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Nature Dec 2017Catalytic cross-metathesis is a central transformation in chemistry, yet corresponding methods for the stereoselective generation of acyclic trisubstituted alkenes in...
Catalytic cross-metathesis is a central transformation in chemistry, yet corresponding methods for the stereoselective generation of acyclic trisubstituted alkenes in either the E or the Z isomeric forms are not known. The key problems are a lack of chemoselectivity-namely, the preponderance of side reactions involving only the less hindered starting alkene, resulting in homo-metathesis by-products-and the formation of short-lived methylidene complexes. By contrast, in catalytic cross-coupling, substrates are more distinct and homocoupling is less of a problem. Here we show that through cross-metathesis reactions involving E- or Z-trisubstituted alkenes, which are easily prepared from commercially available starting materials by cross-coupling reactions, many desirable and otherwise difficult-to-access linear E- or Z-trisubstituted alkenes can be synthesized efficiently and in exceptional stereoisomeric purity (up to 98 per cent E or 95 per cent Z). The utility of the strategy is demonstrated by the concise stereoselective syntheses of biologically active compounds, such as the antifungal indiacen B and the anti-inflammatory coibacin D.
Topics: Alkenes; Anti-Inflammatory Agents; Antifungal Agents; Catalysis; Chemistry Techniques, Synthetic; Indoles; Stereoisomerism
PubMed: 29293209
DOI: 10.1038/nature25002 -
Angewandte Chemie (International Ed. in... Dec 2022Alkene metathesis catalyzed by enantiopure metal alkylidene complexes enables exceptionally versatile strategies to products with configurationally-defined...
Alkene metathesis catalyzed by enantiopure metal alkylidene complexes enables exceptionally versatile strategies to products with configurationally-defined stereocenters. Desymmetrization processes thereby provide reliable stereoselective routes to aliphatic structures, while the differentiation of aromatic stereogenic units remained an outstanding challenge. Herein, we describe the feasibility of alkene metathesis to catalytically control stereogenic axes by traceless arene formation. Stereodynamic trienes are selectively converted into corresponding binaphthalene atropisomers upon exposure to a chiral molybdenum catalyst. Remarkably, stereoselective arene-forming metathesis allows enantioselectivities of up to 98 : 2 e.r. and excellent yields. As the disconnection of each bond of an aromatic target is retrosynthetically conceivable, it is anticipated that forging arenes by means of stereoselective metathesis will enable versatile approaches for the synthesis of a broad range of molecular topologies with precisely defined configuration.
Topics: Alkenes; Stereoisomerism; Catalysis; Molybdenum; Coordination Complexes
PubMed: 36283028
DOI: 10.1002/anie.202211168 -
Nature Communications Dec 2022Vicinal diamines are privileged synthetic motifs in chemistry due to their prevalence and powerful applications in bioactive molecules, pharmaceuticals, and ligand...
Vicinal diamines are privileged synthetic motifs in chemistry due to their prevalence and powerful applications in bioactive molecules, pharmaceuticals, and ligand design for transition metals. With organic diazides being regarded as modular precursors to vicinal diamines, enormous efforts have been devoted to developing efficient strategies to access organic diazide generated from olefins, themselves common feedstock chemicals. However, state-of-the-art methods for alkene diazidation rely on the usage of corrosive and expensive oxidants or complicated electrochemical setups, significantly limiting the substrate tolerance and practicality of these methods on large scale. Toward overcoming these limitations, here we show a photochemical diazidation of alkenes via iron-mediated ligand-to-metal charge transfer (LMCT) and radical ligand transfer (RLT). Leveraging the merger of these two reaction manifolds, we utilize a stable, earth abundant, and inexpensive iron salt to function as both radical initiator and terminator. Mild conditions, broad alkene scope and amenability to continuous-flow chemistry rendering the transformation photocatalytic were demonstrated. Preliminary mechanistic studies support the radical nature of the cooperative process in the photochemical diazidation, revealing this approach to be a powerful means of olefin difunctionalization.
Topics: Alkenes; Ligands; Catalysis; Iron; Diamines
PubMed: 36564375
DOI: 10.1038/s41467-022-35560-3 -
IARC Monographs on the Evaluation of... 1994
Review
Topics: Alkenes; Animals; Carcinogenicity Tests; Carcinogens; Humans
PubMed: 7869569
DOI: No ID Found -
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