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A novel engineering strategy to improve autoantibody detection with peptide fragments derived from the parent antigen is presented. The model system studied was the binding of the putative p53 TAD peptide antigen (residues 46-55) to its cognate anti-p53 antibody, ab28. Each engineered peptide contained the full decapeptide epitope and differed only in the flanking regions. Since minimal structural information was available to guide the design, a simple epitope:paratope binding model was applied. The Hidden Symmetry Model, which we recently reported, was used to guide peptide design and estimate per-residue contributions to interaction free energy as a function of added C- and N-terminal flanking peptides. Twenty-four peptide constructs were designed, synthesized, and assessed for binding affinity to ab28 by surface plasmon resonance, and a subset of these peptides were evaluated in a simulated immunoassay for limit of detection. Many peptides exhibited over 200-fold enhancements in binding affinity and improved limits of detection. The epitope was reevaluated and is proposed to be the undecapeptide corresponding to residues 45-55. HSymM calculated binding free energy and experimental data were found to be in good agreement (R2 > 0.75).

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The separation of n-alkanes from their branched isomers is vitally important to improve octane rating of gasoline. To facilitate mass transfer, adsorptive separation is usually operated under high temperatures in industry, which require considerable energy. Herein, we present a kind of dynamic pillar-layered MOF that exhibits self-adjustable structure and pore space, a behavior induced by guest molecules. A combination of the flexibility of the framework with the commensurate adsorption for n-hexane results in exceptional performance in separating hexane isomers. More significantly, lower temperature prompts the guest molecules to open the dynamic pores, which may provide a new perspective for optimized separation performance at lower temperatures with less energy consumption.

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Fluorocarbons and chlorocarbons are common volatile organic compounds that pose serious risk to the environment and human health and therefore need to be effectively captured. Herein, we report a series of highly fluorinated metal-organic frameworks with high porosity (Brunauer-Emmett-Teller surface area ∼3000 m2/g) and stability. They show exceptionally high capacity and good recyclability toward the adsorption of fluorocarbons and chlorocarbons.

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Fluorescence-based detection is one of the most efficient and cost-effective methods for detecting hazardous, aqueous Hg2+. We designed a fluorescent porous organic polymer (TPA-POP-TSC), with a "fluorophore" backbone and a thiosemicarbazide "receptor" for Hg2+-targeted sensing. Nanometer-sized TPA-POP-TSC spheres (nanoPOP) were synthesized under mini-emulsion conditions and showed excellent solution processability and dispersity in aqueous solution. The nanoPOP sensor exhibits exceptional sensitivity (Ksv = 1.01 × 106 M-1) and outstanding selectivity for Hg2+ over other ions with rapid response and full recyclability. Furthermore, the nanoPOP material can be easily coated onto a paper substrate to afford naked eye-based Hg2+-detecting test strips that are convenient, inexpensive, fast, highly sensitive, and reusable. Our design takes advantage of the efficient and selective capture of Hg2+ by thiosemicarbazides (binding energy = -29.84 kJ mol-1), which facilitates electron transfer from fluorophore to bound receptor, quenching the sensor's fluorescence.

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A concise route to a glycosylated allenic erythronolide was achieved. Key findings include the preparation of a desosamine sulfoxide donor and the use of the donor to glycosylate bulky acceptors. Additionally, the new reagent was used to prepare allene-containing macrocycles and to realize a four-step synthesis of macrolide 6 from bis[allene] 5. The longest linear sequence required to prepare 6 from commercial reagents was 15 steps.

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Here we present a model to estimate the interaction free energy contribution of each amino acid residue of a given protein. Protein interaction energy is described in terms of per-residue interaction factors, µ. Multibody interactions are implicitly captured in µ through the combination of amino acid terms (γ) guided by local conformation indices (σ). The model enables construction of an interaction factor heat map for a protein in a given fold, allows prima facie assessment of the degree of residue-residue interaction, and facilitates a qualitative and quantitative evaluation of protein association properties. The model was used to compute thermal stability of T4 bacteriophage lysozyme mutants across seven sites. Qualitative assessment of mutational effects provides a straightforward rationale regarding whether a particular site primarily perturbs native or non-native states, or both. The presented model was found to be in good agreement with experimental mutational data (R 2 = 0.73) and suggests an approach by which to convert structure space into energy space.

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It has been 60 years since Eschenmoser and Frey disclosed the archetypal CC fragmentation reaction. New fragmentations and several variants of the original quickly followed. Many of these variations, which include the Beckmann, Grob, Wharton, Marshall, and Eschenmoser-Tanabe fragmentations, have been reviewed over the intervening years. A close examination of the origins of fragmentation has not been described. Recently, useful new methods have flourished, particularly fragmentations that give alkynes and allenes, and such reactions have been applied to a range of complex motifs and natural products. This Review traces the origins of fragmentation reactions and provides a summary of the methods, applications, and new insights of heterolytic CC fragmentation reactions advanced over the last 20 years.

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Two concise methods for generating oxetan-3-ones from allenes are reported. The first method employs allene epoxidation, opening of the spirodiepoxide by a halide nucleophile, and then intramolecular displacement of a halide by an alkoxide. The second method involves allene epoxidation and then thermal rearrangement of the corresponding spirodiepoxide to oxetan-3-one. The two methods are complementary and stereochemically divergent. Computational analysis of the thermal rearrangement is also described.

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The complexity and low tractability of antibiotic macrolides pose serious challenges to addressing the problem of resistance through semi- or total synthesis. Here we describe a new strategy involving the preparation of a complex yet tractable macrocycle and the transformation of this macrocycle into a range of erythronolide congeners. These compounds represent valuable sectors of erythromycinoid structure space and constitute intermediates with the potential to provide further purchase in this space. The routes are short. The erythronolides were prepared in three or fewer steps from the macrocycle, which was prepared in a longest linear sequence of 11 steps.

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The synthesis of a model endocyclic allene related to the vernonia allenes is described. Fragmentation of a suitable decalin derivative gave the simplified germacrane scaffold. Computational analysis of this and related substrates provides insight into the stereoelectronic requirements of C-C fragmentation. The overall strategy to access these and other sesquiterpenes and the key steps in the present sequence are also discussed.

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Allene epoxide formation/opening reaction sequences enabled direct access to diverse products. Described here are a single flask procedure for allene preparation and allene oxidation/derivatization reactions that give, among others, diendiol, diyndiol, α'-hydroxy-γ-enone, dihydrofuranone, butenolide, and δ-lactone products.

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Stereoselective chemical synthesis requires the two faces of a π bond to be differentiated. Theoretically sound qualitative models for understanding stereoinduction seem to break down in sterically unbiased cyclic systems. Presented here as the distortional asymmetry model is new insight that identifies circumstances where distortional ground state contributions are highly asymmetric and thereby contribute significantly to face selectivity. Out-of-plane distortional potential calculations, transition state calculations and molecular orbital analysis agree with experimental data that cannot otherwise be attributed to steric, torsion, polar or emergent transition state stabilizing effects. The model is readily understood in terms of reaction theory. The explanatory power of the model is also discussed.

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The synthesis of a C1-C19 precursor to pectenotoxin 4 is presented. The strategy employed the functionalized allene shown. Key features include: olefin metathesis of two simple fragments to prepare the left portion of the allene-precursor, diastereoselective propargylation of an epoxy aldehyde to form the right portion, use of the DMDO-stable m-fluorobenzyl ether, and an allene spirodiepoxidation/C-ring formation cascade.

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A short synthesis of the natural product epi-citreodiol and the method developed to gain access to this target are described. Key advances focus on silyl substituted allenes. Upon exposure to dimethyldioxirane, spirodiepoxides form with high face selectivity and subsequently react at the silyl terminus.

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A new method of allene synthesis is described. Suitably functionalized vinyl triflates undergo fragmentation to give allenes in high yield. Computational and experimental data provide a mechanistic framework for allene formation and the complementary formation of alkynes. The method is stereospecific.

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A concise route to functionalized 14-membered macrolides related to erythronolide A was achieved. Key steps include the simultaneous formation of bis[allenic] substrates, efficient macrolactonization, highly stereoselective oxidation to the corresponding bis[spirodiepoxide], and nucleophilic spirodiepoxide opening. The structure and reactivity of these macrolides, and the strategy that led to their evaluation, are discussed.

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Three closely related analogues of epoxomicin have been synthesized. Allene-derived spirodiepoxides were key intermediates. Spirodiepoxide formation and stereochemical dependence on solvent, oxidant, and allene structure were cataloged. The facial selectivity of the first epoxidation of 1,3-disubstituted and trisubstituted allenes was found to be >20:1 with dimethyldioxirane in chloroform. For stereogenic allenes, the facial selectivity of the second oxidation is dependent primarily on allene structure and secondarily on solvent and oxidant. For the acyclic systems evaluated this ratio was as high as 8:1. A conformational model is advanced to account for these observations.

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Insight derived from a synthetic model, calculated (13)C NMR data, and comparison to experimental data indicate that the proposed allenic structure A, originally assigned to an isolate from Brosimum acutifolium Huber, should be revised to B, a natural product and nonallenic substance, mururin C.

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Presented is a review of the advances in synthetic methodology that make use of the allene functional group, with emphasis on catalytic asymmetric transformations and new mechanistic insights. The review covers the period from January 2007 to May 2008 and focuses on intra- and intermolecular cycloaddition, carbocycle cycloisomerization, heterocycle synthesis, epoxidation, addition and miscellaneous transformations. A brief discussion of allenes as transition metal ligands, the use of allenes in total synthesis and potential medicinal agents that contain the allene functionality is also presented.

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