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1.  The First Example of Nickel-Catalyzed Silyl-Heck Reactions: Direct Activation of Silyl Triflates Without Iodide Additives 
Tetrahedron  2014;70(27-28):4250-4256.
For the first time, nickel-catalyzed silyl-Heck reactions are reported. Using simple phosphine-supported nickel catalysts, direct activation of silyl triflates has been achieved. These results contrast earlier palladium-catalyzed systems, which require iodide additives to activate silyl-triflates. These nickel-based catalysts exhibit good functional group tolerance in the preparation of vinyl silanes, and unlike earlier systems, allows for the incorporation of trialkylsilanes larger than Me3Si.
PMCID: PMC4047519  PMID: 24914247
2.  Concise Synthesis of Functionalized Benzocyclobutenones 
Tetrahedron  2014;70(27-28):4135-4146.
A concise approach to access functionalized benzocyclobutenones from 3-halophenol derivatives is described. This modified synthesis employs a [2+2] cycloaddition between benzynes generated from dehydrohalogenation of aryl halides using LiTMP and acetaldehyde enolate generated from n-BuLi and THF, followed by oxidation of the benzocyclobutenol intermediates to provide benzocyclobutenones. The [2+2] reaction can be run on a 10-gram scale with an increased yield. A number of functional groups including alkenes and alkynes are tolerated. Coupling of benzynes with ketene silyl acetals to give 8-substituted benzocyclobutenones is also demonstrated.
PMCID: PMC4049219  PMID: 24926108
benzocyclobutenone; cycloaddition; benzyne; dehydrohalogenation; benzocyclobutenol
3.  Catalytic acceptorless dehydrogenations: Ru-Macho catalyzed construction of amides and imines 
Tetrahedron  2014;70(27-28):4213-4218.
A commercially available ruthenium (II) PNP type pincer catalyst (Ru-Macho) promotes formation of amides and imines from alcohols and amines via an acceptorless dehydrogenation pathway. The formation of secondary amides, tertiary amides, and secondary ketimines occurs in yields ranging from 35%–95%.
PMCID: PMC4482118  PMID: 26124536
Acceptorless Dehydrogenation; Amide; Imine; Ruthenium Catalysis
4.  Concise total synthesis of (±)-actinophyllic acid 
Tetrahedron  2014;70(27-28):4094-4104.
A concise total synthesis of the complex indole alkaloid (±)-actinophyllic acid was accomplished by a sequence of reactions requiring only 10 steps from readily-available, known starting materials. The approach featured a Lewis acid-catalyzed cascade of reactions involving stabilized carbocations that delivered the tetracyclic core of the natural product in a single chemical operation. Optimal conversion of this key intermediate into (±)-actinophyllic acid required judicious selection of a protecting group strategy.
PMCID: PMC4034156  PMID: 24882888
Total Synthesis; Cascade Reaction; Iminium Ion; Mannich-type Reaction
5.  Manganese terpyridine artificial metalloenzymes for benzylic oxygenation and olefin epoxidation 
Tetrahedron  2014;70(27-28):4245-4249.
New catalysts for non-directed hydrocarbon functionalization have great potential in organic synthesis. We hypothesized that incorporating a Mn-terpyridine cofactor into a protein scaffold would lead to artificial metalloenzymes (ArMs) in which the selectivity of the Mn cofactor could be controlled by the protein scaffold. We designed and synthesized a maleimide-substituted Mn-terpyridine cofactor and demonstrated that this cofactor could be incorporated into two different scaffold proteins to generate the desired ArMs. The structure and reactivity of one of these ArMs was explored, and the broad oxygenation capability of the Mn-terpyridine catalyst was maintained, providing a robust platform for optimization of ArMs for selective hydrocarbon functionalization.
PMCID: PMC4041119  PMID: 24904188
Artificial metalloenzyme; Manganese; C-H functionalization; Epoxidation; Biocatalysis
6.  Facile Access to Cyclooctanoid Ring Systems via Microwave-Assisted Tandem 6-exo dig Cyclization-Rearrangement Sequence 
Tetrahedron  2014;70(27-28):4147-4155.
Appropriately substituted 5-alkyn-1-ol systems bearing a nitrile moiety at the triple bond serve as versatile precursors to a variety of cyclooctenone derivatives via a “one-pot” base-catalyzed oxyanionic 6-exo dig cyclization/Claisen rearrangement sequence under microwave irradiation. It was found that the initially formed cyclic intermediate consists of a mixture of endo and exocyclic isomers, which appear to be in equilibrium under the reaction conditions. However, the only observed products from these reactions are α-cyano substituted cyclooctenones, derived from the exocyclic dihydrofuran intermediates.
PMCID: PMC4074778  PMID: 24994941
7.  Palladium-catalyzed decarboxylative allylic alkylation of diastereomeric β-ketoesters 
Tetrahedron  2014;70(27-28):4208-4212.
The palladium-catalyzed decarboxylative allylic alkylation of diastereomeric β-ketoesters derived from 4-tert-butylcyclohexanone is described. These experiments were performed to elucidate our understanding of stereoablative enantioconvergent catalysis. A detailed analysis of the product distribution, including stereochemical outcome of the products, is included. These studies also reveal an interesting example of selectivity that is governed by competing modes of substrate and catalyst control.
PMCID: PMC4078409  PMID: 24999286
Decarboxylative; Allylic; Alkylation; Ketoesters; Palladium
8.  A broadly applicable and practical oligomeric (salen) Co catalyst for enantioselective epoxide ring-opening reactions 
Tetrahedron  2014;70(27-28):4165-4180.
The (salen) Co catalyst (4a) can be prepared as a mixture of cyclic oligomers in a short, chromatography-free synthesis from inexpensive, commercially available precursors. This catalyst displays remarkable enhancements in reactivity and enantioselectivity relative to monomeric and other multimeric (salen) Co catalysts in a wide variety of enantioselective epoxide ring-opening reactions. The application of catalyst 4a is illustrated in the kinetic resolution of terminal epoxides by nucleophilic ring-opening with water, phenols, and primary alcohols; the desymmetrization of meso epoxides by addition of water and carbamates; and the desymmetrization of oxetanes by intramolecular ring opening with alcohols and phenols. The favorable solubility properties of complex 4a under the catalytic conditions facilitated mechanistic studies, allowing elucidation of the basis for the beneficial effect of oligomerization. Finally, a catalyst selection guide is provided to delineate the specific advantages of oligomeric catalyst 4a relative to (salen) Co monomer 1 for each reaction class.
PMCID: PMC4096935  PMID: 25045188
kinetic resolution; salen; desymmetrization; epoxides; ring-opening
9.  Discovery of the lomaiviticin biosynthetic gene cluster in Salinispora pacifica 
Tetrahedron  2014;70(27-28):4156-4164.
The lomaiviticins are a family of cytotoxic marine natural products that have captured the attention of both synthetic and biological chemists due to their intricate molecular scaffolds and potent biological activities. Here we describe the identification of the gene cluster responsible for lomaiviticin biosynthesis in Salinispora pacifica strains DPJ-0016 and DPJ-0019 using a combination of molecular approaches and genome sequencing. The link between the lom gene cluster and lomaiviticin production was confirmed using bacterial genetics, and subsequent analysis and annotation of this cluster revealed the biosynthetic basis for the core polyketide scaffold. Additionally, we have used comparative genomics to identify candidate enzymes for several unusual tailoring events, including diazo formation and oxidative dimerization. These findings will allow further elucidation of the biosynthetic logic of lomaiviticin assembly and provide useful molecular tools for application in biocatalysis and synthetic biology.
PMCID: PMC4101813  PMID: 25045187
Natural product biosynthesis; Comparative genomics; Diazo group; Polyketide; Dimerization
10.  [3+2] Photooxygenation of aryl cylopropanes via visible light photocatalysis 
Tetrahedron  2014;70(27-28):4270-4278.
We report that Ru(bpz)32+ is an excellent sensitizer for the photooxygenation of aryl cyclopropanes upon irradiation with visible light. The effectiveness of this photocatalyst enables the synthesis of a range of five-membered endoperoxides in excellent yield with quite low (0.5 mol%) catalyst loadings even when standard household light sources are utilized.
PMCID: PMC4142714  PMID: 25170179
Cyclopropanes; Endoperoxide; Photocatalysis; Photooxygenation; Radical cation
11.  A General, Simple Catalyst for Enantiospecific Cross Couplings of Benzylic Ammonium Triflates and Boronic Acids: No Phosphine Ligand Required 
Tetrahedron  2014;70(27-28):4257-4263.
Highly improved conditions for the enantiospecific cross coupling of benzylic ammonium triflates with boronic acids are reported. This method relies on the use of Ni(cod)2 without ancillary phosphine or N-heterocyclic carbene ligands as catalyst. These conditions enable the coupling of new classes of boronic acids and benzylic ammonium triflates. In particular, both heteroaromatic and vinyl boronic acids are well tolerated as coupling partners. In addition, these conditions enable the use of ammonium triflates with a variety of substituents at the benzylic stereocenter. Further, naphthyl-substitution is not required on the benzylic ammonium triflate; ammonium triflates with simple aromatic substituents also undergo this coupling. Good to high yields and levels of stereochemical fidelity are observed. This new catalyst system greatly expands the utility of enantiospecific cross couplings of these amine-derived substrates for the preparation of highly enantioenriched products.
PMCID: PMC4210769  PMID: 25364060
enantiospecific cross coupling; nickel catalysis; carbon–nitrogen bond activation; benzylic electrophiles
12.  Synthesis of phospholipids on a glyceric acid scaffold: design and preparation of phospholipase A2 specific substrates 
Tetrahedron  2014;70(19):3155-3165.
Synthesis of a new series of phospholipid analogues to serve as activity-based probes of secretory phospholipase A2 enzymes is reported. The synthesis is based upon 1) preparation of long-chain esters and amides of glyceric acid, followed by 2) regioselective derivatization of the diol function of the molecule to achieve phosphorylation at the primary hydroxyl group, and to introduce the incipient sn-2-ester group of the target compounds. The sequence has been shown to allow incorporation of fluorescent, paramagnetic, and redox-active reporter groups, leading to phospholipid analogues applicable to detect and measure enzyme activity, to develop highly specific, real-time spectroscopic assay of phospholipase A2 enzymes, as well as to track the metabolic fate of the hydrolysis products. The synthetic method has a great deal of flexibility to open the way to the design and synthesis of activity-probes for other phospholipid metabolizing enzymes as well.
PMCID: PMC4104365  PMID: 25061236
Phospholipid synthesis; Glyceric acid; Phospholipase A2 activity-probe; Reporter group
13.  Thermally-Induced Substrate Release Via Intramolecular Cyclizations of Amino Esters and Amino Carbonates 
Tetrahedron  2014;70(21):3422-3429.
The relative cleavage of an alcohol from a panel of amino esters and amino carbonates via intramolecular cyclization was examined as a mechanism for substrate release. Thermal stability at 37 °C was observed only for the 7-membered ring progenitors. Applicability of the approach was illustrated by δ-lactam formation within a poly(dimethylsiloxane) microchannel for release of a captured fluorescent probe.
PMCID: PMC4104717  PMID: 25061237
lactam; oxazolidinone; drug delivery; poly(dimethylsiloxane) microchannel
14.  Formyl Group Activation of a Bromopyrrole Ester in Suzuki Cross-Coupling Reactions: Application to a Formal Synthesis of Polycitone A and B and Polycitrin A 
Tetrahedron  2014;70(17):2738-2745.
A new pyrrole building block is described, which allows for the regiospecific synthesis of 2,3,5-trisubstituted pyrroles and 2,3,4,5- tetrasubstituted pyrroles. Optimization studies are presented for the preparation of the pyrrole building block along with the evaluation of various cross-coupling conditions and cross-coupling agents. A short, formal synthesis of the natural products Polycitone A, Polycitone B and Polycitrin A from the pyrrole building block is also described.
PMCID: PMC4004070  PMID: 24795487
Suzuki Cross-Coupling; Pyrrole; Vilsmeier Formylation; Marine Natural Products
15.  Efficient Synthesis of the Cyclopentanone Fragrances (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone and Magnolione 
Tetrahedron  2014;70(2):276-279.
This paper describes the selective syntheses of two cis-isomer enriched cyclopentanone fragrances: (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone (4 steps, 62% overall yield, 67% cis) and Magnolione® (5 steps, 60% overall yield, 55% cis). In addition, the asymmetric synthesis of (3aR,7aS)-5-methyl-2,3,3a,4,7,7a-hexahydro-1H-inden-1-one as well as (3a'R,7a'S)-5'-methyl-2',3',3a',4',7',7a'-hexahydrospiro[[1,3]dioxolane-2,1'-indene]) has been realized by an efficient kinetic resolution, which enables the selective synthesis of the 2S,3R-isomer-enriched 3 and 4.
PMCID: PMC3982870  PMID: 24729640
cyclopentanone fragrances; jasmonoids; magnolione; cis-selective synthesis; kinetic resolution
16.  MCRs reshaped into a switchable microwave-assisted protocol toward 5-aminoimidazoles and dihydrotriazines 
Tetrahedron  2013;7(1):54-59.
A tunable microwave-assisted protocol for the synthesis of two biologically relevant families of heterocycles has been designed. Via a simple switch of reaction conditions, the same starting materials can be engaged in either an improved synthesis of the dihydrotriazine scaffold or a novel, first-in-class MCR to render the challenging 5-aminoimidazole nucleus in a single step. An additional first in class MCR is also reported utilizing guanidines to afford 2,5-aminoimidazoles.
PMCID: PMC3925149  PMID: 24535889
Imidazole; Multicomponent Reaction; Strecker; Trimethylsilylcyanide
17.  Indole synthesis: a review and proposed classification 
Tetrahedron  2011;67(38):7195-7210.
PMCID: PMC4255418  PMID: 25484459
18.  Facile synthesis of 4,5,6a,7-tetrahydrodibenzo[de,g]chromene heterocycles and their transformation to phenanthrene alkaloids 
Tetrahedron  2013;69(42):10.1016/j.tet.2013.07.095.
Oxa-Pictet-Spengler cyclization and microwave-assisted C-H arylation have been implemented as key steps in the synthesis of new isochroman heterocycles containing a 4,5,6a,7-tetrahydrodibenzo[de,g]chromene motif. These isochromans may be easily transformed to phenanthrene alkaloids via acidic cleavage of the isochroman ring and standard synthetic manipulations thereafter. The route described is attractive in that it provides access to two biologically interesting scaffolds in simple and high yielding synthetic steps.
PMCID: PMC3810968  PMID: 24187388
C-H activation; Direct arylation; Oxa-Pictet-Spengler; Phenanthrene; Isochroman
19.  Electrophilic aromatic prenylation via cascade cyclization 
Tetrahedron  2013;69(44):9212-9218.
To gain access to prenylated hexahydroxanthenes, tandem cascade cyclization-electrophilic aromatic substitution reactions have been studied on substrates bearing allylic and propargylic substituents. Both BF3·OEt2 and TMSOTf can be used to initiate this reaction sequence, resulting in different ratios of the C-2 and C-6 substitution products. Even though allylic transposition is observed in some cases, the results of a crossover experiment are consistent with an intramolecular reaction sequence. Taken together, these studies now allow preparation of either the C-2 or C-6 prenylated hexahydroxanthene products.
PMCID: PMC3940164  PMID: 24610962
Cationic; Cyclization; Electrophilic aromatic substitution; Prenylation; Tandem reactions
20.  Use of a palladium(II)-catalyzed oxidative kinetic resolution in synthetic efforts toward bielschowskysin 
Tetrahedron  2013;69(36):7627-7635.
Progress toward the cyclobutane core of bielshowskysin is reported. The core was thought to arise from a cyclopropane intermediate via a furan-mediated cyclopropane fragmentation, followed by a 1,4-Michael addition. The synthesis of the cyclopropane intermediate utilizes a Suzuki coupling reaction, an esterification with 2-diazoacetoacetic acid, and a copper catalyzed cyclopropanation. An alcohol intermediate within the synthetic route was obtained in high enantiopurity via a highly selective palladium(II)-catalyzed oxidative kinetic resolution (OKR).
PMCID: PMC3728638  PMID: 23913988
Bielschowskysin; palladium; transesterification; synthesis
21.  Bimolecular Coupling Reactions through Oxidatively Generated Aromatic Cations: Scope and Stereocontrol 
Tetrahedron  2013;69(36):7618-7626.
Chromenes, isochromenes, and benzoxathioles react with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to form stable aromatic cations that react with a range of nucleophiles. These oxidative fragment coupling reactions provide rapid access to structurally diverse heterocycles. Conducting the reactions in the presence of a chiral Brønsted acid results in the formation of an asymmetric ion pair that can provide enantiomerically enriched products in a rare example of a stereoselective process resulting from the generation of a chiral electrophile through oxidative carbon–hydrogen bond cleavage.
PMCID: PMC3728896  PMID: 23913987
oxidation; fragment coupling; heterocycles; chiral counterions; enantioselectivity
22.  A noncovalent, fluoroalkyl coating monomer for phosphonate-covered nanoparticles 
Tetrahedron  2013;69(36):7741-7746.
Gadolinium-containing phosphonate-coated gold nanoparticles were prepared and then non-covalently coated with an amphiphilic fluorous monomer. The monomer spontaneously self-assembles into a non-covalent monolayer shell around the particle. The binding of the shell utilizes a guanidinium-phosphonate interaction analogous to the one exploited by the Wender molecular transporter system. Particle-shell binding was characterized by a 27% decrease in 19F T1 of the fluorous shell upon exposure to the paramagnetic gadolinium in the particle and a corresponding increase in hydrodynamic diameter from 3 nm to 4 nm. Interestingly, a much smaller modulation of 19F T1 is observed when the shell monomer is treated with a phosphonate-free particle. By contrast, the phosphonate-free particle is a much more relaxive 1H T1 agent for water. Together, these observations show that the fluoroalkylguanidinium shell binds selectively to the phosphonate-covered particle. The system’s relaxivity and selectivity give it potential for use in 19F based nanotheranostic agents.
PMCID: PMC3728910  PMID: 23913989
Theranostic; Gold nanoparticle; Surfaces; Relaxivity; Fluorine
23.  Condensation reactions of guanidines with bis-electrophiles: Formation of highly nitrogenous heterocyclesa 
Tetrahedron  2013;69(36):7719-7731.
2-Amino-1,4-dihydropyrimidines were reacted with bis-electrophiles to produce novel fused bi-pyrimidine, pyrimido-aminotriazine, and pyrimido-sulfonamide scaffolds. In addition, a quinazoline library was constructed using a guanidine Atwal-Biginelli reaction with 1-(quinazolin-2-yl)guanidines. The product heterocycles have novel constitutions with high nitrogen atom counts and represent valuable additions to screening libraries for the discovery of new modulators of biological targets.
PMCID: PMC3746774  PMID: 23976798
Guanidines; Pyrimidines; Quinazolines; Atwal-Biginelli reaction; Screening library
24.  Template-induced macrocycle diversity through large ring-forming alkylations of tryptophan 
Tetrahedron  2013;69(36):7683-7691.
Macrocyclic peptidomimetics are valuable in research and serve as lead compounds in drug discovery efforts. New methods to prepare such structures are of considerable interest. In this pilot study, we show that an organic template harboring a latent cinnamyl cation participates in novel Friedel-Crafts macrocyclization reactions with tryptophan. Upon joining the template to Trp-Trp-Tyr, a single operation efficiently generates eight unique macrocycles. Each has been isolated and thoroughly characterized. Product distribution as a function of Brønsted and/or Lewis acidic conditions was explored, and outcomes were compared to rearrangements induced within a corresponding tyrosine-linked cyclic ether. The solution structure of a new macrocyclic pyrroloindoline was solved using a combination of two-dimensional NMR methods and molecular mechanics simulations. Template-induced structural diversification of peptide sequences harboring aromatic residues has potential to create myriad macrocycles that target surfaces involved in protein-protein interactions.
PMCID: PMC3746997  PMID: 23976797
Peptidomimetic; Macrocycle; Friedel-Crafts; Diversity; NMR solution structure
25.  A room temperature copper catalyzed N-selective arylation of β-amino alcohols with iodoanilines and aryl iodides 
Tetrahedron  2013;69(36):7646-7652.
An efficient method is described for the synthesis of N-(2-aminophenyl)-2-hydroxyethylamines via a copper catalyzed N-selective arylation of β-amino alcohols with iodoanilines. The corresponding coupling products are useful intermediates for the synthesis of a variety of N-2-hydroxyethyl-substituted benzimidazoles, benzimidazolones, and iminobenzimidazoles. We found that 2-iodoaniline only arylates certain amino alcohols but not amines lacking a hydroxyl group. We also demonstrate the arylation of sterically demanding β-amino alcohols, such as ephedrine and prolinol with aryl iodides at room temperature.
PMCID: PMC3768125  PMID: 24039306
Cross-coupling; Copper catalysis; Arylation; Amino Alcohol; Iodoaniline; Benzimidazole

Results 1-25 (391)