N-Si Heterolysis by Chiral (BOX)Cu(OTf) Catalysts for the Synthesis of Indole and Carbazole Glycosides.

Chiral Cu(II) bisoxazolines have been shown to catalyze the coupling of acetyl-protected carbohydrates with N-silylated indoles to give the corresponding N-glycosides. Preliminary mechanistic experiments indicated that catalysis occurs through formation of a Cu-indolide complex with concomitant formation of TMS-OTf which together activate the sugar and deliver the indole nucleophile.

Stimulus-Induced Relief of Intentionally Incorporated Frustration Drives Refolding of a Water-Soluble Biomimetic Foldamer.

Frustrated, or nonoptimal, interactions have been proposed to be essential to a protein's ability to display responsive behavior such as allostery, conformational signaling, and signal transduction. However, the intentional incorporation of frustrated noncovalent interactions has not been explored as a design element in the field of dynamic foldamers. Here, we report the design, synthesis, characterization, and molecular dynamics simulations of the first dynamic water-soluble foldamer that, in response to a stimulus, exploits relief of frustration in its noncovalent network to structurally rearrange from a pleated to an intercalated columnar structure.

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Iodenium or Phosphonium: The Ambi-Valent Character of Iodophosphonium Complexes.

The ambi-valent character of the P-I bond in iodophosphonium complexes ensures that it can be electrophilic at either P or I. Herein, we use an ensemble of computational tools and methodologies to probe the nature of this ambi-valent bond. Geometric and atomic electron population analyses yielded strong trends between the electron donating ability of the phosphine and the strength and polarity of the P-I bond.

Precyclization Conformer Profiles of -SiR- and -Bcat-Activated Linear Si-Protected Hexitols Explain Condensative Cyclization Selectivities.

The condensative cyclization of sp C-O bonds in per-silylated hexitols is investigated by computation. Conformer searches using the Monte Carlo algorithm, followed by successively higher levels of theory (MMFF, PM3, and B3LYP), of -SiR- and -Bcat-activated substrates lead to structures primed for intramolecular chemistry. Silane activation features O4 to C1 attack, while borane activation suggests boronium ions that activate O5 to C2 reactivity.

Borane- and Silylium-Catalyzed Difunctionalization of Carbohydrates: 3,6-Anhydrosugar Enabled 1,6-Site Selectivity.

A novel diastereoselective, Lewis acid catalyzed 1,6-difunctionalization of galactose and mannose derivatives has been developed in one pot, via sequential nucleophile additions. Our studies point to the formation of a 3,6-anhydrosugar intermediate as key to the 1,6-site-selectivity. Starting material-specific reactivity occurs when competitive ring-opening C-O cleavage is possible, owed to basicity and stereoelectronic stabilization differences.

Switching between -Pyrano-, -Furano-, and Anhydro--pyranoside Synthesis (X = C, N) under Lewis acid Catalyzed Conditions.

A variety of -glycosides can be obtained from the fluoroarylborane (B(CF)) or silylium (RSi) catalyzed functionalization of 1-MeO- and per-TMS-sugars with TMS-X reagents. A one-step functionalization with a change as simple as the addition order and/or Lewis acid and TMS-X enables one to afford chiral synthons that are common (-pyranosides), have few viable synthetic methods (-furanosides), or are virtually unknown (anhydro--pyranosides), which mechanistically arise from whether a direct substitution, isomerization/substitution, or substitution/isomerization occurs, respectively.

Selective deoxygenation of gibberellic acid with fluoroarylborane catalysts.

Reductive late-stage functionalization of gibberellic acid is reported using three fluoroarylborane Lewis acids; (B(CF), B(3,5-CH(CF)), and B(2,4,6-CHF)) in combination with a tertiary silane and a borane (HBCat) reductant. In each case, C-O bond activation occurs, and different products are obtained depending on the reductant and catalyst employed.

Modulating Electrostatic Interactions in Ion Pair Intermediates To Alter Site Selectivity in the C-O Deoxygenation of Sugars.

Controlling which products one can access from the predefined biomass-derived sugars is challenging. Changing from CH Cl to the greener alternative toluene alters which C-O bonds in a sugar are cleaved by the tris(pentafluorophenyl)borane/HSiR catalyst system. This increases the diversity of high-value products that can be obtained through one-step, high-yielding, catalytic transformations of the mono-, di-, and oligosaccharides.

Silylpalladium Cations Enable the Oxidative Addition of C(sp)-O Bonds.

The synthesis and characterization of the room-temperature and solution-stable silylpalladium cations (PCy)Pd-SiR(CF)B (SiR = SiMeEt, SiHEt) and (Xantphos)Pd-SiR(BAr) (SiR = SiMeEt, SiHEt; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; BAr = (3,5-(CF)CH)B) are reported. Spectroscopic and ligand addition experiments suggest that silylpalladium complexes of the type (PCy)Pd-SiR are three-coordinate and T-shaped. Addition of dialkyl ethers to both the PCy and Xantphos-based silylpalladium cations resulted in the cleavage of C(sp)-O bonds and the generation of cationic Pd-alkyl complexes.

Site Selective Amide Reduction of Cyclosporine A Enables Diverse Derivation of an Important Cyclic Peptide.

Site selective amide reductions of the cyclic undecapeptide, cyclosporine A, have been developed using the combination of a heteroleptic borane catalyst and a silane reductant. Tertiary silane MeEtSiH provides two unique cyclosporine A derivatives, one of which can be readily diversified in subsequent reactions. The secondary silane EtSiH enables divergent reactivity that uses a free hydroxyl group to direct the reduction.

Chemoselective amide reductions by heteroleptic fluoroaryl boron Lewis acids.

The heteroleptic borane catalyst (C6F5)2B(CH2CH2CH2)BPin is found to hydrosilylatively reduce amides under mild conditions. Simple tertiary amides can be reduced using Me2EtSiH, whereas tertiary benzamides required a more reactive secondary silane, Et2SiH2, for efficient reduction. The catalytic system described exhibits exceptional chemoselectivity in the reduction of oligoamides and tolerates functionalities which are prone to reduction under similar conditions.

Computed thermodynamic stabilities of silylium Lewis base adducts.

We report a computational study of the transfer of silylium from phosphine to heteroatom containing Lewis bases including ethers, phosphines, and amines. The relative free energies of these compounds are compared to develop a thermodynamic scale of stabilities that can help to interpret the chemoselectivity observed with complex natural products and biomass-derived sugars. Both the choice of silane and the phosphine Lewis base impact the thermodynamics of this transfer.

Late-stage chemoselective functional-group manipulation of bioactive natural products with super-electrophilic silylium ions.

The selective (and controllable) modification of complex molecules with disparate functional groups (for example, natural products) is a long-standing challenge that has been addressed using catalysts tuned to perform singular transformations (for example, C-H hydroxylation). A method whereby reactions with diverse functional groups within a single natural product are feasible depending on which catalyst or reagent is chosen would widen the possible structures one could obtain. Fluoroarylborane catalysts can heterolytically split Si-H bonds to yield an oxophilic silylium (RSi) equivalent along with a reducing (H) equivalent.

Gold(I) Catalyzed Dearomative Claisen Rearrangement of Allyl, Allenyl Methyl, and Propargyl Aryl Ethers.

Claisen rearrangements of allyl aryl ethers to generate enones bearing all carbon quaternary centers are accelerated by PhPAuNTf under mild conditions in good yields. Multiple C-C bond containing variants of the allyl fragment are viable, including alkylidenecyclopropanes, allenes, and alkynes, which generate all-carbon stereogenic centers substituted with vinyl cyclopropanes, 1,3-butadienyl, and allenyl substituents, respectively, for subsequent synthetic manipulation. With allyl phenyl ethers, the product of the [3,3] rearrangements can be trapped by a tandem [4 + 2] cycloaddition to generate complex molecular scaffolds from readily available, achiral starting materials.

Biomimetic Platinum-Promoted Polyene Polycyclizations: Influence of Alkene Substitution and Pre-cyclization Conformations.

Results of kinetic experiments and quantum chemical computations on a series of platinum-promoted polycyclization reactions are described. Analyses of these results reveal a reactivity model that reaches beyond the energetics of the cascade itself, incorporating an ensemble of pre-cyclization conformations of the platinum-alkene reactant complex, only a subset of which are productive for bi- (or larger) cyclization and lead to products. Similarities and differences between this scenario, including reaction coordinates for polycyclization, for platinum- and enzyme-promoted polycyclization reactions are highlighted.

Gold(i)-catalyzed addition of aldehydes to cyclopropylidene bearing 6-aryl-1,5-enynes.

A diastereoselective, gold-catalyzed cascading cycloisomerization of alkylidene cyclopropane bearing 1,5-enynes that terminates in a cyclo-addition of aldehydes has been developed. This diastereoselective reaction provides convergent access to novel polycyclic molecular structures (18 examples), and tolerates a diverse scope of aldehydes. Mechanistic studies reveal that the catalytic cycle rests at a digold off-cycle intermediate, one of which was isolated.

Investigation of a Catenane with a Responsive Noncovalent Network: Mimicking Long-Range Responses in Proteins.

We report a functional synthetic model for studying the noncovalent networks (NCNs) required for complex protein functions. The model [2]-catenane is self-assembled from dipeptide building blocks and contains an extensive network of hydrogen bonds and aromatic interactions. Perturbations to the catenane cause compensating changes in the NCNs structure and dynamics, resulting in long-distance changes reminiscent of a protein.

Diastereoselective B(C6F5)3-Catalyzed Reductive Carbocyclization of Unsaturated Carbohydrates.

A B(C6F5)3-catalyzed method for the selective conversion of unsaturated carbohydrates to cyclopentanes and cyclopropanes is disclosed. Catalyst activation of tertiary silanes generates the ion pair [(C6F5)3B-H][ROSi2] whose components synergistically activate C-O bonds for diastereoselective C-C bond formation. Sila-THF cations are invoked as key intermediates facilitating carbocyclizations.

Tetrameric psuedo-peptide receptors with allosteric properties.

This paper reports the binding properties of tetrameric pseudo-peptide receptors for protonated cytidines. The receptors, which were isolated from a dynamic combinatorial chemistry (DCC) experiment, bind the analytes with affinities that depend on the presence or absence of excess acid, and with a stoichiometry that is both concentration and temperature dependent.

Promoting C-C Bond Coupling of Benzyne and Methyl Ligands in Electron-Deficient (triphos)Pt-CH Complexes.

In situ generated benzyne reacts at room temperature with (triphos)Pt-CH to form a five-coordinate π-complex () that is isolable and stable in solution. Thermolysis of at 60 °C generates (triphos)Pt(o-tolyl) (), which is the product of formal migratory insertion of CH onto the coordinated benzyne. The reaction of with the acid PhNH yields toluene at room temperature over the course of 8 h, while the same reaction with only proceeds to 40% conversion over 2 days.

Chemoselective conversion of biologically sourced polyols into chiral synthons.

Crude oil currently provides much of the world's energy, but it is also the source of many feedstock chemicals. Methodology for the conversion of biomass into useful chemicals has often focused on either complete deoxygenation or the production of high-volume platform chemicals. Here, we describe the chemoselective partial reduction of silyl-protected C6O6-derived polyols to produce a diverse set of oxygen-functionalized chiral synthons.

Enantioselective Cascade Cyclization/Protodemetalation of Polyenes with NPt Catalysts.

The combination of the N-based pincer ligand PyBOX with Pt leads to new catalysts for the enantioselective cycloisomerization of dienyl- and trienyl-ols. The mechanistic combination of electrophilic cyclization followed by rapid protodemetalation is surprising and leads to a powerful construct for developing new reactions.

Aurophilicity in gold(I) catalysis: for better or worse?

This book chapter discusses the effects of aurophilicity on gold catalysis. First, a brief historic account of aurophilicity in organogold chemistry is given, focusing on the pioneering results which set the stage for its association with catalytic intermediates (gold vinyl and gold aryl complexes); this is followed by an introduction to cationic gold(I) as an electrophilic catalyst, and the first isolation of organogold intermediates from catalysis. In the main section, the growing number of reports observing aurophilic interactions in catalysis or illustrative model systems is reviewed in a non-comprehensive tutorial way.