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Journal of the American Chemical Society Jun 2022We report a total synthesis of the alkaloid myrioneurinol enabled by the recognition of hidden symmetry within its polycyclic structure. Our approach traces...
We report a total synthesis of the alkaloid myrioneurinol enabled by the recognition of hidden symmetry within its polycyclic structure. Our approach traces myrioneurinol's complex framework back to a symmetrical diketone precursor, a double reductive amination of which forges its central piperidine unit. By employing an inexpensive chiral amine in this key desymmetrizing event, four stereocenters of the natural product including the core quaternary stereocenter are set in an absolute sense, providing the first asymmetric entry to this target. Other noteworthy strategic maneuvers include utilizing a bicyclic alkene as a latent -1,3-bis(hydroxymethyl) synthon and a topologically controlled alkene hydrogenation. Overall, our synthesis proceeds in 18 steps and ∼1% yield from commercial materials.
Topics: Alkaloids; Alkenes; Amination; Heterocyclic Compounds, 4 or More Rings; Stereoisomerism
PubMed: 35699935
DOI: 10.1021/jacs.2c04487 -
Angewandte Chemie (International Ed. in... Aug 2022Vinylbenziodoxolones have recently been identified as efficient hypervalent iodine(III) reagents for electrophilic vinylations under transition metal-free conditions....
Vinylbenziodoxolones have recently been identified as efficient hypervalent iodine(III) reagents for electrophilic vinylations under transition metal-free conditions. Their unique reactivity allows synthesis of either internal or terminal alkenes, depending on the nucleophile class. This paper constitutes the first mechanistic investigation of VBX vinylations, and makes use of NMR studies, deuterium labelling and computations to rationalize the observed regio- and stereochemical outcome. Internal alkene formation in S-vinylation was found to proceed through the ligand coupling mechanism typical of diaryliodonium salts, whereas terminal alkene formation in P-vinylations took place via a phosphinous acid-coordinated VBX complex, which underwent concerted deprotonation and Michael-type addition. Subsequent base-assisted protonation and E2 elimination delivered the terminal alkene. The findings can be used to predict the regioselectivity in vinylations of other nucleophile classes.
Topics: Alkenes; Catalysis; Iodine; Ligands
PubMed: 35748793
DOI: 10.1002/anie.202206347 -
Accounts of Chemical Research Mar 2021The development of novel synthetic methods remains a cornerstone in simplifying complex molecule synthesis. Progress in the field of transition metal catalysis has... (Review)
Review
The development of novel synthetic methods remains a cornerstone in simplifying complex molecule synthesis. Progress in the field of transition metal catalysis has enabled new mechanistic strategies to achieve difficult chemical transformations, increased the value of abundant chemical building blocks, and pushed the boundaries of creative and strategic route design to improve step economy in multistep synthesis. Methodologies to introduce an olefin into saturated molecules continue to be essential transformations because of the plethora of reactions available for alkene functionalization. Of particular importance are dehydrogenation reactions adjacent to electron-withdrawing groups such as carbonyls, which advantageously provide activated olefins that can be regioselectively manipulated. Palladium catalysis occupies a central role in the most widely adopted carbonyl dehydrogenation reactions, but limits to the scope of these protocols persist.In this Account, we describe our group's contributions to the area of transition-metal-catalyzed dehydrogenation using palladium catalysis and more sustainable and economical nickel catalysis. These metals are used in conjunction with allyl and aryl halides or pseudohalides that serve as oxidants to access a unique mechanistic approach for one-step α,β-dehydrogenation of various electron-withdrawing groups, including ketones, esters, nitriles, amides, carboxylic acids, and electron-deficient heteroarenes. The pivotal reaction parameters that can be modified to influence reaction efficiency are highlighted, including base and oxidant structure as well as ligand and salt additive effects. This discussion is expected to serve as a guide for troubleshooting challenging dehydrogenation reactions and provide insight for future reaction development in this area.In addition to enabling dehydrogenation reactions, our group's allyl-Pd and -Ni chemistry can be used for C-C and C-X bond-forming reactions, providing novel disconnections with practical applications for expediting multistep synthesis. These transformations include a telescoped process for ketone α,β-vicinal difunctionalization; an oxidative enone β-functionalization, including β-stannylation, β-silylation, and β-alkylation; and an oxidative cycloalkenylation between unstabilized ketone enolates and unactivated alkenes. These bond-forming methodologies broaden the range of transformations accessible from abundant ketone, enone, and alkene moieties. Both the dehydrogenation and C-C and C-X bond-forming methodologies have been implemented in our group's total synthesis campaigns to provide step-efficient synthetic routes toward diverse natural products.Through the lens of multistep synthesis, the utility and robustness of our dehydrogenation and dehydrogenative functionalization methodologies can be better appreciated, and we hope that this Account will inspire practitioners to apply our methodologies to their own synthetic challenges.
Topics: Alkenes; Catalysis; Hydrogenation; Ketones; Molecular Structure; Nickel; Palladium; Stereoisomerism
PubMed: 33592147
DOI: 10.1021/acs.accounts.0c00787 -
Nature Communications Apr 2022Alkene hydrocarbonation reactions have been developed to supplement traditional electrophile-nucleophile cross-coupling reactions. The branch-selective hydroalkylation...
Alkene hydrocarbonation reactions have been developed to supplement traditional electrophile-nucleophile cross-coupling reactions. The branch-selective hydroalkylation method applied to a broad range of unactivated alkenes remains challenging. Herein, we report a NiH-catalysed proximal-selective hydroalkylation of unactivated alkenes to access β- or γ-branched alkyl carboxylic acids and β-, γ- or δ-branched alkyl amines. A broad range of alkyl iodides and bromides with different functional groups can be installed with excellent regiocontrol and availability for site-selective late-stage functionalization of biorelevant molecules. Under modified reaction conditions with NiCl(PPh) as the catalyst, migratory hydroalkylation takes place to provide β- (rather than γ-) branched products. The keys to success are the use of aminoquinoline and picolinamide as suitable directing groups and combined experimental and computational studies of ligand effects on the regioselectivity and detailed reaction mechanisms.
Topics: Alkenes; Bromides; Catalysis; Iodides; Ligands
PubMed: 35393419
DOI: 10.1038/s41467-022-29554-4 -
Angewandte Chemie (International Ed. in... Nov 2020The gold-catalyzed intermolecular oxyarylation of alkenes is reported. This work employed the oxidative addition of aryl iodides to Me-DalphosAu for the formation of a...
The gold-catalyzed intermolecular oxyarylation of alkenes is reported. This work employed the oxidative addition of aryl iodides to Me-DalphosAu for the formation of a Au -Ar intermediate. The better binding ability of alkenes over O nucleophiles ensured the success of intermolecular oxyarylation, giving desired products with a broad substrate scope and high efficiency (>50 examples with up to 95 % yield). One-pot converting of methoxy groups into other nucleophiles allowed achieving alkene difunctionalization with the construction of C-N, C-S, and C-C bonds under mild conditions.
Topics: Alkenes; Catalysis; Gold; Molecular Structure; Oxidation-Reduction; Stereoisomerism
PubMed: 32748527
DOI: 10.1002/anie.202009636 -
Journal of the American Chemical Society Aug 2023Alkene difunctionalizations enable the synthesis of structurally elaborated products from simple and ubiquitous starting materials in a single chemical step....
Alkene difunctionalizations enable the synthesis of structurally elaborated products from simple and ubiquitous starting materials in a single chemical step. Carbohydroxylations of olefins represent a family of reactivity that furnish structurally complex alcohols. While examples of this type of three-component coupling have been reported, catalytic asymmetric examples remain elusive. Here, we report an enzyme-catalyzed asymmetric carbohydroxylation of alkenes catalyzed by flavin-dependent "ene"-reductases to produce enantioenriched tertiary alcohols. Seven rounds of protein engineering reshape the enzyme's active site to increase activity and enantioselectivity. Mechanistic studies suggest that C-O bond formation occurs via a 5-endo-trig cyclization with the pendant ketone to afford an α-oxy radical which is oxidized and hydrolyzed to form the product. This work demonstrates photoenzymatic reactions involving "ene"-reductases can terminate radicals via mechanisms other than hydrogen atom transfer, expanding their utility in chemical synthesis.
Topics: Alkenes; Catalysis; Hydrogen; Oxidoreductases; Alcohols
PubMed: 37498747
DOI: 10.1021/jacs.3c06618 -
Angewandte Chemie (International Ed. in... Sep 2016Human 15-lipoxygenase-1 (15-LOX-1) plays an important role in several inflammatory lung diseases, such as asthma, COPD, and chronic bronchitis, as well as various CNS...
Human 15-lipoxygenase-1 (15-LOX-1) plays an important role in several inflammatory lung diseases, such as asthma, COPD, and chronic bronchitis, as well as various CNS diseases, such as Alzheimer's disease, Parkinson's disease, and stroke. Activity-based probes of 15-LOX-1 are required to explore the role of this enzyme further and to enable drug discovery. In this study, we developed a 15-LOX-1 activity-based probe for the efficient activity-based labeling of recombinant 15-LOX-1. 15-LOX-1-dependent labeling in cell lysates and tissue samples was also possible. To mimic the natural substrate of the enzyme, we designed activity-based probes that covalently bind to the active enzyme and include a terminal alkene as a chemical reporter for the bioorthogonal linkage of a detectable functionality through an oxidative Heck reaction. The activity-based labeling of 15-LOX-1 should enable the investigation and identification of this enzyme in complex biological samples, thus opening up completely new opportunities for drug discovery.
Topics: Alkenes; Animals; Arachidonate 15-Lipoxygenase; Binding Sites; Catalytic Domain; HeLa Cells; Humans; Kinetics; Lipoxygenase Inhibitors; Mice; Molecular Docking Simulation; Myocardium; Protein Binding; Recombinant Proteins; Structure-Activity Relationship; Substrate Specificity
PubMed: 27612308
DOI: 10.1002/anie.201606876 -
Angewandte Chemie (International Ed. in... Jan 2019The direct enantioselective addition of water to unactivated alkenes could simplify the synthesis of chiral alcohols and solve a long-standing challenge in catalysis....
The direct enantioselective addition of water to unactivated alkenes could simplify the synthesis of chiral alcohols and solve a long-standing challenge in catalysis. Here we report that an engineered fatty acid hydratase can catalyze the asymmetric hydration of various terminal and internal alkenes. In the presence of a carboxylic acid decoy molecule for activation of the oleate hydratase from E. meningoseptica, asymmetric hydration of unactivated alkenes was achieved with up to 93 % conversion, excellent selectivity (>99 % ee, >95 % regioselectivity), and on a preparative scale.
Topics: Alkenes; Molecular Structure
PubMed: 30256501
DOI: 10.1002/anie.201810005 -
Chemical Society Reviews Mar 2013The development of new catalytic systems for cis-dihydroxylation and epoxidation of alkenes, based on atom economic and environmentally friendly concepts, is a major... (Review)
Review
The development of new catalytic systems for cis-dihydroxylation and epoxidation of alkenes, based on atom economic and environmentally friendly concepts, is a major contemporary challenge. In recent years, several systems based on manganese catalysts using H(2)O(2) as the terminal oxidant have been developed. In this review, selected homogeneous manganese catalytic systems, including 'ligand free' and pyridyl amine ligand based systems, that have been applied to alkene oxidation will be discussed with a strong focus on the mechanistic studies that have been carried out.
Topics: Alkenes; Catalysis; Hydrogen Peroxide; Hydroxylation; Manganese; Oxidation-Reduction; Stereoisomerism
PubMed: 23238579
DOI: 10.1039/c2cs35443h -
Nature Chemistry Jan 2014The ene reaction is a pericyclic process in which an alkene with an allylic hydrogen atom (the ene donor) reacts with a second unsaturated species (the enophile) to form...
The ene reaction is a pericyclic process in which an alkene with an allylic hydrogen atom (the ene donor) reacts with a second unsaturated species (the enophile) to form a new product with a transposed π-bond. The aromatic ene reaction, in which the alkene component is embedded in an aromatic ring, has only been reported in a few (four) instances and has proceeded in low yield (≤6%). Here, we show efficient aromatic ene reactions in which a thermally generated aryne intermediate engages a pendant m-alkylarene substituent to produce a dearomatized isotoluene, itself another versatile but rare reactive intermediate. Our experiments were guided by computational studies that revealed structural features conducive to the aromatic ene process. We proceeded to identify a cascade comprising three reactions: (1) hexadehydro-Diels-Alder (for aryne generation), (2) intramolecular aromatic ene and (3) bimolecular Alder ene. The power of this cascade is evident from the structural complexity of the final products, the considerable scope, and the overall efficiency of these multistage, reagent- and by-product-free, single-pot transformations.
Topics: Alkenes; Hydrogen Bonding
PubMed: 24345944
DOI: 10.1038/nchem.1797