Synthesis of potent bicyclic bisarylimidazole c-Jun N-terminal kinase inhibitors by catalytic C-H bond activation.
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Binding Sites↗
Biomedical subjects
Robert G Bergman
Publications and source records attributed to Robert G Bergman.
Synthesis and properties of oxygen-centered tetradecaimido hexatantalum clusters.
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Models, Molecular↗
Molecular recognition and stabilization of iminium ions in water.
Iminium ions are known to exist only transiently in aqueous solution due to their high reactivity toward hydrolysis. In this communication, we report on the generation and stabilization of iminium ions in aqueous solution via molecular encapsulation using a K12Ga4L6 host. Our studies revealed that tetrahedral host 1 can encapsulate a variety of iminium cations in a molecular recognition process that is selective based on the charge, hydrophobicity, size, and shape of the guest.
Imines↗
Supramolecular catalysis of unimolecular rearrangements: substrate scope and mechanistic insights.
A cavity-containing metal-ligand assembly is employed as a catalytic host for the 3-aza Cope rearrangement of allyl enammonium cations. Upon binding, the rates of rearrangement are accelerated for all substrates studied, up to 850-fold. Activation parameters were measured for three enammonium cations in order to understand the origins of acceleration. Those parameters reveal that the supramolecular structure is able to reduce both the entropic and enthalpic barriers for rearrangement and is highly sensitive to small structural changes of the substrate. The space-restrictive cavity preferentially binds closely packed, preorganized substrate conformations, which resemble the conformations of the transition states. This hypothesis is also supported by quantitative NOE studies of two encapsulated substrates, which place the two reacting carbon atoms in close proximity. The capsule can act as a true catalyst, since release and hydrolysis facilitate catalytic turnover. The question of product hydrolysis was addressed through detailed kinetic studies. We conclude that the iminium product must dissociate from the cavity interior and the assembly exterior before hydroxide-mediated hydrolysis, and propose the intermediacy of a tight ion pair of the polyanionic host with the exiting product.
Journal Article↗
Scope and mechanism of the C-H bond activation reactivity within a supramolecular host by an iridium guest: a stepwise ion pair guest dissociation mechanism.
A chiral self-assembled supramolecular M(4)L(6) assembly has been shown to be a suitable host for a series of reactive monocationic half-sandwich iridium guests 1, 3, and 4 that are capable of activating C-H bonds. Upon encapsulation, selective C-H bond activation of organic substrates occurs. Precise size and shape selectivity are observed in the C-H bond activation of aldehydes and ether substrates. The reactions exhibit significant kinetic diastereoselectivities. Thermodynamic studies have shown that the iridium starting materials and products are bound strongly by the host assembly. The encapsulation process is largely entropy-driven. Kinetic investigations with water-soluble phosphine traps and added salts have provided evidence for a unique stepwise mechanism of guest dissociation for [4 subset Ga(4)L(6)]. Iridium guest 4 first dissociates from the host cavity to form an ion pair with the host exterior. This species then fully dissociates from the host exterior into the bulk solution. Model ion pair intermediates were characterized directly with (1)H NMR NOESY techniques. The rate of iridium guest dissociation is slower than the rate observed for the C-H bond activation processes, indicating that the selective C-H bond activation reactivity occurs within the cavity of the supramolecular host.
Journal Article↗
Stereoselective alkylation of alpha,beta-unsaturated imines via C-H bond activation.
The stereoselective alkylation of alpha,beta-unsaturated imines via C-H activation followed by imine hydrolysis produces tri- and tetrasubstituted alpha,beta-unsaturated aldehydes. In the presence of a rhodium catalyst, alpha,beta-unsaturated N-benzyl imines derived from methacrolein, crotonaldehyde, and tiglic aldehyde undergo directed C-H activation at the beta-position and react with terminal alkenes and alkynes to form the tri- and tetrasubstituted alpha,beta-unsaturated imines with very high stereoselectivity. Hydrolysis to provide alpha,beta-unsaturated aldehydes can be performed under carefully controlled conditions that maintain the stereochemistry of the beta-alkylated imine products. Alternatively, for beta-alkylation products of the N-benzyl imine of methacrolein, hydrolysis can be performed under conditions that provide complete isomerization to the E isomer.
Alkylation↗
Enantioselective synthesis of a PKC inhibitor via catalytic C-H bond activation.
[reaction: see text] The syntheses of two biologically active molecules possessing dihydropyrroloindole cores (1 and 2) were completed using rhodium-catalyzed imine-directed C-H bond functionalization, with the second of these molecules containing a stereocenter that can be set with 90% ee during cyclization using chiral nonracemic phosphoramidite ligands. Catalytic decarbonylation and direct indole/maleimide coupling provide efficient access to 2.
Catalysis↗
Asymmetric catalytic synthesis of P-stereogenic phosphines via a nucleophilic ruthenium phosphido complex.
Ruthenium phosphido complexes have been shown to be excellent nucleophiles, reacting via two-electron processes with a variety of electrophiles. A catalytic alkylation reaction was developed using an achiral ruthenium complex, which was then elaborated into a catalytic enantioselective synthesis of P-stereogenic phosphines. These useful and synthetically challenging phosphines can now be accessed in a single step from simple secondary phosphines and alkyl halides. Optimization and scope of the enantioselective alkylation are discussed.
Journal Article↗
Rhodium-catalyzed direct C-H addition of 3,4-dihydroquinazolines to alkenes and their use in the total synthesis of vasicoline.
The inter- and intramolecular couplings of unactivated alkenes to 3,4-dihydroquinazolines with a Rh(I) catalyst are reported. Coupling between olefins and NH-3,4-dihydroquinazoline was found to occur consecutively with heterocycle dehydrogenation in the presence of a Rh(I)/PCy3/HCl catalyst. The reaction was used to develop an effective method for the synthesis of 2-substituted quinazolines through an oxidative workup step. The regiocontrolled synthesis and Rh-catalyzed cyclization of alkene-tethered 3,4-dihydroquinazolines are also described. Applying this method, the second total synthesis of vasicoline was achieved. The key Rh-catalyzed cyclization step was made possible by the use of a rigid bicyclic phosphine ligand. The synthesis further demonstrates a challenging Cu-catalyzed amidation of an ortho-substituted aryl chloride.
Alkenes↗
Microwave-promoted rhodium-catalyzed arylation of heterocycles through C--H bond activation.
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Azoles↗
Experimental and computational studies on the mechanism of N-heterocycle C-H activation by Rh(I).
Evidence is presented for a proposed mechanism of C-H activation of 3-methyl-3,4-dihydroquinazoline (1) by (PCy(3))(2)RhCl. One intermediate (3), a coordination complex of 1 with (PCy(3))(2)RhCl, was identified along the path to the Rh-N-heterocyclic carbene product of this reaction (2). Isotopic labeling and reaction-rate studies were used to demonstrate that C-H activation takes place intramolecularly on the reaction coordinate between 3 and 2. Computational studies corroborate the proposed mechanism and suggest that the rate-limiting step is oxidative addition of the C-H bond to the metal center. The consequences of this mechanism for coupling reactions of N-heterocycles that occur via Rh-catalyzed C-H bond activation are discussed.
Catalysis↗
Stabilization of reactive organometallic intermediates inside a self-assembled nanoscale host.
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Gadolinium↗
Reassignment of the configuration of salvianolic acid B and establishment of its identity with lithospermic acid B.
Salvianolic acid B and lithospermic acid B are the major components of Salvia miltiorrhiza, which is one of the most popular herbal traditional medicines in Asian countries. Salvianolic acid B and lithospermic acid B are reported to have identical structures except for the configurational assignments of two stereocenters. Through chemical correlation between a degradation product of salvianolic acid B and synthetic material, the absolute configuration of salvianolic acid B has been corrected to establish that salvianolic acid B and lithospermic acid B are in fact the same compound.
Benzofurans↗
Living ring-opening polymerization of N-sulfonylaziridines: synthesis of high molecular weight linear polyamines.
Sulfonylaziridines have been identified as excellent monomers for living ring-opening polymerization initiated by nucleophilic sulfonylamides. The resulting polymers exhibit low polydispersities and controllable molecular weights. The enantiopurity of the monomer plays a key role: racemic samples yield soluble polymers of target molecular weights, while enantiopure samples produce insoluble polymers with molecular weights significantly below theoretical values. Dynamic light scattering and kinetics of polymerization are discussed.
Journal Article↗
Zirconium-mediated SN2' substitution of allylic ethers: regio- and stereospecific formation of protected allylic amines.
A new zirconium-mediated, regio- and stereospecific SN2' substitution of allylic ethers with a nitrogen nucleophile has been developed. Cbz-protected amine products were isolated in high yield from reactions with a wide range of Z allylic ethers. A mechanism of the allylic substitution consistent with the results of the kinetics and kinetic isotope effect studies was proposed.
Alkenes↗
Olefination and group transfer reactions of an electron deficient tantalum methylidene complex.
The reactivity of an electronically unsaturated tantalum methylidene complex [TolC(NSiMe(3))(2)](2)Ta(CH(2))CH(3) supported by [TolC(NSiMe(3))(2)] amidinate ligands is described. Electrophilic addition and olefination reactions of the Ta=CH(2) functionality are reported. Alkylidene participates in group-transfer reactions not observed in sterically similar, but electronically saturated, analogues. Reactions with substrates containing unsaturated C-X (X = C, N, O) bonds yield [Ta]=X compounds and vinylated organic products; carbon-sulfur cleavage reactions to produce tantalum thioformaldehyde and tantalum sulfido complexes.
Journal Article↗
Proton-catalyzed hydroamination and hydroarylation reactions of anilines and alkenes: a dramatic effect of counteranions on reaction efficiency.
The anilinium salt, [PhNH3][B(C6F5)4], has been identified as a catalyst for the hydroamination and hydroarylation of several different types of alkenes with anilines. The weakly coordinating counterion of this acid plays a key role in this transformation. The reaction is facile for styrenes and tolerates norbornene, cyclic alkenes, and cyclohexadiene. Selectivity between hydroamination and hydroarylation products can be tuned using reaction time, temperature, and substrate substitution. Details regarding the substrate scope and selectivity of this hydroamination/hydroarylation reaction are discussed.
Alkenes↗
Total synthesis of (+)-lithospermic acid by asymmetric intramolecular alkylation via catalytic C-H bond activation.
The total synthesis of (+)-lithospermic acid is described. The efficient synthesis features an asymmetric alkylation via C-H bond activation to assemble the dihydrobenzofuran core of the natural product. This was accomplished via a chiral imine-directed C-H bond functionalization and represents the first application of this C-H activation method to natural product synthesis. Furthermore, a challenging deprotection of a late-stage permethylated lithospermic acid was achieved.
Alkylation↗