The Tungsten-Promoted Synthesis of Piperidyl-Modified erythro-Methylphenidate Derivatives.

Due to its efficacy as a dopamine receptor agonist, methylphenidate (MPH) is of interest as a potential therapeutic for cocaine addiction. While numerous derivatives of MPH have been investigated for their potential medicinal value, functionalization of the piperidine ring has not been explored. The pyridine borane ligand in WTp(NO)(PMe3)(η2-pyBH3) is dearomatized by the metal and can be elaborated to the analogous η2-mesylpyridinium complex. Installing a methyl phenylacetate moiety at the C2' position via a Reformatsky reaction followed by a tandem protonation/nucleophilic addition sequence results in a library of erythro MPH analogues functionalized at the piperidyl C5' position. The functional group is added chemoselectively to C5', cis to the methyl phenylacetate. Repeating this procedure with an enantioenriched source of the tungsten reagent results in enantioenriched MPH derivatives. All identities of the newly reported compounds are supported by comprehensive 2D NMR and HRMS data or crystallographic data.

Imaging Diverse Pathogenic Bacteria In Vivo with 18F-Fluoromannitol PET.

Infectious disease remains the main cause of morbidity and mortality throughout the world. Of growing concern is the rising incidence of multidrug-resistant bacteria, derived from various selection pressures. Many of these bacterial infections are hospital-acquired and have prompted the Centers for Disease Control and Prevention in 2019 to reclassify several pathogens as urgent threats, its most perilous assignment. Consequently, there is an urgent need to improve the clinical management of bacterial infection via new methods to specifically identify bacteria and monitor antibiotic efficacy in vivo. In this work, we developed a novel radiopharmaceutical, 2-18F-fluoro-2-deoxy-mannitol (18F-fluoromannitol), which we found to specifically accumulate in both gram-positive and gram-negative bacteria but not in mammalian cells in vitro or in vivo. Methods: Clinical isolates of bacteria were serially obtained from wounds of combat service members for all in vitro and in vivo studies. Bacterial infection was quantified in vivo using PET/CT, and infected tissue was excised to confirm radioactivity counts ex vivo. We used these same tissues to confirm the presence of bacteria by extracting and correlating radioactive counts with colony-forming units of bacteria. Results: 18F-fluoromannitol was able to differentiate sterile inflammation from Staphylococcus aureus and Escherichia coli infections in vivo in a murine myositis model using PET imaging. Our study was extended to a laceration wound model infected with Acinetobacter baumannii, an important pathogen in the nosocomial and battlefield setting. 18F-fluoromannitol PET rapidly and specifically detected infections caused by A. baumannii and several other important pathogens (Enterococcus faecium, S. aureus, Klebsiella pneumoniae, A. baumannii, Pseudomonas aeruginosa, and Enterobacter spp.). Importantly, 18F-fluoromannitol PET was able to monitor the therapeutic efficacy of vancomycin against S. aureus in vivo. Conclusion: The ease of production of 18F-fluoromannitol is anticipated to facilitate wide radiopharmaceutical dissemination. Furthermore, the broad sensitivity of 18F-fluoromannitol for bacterial infection in vivo suggests that it is an ideal imaging agent for clinical translation to detect and monitor infections and warrants further studies in the clinical setting.

An automated radiosynthesis of [18F]DPA-714 on a commercially available radiosynthesizer, Elixys Flex/Chem.

[18F]DPA-714 is a radiotracer specific to the translocator protein (TSPO) and is useful for in vivo Positron Emission Tomography imaging studies. In this report, we have developed an automated radiosynthesis of [18F]DPA-714 on a commercially-available radiosynthesis platform, which comports with USP <823> guidelines. The wide availability of the radiosynthesis module and ease of dissemination of the production sequence will facilitate preclinical and clinical research of TSPO-related pathology.

Experiments and Direct Dynamics Simulations That Probe η2-Arene/Aryl Hydride Equilibria of Tungsten Benzene Complexes.

Key steps in the functionalization of an unactivated arene often involve its dihaptocoordination by a transition metal followed by insertion into the C-H bond. However, rarely are the η2-arene and aryl hydride species in measurable equilibrium. In this study, the benzene/phenyl hydride equilibrium is explored for the {WTp(NO)(PBu3)} (Bu = n-butyl; Tp = trispyrazoylborate) system as a function of temperature, solvent, ancillary ligand, and arene substituent. Both face-flip and ring-walk isomerizations are identified through spin-saturation exchange measurements, which both appear to operate through scission of a C-H bond. The effect of either an electron-donating or electron-withdrawing substituent is to increase the stability of both arene and aryl hydride isomers. Crystal structures, electrochemical measurements, and extensive NMR data further support these findings. Static density functional theory calculations of the benzene-to-phenyl hydride landscape suggest a single linear sequence for this transformation involving a sigma complex and oxidative cleavage transition state. Static DFT calculations also identified an η2-coordinated benzene complex in which the arene is held more loosely than in the ground state, primarily through dispersion forces. Although a single reaction pathway was identified by static calculations, quasiclassical direct dynamics simulations identified a network of several reaction pathways connecting the η2-benzene and phenyl hydride isomers, due to the relatively flat energy landscape.

A Highly Divergent Synthesis of 3-Aminotetrahydropyridines.

Dihapto-coordinate 1,2-dihydropyridine complexes of the metal fragment {WTp(NO)(PMe3)} (Tp = tris(pyrazolyl)borate), derived from pyridine, are demonstrated to undergo protonation at C6 followed by regioselective amination at C5 with a variety of primary and secondary amines. The addition takes place stereoselectively anti to the metal center, producing exclusively cis-disubstituted products. The resulting 1,2,5,6-tetrahydropyridines can be successfully liberated by oxidation, providing a route to novel molecules of potential medicinal interest.

Spatial Recognition Within Terpenes: Redox and H-bond Promoted Linkage Isomerizations and the Selective Binding of Complex Alkenes.

A method for the resolution of η 2-alkene-complex isomers of the type MoTp(NO)(DMAP)(η 2-alkene) and WTp(NO)(PMe3)(η 2-alkene) (where Tp = hydridotris(pyrazolyl)-borate and DMAP = 4-(dimethylamino)pyridine) has been explored. Alkene and polyene compounds form as a mixture of kinetically trapped isomers. For both types of complexes, it was found that addition of either a fluorinated alcohol or one-electron oxidant reduces the number of isomers in solution. Accelerated ligand exchange was also observed, although these reactions were accompanied by significant decomposition.

η 2 Coordination of Electron-Deficient Arenes with Group 6 Dearomatization Agents.

The exceptionally π-basic metal fragments {MoTp-(NO)(DMAP)} and {WTp(NO)(PMe3)} (Tp = tris(pyrazolyl)borate; DMAP = 4-(N,N-dimethylamino)pyridine) form thermally stable η 2-coordinated complexes with a variety of electron-deficient arenes. The tolerance of substituted arenes with fluorine-containing electron withdrawing groups (EWG; -F, -CF3, -SF5) is examined for both the molybdenum and tungsten systems. When the EWG contains a π bond (nitriles, aldehydes, ketones, ester), η 2 coordination occurs predominantly on the nonaromatic functional group. However, complexation of the tungsten complex with trimethyl orthobenzoate (PhC(OMe)3) followed by hydrolysis allows access to an η 2-coordinated arene with an ester substituent. In general, the tungsten system tolerates sulfur-based withdrawing groups well (e.g., PhSO2Ph, MeSO2Ph), and the integration of multiple electron-withdrawing groups on a benzene ring further enhances the π-back-bonding interaction between the metal and aromatic ligand. While the molybdenum system did not form stable η 2-arene complexes with the sulfones or ortho esters, it was capable of forming rare examples of stable η 2-coordinated arene complexes with a range of fluorinated benzenes (e.g., fluorobenzene, difluorobenzenes). In contrast to what has been observed for the tungsten system, these complexes formed without interference of C-H or C-F insertion.

Molybdenum-Promoted Synthesis of Isoquinuclidines with Bridgehead CF3 Groups.

The preparation of the complex MoTp(NO)(DMAP)(4,5-η2-(2-trifluoromethyl)pyridine) (DMAP = 4-(dimethylamino)pyridine; Tp = tris(pyrazolyl)borate) is described. The CF3 substituent is found to preclude κ-N coordination, allowing for direct coordination without protection of the nitrogen. The dihapto-coordinate complex can be isolated as a single diastereomer, methylated, and reacted with a range of nucleophiles. Oxidative decomplexation affords the free dihydropyridines in good yield (75-90%). As a demonstration of synthetic utility, a series of novel bridgehead CF3-substituted isoquinuclidines was prepared from these decomplexed dihydropyridines.

Molybdenum(0) Dihapto-Coordination of Benzene and Trifluorotoluene: The Stabilizing and Chemo-Directing Influence of a CF3 Group.

The preparation of the complexes TpMo(NO)(DMAP)(η2-PhCF3) (5) and TpMo(NO)(DMAP)(η2-benzene) (3) is described. The CF3 group is found to stabilize the metal-arene bond strength in 5 by roughly 3 kcal/mol compared to that in 3, allowing the large-scale synthesis and isolation of the trifluorotoluene analogue (5, 37 g, 70%). When a benzene solution of 5 is allowed to stand, clean conversion to the benzene analogue 3 occurs, and this complex may be precipitated from solution upon the addition of pentane and isolated. The trifluorotoluene complex is shown to be a synthetic precursor to functionalized cyclohexadienes: In solution, it selectively protonates at the ortho position, and the resulting η2-arenium species undergoes reactions with nucleophiles at the adjacent meta carbon. Thus, reactions of 5, triflic acid, and either N-methylpyrrole or 1-methoxy-2-methyl-1-(trimethylsilyloxy)-1-propene result in 5-substituted-1,3-cyclohexadienes after removal of the metal.