The Synthesis and Initial Evaluation of MerTK Targeted PET Agents.

MerTK (Mer tyrosine kinase), a receptor tyrosine kinase, is ectopically or aberrantly expressed in numerous human hematologic and solid malignancies. Although a variety of MerTK targeting therapies are being developed to enhance outcomes for patients with various cancers, the sensitivity of tumors to MerTK suppression may not be uniform due to the heterogeneity of solid tumors and different tumor stages. In this report, we develop a series of radiolabeled agents as potential MerTK PET (positron emission tomography) agents. In our initial in vivo evaluation, [18F]-MerTK-6 showed prominent uptake rate (4.79 ± 0.24%ID/g) in B16F10 tumor-bearing mice. The tumor to muscle ratio reached 1.86 and 3.09 at 0.5 and 2 h post-injection, respectively. In summary, [18F]-MerTK-6 is a promising PET agent for MerTK imaging and is worth further evaluation in future studies.

Stereoselective Synthesis of 3,3'-Bisindolines by Organocatalytic Michael Additions of Fluorooxindole Enolates to Isatylidene Malononitriles in Aqueous Solution.

A highly diastereoselective organocatalytic reaction for the synthesis of fluorinated 3,3'-bisindolines exhibiting adjacent tetrasubstituted carbon stereocenters is described. A broad variety of heterochiral bisindolines was prepared in 91-99% yield using 3-fluorooxindoles and isatylidene malononitriles in the presence of catalytic amounts of triethylamine in water or aqueous solution. The reaction can be upscaled without compromising yield and diastereoselectivity and the general usefulness of this method was demonstrated with various Michael acceptors and extended to aldol and Mannich reactions.

Organocatalytic Insertion of Isatins into Aryl Difluoronitromethyl Ketones.

An organocatalytic method that achieves insertion of isatins into aryl difluoronitromethyl ketones under mild conditions is described. The reaction occurs in the presence of 20 mol % of DBU and with 100% atom economy. A series of isatin derived difluoronitromethyl substituted tertiary alcohol benzoates and naphthoates were prepared in 81-99% yield. The general synthetic usefulness of these 3-hydroxyoxindole derivatives is demonstrated with the selective reduction to fluorooximes.

Quantitative chirality sensing of amines and amino alcohols via Schiff base formation with a stereodynamic UV/CD probe.

A stereodynamic chemosensor that can be used for simultaneous determination of the absolute configuration, enantiomeric composition and total concentration of chiral amines and amino alcohols based on two fast optical measurements was prepared and tested. The free sensor is CD-silent and produces characteristic blue-shifted UV and CD signals upon substrate binding via Schiff base formation. The potential in high-throughput screening applications and for rational sensor developments are discussed.

A 2D mesoporous imine-linked covalent organic framework for high pressure gas storage applications.

Hole-some mixture: A 2D mesoporous covalent organic framework (see figure) featuring expanded pyrene cores and linked by imine linkages has a high surface area (SA(BET) = 2723 m(2) g(-1)) and exhibits significant gas storage capacities under high pressure, which make this class of material very promising for gas storage applications.

An unusual chemoselective hydrogenation of quinoline compounds using supported gold catalysts.

The pursuit of modern sustainable chemistry has stimulated the development of innovative catalytic processes that enable chemical transformations to be performed under mild and clean conditions with high efficiency. Herein, we report that gold nanoparticles supported on TiO(2) catalyze the chemoselective hydrogenation of functionalized quinolines with H(2) under mild reaction conditions. Our results point toward an unexpected role for quinolines in gold-mediated hydrogenation reactions, namely that of promoter; this is in stark contrast to what prevails in the traditional noble metal Pd-, Pt-, and Ru-based catalyst systems, in which quinolines and their derivatives typically act as poisons. As a result of the remarkable promotional effect of quinoline molecules to H(2) activation over supported gold, the transformation can proceed smoothly under very mild conditions (even at temperatures as low as 25 °C). Of practical significance is that various synthetically useful functional groups including halogens, ketone, and olefin remain intact during the hydrogenation of quinolines. Moreover, the protocol also shows promise for the regiospecific hydrogenation of the heterocyclic ring of a variety of other biologically important heteroaromatic nitrogen compounds, such as isoquinoline, acridine, and 7,8-benzoquinoline, in a facile manner. Apart from its importance in catalytic hydrogenation, we believe that this intriguing self-promoted effect by reactant molecules may have fundamental implications for the broad field of gold catalysis and form the basis for development of new catalytic procedures for other key transformations.

Catalytic Asymmetric Mannich Reaction of α-Fluoronitriles with Ketimines: Enantioselective and Diastereodivergent Construction of Vicinal Tetrasubstituted Stereocenters.

Diastereodivergent and enantioselective conversion of isatin ketimines to α-fluoro-ß-aminonitriles with vicinal tetrasubstituted stereocenters is achieved by a chiral copper complex/guanidine base catalyzed Mannich reaction with proper choice of the bisphosphine ligand. The reaction is broad in scope, scalable, and provides efficient access to a series of 3-aminoindolinones exhibiting a quaternary carbon-fluorine stereocenter with high yields and stereoselectivities. Selective transformations of the Mannich reaction products into multifunctional 3-aminooxindoles without erosion of enantiomeric and diastereomeric purity highlight the synthetic utility.

Organocatalytic Asymmetric Synthesis of α-Oxetanyl and α-Azetidinyl Tertiary Alkyl Fluorides and Chlorides.

Asymmetric thiourea and squaramide catalysis provides access to synthetically versatile α-oxetanyl and α-azetidinyl alkyl halides exhibiting a tetrasubstituted chiral carbon center with high yields and enantioselectivities. The products are readily transformed with negligible erosion of enantiopurity and excellent diastereoselectivity to a diverse group of multifunctional compounds including fluorooxindoles with two contiguous chirality centers, fluorinated heterocyclic spiranes, and polyspiro compounds.

Catalytic insertion of aldehydes into dihalonitroacetophenones via sequential bond scission-aldol reaction-acyl transfer.

A catalytic process that provides dihalogenated nitro alcohols in up to 99% yield and with 100% atom economy is described. In situ cleavage of dihalonitroacetophenones affords nitronates that undergo Lewis acid catalyzed addition to aldehydes. Final benzoylation renders the sequence irreversible and regenerates the bond scission and acyl transfer agent.

C-C cross-coupling of primary and secondary benzylic alcohols using supported gold-based bimetallic catalysts.

Clean alcohol-alcohol cross-coupling: A clean and efficient one-pot direct C-C cross-coupling of equimolar amounts of primary and secondary alcohols by a facile hydrogen autotransfer pathway is achieved over a robust and easily recovered hydrotalcite-supported Au-Pd bimetallic catalyst system. A variety of primary and secondary alcohols have been selectively converted into the corresponding ß-alkylated ketones in good yields.

Highly efficient heterogeneous gold-catalyzed direct synthesis of tertiary and secondary amines from alcohols and urea.

Urea, the white gold: The efficient synthesis of tertiary and secondary amines is achieved by heterogeneous gold-catalyzed direct amination of stoichiometric alcohols with urea in good to excellent yields. Via a hydrogen autotransfer pathway, the reactions of primary alcohols with urea give tertiary amines exclusively, while secondary alcohols selectively afford secondary amines.