LongLarf

Synthesis
DOI: 10.1055/a-1914-1231

This review summarizes the more recent methods (since 2015) for the synthesis of thioethers using homogeneous metals as catalysts. The thioether moiety can be found in numerous compounds for pharmaceutical, agricultural, or material applications and it is therefore important to develop new, efficient methods for their synthesis. The recent efforts in this field focus on the use of non-precious metal catalysts, as well as on the development of new bond-forming processes.1 Introduction2 Cross-Couplings3 C–H Activation4 Hydrothiolation5 Carbothiolation6 Miscellaneous7 Conclusion
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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An organocatalytic cross-coupling of allyl bromides and arylboronic acids was developed using a designer thioether catalyst. Preliminary mechanistic studies suggested the involvement of a key sulfoxonium ylide that binds to the arylboronic acid and triggers 1,2-aryl migration.

Abstract

C(sp³)−C(sp²) cross-coupling reactions are an indispensable tool for organic synthesis. In these reactions transition metals have been extensively employed to promote the formation of valuable carbon-carbon bonds. Herein, we report our recent discovery of a designer thioether as a highly active organocatalyst for reactions between an allyl bromide and an arylboronic acid. The cross-coupling event occurred readily under mild condition in the presence of a weak inorganic base. Preliminary mechanistic studies suggested a sulfonium ylide mechanism.

A mild, chemoselective method for the reduction of carboxylic acids, in the presence of both more nucleophilic and more electrophilic functional groups is reported. Experiments and DFT calculations point to a mechanism driven by hidden borane catalysis.

Abstract

Although considerable advances have been made in developing chemoselective transformations of ubiquitous carboxylic acid groups, many challenges still exist. For instance, their selective reduction is problematic if both more nucleophilic and more electrophilic groups are present in the starting material. Here, we address this problem with a simple and mild protocol using bench-stable reagents at ambient temperatures. This platform is able to tolerate a diverse range of functionality, leaving ketones, esters, nitro-groups, olefins, nitriles and amides untouched. A combination of experimental and computational mechanistic experiments demonstrate that this reaction proceeds via hidden borane catalysis with small quantities of in situ generated BH₃ playing a key role in the exquisite selectivity that is observed.

A BO₃ ³⁻ anion from borate buffer provides a structural bridge between low-cost Cu complexes to form a new in situ trinuclear complex as a fast electrocatalyst for homogeneous water oxidation; likewise, the borate species from the buffer solution at pH 9 facilitate the high turnover frequency (TOF) by playing a significant role in the O-O bond formation step.

Abstract

Borate buffer was found to have both structural and functional roles within a low-cost tri-copper electrocatalyst for homogeneous water oxidation that exhibits a high turnover frequency of 310 s⁻¹. The borate buffer was shown to facilitate the catalytic activity by both bridging the three Cu ions and participating in O−O bond formation. Phosphate and acetate buffers did not show such roles, making borate a unique player in this catalytic system.

Synergistic catalysis offers the unique possibility of simultaneous activation of both the nucleophile and the electrophile in a reaction. This review discusses developments in aminocatalysis and its synergistic combination with other synthetic platforms published since 2015. Through the four sections, a critical overview of the most common systems involving amino-organo, amino-metal, amino-photoredox and amino-electrocatalysis is provided, with particular emphasis on HOMO-raising and LUMO-lowering strategies and asymmetric transformations. For more details, see the Review by F. Pesciaioli and co-workers (DOI: 10.1002/chem.202200818)

Acetate and butyrate esters of aromatic Morita-Baylis-Hillman adducts have been resolved by enzymatic hydrolysis using a range of lipases: P. fluorescens lipase, P. cepacea lipase (PCL), CAL−A, CAL−B and Novozyme 435. The best enantiomeric ratio was observed for the butyrate derivative of the p-cyanophenyl MBH adduct. Transesterification of aromatic MBH adducts in organic solvent in the presence of an acyl donor has been demonstrated for the first time.

Abstract

Acylated Morita-Baylis-Hillman (MBH) adducts were synthesised and subjected to enzymatic kinetic resolution (EKR) by hydrolysis employing various lipase enzymes: from P. fluorescens, P. cepacia (PCL), C. antarctica A (CAL−A), C. antarctica B (CAL−B) and Novozyme 435. In a number of instances enantiopure Morita-Baylis-Hillman acetates or butyrates and their corresponding hydrolysed MBH adducts were obtained with ee values of >90 %, at ca. 50 % conversion, corresponding to enantiomeric ratio (E) values of >200. Enantioselective transesterification reactions on MBH adducts was achieved using acyl anhydrides in THF or the greener organic solvent 2-MeTHF in the presence of CAL−A. This is the first report of successful lipase-catalysed EKR of aromatic MBH adducts by transesterification in organic medium.

Liposomes containing bis-boronic acid lipids (BBALs) to advance cellular delivery through the binding of cell-surface carbohydrates are reported. Multiple BBAL structures containing variable linker units were designed, synthesized, and shown to exhibit differential carbohydrate binding properties using a competitive glycan displacement assay. Fluorescence microscopy experiments showed enhanced cellular delivery using this carbohydrate-targeting liposomal platform.

Abstract

Liposomes are effective therapeutic nanocarriers due to their ability to encapsulate and enhance the pharmacokinetic properties of a wide range of drugs and diagnostic agents. A primary area in which improvement is needed for liposomal drug delivery is to maximize the delivery of these nanocarriers to cells. Cell membrane glycans provide exciting targets for liposomal delivery since they are often densely clustered on cell membranes and glycan overabundance and aberrant glycosylation patterns are a common feature of diseased cells. Herein, we report a liposome platform incorporating bis-boronic acid lipids (BBALs) to increase valency in order to achieve selective saccharide sensing and enhance cell surface recognition based on carbohydrate binding interactions. In order to vary properties, multiple BBALs (1 a–d) with variable linkers in between the binding units were designed and synthesized. Fluorescence-based microplate screening of carbohydrate binding showed that these compounds exhibit varying binding properties depending on their structures. Additionally, fluorescence microscopy experiments indicated enhancements in cellular association when BBALs were incorporated within liposomes. These results demonstrate that multivalent BBALs serve as an exciting glycan binding liposome system for targeted delivery.

The combination of enzymes in multistep reaction cascades offers new opportunities for drug synthesis and is often shorter than their chemical synthesis routes, thus supporting the development of more sustainable and environmentally friendly processes. Recently, several cascades with evolved enzymes have been developed that have led to efficient synthetic pathways for highly complex molecules, thus pushing biocatalysis to a new level.

Abstract

Thanks to advances in enzyme discovery and protein engineering combined with the development of enzymatic multistep reaction cascades, new efficient routes for drug synthesis have been created that are superior to chemical syntheses. This supports the goal of the chemical and pharmaceutical industries to move to more sustainable and environmentally friendly processes. Recently described outstanding examples include the biocatalytic cascade syntheses of the cyclic dinucleotide MK-1454, molnupiravir, and islatravir, as well as the efficient fixation of CO₂ to make starch using an artificial enzyme cascade.

Bicyclic peptides are increasingly popular in drug discovery; however, only few strategies for their synthesis exist. Dicyanopyridine-featured amino acids provide a biocompatible, selective, and catalyst-free pathway to access bicyclic peptides, which are characterized by superior preorganization and high target affinity.

Abstract

Bicyclic peptides possess superior properties for drug discovery; however, their chemical synthesis is not straightforward and often neither biocompatible nor fully orthogonal to all canonical amino acids. The selective reaction between 1,2-aminothiols and 2,6-dicyanopyridine allows direct access to complex bicyclic peptides in high yield. The process can be fully automated using standard solid-phase peptide synthesis. Bicyclization occurs in water at physiological pH within minutes and without the need for a catalyst. The use of various linkers allows tailored bicyclic peptides with qualities such as plasma stability, conformational preorganization, and high target affinity. We demonstrate this for a bicyclic inhibitor of the Zika virus protease NS2B-NS3 as well as for bicyclic versions of the α-helical antimicrobial peptide aurein 1.2.

Nature Communications, Published online: 27 August 2022; doi:10.1038/s41467-022-32726-x

Azahetereocycles represent promising scaffolds in drug discovery. Here, the authors report a Pd-catalyzed migratory cycloannulation strategy for efficient construction of a wide range of azahetereocycles from unactivated aliphatic alkenes.

Incredibly strong C−X bonds such as those in aryl fluorides are catalytically cleaved using an anionic Rh−Ga photoredox catalyst. Excitation of the bimetallic complex with violet light generates a potent photoreductant that is capable of single-electron transfer to even electron-rich aryl fluorides that ultimately results in substrate hydrodefluorination.

Abstract

An anionic Rh−Ga complex catalyzed the hydrodefluorination of challenging C−F bonds in electron-rich aryl fluorides and trifluoromethylarenes when irradiated with violet light in the presence of H₂, a stoichiometric alkoxide base, and a crown-ether additive. Based on theoretical calculations, the lowest unoccupied molecular orbital (LUMO), which is delocalized across both the Rh and Ga atoms, becomes singly occupied upon excitation, thereby poising the Rh−Ga complex for photoinduced single-electron transfer (SET). Stoichiometric and control reactions support that the C−F activation is mediated by the excited anionic Rh−Ga complex. After SET, the proposed neutral Rh⁰ intermediate was detected by EPR spectroscopy, which matched the spectrum of an independently synthesized sample. Deuterium-labeling studies corroborate the generation of aryl radicals during catalysis and their subsequent hydrogen-atom abstraction from the THF solvent to generate the hydrodefluorinated arene products. Altogether, the combined experimental and theoretical data support an unconventional bimetallic excitation that achieves the activation of strong C−F bonds and uses H₂ and base as the terminal reductant.

By the action of a strong Lewis acid, isomerization of the tricyanomethane to the ketenimine, HN=C=C(CN)₂, is triggered, which in turn directly attacks an aromatic species in an electrophilic aromatic substitution.

Abstract

Electrophilic aromatic substitution (EAS) can provide a straightforward approach to the efficient synthesis of functionalized complex aromatic molecules. In general, Lewis acids serve as a beneficial stimulus for the formation of a Wheland complex, the intermediate in the classical S_EAr mechanism of EAS, which is responsible for H/E (E=electrophile) substitution under formal H⁺ elimination. Herein, we report an unusual variant of EAS, in which a complex molecule such as the tricyanomethane, HC(CN)₃, is activated with a strong Lewis acid (B(C₆F₅)₃) to the point where it can finally be used in an EAS. However, the Lewis acid here causes the isomerization of the tricyanomethane to the ketenimine, HN=C=C(CN)₂, which in turn directly attacks the aromatic species in the EAS, with simultaneous proton migration of the aromatic proton to the imino group, so that no elimination occurs that is otherwise observed in the S_EAr mechanism. By this method, it is possible to build up amino-malononitrile-substituted aromatic compounds in one step.

Nature, Published online: 23 August 2022; doi:10.1038/s41586-022-05211-0

Photoexcited Nitroarenes for the Oxidative Cleavage of Alkenes

Synlett
DOI: 10.1055/a-1908-2066

The difference of reaction design principles between traditional, small-molecule synthetic chemistry and biomolecular chemical reactions prevented the simple translation of small-molecule chemistry into biomolecular reactions. One of the key challenges of bioconjugation, or reactions on biomolecules, are the necessity of aqueous solutions as the solvent. In this Synpacts article, we describe our pursuit of using an ionic liquid as a nonaqueous reaction medium to conduct phosphine- and azide-based bioconjugation reactions.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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Nature Communications, Published online: 23 August 2022; doi:10.1038/s41467-022-32710-5

De novo development of a simplified photosynthetic reaction center protein can clarify practical engineering principles needed to build enzymes for efficient energy conversion. Here, the authors develop an artificial photosynthetic reaction center that functions without the need for sacrificial electron donors or acceptors.

Synlett
DOI: 10.1055/a-1904-0152

Carbon–carbon and carbon–heteroatom bond-formation reactions catalyzed by benign and inexpensive metals are of much interest in organic synthesis, as these reactions provide green and cost-effective routes. This account summarizes our recent contributions to the construction of carbon–carbon and carbon–heteroatom bonds by using benign-metal catalysts. A number of carbon–heteroatom bond formations, including C–N, C–O, C–S, C–Se, C–Te, and C–P bond formations, are discussed. Mechanistic insights into several reactions are also reported1 Introduction2 C–C Bond Formation3 C–N and C–O Bond Formation4 Carbon–Chalcogen (C–S, C–Se, C–Te) and C–P Bond Formation5 Conclusions
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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Synthesis
DOI: 10.1055/a-1898-9752

The first electricity-promoted, catalyst-free cascade thia-Michael addition and thioacetalization of cyclic enones with thiols are described. The electro-organic protocol was found to be suitable for both alkyl and aryl thiols, which reacted with a variety of cyclic enones to afford the corresponding tris-sulfane in good to excellent yields. Based on control experiments, it was found that this cascade reaction is chemoselective, involving first thia-Michael addition followed by thioacetalization process.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text