LongLarf

Synlett
DOI: 10.1055/s-0040-1719867

Mechanochemical synthesis of 2,5-disubstituted 1,3,4-oxadiazoles was developed as an environmentally benign alternative to conventional solvent-based methods. In the presence of triphenylphosphine and trichloroisocyanuric acid, N-acylbenzotriazoles condense with acylhydrazides leading to oxadiazoles derivatives in good to excellent yields within minutes. The approach circumvents the need for strictly anhydrous conditions, external heating, long reaction times, as well as tedious multistep procedures. A range of substrates with reactive functionalities was also well tolerated.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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Synthesis
DOI: 10.1055/a-1701-6700

A practical and efficient protocol for the switchable synthesis of sulfoxides, sulfones, and thiosulfonates via Selectfluor-mediated oxidation of sulfides and thiols, respectively, at ambient temperature has been developed. All these organosulfur compounds can be prepared with nearly quantitative yields by applying eco-friendly H2O as O-source. The formation of sulfoxides and thiosulfonates takes only a few minutes (3–20 min). As suggested by the control experiments, the oxidation procedure might proceed through the fluorination of sulfide, nucleophilic addition with H2O, and elimination of hydrogen fluoride.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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Synthesis
DOI: 10.1055/a-1703-6448

The N–O heterocycles are biologically relevant scaffolds and versatile building blocks in contemporary organic synthesis. In this short review, we showcase the involvement and elevation of various cycloaddition strategies towards the production of the N–O heterocycles; 1,2-oxazines and 1,2-oxazinanes, 1,2-oxazepanes, and 1,2-oxazetidines. An overview of the advantages and challenges associated with these synthetic endeavors is provided.1 Introduction2 Six-Membered N–O Heterocycles (1,2-Oxazines and 1,2-Oxazinanes)3 Seven-Membered N–O Heterocycles (1,2-Oxazepanes)4 Four-Membered N–O Heterocycles (1,2-Oxazetidines)5 Summary and Outlook
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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Synthesis
DOI: 10.1055/a-1711-5889

Organoboron compounds continue contributing substantially to advances in organic chemistry with their increasing role as both synthetic intermediates and target compounds for medicinal chemistry. Particularly attractive methods for their synthesis are based on the direct borylation of C–H bonds of available starting materials since no additional pre-functionalization steps are required. However, due to the high abundance of C–H bonds with similar reactivity in organic molecules, synthetically useful C–H borylation protocols demand sophisticated strategies to achieve high regio- and stereoselectivity. For this purpose, selective transition-metal-based catalysts have been developed, with group 9 centered catalysts being among the most commonly utilized. Recently, a multitude of diverse strategies has been developed to push the boundaries of C–H borylation reactions with respect to their regio- and enantioselectivity. Herein, we provide an overview of approaches for the C–H borylation of arenes, alkenes, and alkanes based on group 9 centered catalysts with a focus on the recent literature. Lastly, an outlook is given to assess the future potential of the field.1 Introduction1.1 Mechanistic Considerations1.2 Selectivity Issues in C–H Borylation1.3 Different Modes of Action Employing Directing Group Strategies in C–H Borylation1.4 Scope and Aim of this Short Review2 Trends in C–H Borylation Reactions2.1 Photoinduced Catalysis2.2 Transfer C–H Borylation2.3 Lewis Acid Mediated C–H Borylation2.4 Directed Metalation2.5 Miscellaneous C–H Borylation Reactions2.6 Electrostatic Interactions2.7 Hydrogen Bonding3 Conclusion and Outlook
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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Bis-ethynylphosphonamidate building blocks were used for a chemoselective addition of two thiol-containing modules in a row to facilitate a simple protocol for the construction of protein-protein conjugates and homogeneous Antibody-Drug-Conjugates (ADCs). A third chemoselective modification step allows a highly modular assembly that yields homogeneous and precise Antibody-Drug-Fluorophore-Conjugates (ADFCs).

Abstract

Bis-ethynylphosphonamidates allow for a simple chemoselective addition of two thiol-containing modules in a row. We describe four such bis-electrophiles that carry different functional O-substituents with tunable hydrophilicity and enable further subsequent conjugations, thus facilitating a simple protocol for constructing protein-protein conjugates. An increased spacer length between the two ethynylphosphonamidates simplifies the formation of a conjugate from two bulky proteins. We apply these reagents to obtain homogeneous Antibody-Drug-Conjugates (ADCs) from DM1 and trastuzumab with excellent cytotoxicity and selectivity for the targeted cell line. Moreover, a bis-ethynylphosphonamidate, carrying an additional alkyne for a chemoselective triple conjugation, has been subjected to fluorescent labeling of an ADC specifically at the drug site give an Antibody-Drug-Fluorophore-Conjugate (ADFC), allowing for the observation of intracellular trafficking after ADC uptake into the targeted cell.

A way forward: The chemical industry is transitioning to a biorefinery network using biocatalysis, autotrophic and heterotrophic fermentation, electrobiocatalysis, and photobiocatalysis to retain carbon in a circular economy.

Abstract

In the movement to decarbonize our economy and move away from fossil fuels we will need to harness the waste products of our activities, such as waste lignocellulose, methane, and carbon dioxide. Our wastes need to be integrated into a circular economy where used products are recycled into a manufacturing carbon cycle. Key to this will be the recycling of plastics at the resin and monomer levels. Biotechnology is well suited to a future chemical industry that must adapt to widely distributed and diverse biological chemical feedstocks. Our increasing mastery of biotechnology is allowing us to develop enzymes and organisms that can synthesize a widening selection of desirable bulk chemicals, including plastics, at commercially viable productivities. Integration of bioreactors with electrochemical systems will permit new production opportunities with enhanced productivities and the advantage of using a low-carbon electricity from renewable and sustainable sources.

Nature Chemistry, Published online: 13 January 2022; doi:10.1038/s41557-021-00846-4

No noble metal needed: The cobalt-catalysed reductive etherification of aldehydes with alcohols under syngas conditions has been investigated and proved to be efficient for a broad range of coupling partners. The promoting effect of phosphine oxides allows for a milder and more general reaction: the methodology presented a good functional group tolerance and could be applied to natural alcohols.

Abstract

A phosphine-oxide-promoted, cobalt-catalysed reductive etherification using syngas as a reductant is reported. This novel methodology was successfully used to prepare a broad range of unsymmetrical ethers from various aldehydes and alcohols containing diverse functional groups, and was scaled-up to multigram scale under comparably mild conditions. Mechanistic experiments support an acetalization–hydrogenation sequence.

Oocydin-type complex polyketides feature a wide array of structural moieties, resembling the versatility of a Swiss army knife. These include a vinyl chloride, vicinal bis-oxygens, an O-acetylation, and other features. Here it is shown that a functionally greatly expanded polyketide synthase with numerous non-canonical features assembles these compounds entirely in a modular fashion.

Abstract

Bacterial multimodular polyketide synthases (PKSs) are large enzymatic assembly lines that synthesize many bioactive natural products of therapeutic relevance. While PKS catalysis is mostly based on fatty acid biosynthetic principles, polyketides can be further diversified by post-PKS enzymes. Here, we characterized a remarkably versatile trans-acyltransferase (trans-AT) PKS from Serratia that builds structurally complex macrolides via more than ten functionally distinct PKS modules. In the oocydin PKS, we identified a new oxygenation module that α-hydroxylates polyketide intermediates, a halogenating module catalyzing backbone γ-chlorination, and modular O-acetylation by a thioesterase-like domain. These results from a single biosynthetic assembly line highlight the expansive biochemical repertoire of trans-AT PKSs and provide diverse modular tools for engineered biosynthesis from a close relative of E. coli.

The development of substrate mimetics for an asparaginyl ligase, a highly efficient transpeptidase, including a C-terminal reversed sequence mimetic of the native N-terminal substrate is reported. This retro substrate mimetic can be introduced onto recombinant proteins and synthetic peptides, enabling enzyme-catalyzed protein or peptide C-to-C ligation.

Abstract

Transpeptidase-catalyzed protein and peptide modifications have been widely utilized for generating conjugates of interest for biological investigation or therapeutic applications. However, all known transpeptidases are constrained to ligating in the N-to-C orientation, limiting the scope of attainable products. Here, we report that an engineered asparaginyl ligase accepts diverse incoming nucleophile substrate mimetics, particularly when a means of selectively quenching the reactivity of byproducts released from the recognition sequence is employed. In addition to directly catalyzing formation of l-/d- or α-/β-amino acid junctions, we find C-terminal Leu-ethylenediamine (Leu-Eda) motifs to be bona fide mimetics of native N-terminal Gly-Leu sequences. Appending a C-terminal Leu-Eda to synthetic peptides or, via an intein-splicing approach, to recombinant proteins enables direct transpeptidase-catalyzed C-to-C ligations. This work significantly expands the synthetic scope of enzyme-catalyzed protein transpeptidation reactions.

Active site residues in terpene synthases each have a unique and precise function in guiding the reactive carbocation intermediates to the final product. Here we used a combined experimental and computational approach to unravel the role of several active site residues in bacterial monoterpene synthases. These residues are often not conserved even in closely related enzymes demonstrating the importance of a tailored active site for each terpene product.

Abstract

Monoterpene synthases are often promiscuous enzymes, yielding product mixtures rather than pure compounds due to the nature of the branched reaction mechanism involving reactive carbocations. Two previously identified bacterial monoterpene synthases, a linalool synthase (bLinS) and a cineole synthase (bCinS), produce nearly pure linalool and cineole from geranyl diphosphate, respectively. We used a combined experimental and computational approach to identify critical residues involved in bacterial monoterpenoid synthesis. Phe77 is essential for bCinS activity, guiding the linear carbocation intermediate towards the formation of the cyclic α-terpinyl intermediate; removal of the aromatic ring results in variants that produce acyclic products only. Computational chemistry confirmed the importance of Phe77 in carbocation stabilisation. Phe74, Phe78 and Phe179 are involved in maintaining the active site shape in bCinS without a specific role for the aromatic ring. Phe295 in bLinS, and the equivalent Ala301 in bCinS, are essential for linalool and cineole formation, respectively. Where Phe295 places steric constraints on the carbocation intermediates, Ala301 is essential for bCinS initial cyclisation and activity. Our multidisciplinary approach gives unique insights into how carefully placed amino acid residues in the active site can direct carbocations down specific paths, by placing steric constraints or offering stabilisation via cation-π interactions.