Boronic Acid-Catalyzed Regio- and Stereoselective N-Glycosylations of Purines and Other Azole Heterocycles: Access to Nucleoside Analogues.

In the presence of an arylboronic acid catalyst, azole-type heterocycles, including purines, tetrazoles, triazoles, indazoles, and benzo-fused congeners, undergo regio- and stereoselective N-glycosylations with furanosyl and pyranosyl trichloroacetimidate donors. The protocol, which does not require stoichiometric activators, specialized leaving groups, or drying agents, provides access to nucleoside analogues and enables late-stage N-glycosylation of azole-containing pharmaceutical agents. A mechanism involving simultaneous activation of the glycosyl donor and acceptor by the organoboron catalyst has been proposed, supported by kinetic analysis and computational modeling.

On the mechanism of carboxylate elimination from carbohydrate monoester-derived radicals.

A computational study of the mechanism of hydrogen atom transfer-induced carboxylate elimination from monoacylated 1,2-diol groups in pyranosides is presented. A comprehensive analysis of the 1,2-migration, elimination and fragmentation pathways reveals that concerted elimination via a 7-membered, hydrogen-bonded transition state is favored. Relative rates of elimination inferred from an intramolecular competition experiment are consistent with the trends obtained from the calculations.

Understanding the Origins of Site Selectivity in Hydrogen Atom Transfer Reactions from Carbohydrates to the Quinuclidinium Radical Cation: A Computational Study.

The use of quinuclidine as a hydrogen atom transfer (HAT) mediator, along with a light-absorbing photoredox catalyst, has proved to be a powerful and general approach for achieving site-selective radical formation from carbohydrate substrates. Despite numerous literature reports documenting the scope and limitations of such processes, a general rationale for the origins of site selectivity in the key HAT step has not been advanced. In this study, density functional theory calculations (M06-2X/def2-TZVP/PCM(acetonitrile)) were used to model transition states for HAT to the quinuclidinium radical cation from pyranosides and furanosides having various configurations and substitution patterns. The data set (>120 transition state geometries and energies) has allowed for a detailed examination of the factors that influence the relative rates, augmented by additional analysis using the atoms in molecules (AIM) and distortion/interaction-activation strain frameworks. The trends that have emerged regarding the effects of configuration, conformation, substitution, and noncovalent interactions are consistent with experimental observations and reveal a key role for C-H···O hydrogen bonds in stabilizing transition states for HAT to the quinuclidinium radical cation.

Chimeric GFP-uracil based molecular rotor fluorophores.

Uracil has been modified at the 5-position to derive a small library of nucleobase-chromophores which were inspired by green fluorescent protein (GFP). The key steps in the syntheses were Erlenmeyer azlactone synthesis followed by amination by use of hexamethyl disilazane (HMDS) to produce the imidazolinone derivatives. The uracil analogues displayed emission in the green region of visible spectrum and exhibited microenvironmental sensitivity exemplified by polarity-based solvatochromism and viscosity-dependent emission enhancement. Solid-state quantum yields of approximately 0.2 and solvent dependent emission wavelengths beyond 500 nm were observed. Select analogues were incorporated into peptide nucleic acid (PNA) strands which upon duplex formation with DNA showed good response ranging from a turn-off of fluorescence in presence of an opposing mismatched residue to a greater than 3-fold turn-on of fluorescence upon binding to fully complementary DNA strand.

Effects of Configuration and Substitution on C-H Bond Dissociation Enthalpies in Carbohydrate Derivatives: A Systematic Computational Study.

Density functional theory was used to calculate C-H bond dissociation enthalpies (BDEs) at each position of a diverse collection of pyranosides and furanosides differing in relative configuration and substitution patterns. A detailed analysis of the resulting data set (186 BDEs, calculated at the M06-2X/def2-TZVP level of theory) highlights the ways in which stereoelectronic effects, conformational properties, and noncovalent interactions can influence the strengths of C-H bonds in carbohydrates. The results point toward opportunities to alter the radical reactivity of carbohydrate derivatives by variation of their stereochemical configuration or the positions and types of protective groups.

Transformations of carbohydrate derivatives enabled by photocatalysis and visible light photochemistry.

This review article highlights the diverse ways in which recent developments in the areas of photocatalysis and visible light photochemistry are impacting synthetic carbohydrate chemistry. The major topics covered are photocatalytic glycosylations, generation of radicals at the anomeric position, transformations involving radical formation at non-anomeric positions, additions to glycals, processes initiated by photocatalytic hydrogen atom transfer from sugars, and functional group interconversions at OH and SH groups. Factors influencing stereo- and site-selectivity in these processes, along with mechanistic aspects, are discussed.

Synthesis of Borylated (Aminomethyl)cyclopropanes Using C1-Bisnucleophiles.

Lithiated 1,1-diborylalkanes have been used as nucleophilic coupling partners with a range of oxygen-based electrophiles, including esters, carbonyls, and epoxides. However, their reactivity with nitrogen-based electrophiles, such as aziridines, has remained relatively understudied. Herein, we show that lithiated 1,1-diborylalkanes react with α-halo and α-tosyl aziridines to yield borylated (aminomethyl)cyclopropanes-a privileged scaffold within medicinal chemistry. The reaction displays high levels of diastereoselectivity, enabling careful control of up to three stereocenters within a single transformation. DFT studies provide insight into the reaction mechanism, which diverges from that observed with analogous epihalohydrin starting materials. Derivatization studies were also performed on the products to demonstrate the utility of the boron and amine handles.

Catalyst-Controlled, Site-Selective Sulfamoylation of Carbohydrate Derivatives.

Methods for site-selective sulfamoylation of secondary hydroxyl groups in pyranosides are described. Using a boronic acid catalyst, selective installation of a Boc-protected sulfamoyl group at the equatorial position of cis-diols in manno- and galacto-configured substrates has been achieved. Activation of trans-diol groups in gluco- and galacto-configured substrates is also possible by employing an organotin catalyst.

Site- and Stereoselective C-H Alkylations of Carbohydrates Enabled by Cooperative Photoredox, Hydrogen Atom Transfer, and Organotin Catalysis.

Diorganotin dihalides act as cocatalysts for site-selective and stereoselective couplings of diol-containing carbohydrates with electron-deficient alkenes in the presence of an Ir(III) photoredox catalyst and quinuclidine, a hydrogen atom transfer mediator. Quantum-chemical calculations support a proposed mechanism involving the formation of a cyclic stannylene acetal intermediate that shows enhanced reactivity toward hydrogen atom abstraction by the quinuclidinium radical cation. Addition of the carbon-centered radical to the alkene partner results in C-alkylation of the carbohydrate substrate.

Modeling Controlled Cortical Impact Injury in 3D Brain-Like Tissue Cultures.

Traumatic brain injury (TBI) survivors suffer long term from mental illness, neurodegeneration, and neuroinflammation. Studies of 3D tissue models have provided new insights into the pathobiology of many brain diseases. Here, a 3D in vitro contusion model is developed consisting of mouse cortical neurons grown on a silk scaffold embedded in collagen and used outcomes from an in vivo model for benchmarking. Molecular, cellular, and network events are characterized in response to controlled cortical impact (CCI). In this model, CCI induces degradation of neural network structure and function and release of glutamate, which are associated with the expression of programmed necrosis marker phosphorylated Mixed Lineage Kinase Domain Like Pseudokinase (pMLKL). Neurodegeneration is observed first in the directly impacted area and it subsequently spreads over time in 3D space. CCI reduces phosphorylated protein kinase B (pAKT) and Glycogen synthase kinase 3 beta (GSK3ß) in neurons in vitro and in vivo, but discordant responses are observed in phosphprylated ribosomal S6 kinase (pS6) and phosphorylated Tau (pTau) expression. In summary, the 3D brain-like culture system mimicked many aspects of in vivo responses to CCI, providing evidence that the model can be used to study the molecular, cellular, and functional sequelae of TBI, opening up new possibilities for discovery of therapeutics.