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. Thus, relief of frustration provides the energetic driving force for structural rearrangement. This work represents a previously unexplored design element for the development of stimulus-responsive systems that has potential application to materials chemistry, synthetic biology, and molecular machines.

Precyclization Conformer Profiles of -SiR3+- and -Bcat+-Activated Linear Si-Protected Hexitols Explain Condensative Cyclization Selectivities.

The condensative cyclization of sp3 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 -SiR3+- 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. This, in conjunction with Boltzmann population analysis, parallels reported reactivity for sorbitol, mannitol, and galactitol. Calculations using the meta-hybrid M06-2X functional additionally provide free-energy profiles for each cyclization event. In most of the cases presented, precyclization conformers that position a nucleophilic oxygen less than 3.0 Å from the C-O leaving group correlate to efficient experimental reactivities. Two examples of galactitol containing bridging silyl groups are analyzed computationally, and the experimental outcomes match predictions. The computational regime presented is a step closer to providing predictive power for the reduction of per-functionalized molecules.

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. Quasi-atomic orbital analysis demonstrated the near homo-polarity of the P-I bond, and energy decomposition analysis calculations demonstrated the ability to tune the polarization of the bond with only mild changes in secondary structural features. Finally, the ambi-valent nature of the P-I bond was demonstrated to follow hard-soft considerations in reactions with nucleophiles, with harder nucleophiles preferentially forming products of addition to P and softer nucleophiles to I.

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 CH2 Cl2 to the greener alternative toluene alters which C-O bonds in a sugar are cleaved by the tris(pentafluorophenyl)borane/HSiR3 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. Computational methods helped identify this non-intuitive outcome in low dielectric solvents to non-isotropic electrostatic enhancements in the key ion pair intermediates, which influence the reaction coordinate in the reactivity-/selectivity-determining step. Molecular-level models for these effects have far-reaching consequences in stereoselective ion pair catalysis.

Silylpalladium Cations Enable the Oxidative Addition of C(sp3)-O Bonds.

The synthesis and characterization of the room-temperature and solution-stable silylpalladium cations (PCy3)2Pd-SiR3+(C6F5)4B- (SiR3 = SiMe2Et, SiHEt2) and (Xantphos)Pd-SiR3+(BArf4) (SiR3 = SiMe2Et, SiHEt2; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; BArf4 = (3,5-(CF3)2C6H3)4B-) are reported. Spectroscopic and ligand addition experiments suggest that silylpalladium complexes of the type (PCy3)2Pd-SiR3+ are three-coordinate and T-shaped. Addition of dialkyl ethers to both the PCy3 and Xantphos-based silylpalladium cations resulted in the cleavage of C(sp3)-O bonds and the generation of cationic Pd-alkyl complexes. Mechanistically enabling is the ability of silylpalladium cations to behave as sources of both electrophilic silylium ions and nucleophilic LnPd(0).

Selective deoxygenation of gibberellic acid with fluoroarylborane catalysts.

Reductive late-stage functionalization of gibberellic acid is reported using three fluoroarylborane Lewis acids; (B(C6F5)3, B(3,5-C6H3(CF3)2), and B(2,4,6-C6H2F3)3) 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.

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.

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.

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. Key findings include the notion that NCNs require regions of negative cooperativity, or "frustrated" noncovalent interactions, as a source of potential energy for driving the response. We refer to this potential energy as latent free energy and describe a mechanistic and energetic model for responsive systems.

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.

Electrophilic Pt(II) complexes: precision instruments for the initiation of transformations mediated by the cation-olefin reaction.

A discontinuity exists between the importance of the cation-olefin reaction as the principal C-C bond forming reaction in terpene biosynthesis and the synthetic tools for mimicking this reaction under catalyst control; that is, having the product identity, stereochemistry, and functionality under the control of a catalyst. The main reason for this deficiency is that the cation-olefin reaction starts with a reactive intermediate (a carbocation) that reacts exothermically with an alkene to reform the reactive intermediate; not to mention that reactive intermediates can also react in nonproductive fashions. In this Account, we detail our efforts to realize catalyst control over this most fundamental of reactions and thereby access steroid like compounds. Our story is organized around our progress in each component of the cascade reaction: the metal controlled electrophilic initiation, the propagation and termination of the cyclization (the cyclase phase), and the turnover deplatinating events. Electrophilic Pt(II) complexes efficiently initiate the cation-olefin reaction by first coordinating to the alkene with selection rules that favor less substituted alkenes over more substituted alkenes. In complex substrates with multiple alkenes, this preference ensures that the least substituted alkene is always the better ligand for the Pt(II) initiator, and consequently the site at which all electrophilic chemistry is initiated. This control element is invariant. With a suitably electron deficient ligand set, the catalyst then activates the coordinated alkene to intramolecular addition by a second alkene, which initiates the cation-olefin reaction cascade and generates an organometallic Pt(II)-alkyl. Deplatination by a range of mechanisms (ß-H elimination, single electron oxidation, two-electron oxidation, etc.) provides an additional level of control that ultimately enables A-ring functionalizations that are orthogonal to the cyclase cascade. We particularly focus on reactions that combine an initiated cyclization reaction with a turnover defining ß-hydride elimination, fluorination, and oxygenation. These latter demetalation schemes lead to new compounds functionalized at the C3 carbon of the A-ring (steroid numbering convention) and thus provide access to interesting potentially bioactive targets. Progress toward efficient and diverse polycyclization reactions has been achieved by investing in both synthetic challenges and fundamental organometallic reactivity. In addition to an interest in the entrance and exit of the metal catalyst from this reaction scheme, we have been intrigued by the role of neighboring group participation in the cyclase phase. Computational studies have served to provide nuance and clarity on several key aspects, including the role (and consequences) of neighboring group participation in cation generation and stabilization. For example, these calculations have demonstrated that traversing carbonium ion transition states significantly impacts the kinetics of competitive 6-endo and 5-exo A-ring forming reactions. The resulting nonclassical transition states then become subject to a portion of the strain energy inherent to bicyclic structures, with the net result being that the 6-endo pathway becomes kinetically favored for alkene nucleophiles, in contrast to heteroatom nucleophiles which progress through classical transition states and preferentially follow 5-exo pathways. These vignettes articulate our approach to achieving the desired catalyst control.

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. The effects of aurophilicity are discussed in the following structures: (1) the geminal diauration of C(sp²)-atoms; (2) geminal diauration of other atoms; (3) σ-π-diauration of terminal alkynes. It is apparent that in most cases efficient catalysis is hindered by aurophilic effects as less active aggregates tend to be formed from more active species [LAu]⁺, but there are a growing number of reports using aurophilicity as a driving force to access new reactivity and selectivity.

Diastereoselective Pt catalyzed cycloisomerization of polyenes to polycycles.

Application of a tridentate NHC containing pincer ligand to Pt catalyzed cascade cyclization reactions has allowed for the catalytic, diastereoselective cycloisomerization of biogenic alkene terminated substrates to the their polycyclic counterparts.

A catalyst selection protocol that identifies biomimetic motifs from ß-hairpin libraries.

Assaying a solid-phase library of histidine-containing ß-hairpin peptides by a reactive tagging scheme in organic solvents selects for catalysts that reproduce the strategies used by His-based enzyme active sites to accelerate acyl- and phosphonyl-transfer reactions. Rate accelerations (k(rel)) in organic solvents of up to 2.4 × 10(8) are observed.

Selective transamidation of 3-oxo-N-acyl homoserine lactones by hydrazine derivatives.

A method for the selective transamidation of the 3-oxo sub-family of N-acyl homoserine lactones (3-oxo-AHLs) under physiologically relevant conditions has been developed. The reaction has the potential to serve as a strategy for selective knockdown of key autoinducers in a multicellular environment.

Identification and optimization of short helical peptides with novel reactive functionality as catalysts for acyl transfer by reactive tagging.

Herein we describe the screening and subsequent optimization of peptide catalysts for ester activation. A combinatorial methodology using dye-tagged substrate analogs is described for determining which components of a His-containing helical library display acyl transfer activity. We found that helical peptides display high activity, and amino acids that reinforce this propensity are advantaged. Through this approach two new structural motifs have been discovered that are capable of activating esters in organic solvents. Unlike most acyl transfer catalysts functioning in organic solvents, these catalysts are histidine- rather than N-alkyl histidine-based. Longer peptides with localization of reactive groups on the C-terminal end of the peptide were found to further enhance catalytic activity up to ∼2800-fold over background.

Gold-catalyzed diastereoselective cycloisomerization of alkylidene-cyclopropane-bearing 1,6-diynes.

An unprecedented gold-catalyzed diastereoselective cycloisomerization of 1,6-diynes bearing an alkylidene cyclopropane moiety has been developed. This methodology enables rapid access to a variety of 1,2-trimethylenenorbornanes, which are important building blocks in the preparations of abiotic and sesquiterpene core structures.

Metal-free deoxygenation of carbohydrates.

The conversion of readily available cellulosic biomass to valuable feedstocks and fuels is an attrative goal but a challenging transformation that requires the cleavage of multiple nonactivated CO bonds. Herein, the Lewis acid trispentafluorophenylborane (B(C6 F5 )3 ) is shown to catalyze the metal-free hydrosilylative reduction of monosaccharides and polysaccharides to give hydrocarbons with reduced oxygen content. The choice of the silane reductant influences the degree of deoxygenation, with diethylsilane effecting the complete reduction to produce hexanes while tertiary silanes give partially deoxygenated tetraol and triol products.

N-Si Heterolysis by Chiral (BOX)Cu(OTf)2 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.

Catalytic enantioselective cyclization and C3-fluorination of polyenes.

(Xylyl-phanephos)Pt(2+) in combination with XeF(2) mediates the consecutive diastereoselective cation-olefin cyclization/fluorination of polyene substrates. Isolated yields were typically in the 60-69% range while enantioselectivities reached as high as 87%. The data are consistent with a stereoretentive fluorination of a P(2)Pt-alkyl cation intermediate.