Design and construction of a stereochemically diverse piperazine-based DNA-encoded chemical library.

Here we report the successful construction of a novel, stereochemically diverse DNA-Encoded Chemical Library (DECL) by utilizing 24 enantiomerically pure trifunctional 2, 6- di-substituted piperazines as central cores. We introduce the concept of positional diversity by placing the DNA attachment at either of two possible sites on the piperazine scaffold. Using a wide range of building blocks, a diverse library of 77 million compounds was produced. Cheminformatic analysis demonstrates that this library occupies a wide swath of chemical space, and that the piperazine scaffolds confers different shape diversity compared to the commonly used triazine core.

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.

Self-assembled multi-component catenanes: the effect of multivalency and cooperativity on structure and stability.

Using dynamic combinatorial chemistry, mixtures of dipeptide monomers were combined to probe how the structural elements of a family of self-assembled [2]-catenanes affect their equilibrium stability versus competing non-catenated structures. Of particular interest were experiments to target the effects of CH-π interactions, inter-ring hydrogen bonds, and ß-turn types on [2]-catenane energetics. The non-variant core of the [2]-catenane was shown only to adopt type II' and type VIII turns at the ß-2 and ß-4 positions, respectively. Monomers were designed to delineate how these factors contribute to [2]-catenane equilibrium speciation/stability. Dipeptide turn adaptation studies, including three-component dynamic self-assembly experiments, suggested that stability losses are localized to the mutated sites, and that the turn types for the core ß-2 and ß-4 positions, type II' and type VIII, respectively, cannot be modified. Mutagenesis studies on the core Aib residue involved in a seemingly key CH-π-CH sandwich reported on how CH-π interactions and inter-ring hydrogen bonds affect stability. The interacting methyl group of Aib could be replaced with a range of alkyl and aryl substituents with monotonic affects on stability, though polar heteroatoms were disproportionately destabilizing. The importance of a key cross-ring H-bond was also probed by examining an Aib for l-Pro variant. Inductive affects and the effect of CH donor multiplicity on the core proline-π interaction also demonstrated that electronegative substituents and the number of CH donors can enhance the effectiveness of a CH-π interaction. These data were interpreted using a cooperative binding model wherein multiple non-covalent interactions create a web of interdependent interactions. In some cases, changes to a component of the web lead to compensating effects in the linked interactions, while in others, the perturbations create a cascade of destabilizing interactions that lead to disproportionate losses in stability.

Self-assembled multi-component catenanes: structural insights into an adaptable class of molecular receptors and [2]-catenanes.

Under acidic conditions (50 equiv of TFA), combinations of hydrazide A-B monomers self-assemble into octameric [2]-catenanes with high selectivity for [1(3)2](2), where 1 is a D-Pro-X (X = Aib, Ac(4)c, Ac(6)c, L-4-Cl-PhGly)-derived monomer and 2 is an L-Pro'-L-arylGly (Pro' = Pro, trans-F-Pro, trans-HO-Pro, aryl = naphthyl, phenyl)-derived monomer. Five different combinations of monomers were studied by X-ray crystallography. In each case, the unique aryl glycine unit is located in the core of the structure where the aryl ring templates a CH-π-CH sandwich. Analysis of metrical parameters indicates that this core region is highly conserved, while the more peripheral zones are flexible. (1)H NMR spectroscopy indicate that the solid-state structures are largely retained in solution, though several non-C(2)-symmetric compounds have a net C(2)-symmetry that indicates accessible dynamic processes. Catenane dynamic processes were additionally probed through H/D exchange, with the core being inflexible relative to the peripheral structure. Mass spectrometry was utilized to identify the constitutional isomerism in the minor asymmetric [1(5)2(3)] catenanes.

Deracemization of a dynamic combinatorial library induced by (-)-cytidine and (-)-2-thiocytidine.

A dynamic combinatorial library composed of racemic hydrazone-based dipeptides becomes deracemized on binding to the chiral analytes (-)-cytidine and (-)-2-thiocytidine through the amplification of two receptors, (SS)-dimer and (RRRR)-tetramer. The deracemization phenomenon was investigated by laser polarimetry, mass-tagged pseudo-enantiomers in conjunction with electrospray ionization mass spectrometry, HPLC/UV-MS, UPLC/UV-MS, rapid-resolution LC-MS, collision-induced dissociation MS/MS, and numerical simulations. These data were consistent with a phenomenon where (SS)-dimer and (RRRR)-tetramer selectively bind the chiral analyte in preference to their enantiomeric counterparts, which ultimately causes them to be amplified and the library to become deracemized.

The effect of gas-phase reactions on the quantitation of cyclic hydrazone libraries by electrospray ionization (ESI) mass spectrometry.

Using mass spectrometry coupled with LC analysis we report evidence of diastereomer dependent fragmentation and oligomerization reactions in the ionization of acyl-hydrazone-based libraries of cyclic oligomers. These effects can significantly affect the accuracy of MS-based quantitations, but also provide a venue for examining ionization effects in dynamic combinatorial libraries (DCLs).

Synthesis of sterically hindered ortho-substituted tetraphenylethenes. Electronic effects in the McMurry olefination reaction.

[reaction: see text] Contrary to literature consensus, the McMurry olefination reaction can be extended to the direct synthesis of sterically encumbered tetrakis(2-substituted) tetraphenylethenes from the corresponding 2,2'-disubstituted benzophenones. The reaction exploits previously unrecognized substrate-based electronic effects that dominate over otherwise controlling steric considerations and provides highly efficient access to derivatives of tetrakis(2-hydroxyphenyl)ethene, a novel preorganized ligand system for polymetallic coordination chemistry and catalysis.

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.

Ortho-silylated derivatives of tetrakis(2-hydroxyphenyl)ethene: a sterically isolated structural model for oxo-surface binding domains.

The introduction of sterically isolating ortho-trialkylsilyl, -aryldialkylsilyl, and -diarylalkylsilyl substituents onto the structurally preorganized tetrakis(2-hydroxyphenyl)ethene ligand framework has been accomplished by a 4-fold retro-Brook rearrangement. Installation of the most sterically demanding silyl substituents required the development of an iterative procedure, involving successive double silylation/metalation/migration sequences without the isolation of intermediates. This system was designed to function as a soluble structural model for the planar binding domains of heterogeneous "oxo-surfaces" of silica and alumina supports.

Regioselectively trisilylated hexopyranosides through homogeneously catalyzed silane alcoholysis.

The iridium complex [Ir(COD)(PPh3)2]+ SbF6- reacts with tert-butyldimethylsilane in DMA to form [IrH2(Sol)2(PPh3)2]+ SbF6-, which is an active catalyst for the regioselective di- and trisilylation of a series of representative methyl hexopyranosides, beta-1,6-anhydrohexopyranosides and 1,3,5-O-methylidene inositol. The corresponding 2,3,6- and 2,4,6-silylated glycosides are obtained in a separable mixture of 47-89% (2,3,6-isomers) and 9-25% (2,4,6-isomers) yield in a single-pot reaction. The 2,4-disilylated derivatives of mannosan, galactosan, and 1,3,5-O-methylidene inositol as well as persilylated levoglucosan are accessible in >85% yield by this method. The homogeneous nature of the catalysts is a prerequisite for the effective di-/trisilylation, as nanoparticle colloid catalysts generated in situ from Pd2(dba)3 (approximately 1.5 nm average particle size) or Ru2Cl5(MeCN)7 (approximately 0.65 nm average particle size) result in only low yields.

A catalytic synthesis of thiosilanes and silthianes: palladium nanoparticle-mediated cross-coupling of silanes with thio phenyl and thio vinyl ethers through selective carbon-sulfur bond activation.

Palladium nanoparticles generated in situ from N,N-dimethyl-acetamide (DMA) solutions of PdX(2) (X = Cl(-), OAc(-), OCOCF(3)(-)) or Pd(2)(dba)(3) by reduction with alkyl silanes R(3)SiH (R = Me, Et, i-Pr, t-Bu) are selective catalysts for the cross-coupling of the silanes R(3)SiH with phenyl and vinyl thioethers forming the corresponding thiosilanes and silthianes in high yields and under mild conditions. The method is applicable to phenyl thioglycosides, giving access to thiosilyl glycosides a new class of sugar derivatives.

Regioselective silylation of sugars through palladium nanoparticle-catalyzed silane alcoholysis.

Palladium(0)-catalyzed silane alcoholysis was applied to sugars for the first time using tert-butyldimethylsilane (TBDMS-H) and Ph(3)SiH as the silanes. The catalyst is a colloidal solution of Pd(0) generated in situ from PdX(2) (X = Cl(-), OAc(-)) and TBDMS-H in N,N-dimethylacetamide. The colloid has been characterized by dynamic light scattering and transmission electron microscopy and consists of catalytically highly active nanoparticles of approximately 2 nm diameter. The silane alcoholysis reaction is an effective method for the regioselective silylation of methyl and phenyl glycosides and generates hydrogen gas as the only side product. For many of the sugar substrates investigated, the distribution of regioisomers obtained is complementary to that of the traditional R(3)SiCl/base (base = pyridine, imidazole) methodology and gives convenient access to the 3,6- rather than the 2,6-silylated pyranosides, obtained as the main product by the silyl chloride method. The method also allows a selective axial silylation of levoglucosan and 1,3,5-O-methylidene-myo-inositol. In an attempt to rationalize the observed regioselectivities, ab initio predictions (HF/3-21G) have been made on the relative energies of some of the silylated products. They suggest that the observed regioselectivities do not reflect a kinetic vs thermodynamic product distribution but are induced by the silylation agent employed. Models for the possible origin of the observed regioselectivity in both silylation methods (silane- and silyl chloride-based) are discussed.