Correction: Convergent synthesis of thiodiazole dioxides from simple ketones and amines through an unusual nitrogen-migration mechanism.

[This corrects the article DOI: 10.1039/D3SC04478E.].

Structure-Based Optimization of Selective and Brain Penetrant CK1δ Inhibitors for the Treatment of Circadian Disruptions.

Neuropsychiatric disorders such as major depressive disorders and schizophrenia are often associated with disruptions to the normal 24 h sleep wake cycle. Casein kinase 1 (CK1δ) is an integral part of the molecular machinery that regulates circadian rhythms. Starting from a cluster of bicyclic pyrazoles identified from a virtual screening effort, we utilized structure-based drug design to identify and reinforce a unique "hinge-flip" binding mode that provides a high degree of selectivity for CK1δ versus the kinome.

Convergent synthesis of thiodiazole dioxides from simple ketones and amines through an unusual nitrogen-migration mechanism.

We report the modular preparation of dihydro-1,2,5-thiodiazole dioxide heterocycles starting from methyl ketones and primary amines. This one-pot, three-component coupling employs 2,3-dimethylimidazole-1-sulfonyl azide triflate as a coupling reagent and oxidant. The transformation is scalable and various ketones and amines can be used, yielding thiodiazole dioxide products in up to 89% yield.

Synthesis of Highly Functionalized 4-Iodo-7-azaindazoles via Condensation/Diels-Alder/Retro-Diels-Alder Cyclization of Iodoalkynones and 2-Hydrazineylpyrimidines.

A method for the preparation of highly functionalized 4-iodo-7-azaindazoles is reported. These valuable heterocycles are synthesized via condensation of 2-hydrazineylpyrimidines with various iodoalkynones followed by Diels-Alder/retro-Diels-Alder cyclization. The method is general to the formation of products with a variety of C, C, and C substituents while preserving the C iodide functional handle for further late-stage functionalization.

Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes.

Azabicyclo[2.1.1]hexanes (aza-BCHs) and bicyclo[1.

Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans.

Orexin neurons originating in the perifornical and lateral hypothalamic area project to anxiety- and panic-associated neural circuitry, and are highly reactive to anxiogenic stimuli. Preclinical evidence suggests that the orexin system, and particularly the orexin-1 receptor (OX1R), may be involved in the pathophysiology of panic and anxiety. Selective OX1R antagonists thus may constitute a potential new treatment strategy for panic- and anxiety-related disorders.

A Benzyne Insertion Approach to Hetisine-Type Diterpenoid Alkaloids: Synthesis of Cossonidine (Davisine).

The hetisine-type natural products exhibit one of the most complex carbon skeletons within the diterpenoid alkaloid family. The use of network analysis has enabled a synthesis strategy to access alkaloids in this class with hydroxylation on the A-ring. Key transformations include a benzyne acyl-alkylation to construct a key fused 6-7-6 tricycle, a chemoselective nitrile reduction, and sequential C-N bond formations using a reductive cyclization and a photochemical hydroamination to construct an embedded azabicycle.

A Unifying Synthesis Approach to the C-, C-, and C-Diterpenoid Alkaloids.

The secondary metabolites that comprise the diterpenoid alkaloids are categorized into C, C, and C families depending on the number of contiguous carbon atoms that constitute their central framework. Herein, we detail our efforts to prepare these molecules by chemical synthesis, including a photochemical approach, and ultimately a bioinspired strategy that has resulted in the development of a unifying synthesis of one C (weisaconitine D), one C (liljestrandinine), and three C (cochlearenine, paniculamine, and N-ethyl-1α-hydroxy-17-veratroyldictyzine) natural products from a common intermediate.

Syntheses of Denudatine Diterpenoid Alkaloids: Cochlearenine, N-Ethyl-1α-hydroxy-17-veratroyldictyzine, and Paniculamine.

The denudatine-type diterpenoid alkaloids cochlearenine, N-ethyl-1α-hydroxy-17-veratroyldictyzine, and paniculamine have been synthesized for the first time (25, 26, and 26 steps from 16, respectively). These syntheses take advantage of a common intermediate (8) that we have previously employed in preparing aconitine-type natural products. The syntheses reported herein complete the realization of a unified strategy for the preparation of C20, C19, and C18 diterpenoid alkaloids.

A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects.

Orexins (OXs) are peptides produced by perifornical (PeF) and lateral hypothalamic neurons that exert a prominent role in arousal-related processes, including stress. A critical role for the orexin-1 receptor (OX1R) in complex emotional behavior is emerging, such as overactivation of the OX1R pathway being associated with panic or anxiety states. Here we characterize a brain-penetrant, selective, and high-affinity OX1R antagonist, compound 56 [N-({3-[(3-ethoxy-6-methylpyridin-2-yl)carbonyl]-3-azabicyclo[4.

Selective orexin receptor antagonists.

The orexin, or hypocretin, neuropeptides (orexin-A and orexin-B) are produced on neurons in the hypothalamus which project to key areas of the brain that control sleep-wake states, modulation of food intake, panic, anxiety, emotion, reward and addictive behaviors. These neuropeptides exert their effects on a pair of G-protein coupled receptors termed the orexin-1 (OX1) and orexin-2 (OX2) receptors. Emerging biology suggests the involvement of these receptors in psychiatric disorders as they are thought to play a key role in the regulation of multiple systems.

A divergent approach to the synthesis of the yohimbinoid alkaloids venenatine and alstovenine.

The yohimbinoid alkaloids continue to receive considerable attention from the synthetic community because of their interesting chemical structures and varied biological activity. Although there are several elegant syntheses of certain members of this group of alkaloids, a truly unified approach has yet to be developed. In short, general approaches to this compound class are hampered by a lack of complete control in setting the C(3) stereocentre at a late stage.

Synthesis of the bridging framework of phragmalin-type limonoids.

An efficient synthesis of the octahydro-1H-2,4-methanoindene core of phragmalin-type limonoids, such as xyloccensins O and P, is reported. The success of the synthetic route is predicated on the use of network analysis in the retrosynthetic analysis and a Diels-Alder reaction for the synthesis of a key hydrindanone derivative.

Tandem cyclopropane ring-opening/Conia-ene reactions of 2-alkynyl indoles: a [3 + 3] annulative route to tetrahydrocarbazoles.

A Zn(NTf(2))(2) catalyzed tandem reaction consisting of a nucelophilic ring opening of 1,1-cyclopropanediesters by 2-alkynyl indoles followed by a Conia-ene ring closure results in the efficient one-step synthesis of tetrahydrocarbazoles. The adducts may be further elaborated to carbazoles.

Synthesis of tetrahydropyrans from propargyl alcohols and 1,1-cyclopropanediesters: a one-pot ring-opening/Conia-ene protocol.

Lewis acid catalyzed ring opening of 1,1-cyclopropanediesters by the hydroxyl group of a propargyl alcohol sets up a subsequent Conia-ene cyclization to afford substituted tetrahydropyrans in a one-pot, high-yielding procedure.

Stereodivergent synthesis of fused bicyclopyrazolidines: access to pyrazolines and pyrrolidines.

The reaction of hydrazinoethyl 1,1-cyclopropanediesters with aldehydes in the presence of catalytic Yb(OTf)(3) allows access to structurally complex fused bicyclo pyrazolidines. Either 2,5-cis or 2,5-trans adducts can be obtained in good to excellent yields in most cases by simply controlling the order of addition of the catalyst and aldehyde.

Zn(II)-Catalyzed synthesis of piperidines from propargyl amines and cyclopropanes.

The reaction of benzyl-protected propargyl amines and 1,1-cyclopropane diesters in the presence of catalytic Zn(NTf(2))(2) allows access to highly functionalized piperidines in excellent yields. The process proceeds via a tandem cyclopropane ring-opening/Conia-ene cyclization.

Total syntheses of clausamines A-C and clausevatine D.

The first total syntheses of clausamines A-C and clausevatine D are reported. The key step involves a Diels-Alder reaction between an imine quinone and cyclic diene, allowing for the subsequent construction of the carbazole core in a regiospecific manner. Stereochemistry of the natural products is also discussed.

Total synthesis of eustifolines A-D and glycomaurrol via a divergent Diels-Alder strategy.

The Diels-Alder reaction between a quinone monoimine and cyclic diene allows for the construction of substituted carbazoles in a regiospecific manner. This methodology has sucessfully been employed in a divergent strategy, culminating in the synthesis of eustifolines A-D and glycomaurrol.

Fluorescence quenching of the S1 and S2 states of zinc meso-tetrakis(4-sulfonatophenyl)porphyrin by halide ions.

The excited-state quenching of zinc meso-tetrakis(4-sulfonatophenyl)porphyrin (ZnTPPS) by halide ions has been studied in water and various aqueous micellar solutions using both steady-state and time-resolved fluorescence techniques. The quenching efficiencies of the S(1) state of ZnTPPS ([small tau][approximate] 1.93 ns) by halide ions in homogeneous aqueous solution increase in the order Cl(-) < Br(-) < I(-); both dynamic and static quenching processes are involved.

Functionalizing the surface of II-VI clusters: redox active centres on the adamantoid complex [Cd4Cl4[mu-(SeC5H4)Fe(C5H5)]6]2-.

Trimethylsilylselenoferrocene 1 has been prepared in good yield. The reactive silyl group on 1 is used as a driving force for the synthesis [Cl4Cd4[mu2-Se(C5H4)Fe(C5H5))6]2- 2, a Cd4Se6 adamantoid cluster with six surface ferrocenyl groups.