LongLarf

Synlett
DOI: 10.1055/s-0040-1719875

A new general process for constructing ortho-tert-butyl phenols is presented within the context of other known methods. All are briefly evaluated with regards to regioselectivity, efficiency, and functional group tolerance. In addition, we present an assortment of tert-butyl substrates accessed through o-QM chemistry. Our conclusion is that the o-QM process provides greater yields, flexibility, and generality than most other known methods for delivering ortho-tert-buytlated phenols and their derivatives.1 Introduction2 Friedel–Crafts Alkylation3 Addition of t-Bu– or t-Bu• to Carbonyl Compounds4 ipso-SNAr Reactions of Aryl Methoxy and tert-Butylsulfoxide Moieties5 Metal-Mediated Coupling of Aryl Bromides6 Applications of o-Quinone Methides (o-QMs)7 Conclusion
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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An overview of the recent strategies towards the total synthesis of heterocyclic natural products enabled by C−H functionalization is presented. The review is focused on transition-metal-catalyzed approaches, such as palladium catalysis, gold catalysis, iridium and ruthenium catalysis, and also presents transition-metal-free radical strategies as well as electrophilic-type metal-free C−H functionalization reactions and direct deprotonation approaches driven by the properties of heterocycles. The implementation of C−H functionalization of heterocycles enables novel tactics in the construction of core architectures, while changing the logic design of retrosynthetic strategies and permitting access to natural product scaffolds with novel and enhanced biological activities.

Abstract

Total synthesis is considered by many as the finest combination of art and science. During the last decades, several concepts were proposed for achieving the perfect vision of total synthesis, such as atom economy, step economy, or redox economy. In this context, C−H functionalization represents the most powerful platform that has emerged in the last years, empowering rapid synthesis of complex natural products and enabling diversification of bioactive scaffolds based on natural product architectures. In this review, we present an overview of the recent strategies towards the total synthesis of heterocyclic natural products enabled by C−H functionalization. Heterocycles represent the most common motifs in drug discovery and marketed drugs. The implementation of C−H functionalization of heterocycles enables novel tactics in the construction of core architectures, but also changes the logic design of retrosynthetic strategies and permits access to natural product scaffolds with novel and enhanced biological activities.

How sustainable is it really? Enzyme-based biocatalysis offers selective catalysis under mild conditions with a renewable, biodegradable, and tunable catalyst. A close dialogue between protein engineers and process engineers will be essential to ensure the sustainability of scalable biocatalytic processes, operating at high product concentrations (to reduce E-factor) and high enzyme stability (to reduce costs).

Abstract

Abstract: Biocatalysis offers many attractive features for the synthetic chemist. In many cases, the high selectivity and ability to tailor specific enzyme features via protein engineering already make it the catalyst of choice. From the perspective of sustainability, several features such as catalysis under mild conditions and use of a renewable and biodegradable catalyst also look attractive. Nevertheless, to be sustainable at a larger scale it will be essential to develop processes operating at far higher concentrations of product, and which make better use of the enzyme via improved stability. In this Concept, it is argued that a particular emphasis on these specific metrics is of particular importance for the future implementation of biocatalysis in industry, at a level that fulfills its true potential.

Synthesis
DOI: 10.1055/a-1709-3426

A convenient procedure for the chemoselective reduction of tertiary amides at room temperature in the presence of air and moisture using 1,3-diphenyldisiloxane (DPDS) is developed. The reaction conditions tolerate a significant number of functional groups including esters, nitriles, secondary amides, carbamates, sulfoxides, sulfones, sulfonyl fluorides, halogens, aryl-nitro groups, and arylamines. The conditions reported are the mildest to date and utilize EtOAc, a preferred solvent given its excellent safety profile and lower environmental impact. The ease of setup and broad chemoselectivity make this method attractive for organic synthesis, and the results further demonstrate the utility of DPDS as a selective reducing agent.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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Nature, Published online: 24 January 2022; doi:10.1038/d41586-022-00162-y

Nature Reviews Chemistry, Published online: 20 January 2022; doi:10.1038/s41570-021-00353-7

Synthesis
DOI: 10.1055/a-1701-7500

An enantioselective β-silylation of α,β-unsaturated phosphine oxide derivatives using a silylboronic ester as the silicon pronucleophile is reported. The reaction is catalyzed by copper salts in the presence of chiral pyridine–oxazoline (PyOx) ligands. Good to high enantioselectivities (≤95% ee) are obtained for β-aryl-substituted acceptors whereas alkyl residues in the β-position led to a lower ee value for 1° and no reaction for 2° and 3°. The new method represents another way of accessing α-chiral silanes and complements the known β-borylation.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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This paper focuses on key aspects of academic research culture that can impact STEM researcher mental health: bullying and harassment; precarity of contracts; diversity, inclusion, and accessibility; and the competitive research landscape, as well as exploring why mental health matters for researchers. Further, key recommendations are provided and actionable steps are outlined that institutions can take to make research in STEM inclusive for all.

Abstract

The onset of COVID-19, coupled with the finer lens placed on systemic racial disparities within our society, has resulted in increased discussions around mental health. Despite this, mental health struggles in research are still often viewed as individual weaknesses and not the result of a larger dysfunctional research culture. Mental health interventions in the science, technology, engineering, and mathematics (STEM) academic community often focus on what individuals can do to improve their mental health instead of focusing on improving the research environment. In this paper, we present four aspects of research that may heavily impact mental health based on our experiences as research scientists: bullying and harassment; precarity of contracts; diversity, inclusion, and accessibility; and the competitive research landscape. Based on these aspects, we propose systemic changes that institutions must adopt to ensure their research culture is supportive and allows everyone to thrive.

A new strategy for the synthesis of diverse heteroatom-functionalized imidazolium and imidazolinium salts in one step via cascade reactions of easily available 1,4-diaza-1,3-butadienes with trialkyl orthoformates and heteroatomic nucleophiles was developed. Feasibility of the new imidazol(in)ium salts for direct metallation to give M/NHC complexes (M=Pd, Ni, Cu, Ag, Au) was demonstrated.

Abstract

Imidazolium salts have ubiquitous applications in energy research, catalysis, materials and medicinal sciences. Here, we report a new strategy for the synthesis of diverse heteroatom-functionalized imidazolium and imidazolinium salts from easily available 1,4-diaza-1,3-butadienes in one step. The strategy relies on a discovered family of unprecedented nucleophilic addition/cyclization reactions with trialkyl orthoformates and heteroatomic nucleophiles. To probe general areas of application, synthesized N-heterocyclic carbene (NHC) precursors were feasible for direct metallation to give functionalized M/carbene complexes (M=Pd, Ni, Cu, Ag, Au), which were isolated in individual form. The utility of the chloromethyl function for the postmodification of the synthesized salts and Pd/carbene complexes was demonstrated. The obtained complexes and imidazolium salts demonstrated good activities in Pd- or Ni-catalyzed model cross-coupling and C−H activation reactions.

Abstract

The iridium catalyzed transfer vinylation of bio-based polyols and of other alcohols and phenols with interesting structural motifs was accomplished with vinyl acetate in 2-MeTHF as a green solvent. The optimized synthetic procedure has as main advantages the use of catalytic instead of stoichiometric amounts of base and high selectivities towards the formation of bis-vinyl ethers as a result of the suppression of the acetal formation reaction that typically occurs in the vinylation of diols. In addition, the thermodynamically preferred transesterification reaction leading to the acetate esters and bis-esters was completely suppressed. DFT calculations revealed an iridium-acetate complex as the active catalytic species and they disclosed the importance of the carbonyl group of vinyl acetate for the formation of a six-membered cyclic intermediate.

A palladium-catalyzed benzylic silylation reaction of diarylmethyl carbonates with silylboranes has been developed. By taking advantage of in-situ generated alkoxide ligand arising from the carbonate substrate, the reaction proceeds smoothly even under external base-free conditions. The resulting benzyl silane moiety can undergo the post functionalizations to deliver the more complex diarylmethane derivatives. Additionally, the related base-free allylic silylation reaction is also demonstrated.

Abstract

A palladium-catalyzed benzylic silylation of diarylmethyl carbonates with silylboranes has been developed. The reaction proceeds smoothly even under external base-free conditions, and the corresponding benzylic silanes are formed in good to high yields. The obtained benzyl silane derivatives can work as the benzylic nucleophiles by the action of a suitable fluoride source and react with some carbon electrophiles to deliver the corresponding benzylic C−C cross-coupled products. Additionally, while still preliminary, the allylic silylation of the isoelectronic allylic carbonates is also achieved.

Enantiocomplementary Michael additions: The application of two tailor-made enantiocomplementary carboligases allow for the stereodivergent synthesis of aliphatic γ-nitroaldehydes, which are useful precursors for pharmaceutically active analogues of the blockbuster drug, Pregabalin. Good isolated product yields and excellent enantiopurity (up to >99 : 1 e.r.) were achieved.

Abstract

The blockbuster drug Pregabalin is widely prescribed for the treatment of painful diabetic neuropathy. Given the continuous epidemic growth of diabetes, the development of sustainable synthesis routes for Pregabalin and structurally related pharmaceutically active γ-aminobutyric acid (GABA) derivatives is of high interest. Enantioenriched γ-nitroaldehydes are versatile synthons for the production of GABA derivatives, which can be prepared through a Michael-type addition of acetaldehyde to α,β-unsaturated nitroalkenes. Here we report that tailored variants of the promiscuous enzyme 4-oxalocrotonate tautomerase (4-OT) can accept diverse aliphatic α,β-unsaturated nitroalkenes as substrates for acetaldehyde addition. Highly enantioenriched aliphatic (R)- and (S)-γ-nitroaldehydes were obtained in good yields using two enantiocomplementary 4-OT variants. Our results underscore the synthetic potential of 4-OT for the preparation of structurally diverse synthons for bioactive analogues of Pregabalin.

A novel strategy, based on the regioselective S-cyanylation and hydrazinolysis at a C-terminal tetracysteine fusion tag, affording the expressed protein α-hydrazides is reported. It overcomes some of the major limitations of present expressed protein ligation techniques, and thus significantly complements the chemical protein synthesis toolbox.

Abstract

The hydrazinolysis of S-cyanylated peptide provides an alternative way to afford protein α-hydrazide, a key reagent used in native chemical ligation (NCL), without the aid of any inteins or enzymes. The currently used non-selective S-cyanylation, however, allows no other cysteine in the protein besides the one at the cleavage site. Herein, we report a regioselective S-cyanylation and hydrazinolysis strategy achieved via the fusion of a tetracysteine tag to the C-terminal of the protein of interest. We term it tetracysteine enabled protein ligation (TCEPL). While highly selective, the strategy is applicable for proteins expressed as inclusion bodies, and this was showcased by the efficient semi-synthesis of an iron-sulfur protein rubredoxin and the catalytic and hinge domains of matrix metalloprotease-14 (MMP-14) containing 207 amino acid residues. Furthermore, the TCEPL strategy was exploited for protein C-terminal labeling with amino reagents bearing a variety of functional groups, demonstrating its versatility and generality.

Nucleophilic catalysis is key to the acceleration of the native chemical ligation (NCL) reaction and thus, to its application for protein synthesis, functionalization and utilization in chemical biology. The present concept article discusses the fundamental principles of NCL rate and catalysis with emphasis on thiol nucleophiles.

Abstract

The native chemical ligation reaction of peptide thioesters with cysteinyl peptides is a pivotal chemical process in the production of native or modified peptides and proteins, and well beyond in the preparation of various biomolecule analogs and materials. To benefit from this reaction at its fullest and to access all the possible applications, the experimentalist needs to know the factors affecting its rate and how to control it. This concept article presents the fundamental principles underlying the rate of the native chemical ligation and its homogeneous catalysis by nucleophiles. It has been prepared to serve as a quick guide in the search for an appropriate catalyst.