Aryl alkynoate esters undergo gold-catalyzed spirocyclization under mild conditions, affording spirolactones in high yields. This approach obviates the need for stoichiometric halogenating reagents ...typically employed for alkyne activation in related transformations. Water was found to play a critical role in governing the product selectivity. Anhydrous conditions lead selectively to coumarin products, as has previously been observed for aryl alkynoate esters, while the addition of 1 equiv of water leads selectively to spirocycle formation.
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We report a catalytic intramolecular coupling between terminal unactivated alkynes and sp(3) C-H bonds via through-space hydride transfer (HT-cyclization of alkynes). This method enables one-step ...preparation of complex heterocyclic compounds by alpha-alkenylation of readily available cyclic ethers and amines. We show that PtI(4) is an effective Lewis acid catalyst for the activation of terminal alkynes for hydride attack and subsequent C-C bond formation. In addition, we have shown that the activity of neutral platinum salts (PtX(n)) can be modulated by the halide ligands. This modulation in turn allows for fine-tuning of the platinum center reactivity to match the reactivity and stability of selected substrates and products.
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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 PtCl4 or Au(PPh3)Cl/AgSbF6 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.
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We here report a study of the intramolecular amination of sp3 C–H bonds via the hydride transfer cyclization of N-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to ...N-toluenesulfonamide in the presence of BF3·OEt2 to effect imine formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-tetrahydroisoquinolines in a one-pot procedure. We examined the reactivity of a range of aldehyde substrates as a function of their conformational flexibility. Substrates of higher conformational rigidity were more reactive, giving higher yields of the desired products. However, a single substituent on the alkyl chain linking the N-tosylimine and the benzylic sp3 C–H bonds was sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the hydridic C–H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly stereoselective; 2-substituted aldehydes yield cis-2,5-disubstituted piperidines, while 3-substituted aldehydes afford trans-2,4-disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity.
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A catalytic redox-neutral method for the synthesis of spirolactams proceeding through the dearomative spirocyclization of N-aryl alkynamides is reported. In contrast to stoichiometric activating ...agents employed for related transformations, we show that the use of 5 mol % of Au(PPh3)Cl and AgOTf in dichloroethane at 50–80 °C leads to selective spirocyclization, furnishing the products in yields of 35–87%. The substrate scope of the reaction is good, with both electron-donating and electron-withdrawing groups being tolerated around the arene ring, as well as substitution at the amide nitrogen. The identity of the para-alkoxy group on the arene ring is key to achieving selectivity for spirocyclization over alternative mechanistic pathways. While the presence of a para-methoxy group leads to trace amounts of the desired spirolactams, the para-tert-butoxy or para-hydroxy substrate analogues furnish the spirolactams in good yield with high selectivity.
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A mild method for the synthesis of 2-quinolinones via hydroarylation of N-aryl alkynamides is reported. While traditional methods have relied on the use of strong Brønsted or Lewis acids, this report ...describes the development of mild reaction conditions that yield 2-quinolinones in good to excellent yield using a commercially available gold catalyst. Substrates bearing a variety of functional groups are presented, with N-substitution proving to be key to the reactivity of several substrates.
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The 2-quinolinone family of molecules, also known as carbostyrils, have been proposed as light absorbing donor molecules in energy transfer based sensing schemes and as possible photocatalysts. Both ...of these applications make use of electronic excited states, but the photophysics of 2-quinolinones have not yet been examined closely. This study applies static and dynamic spectroscopy, with supporting density functional theory calculations, to reveal the electronic relaxation dynamics of a family of five 2-quinolinones with extended conjugated rings. These modifications lead to red-shifted absorbance and emission maxima, relative to unmodified 2-quinolinone. Optical excitation of these molecules with near UV light resulted in transitions with strong π → π* and HOMO → LUMO character. Time-correlated single photon counting measurements yielded fluorescence lifetimes ranging from 849.3 (±0.6) ps to 4.586 (±0.002) ns. Transient absorption spectroscopy revealed relaxation dynamics of the S1 excited state formed by photoexcitation at 350 nm, along with formation of a long-lived signal assigned as excited state absorption by a triplet excited state. Vibrational relaxation in the S1 state was also characterized in some compounds. Overlapping signals of S1 decay and triplet growth in the transient absorption data set could not be fully disentangled. These results demonstrate a highly competitive relaxation scheme following multiple simultaneous pathways, a promising situation for establishing chemical control of electronic relaxation in the 2-quinolinone family.
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The nervous system transmits signals between neurons via neurotransmitter release during synaptic vesicle fusion. In order to observe neurotransmitter uptake and release from individual presynaptic ...terminals directly, we designed fluorescent false neurotransmitters as substrates for the synaptic vesicle monoamine transporter. Using these probes to image dopamine release in the striatum, we made several observations pertinent to synaptic plasticity. We found that the fraction of synaptic vesicles releasing neurotransmitter per stimulus was dependent on the stimulus frequency. A kinetically distinct "reserve" synaptic vesicle population was not observed under these experimental conditions. A frequency-dependent heterogeneity of presynaptic terminals was revealed that was dependent in part on D2 dopamine receptors, indicating a mechanism for frequency-dependent coding of presynaptic selection.
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We describe herein our recent explorations in the field of isonitrile chemistry. An array of broadly useful coupling methodologies has been developed for the formation of peptidyl and glycopeptidyl ...amide bonds. We further describe the application of these methods to the syntheses of complex systems, including the cyclic peptide cyclosporine A, constrained peptide systems, and heterocycles.
New take on an old classic: Recent explorations in the field of isonitrile chemistry led to the development of an array of broadly useful coupling methods for the formation of peptidyl and glycopeptidyl amide bonds. The methods were applied to the syntheses of complex systems, including the cyclic peptide cyclosporine A, constrained peptide systems, and heterocycles (see scheme; FCMA=formimidate carboxylate mixed anhydride).
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Human luteinizing hormone (hLH) and human chorionic gonadotropin (hCG) are human glycoprotein hormones each consisting of two subunits, an identical α-subunit and a unique β-subunit, that form ...noncovalent heterodimers. Structurally, β-hCG shares a high degree of sequence similarity with β-hLH, including a common N-glycosylation site at the N-terminus but differs mainly in the presence of an extended C-terminal portion incorporating four closely spaced O-linked glycans. These glycoproteins play important roles in reproduction and are used clinically in the treatment of infertility. In addition, the role of hCG as a tumor marker in a variety of cancers has also attracted significant interest for the development of cancer vaccines. In clinical applications, these hormones are administered as mixtures of glycoforms due to limitations of biological methods in producing homogeneous samples of these glycoproteins. Using the powerful tools of chemical synthesis, the work presented herein focuses on the highly convergent syntheses of homogeneous β-hLH and β-hCG bearing model glycans at all native glycosylation sites. Key steps in these syntheses include a successful double Lansbury glycosylation en route to the N-terminal fragment of β-hCG and the sequential installation of four O-linked glycosyl-amino acid cassettes into closely spaced O-glycosylation sites in a single, high-yielding solid-supported synthesis to access the C-terminal portion of the molecule. The final assembly of the individual glycopeptide fragments involved a stepwise native chemical ligation strategy to provide the longest and most complex human glycoprotein hormone (β-hCG) as well as its closely related homologue (β-hLH) as discrete glycoforms.
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