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Chemistry (Weinheim An Der Bergstrasse,... Aug 2022Heteroaryl boronic acids and esters are extremely important and valuable intermediates because of their wide application in the synthesis of marketed drugs and bioactive... (Review)
Review
Heteroaryl boronic acids and esters are extremely important and valuable intermediates because of their wide application in the synthesis of marketed drugs and bioactive compounds. Over the last couple of decades, the construction of highly important heteroaryl carbon-boron bonds has created huge attention. The transition-metal-free protocols are more green, less sensitive to air and moisture, and also economically advantageous over the transition-metal-based protocols. The transition-metal-free C-H borylation of heteroarenes and C-X (X=halogen) borylation of heteroaryl halides represents an excellent approach for their synthesis. Also, various cyclization and alkyne activation protocols have been recently established for their synthesis. The goal of this review article is to summarize the existing literature and the current state of the art for transition-metal-free synthesis of heteroaryl boronic acid and esters.
Topics: Alkynes; Boron; Boronic Acids; Carbon; Catalysis; Esters; Transition Elements
PubMed: 35438817
DOI: 10.1002/chem.202200556 -
Annual Review of Chemical and... Jun 2022Natural products are a diverse class of biologically produced compounds that participate in fundamental biological processes such as cell signaling, nutrient... (Review)
Review
Natural products are a diverse class of biologically produced compounds that participate in fundamental biological processes such as cell signaling, nutrient acquisition, and interference competition. Unique triple-bond functionalities like isonitriles and alkynes often drive bioactivity and may serve as indicators of novel chemical logic and enzymatic machinery. Yet, the biosynthetic underpinnings of these groups remain only partially understood, constraining the opportunity to rationally engineer biomolecules with these functionalities for applications in pharmaceuticals, bioorthogonal chemistry, and other value-added chemical processes. Here, we focus our review on characterized biosynthetic pathways for isonitrile and alkyne functionalities, their bioorthogonal transformations, and prospects for engineering their biosynthetic machinery for biotechnological applications.
Topics: Alkynes; Biological Products; Biosynthetic Pathways
PubMed: 35236086
DOI: 10.1146/annurev-chembioeng-092120-025140 -
Bioconjugate Chemistry Nov 2023The term "click chemistry" describes a class of organic transformations that were developed to make chemical synthesis simpler and easier, in essence allowing chemists... (Review)
Review
The term "click chemistry" describes a class of organic transformations that were developed to make chemical synthesis simpler and easier, in essence allowing chemists to combine molecular subunits as if they were puzzle pieces. Over the last 25 years, the click chemistry toolbox has swelled from the canonical copper-catalyzed azide-alkyne cycloaddition to encompass an array of ligations, including bioorthogonal variants, such as the strain-promoted azide-alkyne cycloaddition and the inverse electron-demand Diels-Alder reaction. Without question, the rise of click chemistry has impacted all areas of chemical and biological science. Yet the unique traits of radiopharmaceutical chemistry have made it particularly fertile ground for this technology. In this update, we seek to provide a comprehensive guide to recent developments at the intersection of click chemistry and radiopharmaceutical chemistry and to illuminate several exciting trends in the field, including the use of emergent click transformations in radiosynthesis, the clinical translation of novel probes synthesized using click chemistry, and the advent of click-based pretargeting.
Topics: Click Chemistry; Radiochemistry; Azides; Radiopharmaceuticals; Cycloaddition Reaction; Alkynes
PubMed: 37737084
DOI: 10.1021/acs.bioconjchem.3c00286 -
Angewandte Chemie (International Ed. in... Jul 2021A bioorthogonal reaction between N,N-dialkylhydroxylamines and push-pull-activated halogenated alkynes is described. We explore the use of rehybridization effects in...
A bioorthogonal reaction between N,N-dialkylhydroxylamines and push-pull-activated halogenated alkynes is described. We explore the use of rehybridization effects in activating alkynes, and we show that electronic effects, when competing stereoelectronic and inductive factors are properly balanced, sufficiently activate a linear alkyne in the uncatalyzed conjugative retro-Cope elimination reaction while adequately protecting it against cellular nucleophiles. This design preserves the low steric profile of an alkyne and pairs it with a comparably unobtrusive hydroxylamine. The kinetics are on par with those of the fastest strain-promoted azide-alkyne cycloaddition reactions, the products regioselectively formed, the components sufficiently stable and easily installed, and the reaction suitable for cellular labeling.
Topics: Alkynes; Amination; Azides; Cycloaddition Reaction; Molecular Structure
PubMed: 34019705
DOI: 10.1002/anie.202104863 -
Nature Communications Jun 2023The alkyne unit is a versatile building block in organic synthesis and the development of selective multifunctionalization of alkynes is an important object of research...
The alkyne unit is a versatile building block in organic synthesis and the development of selective multifunctionalization of alkynes is an important object of research in this field. Herein, we report an interesting gold-catalyzed, four-component reaction that achieves the oxo-arylfluorination or oxo-arylalkenylation of internal aromatic or aliphatic alkynes, efficiently breaking a carbon-carbon triple bond and forming four new chemical bonds. The reaction divergence can be controlled by site-directing functional groups in the alkynes; the presence of a phosphonate unit favors the oxo-arylfluorination, while the carboxylate motif benefits oxo-arylalkenylation. This reaction is enabled by an Au(I)/Au(III) redox coupling process using Selectfluor as both an oxidant and a fluorinating reagent. A wide range of structurally diverse α,α-disubstituted ketones, and tri- or tetra-substituted unsaturated ketones have been prepared in synthetically valuable yields and with excellent chemo-, regio- and stereoselectivity. The gram-scale preparation and late-stage application of complex alkynes have further enhanced their synthetic value.
Topics: Gold; Alkynes; Catalysis; Ketones; Carbon
PubMed: 37322071
DOI: 10.1038/s41467-023-39243-5 -
Organic & Biomolecular Chemistry Sep 2022The hydroarylation of alkynes, alkenes, and allenes is a cost-effective and efficient way to incorporate unsaturated moieties into aromatic substrates. This review... (Review)
Review
The hydroarylation of alkynes, alkenes, and allenes is a cost-effective and efficient way to incorporate unsaturated moieties into aromatic substrates. This review focuses on gold-catalyzed hydroarylation, which produces aromatic alkenes, diaryl-alkanes, heterocycles, carbocycles, and arylbutadienes by directly functionalizing C-H bonds. Without the need for prefunctionalization, direct functionalization of aromatic C-H bonds with unsaturated moieties (alkyne, alkene, allene) provides an efficient synthetic strategy with fewer reaction steps. This review offers an overview of the recently developed hydroarylation processes catalyzed by gold. Mechanisms of hydroarylation alkyne, alkene, allene, and arene activation receive special attention.
Topics: Alkadienes; Alkanes; Alkenes; Alkynes; Catalysis; Gold
PubMed: 36069264
DOI: 10.1039/d2ob00960a -
Journal of the American Chemical Society Aug 2023The biosynthetic installation of halogen atoms is largely performed by oxidative halogenases that target a wide array of electron-rich substrates, including aromatic...
The biosynthetic installation of halogen atoms is largely performed by oxidative halogenases that target a wide array of electron-rich substrates, including aromatic compounds and conjugated systems. Halogenated alkyne-containing molecules are known to occur in Nature; however, halogen atom installation on the terminus of an alkyne has not been demonstrated in enzyme catalysis. Herein, we report the discovery and characterization of an alkynyl halogenase in natural product biosynthesis. We show that the flavin-dependent halogenase from the jamaicamide biosynthetic pathway, JamD, is not only capable of terminal alkyne halogenation on a late-stage intermediate en route to the final natural product but also has broad substrate tolerance for simple to complex alkynes. Furthermore, JamD is specific for terminal alkynes over other electron-rich aromatic substrates and belongs to a newly identified family of halogenases from marine cyanobacteria, indicating its potential as a chemoselective biocatalyst for the formation of haloalkynes.
Topics: Halogenation; Halogens; Alkynes; Biological Products; Catalysis
PubMed: 37594919
DOI: 10.1021/jacs.3c05750 -
Methods in Enzymology 2022Polyketides have demonstrated their significance as therapeutics, industrial products, pesticides, and biological probes following intense study over the past decades....
Polyketides have demonstrated their significance as therapeutics, industrial products, pesticides, and biological probes following intense study over the past decades. Tagging polyketides with a bioorthogonal functionality enables various applications such as diversification, quantification, visualization and mode-of-action elucidation. The terminal alkyne moiety, as a small, stable and highly selective clickable functionality, is widely adopted in tagging natural products. De novo biosynthesis of alkyne-tagged polyketides offers the unique advantage of reducing the background from feeding the biorthogonal moiety itself, leading to the accomplishment of in situ generation of a clickable functionality for bioorthogonal reactions. Here, we introduce several engineering strategies to apply terminal alkyne biosynthetic machinery, represented by JamABC, which produces a short terminal alkyne-bearing fatty acyl chain on a carrier protein, to functions with different downstream polyketide synthases (PKSs). Successful results in engineering type III and type I PKSs provide engineering guidelines and strategies that are applicable to additional PKSs to produce targeted alkyne-tagged metabolites for chemical and biological applications.
Topics: Alkynes; Biological Products; Polyketide Synthases; Polyketides
PubMed: 35379442
DOI: 10.1016/bs.mie.2021.11.013 -
Organic & Biomolecular Chemistry Apr 2021Biomimetic natural product synthesis is generally straightforward and efficient because of its established feasibility in nature and utility in comprehensive synthesis,... (Review)
Review
Biomimetic natural product synthesis is generally straightforward and efficient because of its established feasibility in nature and utility in comprehensive synthesis, and the cost-effectiveness of naturally derived starting materials. On the other hand, nonbiomimetic strategies can be an important option in natural product synthesis since (1) nonbiomimetic synthesis offers more flexibility and can demonstrate the originality of chemists, and (2) the structures of derivatives accessible by nonbiomimetic synthesis can be considerably different from those that are synthesised in nature. This review summarises nonbiomimetic total syntheses of indole alkaloids using alkyne chemistry for constructing core structures, including ergot alkaloids, monoterpene indole alkaloids (mainly corynanthe, aspidosperma, strychnos, and akuammiline), and pyrroloindole and related alkaloids. To clarify the differences between alkyne-based strategies and biosynthesis, the alkynes in nature and the biosyntheses of indole alkaloids are also outlined.
Topics: Alkynes; Indole Alkaloids; Molecular Structure; Stereoisomerism
PubMed: 33908430
DOI: 10.1039/d0ob02577a -
Chemical Communications (Cambridge,... Oct 2017Sydnones are among the most popular mesoionic compounds studied so far for cycloaddition reactions. However, despite their good chemical stability and versatility, only... (Review)
Review
Sydnones are among the most popular mesoionic compounds studied so far for cycloaddition reactions. However, despite their good chemical stability and versatility, only a limited number of research groups have worked on their chemistry and use in organic synthesis. This feature article aims at providing an overview of the most recent developments in sydnone-alkyne cycloadditions, with particular attention on the strategies that allow us to achieving high regiocontrol and milder reaction conditions. The recent discovery that this dipole is able to undergo click and biorthogonal reactions with cycloalkynes may stimulate renewed interest from the scientific community. Given the high potential and flexibility of this family of mesoionics, we believe that major developments are to be expected both in terms of organic synthetic methodologies and biorthogonal chemistry applications in the field of chemical biology.
Topics: Alkynes; Click Chemistry; Cycloaddition Reaction; Sydnones
PubMed: 28959814
DOI: 10.1039/c7cc06405e