme engineering opens up an immense variety of selective reactions. Biocatalysis especially provides excellent opportunities for late-stage modification often superior to conventional de novo synthesis. Enzymes have proven to be useful for direct introduction of functional groups into complex scaffolds, as well as for rapid diversification of compound libraries. Particularly important and highly topical are enzyme-catalysed oxyfunctionalisations, halogenations, methylations, reductions, and amide bond formations due to the high prevalence of these motifs in pharmaceuticals. This Review gives an overview of the strengths and limitations of enzymatic late-stage modifications using native and engineered enzymes in synthesis while focusing on important examples in drug development.

Hydrogen borrowing: An efficient NiAl hydrotalcite‐derived nickel catalyst has been developed for the direct amination of biomass‐based furfuryl alcohol and 5‐(aminomethyl)‐2‐furanmethanol with NH₃ via the “hydrogen borrowing” strategy. The synergistic catalysis of Ni⁰ and Al^δ+‐Al‐O^δ− site was of vital importance for the amination of alcohols into corresponding primary amines.

Abstract

A series of hydrotalcite‐derived nickel catalysts were synthesized and employed for the direct amination of biomass‐based furfuryl alcohol with NH₃ via the hydrogen borrowing strategy. The effects of the Ni/Al molar ratio and calcination temperature of the NiAl hydrotalcite‐like precursors on the performance of the Ni_xAl‐CT catalyst were investigated. The systematic characterization showed that the synergistic catalysis of the metal and acid‐base sites was of vital importance for the amination of alcohols. In particular, the Ni₂Al‐600 catalyst with high amount of Ni⁰ sites (1.26 mmol g⁻¹) and suitable density of acid‐base sites (0.71 mmol g⁻¹ and 1.10 mmol g⁻¹, respectively) exhibited the best dehydrogenation capability and therefore excellent catalytic activity. An 84.1 % yield of furfurylamine with complete conversion of furfuryl alcohol was obtained under the reaction conditions of 180 °C and 0.4 MPa NH₃ in 36 h. The presence of Ni₃N in the spent catalyst, confirmed by XRD, TEM and XPS characterizations, was demonstrated to be responsible for the deactivation of the Ni_xAl‐CT catalyst. In addition, the Ni₂Al‐600 catalyst exhibited satisfactory performance toward another important biomass‐related transformation of 5‐(aminomethyl)‐2‐furanmethanol to 2,5‐bis(aminomethyl)furan, with a yield of 70.5 %.

Cu(OTf)₂ promotes the oxidative arylation of nitriles and N‐heterocycles to generate ionic products. Mechanistic studies suggest the process operates via reductive elimination from a Cu^III complex bearing neutral N‐ligands to generate nitrilium and pyridinium products. The reaction is general for a range of N(sp) and N(sp²) precursors and can be applied to drug synthesis and late‐stage N‐arylation.

Abstract

Metal‐catalyzed C–N cross‐coupling generally forms C−N bonds by reductive elimination from metal complexes bearing covalent C‐ and N‐ligands. We have identified a Cu‐mediated C–N cross‐coupling that uses a dative N‐ligand in the bond‐forming event, which, in contrast to conventional methods, generates reactive cationic products. Mechanistic studies suggest the process operates via transmetalation of an aryl organoboron to a Cu^II complex bearing neutral N‐ligands, such as nitriles or N‐heterocycles. Subsequent generation of a putative Cu^III complex enables the oxidative C–N coupling to take place, delivering nitrilium intermediates and pyridinium products. The reaction is general for a range of N(sp) and N(sp²) precursors and can be applied to drug synthesis and late‐stage N‐arylation, and the limitations in the methodology are mechanistically evidenced.