LongLarf

Synlett
DOI: 10.1055/a-1787-1159

We recently discovered a functional group tolerant and transition-metal-free conjunctive olefination reaction with applications in late-stage functionalization chemistry. In this Synpacts contribution, we analyze the conceptual background that has stimulated the discovery of this reactivity and reflect on the key aspects of its development.1 Introduction2 Conceptual Background2.1 Photoredox-Mediated Giese Reaction2.2 Photoredox Radical-Polar Reactivity3 The Development of the Process4 Conclusion
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Organocatalytic dearomatization: With the growing interest in N-heterocyclic carbene (NHC) organocatalysis as a powerful strategy for synthesizing diverse molecules, mainly by polarity-reversal (umpolung) approaches, NHC-catalyzed dearomatization reactions have recently been successfully used for the construction of the skeletons of natural products and drugs. By generating various key intermediates (i. e., Breslow intermediates, acyl azolium intermediates, homoenolate intermediates, enolate intermediates, and azolium dienolate intermediates), NHCs can readily break up aromaticity by electrophilic or nucleophilic interactions with aromatic compounds.

Abstract

Dearomative reactions allow for concise assembly of structurally complex, highly functionalized three-dimensional molecules by breaking the plane of two-dimensional aromatic starting materials. With the growing interest in N-heterocyclic carbene (NHC) organocatalysis as a powerful strategy for synthesizing diversiform molecules, mainly by polarity-reversal (umpolung) approaches, NHC-catalyzed dearomatization reactions have recently been successfully used for the construction of the skeletons of natural products and drugs. By generating various key intermediates (i. e., Breslow intermediates, acyl azolium intermediates, homoenolate intermediates, enolate intermediates, and azolium dienolate intermediates), NHCs can readily destroy aromaticity by electrophilic or nucleophilic interactions with aromatic compounds. In this overview, progress in NHC-catalyzed dearomative reactions is summarized; the reactions are grouped according to reaction modes and categories of intermediates, and representative mechanisms are provided. This review aims to serve as a comprehensive reference for work in the emerging field of organocatalytic dearomatization.

An intramolecular hydroacylation of olefins with carboxylic acids (CAs) has been developed, which is based on visible-light photoredox/boronic acid catalysis. The direct use of CAs as acyl-radical precursors was made possible with the aid of boronic acid, and CAs were easily converted into the corresponding cyclic ketones without the need for any stoichiometric activating reagents.

Abstract

An intramolecular hydroacylation of olefins using carboxylic acids (CAs) has been developed. With the aid of a boronic acid, CAs can be used as acyl-radical precursors in catalytic photoredox reactions driven by visible light. The CAs are easily converted into their corresponding cyclic ketones without the need to use any stoichiometric activating reagents. Mechanistic studies implied that the formation of an “ate” complex from the CA and boronic acid is crucial for the generation of the acyl radical equivalent from the unreactive carboxy group.

Macrocyclic catalysts having a phenol-acetylene-phenol triad were developed. The rigid macrocyclic framework enabled the triads to form efficient hydrogen-bonds with carbonyl groups of substrates. The catalysts accelerated Diels-Alder reactions, and the catalytic abilities were higher than that of an acyclic counterpart.

Abstract

Macrocyclic catalysts having a phenol-acetylene-phenol triad were developed as a hydrogen-bond donor catalyst. The rigid macrocyclic framework suppressed intramolecular hydrogen bonds between neighboring phenolic hydroxy groups. The preorganized phenol-acetylene-phenol moiety formed efficient intermolecular hydrogen bonds with carbonyl groups of substrates. The hydrogen-bond donor catalysts accelerated the Diels-Alder reaction of methyl vinyl ketone with cyclopentadiene. The catalytic ability was higher than that of an acyclic counterpart.

Directed evolution of enzymes did not attract the attention of organic chemists until the control of stereoselectivity was successfully achieved 25 years ago. Traditionally, semi-rational directed evolution based on focused saturation mutagenesis at sites lining the binding pocket and rational enzyme design were considered to be two different approaches, especially when evolving stereoselectivity. However, because the former has become more and more rational, the two approaches have merged with the development of focused rational iterative site-specific mutagenesis (FRISM).

Abstract

This review outlines recent developments in protein engineering of stereo- and regioselective enzymes, which are of prime interest in organic and pharmaceutical chemistry as well as biotechnology. The widespread application of enzymes was hampered for decades due to limited enantio-, diastereo- and regioselectivity, which was the reason why most organic chemists were not interested in biocatalysis. This attitude began to change with the advent of semi-rational directed evolution methods based on focused saturation mutagenesis at sites lining the binding pocket. Screening constitutes the labor-intensive step (bottleneck), which is the reason why various research groups are continuing to develop techniques for the generation of small and smart mutant libraries. Rational enzyme design, traditionally an alternative to directed evolution, provides small collections of mutants which require minimal screening. This approach first focused on thermostabilization, and did not enter the field of stereoselectivity until later. Computational guides such as the Rosetta algorithms, HotSpot Wizard metric, and machine learning (ML) contribute significantly to decision making. The newest advancements show that semi-rational directed evolution such as CAST/ISM and rational enzyme design no longer develop on separate tracks, instead, they have started to merge. Indeed, researchers utilizing the two approaches have learned from each other. Today, the toolbox of organic chemists includes enzymes, primarily because the possibility of controlling stereoselectivity by protein engineering has ensured reliability when facing synthetic challenges. This review was also written with the hope that undergraduate and graduate education will include enzymes more so than in the past.

Hydrodefluorination (HDF) is a very important fundamental transformation for conversion of the C−F bond into the C−H bond in organic synthesis. In this Review, we mainly focus on the HDF of fluorinated organic compounds (FOCs) by photo- and electrochemical strategies, along with mechanistic insights.

Abstract

Hydrodefluorination (HDF) is a very important fundamental transformation for conversion of the C−F bond into the C−H bond in organic synthesis. In the past decade, much progress has been achieved with HDF through the utility of low-valent metals, transition-metal complexes and main-group Lewis acids. Recently, novel methods have been introduced for this purpose through photo- and electrochemical pathways, which are of great significance, due to their considerable environmental and economical advantages. This Review highlights the HDF of fluorinated organic compounds (FOCs) through photo- and electrochemical strategies, along with mechanistic insights.

The more fluorine the better? Pentafluorophosphato amino acids A and B are stable new molecular entities showing surprisingly high binding affinities to the phosphotyrosine binding site of a protein tyrosine phosphatase—better than the current gold standard for phosphotyrosine mimetics. PF₅ motifs display remarkable fluorine-specific interactions and thus might enable a new class of potent tools for medicinal chemistry and chemical biology.

Abstract

Phosphotyrosine residues are essential functional switches in health and disease. Thus, phosphotyrosine biomimetics are crucial for the development of chemical tools and drug molecules. We report here the discovery and investigation of pentafluorophosphato amino acids as novel phosphotyrosine biomimetics. A mild acidic pentafluorination protocol was developed and two PF₅-amino acids were prepared and employed in peptide synthesis. Their structures, reactivities, and fluorine-specific interactions were studied by NMR and IR spectroscopy, X-ray diffraction, and in bioactivity assays. The mono-anionic PF₅ motif displayed an amphiphilic character binding to hydrophobic surfaces, to water molecules, and to protein-binding sites, exploiting charge and H−F-bonding interactions. The novel motifs bind 25- to 30-fold stronger to the phosphotyrosine binding site of the protein tyrosine phosphatase PTP1B than the best current biomimetics, as rationalized by computational methods, including molecular dynamics simulations.

A highly enantioselective Michael addition reaction of alkyl selenols to enones is reported. The development of a chiral bifunctional N-heterocyclic carbene (NHC)/thiourea catalyst was key in obtaining the chiral β-seleno ketones with remarkable selectivity.

Abstract

The Michael reaction is a conjugate addition and is one of the most powerful methods with which to prepare functional molecules with a β-stereogenic center. Despite its success in the formation of various asymmetric carbon–carbon and carbon–heteroatom bonds, enantioselective seleno-Michael addition remains essentially unexplored. We report here a highly enantioselective Michael addition reaction of alkyl selenols to enones. This method conveniently introduces a Se atom to an electron-deficient double bond asymmetrically. A chiral bifunctional N-heterocyclic carbene (NHC)/thiourea catalyst was developed as a key ingredient that delivers chiral β-seleno ketones with remarkable selectivity. This new catalyst and its mode of action support broad applications in the catalytic activation of nucleophilic reactions.

Flavin-tag 2.0: The Flavin-tag method can be used for labelling of proteins with various chromo- and fluorophores and redox-active probes, including flavin (yellow), roseoflavin (red), 5-deazaflavin (fluorescent), and nicotinamide.

Abstract

Methods for facile site-selective modifications of proteins are in high demand. We have recently shown that a flavin transferase can be used for site-specific covalent attachment of a chromo- and fluorogenic flavin (FMN) to any targeted protein. Although this Flavin-tag method resulted in efficient labeling of proteins in vitro, labelling in E. coli cells resulted in partial flavin incorporation. It was also restricted in the type of installed label with only one type of flavin, FMN, being incorporated. Here, we report on an extension of the Flavin-tag method that addresses previous limitations. We demonstrate that co-expression of FAD synthetase improves the flavin incorporation efficiency, allowing complete flavin-labeling of a target protein in E. coli cells. Furthermore, we have found that various flavin derivatives and even a nicotinamide can be covalently attached to a target protein, rendering this method even more versatile and valuable.

Nature, Published online: 05 April 2022; doi:10.1038/s41586-022-04691-4

Electron-rich aryl acetates derived from (renewable) phenolics were selectively reduced to the corresponding arenes using pinacolborane (HBpin) and a nickel-N-heterocyclic carbene (NHC) catalytic system in the green solvent dimethylcarbonate (DMC). The method is applicable to 4-propylguaiacyl acetate derived from pine wood.

Abstract

Acetate serves as a renewable and easily installed leaving group for selective deoxygenation of phenolics (ArOH). Ni-catalyzed hydrodeacetoxylation of aryl acetates (Ar−OAc) with HBpin in a green carbonate solvent selectively delivers the corresponding deoxygenated arenes (ArH). The method is also applicable to highly challenging guaiacyl and syringyl acetates, leaving −OMe groups intact without arene reduction. Renewable 4-propylguaiacol obtained from pine can also be transformed without significant loss in yield versus oil derived feedstock. The observed chemoselectivity for Ar−OAc versus ArO−Ac bond cleavage was rationalized based on mechanistic experiments and DFT calculations. ArOH side-product formation is attributed to direct competitive Ni-catalyzed reduction of the C=O bond. Hydrodeacyloxylation of a set of aryl alkanoates featured interesting chemoselectivity with a dramatic influence of the length and structure of the alkyl chain on catalysis.