Catalytic coupling of arene C-H bonds and alkynes for the synthesis of coumarins: substrate scope and application to the development of neuroimaging agents.
ABSTRACT: C-H bond functionalization offers strategically novel approaches to complex organic compounds. However, many C-H functionalization reactions suffer from poor compatibility with Lewis basic functional groups, especially amines, which are often essential for biological activity. This study describes a systematic examination of the substrate scope of catalytic hydroarylation in the context of complex amino coumarin synthesis. The choice of substrates was guided by the design and development of the next generation of fluorescent false neurotransmitters (FFNs), neuroimaging probes we recently introduced for optical imaging of neurotransmission in the brain. Comparison of two mild protocols using catalytic PtCl(4) or Au(PPh(3))Cl/AgSbF(6)revealed that each method has a broad and mutually complementary substrate scope. The relatively less active platinum system out-performed the gold catalyst with indole substrates lacking substitution at the C-3 position and provided higher regioselectivity in the case of carbazole-based substrates. On the other hand, the more active gold catalyst demonstrated excellent functional group tolerance, and the ability to catalyze the formation of strained, helical products. The development of these two protocols offers enhanced substrate scope and provides versatile synthetic tools required for the structure-activity examination of FFN neuroimaging probes as well as for the synthesis of complex coumarins in general.
Project description:We have previously introduced fluorescent false neurotransmitters (FFNs) as optical reporters that enable visualization of individual dopaminergic presynaptic terminals and their activity in the brain. In this context, we examined the fluorescent pyridinium dye 4-(4-dimethylamino)phenyl-1-methylpyridinium (APP+), a fluorescent analogue of the dopaminergic neurotoxin MPP+, in acute mouse brain tissue. APP+ is a substrate for the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), and as such represented a candidate for the development of new FFN probes. Here we report that APP+ labels cell bodies of catecholaminergic neurons in the midbrain in a DAT- and NET-dependent manner, as well as fine dopaminergic axonal processes in the dorsal striatum. APP+ destaining from presynaptic terminals in the dorsal striatum was also examined under the conditions inducing depolarization and exocytotic neurotransmitter release. Application of KCl led to a small but significant degree of destaining (approximately 15% compared to control), which stands in contrast to a nearly complete destaining of the new generation FFN agent, FFN102. Electrical stimulation of brain slices at 10 Hz afforded no significant change in the APP+ signal. These results indicate that the majority of the APP+ signal in axonal processes originates from labeled organelles including mitochondria, whereas only a minor component of the APP+ signal represents the releasable synaptic vesicular pool. These results also show that APP+ may serve as a useful probe for identifying catecholaminergic innervations in the brain, although it is a poor candidate for the development of FFNs.
Project description:Ongoing efforts in our laboratories focus on design of optical reporters known as fluorescent false neurotransmitters (FFNs) that enable the visualization of uptake into, packaging within, and release from individual monoaminergic neurons and presynaptic sites in the brain. Here, we introduce the molecular probe FFN246 as an expansion of the FFN platform to the serotonergic system. Combining the acridone fluorophore with the ethylamine recognition element of serotonin, we identified FFN54 and FFN246 as substrates for both the serotonin transporter and the vesicular monoamine transporter 2 (VMAT2). A systematic structure-activity study revealed the basic structural chemotype of aminoalkyl acridones required for serotonin transporter (SERT) activity and enabled lowering the background labeling of these probes while maintaining SERT activity, which proved essential for obtaining sufficient signal in the brain tissue (FFN246). We demonstrate the utility of FFN246 for direct examination of SERT activity and SERT inhibitors in 96-well cell culture assays, as well as specific labeling of serotonergic neurons of the dorsal raphe nucleus in the living tissue of acute mouse brain slices. While we found only minor FFN246 accumulation in serotonergic axons in murine brain tissue, FFN246 effectively traces serotonin uptake and packaging in the soma of serotonergic neurons with improved photophysical properties and loading parameters compared to known serotonin-based fluorescent tracers.
Project description:The present study describes an AuPPh?Cl/AgSbF?-catalyzed cascade reaction between amine nucleophiles and alkynoic acids in water. This process proceeds in high step economy with water as the sole coproduct, and leads to the generation of two rings, together with the formation of three new bonds in a single operation. This green cascade process exhibits valuable features such as low catalyst loading, good to excellent yields, high efficiency in bond formation, excellent selectivity, great tolerance of functional groups, and extraordinarily broad substrate scope. In addition, this is the first example of the generation of an indole/thiophene/pyrrole/pyridine/naphthalene/benzene-fused N-heterocycle library through gold catalysis in water from readily available materials. Notably, the discovery of antibacterial molecules from this library demonstrates its high quality and potential for the identification of active pharmaceutical ingredients.
Project description:Cross-coupling reactions enable rapid, convergent synthesis of diverse molecules and provide the foundation for modern chemical synthesis. The most widely used methods employ sp2-hybridized coupling partners, such as aryl halides or related pre-functionalized substrates. Here, we demonstrate copper-catalysed oxidative cross coupling of benzylic C-H bonds with alcohols to afford benzyl ethers, enabled by a redox-buffering strategy that maintains the activity of the copper catalyst throughout the reaction. The reactions employ the C-H substrate as the limiting reagent and exhibit broad scope with respect to both coupling partners. This approach to direct site-selective functionalization of C(sp3)-H bonds provides the basis for efficient three-dimensional diversification of organic molecules and should find widespread utility in organic synthesis, particularly for medicinal chemistry applications.
Project description:A volatile organic solvent-free and choline chloride (ChCl)-based deep eutectic system (DES)-mediated sp3-CH functionalization of acetophenones 1 with benzyl alcohols 2 to the corresponding ?, ?-saturated ketones 3 is accounted for. The domino dehydrogenation-aldol condensation (hydrogenation borrowing concept) has been successfully attempted with palladium-tetrakis(triphenylphosphine) [Pd(PPh3)4] catalyst-xantphos ligand combination. Furthermore, a sequential Friedländer reaction of 2-aminobenzophenone 4 and palladium-catalyzed ?-alkylation of the quinolinyl methyl ketone with benzyl alcohols 2 in ChCl-based DES have been successfully investigated. The C-C bond formation through sp3-CH functionalization involves a wide scope of the substrates, high atom efficiency, chemoselectivity, and environmentally friendly strategy.
Project description:We recently introduced fluorescent false neurotransmitters (FFNs) as optical tracers that enable the visualization of neurotransmitter release at individual presynaptic terminals. Here, we describe a pH-responsive FFN probe, FFN102, which as a polar dopamine transporter substrate selectively labels dopamine cell bodies and dendrites in ventral midbrain and dopaminergic synaptic terminals in dorsal striatum. FFN102 exhibits greater fluorescence emission in neutral than acidic environments, and thus affords a means to optically measure evoked release of synaptic vesicle content into the extracellular space. Simultaneously, FFN102 allows the measurement of individual synaptic terminal activity by following fluorescence loss upon stimulation. Thus, FFN102 enables not only the identification of dopamine cells and their processes in brain tissue, but also the optical measurement of functional parameters including dopamine transporter activity and dopamine release at the level of individual synapses. As such, the development of FFN102 demonstrates that, by bringing together organic chemistry and neuroscience, molecular entities can be generated that match the endogenous transmitters in selectivity and distribution, allowing for the study of both the microanatomy and functional plasticity of the normal and diseased nervous system.
Project description:Background and purpose - The operative treatment of hip fractures in Norway has changed considerably during the last decade. We used data in the Norwegian Hip Fracture Register to investigate possible effects of these changes on reoperations and 1-year mortality. Patients and methods - 72,741 femoral neck (FFN) fractures and trochanteric fractures in patients 60 years or older were analyzed. The fractures were divided into 5 time periods (2005-2006, 2007-2008, 2009-2010, 2011-2012, 2013-2014). Cox regression models were used to calculate unadjusted and adjusted (age group, sex, and ASA class) relative risks (RRs) of reoperation and of 1-year mortality in the different time periods. Results - For undisplaced FFNs treatment with hemiarthroplasty increased from 2.1% to 9.7% during the study period. For displaced FFNs treatment with arthroplasty increased from 56% to 93%. The use of intramedullary nails increased from 9.1% to 26% for stable 2-fragment (AO/OTA A1) trochanteric fractures, from 15% to 33% for multifragment (AO/OTA A2) trochanteric fractures, and from 27% to 61% for intertrochanteric fractures (AO/OTA A3)/subtrochanteric fractures. Compared with the first time period the adjusted 1-year RR for reoperation was 0.43 (95% CI: 0.37-0.49) for displaced FFNs in the last time period. The adjusted 1-year mortality in the last time period was lower for all fractures (RR: 0.87 (0.83-0.91)), displaced FFNs (RR: 0.86 (0.80-0.93)), AO/OTA A1 trochanteric fractures (RR: 0.79 (0.71-0.88)), and AO/OTA A2 trochanteric fractures (RR: 0.87 (0.77-0.98)) when compared with the first study period. Interpretation - Hip fracture treatment in Norway has improved: The risk of reoperation and the 1-year mortality after displaced femoral neck fractures have decreased over a 10-year period. National registration is useful to monitor trends in treatment and outcomes after hip fractures.
Project description:The scope of palladium-catalyzed, auxiliary-assisted direct arylation and alkylation of sp(2) and sp(3) C-H bonds of amine and carboxylic acid derivatives has been investigated. The method employs a palladium acetate catalyst, substrate, aryl, alkyl, benzyl, or allyl halide, and inorganic base in tert-amyl alcohol or water solvent at 100-140 °C. Aryl and alkyl iodides as well as benzyl and allyl bromides are competent reagents in this transformation. The picolinic acid auxiliary is used for amine ?-functionalization, and the 8-aminoquinoline auxiliary is used for carboxylic acid ?-functionalization. Some optimization of base, additives, and solvent is required for achieving best results.
Project description:Site-specific functionalization of unprotected native peptides and biomolecules remains a useful transformation in synthetic design and chemical biology, yet until recently, advancements in transition metal-catalyzed methods, which have prevailed in organic synthesis, have been relatively ineffective when applied to large and structurally complex biomolecules. Here, the mechanistically distinct, Ni/photoredox-catalyzed arylation of unprotected, native thiols (e.g., cysteine residues) is reported - a process initiated through a visible light-promoted, hydrogen atom transfer (HAT) event under ambient conditions. Sub-stoichiometric loadings of the dual-catalyst system (?5 mol%) are employed, granting excellent site-specificity, broad substrate scope, and low chemical waste. Reaction scalability (from ?g to grams) has been achieved through modest reagent adjustments, and high throughput experimentation (HTE) demonstrates the ease of reaction setup, enabling prompt screening of aryl halide coupling partners and conditions. Scores of thiol substrates and aryl entities were examined and effectively conjugated, suggesting further diverse, practical applications.
Project description:The enantioselective transformations of indoles preferentially take place in the more-reactive azole ring. However, the methods for the enantioselective functionalization of the indole benzene ring are scarce. In this paper, a series of bifunctional (thio)urea derivatives were used to organocatalyze the enantioselective Friedel-Crafts hydroxyalkylation of indoles with isatins. The resulting products were obtained in good yields (65-90%) with up to 94% enantiomer excess (ee). The catalyst type and the substrate scope were broadened in this methodology.