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IARC Monographs on the Evaluation of... 1994
Review
Topics: Alkenes; Animals; Carcinogenicity Tests; Carcinogens; Humans
PubMed: 7869569
DOI: No ID Found -
Nature Aug 2021Aziridines-three-membered nitrogen-containing cyclic molecules-are important synthetic targets. Their substantial ring strain and resultant proclivity towards...
Aziridines-three-membered nitrogen-containing cyclic molecules-are important synthetic targets. Their substantial ring strain and resultant proclivity towards ring-opening reactions makes them versatile precursors of diverse amine products, and, in some cases, the aziridine functional group itself imbues important biological (for example, anti-tumour) activity. Transformation of ubiquitous alkenes into aziridines is an attractive synthetic strategy, but is typically accomplished using electrophilic nitrogen sources rather than widely available amine nucleophiles. Here we show that unactivated alkenes can be electrochemically transformed into a metastable, dicationic intermediate that undergoes aziridination with primary amines under basic conditions. This new approach expands the scope of readily accessible N-alkyl aziridine products relative to those obtained through existing state-of-the-art methods. A key strategic advantage of this approach is that oxidative alkene activation is decoupled from the aziridination step, enabling a wide range of commercially available but oxidatively sensitive amines to act as coupling partners for this strain-inducing transformation. More broadly, our work lays the foundations for a diverse array of difunctionalization reactions using this dication pool approach.
Topics: Alkenes; Amines; Aziridines; Chemistry Techniques, Synthetic; Electrochemistry; Oxidation-Reduction; Thermodynamics
PubMed: 34157720
DOI: 10.1038/s41586-021-03717-7 -
Nature Dec 2020Hydroamination of alkenes, the addition of the N-H bond of an amine across an alkene, is a fundamental, yet challenging, organic transformation that creates an...
Hydroamination of alkenes, the addition of the N-H bond of an amine across an alkene, is a fundamental, yet challenging, organic transformation that creates an alkylamine from two abundant chemical feedstocks, alkenes and amines, with full atom economy. The reaction is particularly important because amines, especially chiral amines, are prevalent substructures in a wide range of natural products and drugs. Although extensive efforts have been dedicated to developing catalysts for hydroamination, the vast majority of alkenes that undergo intermolecular hydroamination have been limited to conjugated, strained, or terminal alkenes; only a few examples occur by the direct addition of the N-H bond of amines across unactivated internal alkenes, including photocatalytic hydroamination, and no asymmetric intermolecular additions to such alkenes are known. In fact, current examples of direct, enantioselective intermolecular hydroamination of any type of unactivated alkene lacking a directing group occur with only moderate enantioselectivity. Here we report a cationic iridium system that catalyses intermolecular hydroamination of a range of unactivated, internal alkenes, including those in both acyclic and cyclic alkenes, to afford chiral amines with high enantioselectivity. The catalyst contains a phosphine ligand bearing trimethylsilyl-substituted aryl groups and a triflimide counteranion, and the reaction design includes 2-amino-6-methylpyridine as the amine to enhance the rates of multiple steps within the catalytic cycle while serving as an ammonia surrogate. These design principles point the way to the addition of N-H bonds of other reagents, as well as O-H and C-H bonds, across unactivated internal alkenes to streamline the synthesis of functional molecules from basic feedstocks.
Topics: Alkenes; Amination; Amines; Aminopyridines; Ammonia; Catalysis; Chemistry Techniques, Synthetic; Hydrogen; Indicators and Reagents; Iridium; Ligands; Nitrogen; Phosphines
PubMed: 33142305
DOI: 10.1038/s41586-020-2919-z -
Angewandte Chemie (International Ed. in... Jul 2021The trifluoromethoxy group has elicited much interest among drug and agrochemical discovery teams because of its unique properties. We developed trifluoromethyl...
The trifluoromethoxy group has elicited much interest among drug and agrochemical discovery teams because of its unique properties. We developed trifluoromethyl nonafluorobutanesulfonate (nonaflate), TFNf, an easy-to-handle, bench-stable, reactive, and scalable trifluoromethoxylating reagent. TFNf is easily and safely prepared in a simple process in large scale and the nonaflyl part of TFNf can easily be recovered as nonaflyl fluoride after usage and recycled. The synthetic potency of TFNf was showcased with the underexplored synthesis of various trifluoromethoxylated alkenes, through a high regio- and stereoselective hydro(halo)trifluoromethoxylation of alkyne derivatives such as haloalkynes, alkynyl esters, and alkynyl sulfones. The synthetic merits of TFNf were further underscored with a high-yielding and smooth nucleophilic trifluoromethoxylation of alkyl triflates/bromides and primary/secondary alcohols.
Topics: Alkenes; Catalysis; Chemistry Techniques, Synthetic; Hydrocarbons, Fluorinated; Indicators and Reagents; Stereoisomerism
PubMed: 34010513
DOI: 10.1002/anie.202104975 -
Nature Communications Jun 2016New types of asymmetric functionalizations of alkenes are highly desirable for chemical synthesis. Here, we develop three novel types of regio- and enantioselective...
New types of asymmetric functionalizations of alkenes are highly desirable for chemical synthesis. Here, we develop three novel types of regio- and enantioselective multiple oxy- and amino-functionalizations of terminal alkenes via cascade biocatalysis to produce chiral α-hydroxy acids, 1,2-amino alcohols and α-amino acids, respectively. Basic enzyme modules 1-4 are developed to convert alkenes to (S)-1,2-diols, (S)-1,2-diols to (S)-α-hydroxyacids, (S)-1,2-diols to (S)-aminoalcohols and (S)-α-hydroxyacids to (S)-α-aminoacids, respectively. Engineering of enzyme modules 1 &2, 1 &3 and 1, 2 &4 in Escherichia coli affords three biocatalysts over-expressing 4-8 enzymes for one-pot conversion of styrenes to the corresponding (S)-α-hydroxyacids, (S)-aminoalcohols and (S)-α-aminoacids in high e.e. and high yields, respectively. The new types of asymmetric alkene functionalizations provide green, safe and useful alternatives to the chemical syntheses of these compounds. The modular approach for engineering multi-step cascade biocatalysis is useful for developing other new types of one-pot biotransformations for chemical synthesis.
Topics: Alkenes; Amino Acids; Amino Alcohols; Biocatalysis; Escherichia coli; Models, Chemical; Molecular Structure; Stereoisomerism; Styrenes
PubMed: 27297777
DOI: 10.1038/ncomms11917 -
Journal of the American Chemical Society Mar 2021Alkenes, ethers, and alcohols account for a significant percentage of bulk reagents available to the chemistry community. The petrochemical, pharmaceutical, and...
Alkenes, ethers, and alcohols account for a significant percentage of bulk reagents available to the chemistry community. The petrochemical, pharmaceutical, and agrochemical industries each consume gigagrams of these materials as fuels and solvents each year. However, the utilization of such materials as building blocks for the construction of complex small molecules is limited by the necessity of prefunctionalization to achieve chemoselective reactivity. Herein, we report the implementation of efficient, sustainable, diaryl ketone hydrogen-atom transfer (HAT) catalysis to activate native C-H bonds for multicomponent dicarbofunctionalization of alkenes. The ability to forge new carbon-carbon bonds between reagents typically viewed as commodity solvents provides a new, more atom-economic outlook for organic synthesis. Through detailed experimental and computational investigation, the critical effect of hydrogen bonding on the reactivity of this transformation was uncovered.
Topics: Alkenes; Carbon; Catalysis; Hydrogen; Hydrogen Bonding; Nickel; Quantum Theory
PubMed: 33660996
DOI: 10.1021/jacs.0c13077 -
Nature Jan 2017Macrocyclic compounds are central to the development of new drugs, but preparing them can be challenging because of the energy barrier that must be surmounted in order...
Macrocyclic compounds are central to the development of new drugs, but preparing them can be challenging because of the energy barrier that must be surmounted in order to bring together and fuse the two ends of an acyclic precursor such as an alkene (also known as an olefin). To this end, the catalytic process known as ring-closing metathesis (RCM) has allowed access to countless biologically active macrocyclic organic molecules, even for large-scale production. Stereoselectivity is often critical in such cases: the potency of a macrocyclic compound can depend on the stereochemistry of its alkene; alternatively, one isomer of the compound can be subjected to stereoselective modification (such as dihydroxylation). Kinetically controlled Z-selective RCM reactions have been reported, but the only available metathesis approach for accessing macrocyclic E-olefins entails selective removal of the Z-component of a stereoisomeric mixture by ethenolysis, sacrificing substantial quantities of material if E/Z ratios are near unity. Use of ethylene can also cause adventitious olefin isomerization-a particularly serious problem when the E-alkene is energetically less favoured. Here, we show that dienes containing an E-alkenyl-B(pinacolato) group, widely used in catalytic cross-coupling, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E-macrocyclic alkenes. The reaction is promoted by a molybdenum monoaryloxide pyrrolide complex and affords products at a yield of up to 73 per cent and an E/Z ratio greater than 98/2. We highlight the utility of the approach by preparing recifeiolide (a 12-membered-ring antibiotic) and pacritinib (an 18-membered-ring enzyme inhibitor), the Z-isomer of which is less potent than the E-isomer. Notably, the 18-membered-ring moiety of pacritinib-a potent anti-cancer agent that is in advanced clinical trials for treating lymphoma and myelofibrosis-was prepared by RCM carried out at a substrate concentration 20 times greater than when a ruthenium carbene was used.
Topics: Alkenes; Antineoplastic Agents; Bridged-Ring Compounds; Catalysis; Cyclization; Kinetics; Lactones; Macrocyclic Compounds; Molecular Structure; Molybdenum; Organometallic Compounds; Pyrimidines; Ruthenium; Stereoisomerism
PubMed: 28068669
DOI: 10.1038/nature20800 -
The Journal of Organic Chemistry Mar 2022Photoredox catalysis has become a powerful method to generate free radical intermediates in organic synthesis. This report describes the use of photoredox catalysis to...
Photoredox catalysis has become a powerful method to generate free radical intermediates in organic synthesis. This report describes the use of photoredox catalysis to directly oxidize common nucleophilic anions to access electrophilic 1,3-dicarbonyl and amidyl radical intermediates. First, conjugate bases of 1,3-dicarbonyls were oxidized to neutral radical species for intramolecular hydro- and dialkylation of alkenes. This overall redox-neutral process provided cyclopentanone products in excellent yields (up to 96%). The scope included a variety of styrene radical acceptors and products with newly formed vicinal quaternary carbons. This process was then extended to the synthesis of pyrrolidinones by alkene amidoalkylation that proceeded via -aryl amidyl radical intermediates in good yield (up to 85%). These reactions were characterized by their mild conditions, high atom economy, and the absence of stoichiometric byproducts. Mechanistic and computational studies supported a stepwise proton-coupled electron transfer mechanism, where an "electron borrowing" photocatalyst oxidizes an anion and reduces a benzylic radical after bond formation.
Topics: Alkenes; Anions; Catalysis; Oxidation-Reduction; Protons
PubMed: 35133155
DOI: 10.1021/acs.joc.1c03055 -
Angewandte Chemie (International Ed. in... Apr 2020Allylation and conjunctive cross-coupling represent two useful, yet largely distinct, reactivity paradigms in catalysis. The union of these two processes would offer...
Allylation and conjunctive cross-coupling represent two useful, yet largely distinct, reactivity paradigms in catalysis. The union of these two processes would offer exciting possibilities in organic synthesis but remains largely unknown. Herein, we report the use of allyl electrophiles in nickel-catalyzed conjunctive cross-coupling with a non-conjugated alkene and dimethylzinc. The transformation is enabled by weakly coordinating, monodentate aza-heterocycle directing groups that are useful building blocks in synthesis, including saccharin, pyridones, pyrazoles, and triazoles. The reaction occurs under mild conditions and is compatible with a wide range of allyl electrophiles. High chemoselectivity through substrate directivity is demonstrated by the facile reactivity of the β-γ alkene of the starting material, whereas the ϵ-ζ alkene of the product is preserved. The generality of this approach is further illustrated through the development of an analogous method with alkyne substrates. Mechanistic studies reveal the importance of the dissociation of the weakly coordinating directing group to allow the allyl moiety to bind and facilitate C(sp )-C(sp ) reductive elimination.
Topics: Alkenes; Alkylation; Allyl Compounds; Catalysis; Molecular Structure; Nickel; Organometallic Compounds; Pyrazoles; Pyridones; Saccharin; Stereoisomerism; Triazoles
PubMed: 31958202
DOI: 10.1002/anie.201915454 -
Proceedings of the Japan Academy.... 2015Shortly after the discovery of Zr-catalyzed carboalumination of alkynes in 1978, we sought expansion of the scope of this reaction so as to develop its alkene version... (Review)
Review
Shortly after the discovery of Zr-catalyzed carboalumination of alkynes in 1978, we sought expansion of the scope of this reaction so as to develop its alkene version for catalytic asymmetric C-C bond formation, namely the ZACA (Zr-catalyzed asymmetric carboalumination of alkenes). However, this seemingly easy task proved to be quite challenging. The ZACA reaction was finally discovered in 1995 by suppressing three competitive side reactions, i.e., (i) cyclic carbometalation, (ii) β-H transfer hydrometalation, and (iii) alkene polymerization. The ZACA reaction has been used to significantly modernize and improve syntheses of various natural products including deoxypolypropionates and isoprenoids. This review focuses on our recent progress on the development of ZACA-lipase-catalyzed acetylation-transition metal-catalyzed cross-coupling processes for highly efficient and enantioselective syntheses of a wide range of chiral organic compounds with ultra-high enantiomeric purities.
Topics: Alkenes; Catalysis; Chemistry Techniques, Synthetic; Lipase; Stereoisomerism; Zirconium
PubMed: 26460317
DOI: 10.2183/pjab.91.369