Copper(I)-Catalyzed Synthesis of 1,4-Disubstituted 1,2,3-Triazoles from Azidoformates and Aryl Terminal Alkynes

The copper­(I)-catalyzed azide–alkyne cycloaddition reaction has been extensively studied and widely applied in organic synthesis. However, the formation of 1,2,3-triazoles with electron-deficient azide has been a challenging problem. In this report, we have demonstrated the formation of regioselective 1,4-disubstituted 1,2,3-triazoles from various types of aryl terminal alkynes and azidoformates, which are electron-deficient azides, using a commercialized [Cu­(CH₃CN)₄]­PF₆ copper­(I) catalyst under mild conditions

Copper(I)-Catalyzed Synthesis of 1,4-Disubstituted 1,2,3-Triazoles from Azidoformates and Aryl Terminal Alkynes

The copper­(I)-catalyzed azide–alkyne cycloaddition reaction has been extensively studied and widely applied in organic synthesis. However, the formation of 1,2,3-triazoles with electron-deficient azide has been a challenging problem. In this report, we have demonstrated the formation of regioselective 1,4-disubstituted 1,2,3-triazoles from various types of aryl terminal alkynes and azidoformates, which are electron-deficient azides, using a commercialized [Cu­(CH₃CN)₄]­PF₆ copper­(I) catalyst under mild conditions

Copper(I)-Catalyzed Synthesis of 1,4-Disubstituted 1,2,3-Triazoles from Azidoformates and Aryl Terminal Alkynes

The copper­(I)-catalyzed azide–alkyne cycloaddition reaction has been extensively studied and widely applied in organic synthesis. However, the formation of 1,2,3-triazoles with electron-deficient azide has been a challenging problem. In this report, we have demonstrated the formation of regioselective 1,4-disubstituted 1,2,3-triazoles from various types of aryl terminal alkynes and azidoformates, which are electron-deficient azides, using a commercialized [Cu­(CH₃CN)₄]­PF₆ copper­(I) catalyst under mild conditions

Synthesis of the Tricyclic Ring Structure of Daphnanes via Intramolecular [4 + 3] Cycloaddition/SmI₂‑Pinacol Coupling

A synthetic approach toward the tricyclic 5,7,6-membered ring structure of daphnane-family natural products is described. An intramolecular [4 + 3] cycloaddition reaction of furan with an oxypentadienyl cation constructed the oxa-bridged bicyclic structure in a stereoselective fashion. Structural analysis revealed that the desired <i>exo</i> isomer was predominantly acquired through epimerization. Finally, formation of the five-membered ring was achieved through SmI₂-mediated pinacol coupling

Construction of 8‑Azabicyclo[3.2.1]octanes via Sequential DDQ-Mediated Oxidative Mannich Reactions of <i>N</i>‑Aryl Pyrrolidines

A concise synthesis of 8-azabicyclo­[3.2.1]­octanes via sequential oxidative Mannich reactions is described. This approach involves an intermolecular oxidative Mannich coupling reaction between <i>N</i>-aryl pyrrolidines with TMS enol ether and a subsequent intramolecular oxidative Mannich cyclization of the corresponding silyl enol ether. DDQ is used as a key oxidant for both reactions

Discovery of β‑Arrestin Biased Ligands of 5‑HT₇R

Though many studies have been published about therapeutic potentials of selective 5-HT₇R ligands, there have been few biased ligands of 5-HT₇R. The development of potent and selective biased ligands of 5-HT₇R would be of great help in understanding the relationship between pharmacological effects and G protein/β-arrestin signaling pathways of 5-HT₇R. In order to identify 5-HT₇R ligands with biased agonism, we designed and synthesized a series of tetrahydroazepine derivatives <b>1</b> and <b>2</b> with arylpyrazolo moiety or arylisoxazolo moiety. Through several biological evaluations such as binding affinity, selectivity profile, and functions in G protein and β-arrestin signaling pathways, 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo­[3,4-<i>d</i>]­azepine <b>1g</b> was discovered as the β-arrestin biased ligand of 5-HT₇R. In an electroencephalogram (EEG) test, <b>1g</b> increased total non-rapid eye movement (NREM) sleep time and decreased total rapid eye movement (REM) sleep time

Discovery of β‑Arrestin Biased Ligands of 5‑HT₇R

Though many studies have been published about therapeutic potentials of selective 5-HT₇R ligands, there have been few biased ligands of 5-HT₇R. The development of potent and selective biased ligands of 5-HT₇R would be of great help in understanding the relationship between pharmacological effects and G protein/β-arrestin signaling pathways of 5-HT₇R. In order to identify 5-HT₇R ligands with biased agonism, we designed and synthesized a series of tetrahydroazepine derivatives <b>1</b> and <b>2</b> with arylpyrazolo moiety or arylisoxazolo moiety. Through several biological evaluations such as binding affinity, selectivity profile, and functions in G protein and β-arrestin signaling pathways, 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo­[3,4-<i>d</i>]­azepine <b>1g</b> was discovered as the β-arrestin biased ligand of 5-HT₇R. In an electroencephalogram (EEG) test, <b>1g</b> increased total non-rapid eye movement (NREM) sleep time and decreased total rapid eye movement (REM) sleep time

Discovery of β‑Arrestin Biased Ligands of 5‑HT₇R

Though many studies have been published about therapeutic potentials of selective 5-HT₇R ligands, there have been few biased ligands of 5-HT₇R. The development of potent and selective biased ligands of 5-HT₇R would be of great help in understanding the relationship between pharmacological effects and G protein/β-arrestin signaling pathways of 5-HT₇R. In order to identify 5-HT₇R ligands with biased agonism, we designed and synthesized a series of tetrahydroazepine derivatives <b>1</b> and <b>2</b> with arylpyrazolo moiety or arylisoxazolo moiety. Through several biological evaluations such as binding affinity, selectivity profile, and functions in G protein and β-arrestin signaling pathways, 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo­[3,4-<i>d</i>]­azepine <b>1g</b> was discovered as the β-arrestin biased ligand of 5-HT₇R. In an electroencephalogram (EEG) test, <b>1g</b> increased total non-rapid eye movement (NREM) sleep time and decreased total rapid eye movement (REM) sleep time

A Potential PET Radiotracer for the 5‑HT_2C Receptor: Synthesis and in Vivo Evaluation of 4‑(3‑[¹⁸F]fluorophenethoxy)pyrimidine

The serotonin 2C receptor subtype (5-HT_2C) is an excitatory 5-HT receptor widely distributed throughout the central nervous system. As the 5-HT_2C receptor displays multiple actions on various neurotransmitter systems including glutamate, dopamine, epinephrine, and γ-aminobutyric acid (GABA), abnormalities of the 5-HT_2C receptor are associated with psychiatric diseases such as depression, schizophrenia, drug abuse, and anxiety. Up to date, three kinds of 5-HT_2C PET radiotracers such as [¹¹C]<i>N</i>-methylated arylazepine (<b>1</b>), [¹¹C]­WAY-163909 (<b>2</b>), and [¹⁸F]­fluorophenylcyclopropane (<b>3</b>) have been developed, but they may not be suitable for in vivo 5-HT_2C imaging study due to their modest specific binding. Herein, the synthesis and in vivo evaluation of 4-(3-[¹⁸F]­fluorophenethoxy)­pyrimidine <b>[</b>^<b>18</b><b>F]­4</b> as a potential PET radiotracer for the 5-HT_2C receptor is described. <b>[</b>^<b>18</b><b>F]­4</b> was synthesized by nucleophilic aromatic substitution of diaryliodonium precursor <b>17a</b> with a 7.8 ± 2.7% (<i>n</i> = 6, decay corrected) radiochemical yield and over 99% radiochemical purity, showing an 89 ± 14 GBq/μmol specific radioactivity. The in vivo PET imaging studies of <b>[</b>^<b>18</b><b>F]­4</b> with or without lorcaserin, a U.S. Food and Drug Administration approved selective 5-HT_2C agonist, demonstrated that <b>[</b>^<b>18</b><b>F]­4</b> exhibits a high level of specific binding to 5-HT_2C receptors in the rat brain

Dynamic Nuclear Polarization of Selectively ²⁹Si-Enriched Core@shell Silica Nanoparticles

29Si silica nanoparticles (SiO2 NPs) are promising magnetic resonance imaging (MRI) probes that possess advantageous properties for in vivo applications, including suitable biocompatibility, tailorable properties, and high water dispersibility. Dynamic nuclear polarization (DNP) is used to enhance 29Si MR signals via enhanced nuclear spin alignment; to date, there has been limited success employing DNP for SiO2 NPs due to the lack of endogenous electronic defects that are required for the process. To create opportunities for SiO2-based 29Si MRI probes, we synthesized variously featured SiO2 NPs with selective 29Si isotope enrichment on homogeneous and core@shell structures (shell thickness: 10 nm, core size: 40 nm), and identified the critical factors for optimal DNP signal enhancement as well as the effective hyperpolarization depth when using an exogenous radical. Based on the synthetic design, this critical factor is the proportion of 29Si in the shell layer regardless of core enrichment. Furthermore, the effective depth of hyperpolarization is less than 10 nm between the surface and core, which demonstrates an approximately 40% elongated diffusion length for the shell-enriched NPs compared to the natural abundance NPs. This improved regulation of surface properties facilitates the development of isotopically enriched SiO2 NPs as hyperpolarized contrast agents for in vivo MRI