Attochemistry Regulation of Charge Migration.

Charge migration (CM) is a coherent attosecond process that involves the movement of localized holes across a molecule. To determine the relationship between a molecule's structure and the CM dynamics it exhibits, we perform systematic studies of para-functionalized bromobenzene molecules (X-C6H4-R) using real-time time-dependent density functional theory. We initiate valence-electron dynamics by emulating rapid strong-field ionization leading to a localized hole on the bromine atom. The resulting CM, which takes on the order of 1 fs, occurs via an X localized → C6H4 delocalized → R localized mechanism. Interestingly, the hole contrast on the acceptor functional group increases with increasing electron-donating strength. This trend is well-described by the Hammett σ value of the group, which is a commonly used metric for quantifying the effect of functionalization on the chemical reactivity of benzene derivatives. These results suggest that simple attochemistry principles and a density-based picture can be used to predict and understand CM.

Total Synthesis of a Pentasaccharide O-Glycan from Acinetobacter baumannii.

Acinetobacter baumannii is a Gram-negative bacteria associated with drug resistance and infection in healthcare settings. An understanding of both the biological roles and antigenicity of surface molecules of this organism may provide an important step in the prevention and treatment of infection through vaccination or the development of monoclonal antibodies. With this in mind, we have performed the multistep synthesis of a conjugation-ready pentasaccharide O-glycan from A. baumannii with a longest linear synthetic sequence of 19 steps. This target is particularly relevant due to its role in both fitness and virulence across an apparently broad range of clinically relevant strains. Synthetic challenges include formulating an effective protecting group scheme as well as the installation of a particularly difficult glycosidic linkage between the anomeric position of a 2,3-diacetamido-2,3-dideoxy-D-glucuronic acid and the 4-position of D-galactose.

1,2-cis-Selective glucosylation enabled by halogenated benzyl protecting groups.

We report on our initial results from a systematic effort to implement electron-withdrawing protecting groups and Lewis basic solvents/additives as an approach to 1,2-cis(α)-selective O-glucosylation. 1,2-cis-Selective O-glucosylations are reported with thioglucosides and glucosyl trichloroacetimidates and a range of acceptors. A correlation between electron-withdrawing effects and 1,2-cis selectivity has been established. This phenomenon may prove to be broadly applicable in the area of chemical O-glycosylation.

A Visible-Light-Promoted O-Glycosylation with a Thioglycoside Donor.

Visible-light irradiation of 4-p-methoxyphenyl-3-butenylthioglucoside donors in the presence of Umemoto's reagent and alcohol acceptors serves as a mild approach to O-glycosylation. Visible-light photocatalysts are not required for activation, and alkyl- and arylthioglycosides not bearing the p-methoxystyrene are inert to these conditions. Experimental and computational evidence for an intervening electron donor-acceptor complex, which is necessary for reactivity, is provided. Yields with primary, secondary, and tertiary alcohol acceptors range from moderate to high. Complete ß-selectivity can be attained through neighboring-group participation.

Remote Hydroxylation through Radical Translocation and Polar Crossover.

Mild conditions are reported for the hydroxylation of aliphatic C-H bonds through radical translocation, oxidation to carbocation, and nucleophilic trapping with H2O. This remote functionalization employs fac-[Ir(ppy)3] together with Tz(o) sulfonate esters and sulfonamides to facilitate the site-selective replacement of relatively inert C-H bonds with the more synthetically useful C-OH group. The hydroxylation of a range of substrates and the methoxylation of two substrates through 1,6- and 1,7-hydrogen-atom transfer are demonstrated. In addition, a synthesis of the antidepressant fluoxetine using remote hydroxylation as a key step is presented.

Application of visible light photocatalysis with particle lithography to generate polynitrophenylene nanostructures.

Visible light photoredox catalysis was combined with immersion particle lithography to prepare polynitrophenylene organic films on Au(111) surfaces, forming a periodic arrangement of nanopores. Surfaces masked with mesospheres were immersed in solutions of p-nitrobenzenediazonium tetrafluoroborate and irradiated with blue LEDs in the presence of the photoredox catalyst Ru(bpy)3(PF6)2 to produce p-nitrophenyl radicals that graft onto gold substrates. Surface masks of silica mesospheres were used to protect small, discrete regions of the Au(111) surface from grafting. Nanopores were formed where the silica mesospheres touched the surface; the mask effectively protected nanoscopic local areas from the photocatalysis grafting reaction. Further reaction of the grafted arenes with aryl radicals resulted in polymerization to form polynitrophenylene structures with thicknesses that were dependent on both the initial concentration of diazonium salt and the duration of irradiation. Photoredox catalysis with visible light provides mild, user-friendly conditions for the reproducible generation of multilayers with thicknesses ranging from 2 to 100 nm. Images acquired with atomic force microscopy (AFM) disclose the film morphology and periodicity of the polymer nanostructures. The exposed sites of the nanopores provide a baseline to enable local measurements of film thickness with AFM. The resulting films of polynitrophenylene punctuated with nanopores provide a robust foundation for further chemical steps. Spatially selective binding of mercaptoundecanoic acid to exposed sites of Au(111) was demonstrated, producing a periodic arrangement of thiol-based nanopatterns within a matrix of polynitrophenylene.

Ascaroside activity in Caenorhabditis elegans is highly dependent on chemical structure.

The nematode Caenorhabditis elegans secretes ascarosides, structurally diverse derivatives of the 3,6-dideoxysugar ascarylose, and uses them in chemical communication. At high population densities, specific ascarosides, which are together known as the dauer pheromone, trigger entry into the stress-resistant dauer larval stage. In order to study the structure-activity relationships for the ascarosides, we synthesized a panel of ascarosides and tested them for dauer-inducing activity. This panel includes a number of natural ascarosides that were detected in crude pheromone extract, but as yet have no assigned function, as well as many unnatural ascaroside derivatives. Most of these ascarosides, some of which have significant structural similarity to the natural dauer pheromone components, have very little dauer-inducing activity. Our results provide a primer to ascaroside structure-activity relationships and suggest that slight modifications to ascaroside structure dramatically influence binding to the relevant G protein-coupled receptors that control dauer formation.

Benzyne-Promoted, 1,2-cis-Selective O-Glycosylation with Benzylchalcogenoglycoside Donors.

Here, we show that the reaction of benzylchalcogenoglycosides with benzyne in the presence of alcohols results in highly 1,2-cis-selective O-glycosylation in a solvent-dependent manner. Thioglycosides, selenoglycosides, and alcohols with a range of nucleophilicities lead to a productive reaction, and unusual protecting groups, auxiliary groups, and additives are avoided.

Biosynthesis of the Caenorhabditis elegans dauer pheromone.

To sense its population density and to trigger entry into the stress-resistant dauer larval stage, Caenorhabditis elegans uses the dauer pheromone, which consists of ascaroside derivatives with short, fatty acid-like side chains. Although the dauer pheromone has been studied for 25 years, its biosynthesis is completely uncharacterized. The daf-22 mutant is the only known mutant defective in dauer pheromone production. Here, we show that daf-22 encodes a homolog of human sterol carrier protein SCPx, which catalyzes the final step in peroxisomal fatty acid beta-oxidation. We also show that dhs-28, which encodes a homolog of the human d-bifunctional protein that acts just upstream of SCPx, is also required for pheromone production. Long-term daf-22 and dhs-28 cultures develop dauer-inducing activity by accumulating less active, long-chain fatty acid ascaroside derivatives. Thus, daf-22 and dhs-28 are required for the biosynthesis of the short-chain fatty acid-derived side chains of the dauer pheromone and link dauer pheromone production to metabolic state.

Total Synthesis of an All-1,2-cis-Linked Repeating Unit from the Acinetobacter baumannii D78 Capsular Polysaccharide.

Chemical synthetic efforts have resulted in the preparation of the assigned tetrasaccharide repeating subunit from the Acinetobacter baumannii KL4-associated capsular polysaccharide. A convergent synthetic strategy hinging on a 1,2-cis-selective [2+2] glycosylation to generate the fully protected tetrasaccharide was key to the success of this synthesis.

A potent dauer pheromone component in Caenorhabditis elegans that acts synergistically with other components.

In the model organism Caenorhabditis elegans, the dauer pheromone is the primary cue for entry into the developmentally arrested, dauer larval stage. The dauer is specialized for survival under harsh environmental conditions and is considered "nonaging" because larvae that exit dauer have a normal life span. C. elegans constitutively secretes the dauer pheromone into its environment, enabling it to sense its population density. Several components of the dauer pheromone have been identified as derivatives of the dideoxy sugar ascarylose, but additional unidentified components of the dauer pheromone contribute to its activity. Here, we show that an ascaroside with a 3-hydroxypropionate side chain is a highly potent component of the dauer pheromone that acts synergistically with previously identified components. Furthermore, we show that the active dauer pheromone components that are produced by C. elegans vary depending on cultivation conditions. Identifying the active components of the dauer pheromone, the conditions under which they are produced, and their mechanisms of action will greatly extend our understanding of how chemosensory cues from the environment can influence such fundamental processes as development, metabolism, and aging in nematodes and in higher organisms.

Single-particle kinetics of influenza virus membrane fusion.

Membrane fusion is an essential step during entry of enveloped viruses into cells. Conventional fusion assays are generally limited to observation of ensembles of multiple fusion events, confounding more detailed analysis of the sequence of the molecular steps involved. We have developed an in vitro, two-color fluorescence assay to monitor kinetics of single virus particles fusing with a target bilayer on an essentially fluid support. Analysis of lipid- and content-mixing trajectories on a particle-by-particle basis provides evidence for multiple, long-lived kinetic intermediates leading to hemifusion, followed by a single, rate-limiting step to pore formation. We interpret the series of intermediates preceding hemifusion as a result of the requirement that multiple copies of the trimeric hemagglutinin fusion protein be activated to initiate the fusion process.

Leveraging Trifluoromethylated Benzyl Groups toward the Highly 1,2-Cis-Selective Glucosylation of Reactive Alcohols.

Here, we demonstrate that substitution of the benzyl groups of glucosyl imidate donors with trifluoromethyl results in a substantial increase in 1,2-cis-selectivity when activated with TMS-I in the presence of triphenylphosphine oxide. Stereoselectivity is dependent on the number of trifluoromethyl groups (4-trifluoromethylbenzyl vs 3,5-bis-trifluoromethylbenzyl). Particularly encouraging is that we observe high 1,2-cis-selectivity with reactive alcohol acceptors.

MPTGs: Thioglycoside Donors for Acid-Catalyzed O-Glycosylation and Latent-Active Synthetic Strategies.

4-( p-Methoxyphenyl)-4-pentenylthioglycosides (MPTGs) undergo acid-catalyzed O-glycosylation with a range of alcohol acceptors in the presence of 10 mol % of triflic acid at room temperature. Particularly encouraging is the reactivity of MPTGs toward unreactive acceptors. MPTGs can be synthesized from the requisite vinyl bromides using the Suzuki reaction, and this chemistry can be leveraged toward a "latent-active" strategy for oligosaccharide synthesis.

Acid-Catalyzed O-Glycosylation with Stable Thioglycoside Donors.

Two classes of thioglycoside, 4-(4-methoxyphenyl)-3-butenylthioglycosides (MBTGs) and 4-(4-methoxyphenyl)-4-pentenylthioglycosides (MPTGs), undergo acid-catalyzed O-glycosylations with a range of sugar and nonsugar alcohols at 25 °C. Electron density at the styrene alkene is critical for reactivity while sugar protecting group patterns have a minimal effect. In contrast with most methods for thioglycoside activation, acid-catalyzed activation of MBTGs is compatible with electroneutral alkenes.

Visible-Light-Promoted Remote C-H Functionalization of o-Diazoniaphenyl Alkyl Sulfones.

Visible-light irradiation of ortho-diazoniaphenyl alkyl sulfones in the presence of Ru(bpy)32+ results in remote Csp3-H functionalization. Key mechanistic steps in these processes involve intramolecular hydrogen atom transfer from Csp3-H bonds to aryl radicals to generate alkyl/benzyl radicals. Subsequent polar crossover occurs by single-electron oxidation of the alkyl/benzyl radicals to carbenium ions that then intercept nucleophiles. We have developed remote hydroxylations, etherifications, an amidation, and C-C bond formation processes using this strategy.

Application of visible-light photosensitization to form alkyl-radical-derived thin films on gold.

Visible-light irradiation of phthalimide esters in the presence of the photosensitizer [Ru(bpy)3]2+ and the stoichiometric reducing agent benzyl nicotinamide results in the formation of alkyl radicals under mild conditions. This approach to radical generation has proven useful for the synthesis of small organic molecules. Herein, we demonstrate for the first time the visible-light photosensitized deposition of robust alkyl thin films on Au surfaces using phthalimide esters as the alkyl radical precursors. In particular, we combine visible-light photosensitization with particle lithography to produce nanostructured thin films, the thickness of which can be measured easily using AFM cursor profiles. Analysis with AFM demonstrated that the films are robust and resistant to mechanical force while contact angle goniometry suggests a multilayered and disordered film structure. Analysis with IRRAS, XPS, and TOF SIMS provides further insights.

Pseudosymmetry in azabicyclo[2.1.1]hexanes. A stereoselective construction of the bicyclic core of peduncularine.

Intramolecular photocycloaddition of 41 or its equivalent leads to the formation of photoadduct 25. While retro-Mannich fragmentation of the "b" bond in 25 leads to the formation of 44 (via 43), with the incorrect relative stereochemistry for the synthesis of peduncularine 5, selective fragmentation of the "a" bond in 25 leads to the formation of 42 (via 26) with the correct relative stereochemistry for the synthesis of 5.

Intramolecular photoaddition of vinylogous amides with allenes: a novel approach to the synthesis of pyrroles.

Irradiation of vinylogous amide or imide 5 (R = H, alkyl, or Ac) leads to the selective formation of either crossed photoadduct 7 (R = Ac) or parallel photoadduct 8 (R = H or alkyl) as a function of the nature of the group R. The latter result leads to a novel approach to the synthesis of pyrroles, that is, 8'.

Synthesis and biological evaluation of manzamine analogues.

[Structure: see text] The synthesis and biological evaluation of a series of analogues of manzamine A, representing partial structures of the pentacyclic ABCDE diamine core, is described. All new compounds were screened against Plasmodium falciparum and demonstrated attenuated antimalarial activity relative to that of manzamine A.