Intramolecular cyclization of N-cyano sulfoximines by N-CN bond activation.

Metal-free halogenated anhydrides promote the intramolecular cyclization of N-cyano sulfoximines. Trifluoro- or trichloroacetic anhydride (TFAA or TCAA, respectively) activate the N-cyano groups of N-cyano sulfoximines, leading to the intramolecular cyclization of 2-benzamide-N-cyano sulfoximines 1. This method results in excellent yields of thiadiazinone 1-oxides 2. A full intramolecular cyclization pattern was suggested by (i) labeling experiments with 13C, (ii) isolating of N-trifluoroacetyl sulfoximine 1ac, and (iii) confirming the generation of the intermediate 1ad by LC/MS analysis.

N-Cyano sulfilimine functional group as a nonclassical amide bond bioisostere in the design of a potent analogue to anthranilic diamide insecticide.

To explore the potential of the N-cyano sulfilimine group as an amide bond isostere, a derivative of the blockbuster anthranilic diamide, chlorantramiliprole, was synthesized and evaluated with regard to its physicochemical properties, permeability, and biological activity. Given the combination of N-cyano sulfilimine chlorantraniliprole 1 and its strong hydrogen bond acceptor character, high permeability, and excellent insecticidal activity, the N-cyano sulfilimine functional group could be considered as an amide bond isostere.

Acid-Catalyzed Hydrolysis and Intramolecular Cyclization of N-Cyano Sulfoximines for the Synthesis of Thiadiazine 1-Oxides.

Herein, we describe a novel approach for the practical synthesis of thiadiazine 1-oxides 10. The first example of an intramolecular cyclization with 2-N-cyano-sulfonimidoyl amides 9 to form the desired thiadiazine 1-oxides 10 was developed. One-pot acid-induced hydrolysis of the cyano group and the intramolecular cyclocondensation protocol readily provided various heterocyclic frameworks in good to moderate yields. Notably, the crystal structures of N-urea sulfoximine 11 and thiadiazine 1-oxide 10i have been determined using X-ray crystallography.

Synthesis and Properties of Pentafluorosulfanyl Group (SF5)-Containing Meta-Diamide Insecticides.

Herein, we describe novel pentafluorosulfanyl (SF5) group-containing meta-diamide insecticides. For the facile preparation of the SF5-based compounds 4a-d, practical synthetic methods were applied. Among newly synthesized compounds, 3-benzamido-N-(2,6-dimethyl-4-(pentafluoro-λ6-sulfanyl)phenyl)-2-fluorobenzamide 4d showed (i) a high insecticidal activity, (ii) an excellent selectivity to insects, and (iii) good levels of water solubility and log P values. In this study, we demonstrated that the pentafluorosulfanyl moiety could serve as an attractive functionality for the discovery of a new scope of crop-protecting agents.

Selective Synthesis of N-Cyano Sulfilimines by Dearomatizing Stable Thionium Ions.

For the selective synthesis of N-cyano sulfilimines, we have developed a new method based on the soft-soft interaction between thionium ion electrophiles and cyanonitrene nucleophiles. The stable thionium ion was successfully obtained by oxidative dearomatization using phenyliodine (III) diacetate (PIDA) in N,N-dimethylformamide (DMF). The sulfur imination reactions were tolerant to a wide range of functional groups and exhibited high selectivities and excellent yields. The existence of thionium ion intermediates was confirmed by ultraviolet/visible (UV/vis) spectroscopy and 1H NMR experiments.

Synthesis, Physicochemical Properties, and Biological Activities of 4-(S-Methyl-N-(2,2,2-Trifluoroacetyl)Sulfilimidoyl) Anthranilic Diamide.

Novel anthranilic diamides with sulfilimidoyl and sulfoximidoyl functionalities were successfully prepared. Among newly-prepared organosulfur compounds, 3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-6-(methylcarbamoyl)-4-(methylthio)phenyl)-1H-pyrazole-5-carboxamide and (S,E)-3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-4-(S-methyl-N-(2,2,2-trifluoroacetyl)sulfinimidoyl)-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide showed good levels of efficacy and a strong correlation between insecticidal activities and physical properties, respectively. In particular, available data indicated that the N-trifluoroacetyl sulfilimine moiety could be an appealing structural scaffold for the discovery of a new crop-protecting agent.

Differences in the molecular signatures of mucosal-associated invariant T cells and conventional T cells.

Mucosal-associated invariant T (MAIT) cells exhibit different characteristics from those of TCRα7.2- conventional T cells. They play important roles in various inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. MAIT cells express a single T cell receptor alpha chain, TCRα7.2 segment associated with Jα33 and CDR3 with fixed length, which recognizes bacteria-derived vitamin B metabolites. However, the characteristics of MAIT cells and TCRα7.2+ CD161- T cells have never been compared. Here, we performed RNA sequencing to compare the properties of MAIT cells, TCRα7.2- conventional T cells and TCRα7.2+ CD161- T cells. Genome-wide transcriptomes of MAIT cells, TCRα7.2- conventional T cells, and TCRα7.2+ CD161- T cells were compared and analyzed using causal network analysis. This is the first report comparing the transcriptomes of MAIT cells, TCRα7.2- conventional T cells and TCRα7.2+ CD161- T cells. We also identified the predominant signaling pathways of MAIT cells, which differed from those of TCRα7.2- conventional T cells and TCRα7.2+ CD161- T cells, through a gene set enrichment test and upstream regulator analysis and identified the genes responsible for the characteristic MAIT cell phenotypes. Our study advances the complete understanding of MAIT biology.

Broadly Applicable Stereoselective Syntheses of Serrulatane, Amphilectane Diterpenes, and Their Diastereoisomeric Congeners Using Asymmetric Hydrovinylation for Absolute Stereochemical Control.

A stereogenic center, placed at an exocyclic location next to a chiral carbon in a ring to which it is attached, is a ubiquitous structural motif seen in many bioactive natural products, including di- and triterpenes and steroids. Installation of these centers has been a long-standing problem in organic chemistry. Few classes of compounds illustrate this problem better than serrulatanes and amphilectanes, which carry multiple methyl-bearing exocyclic chiral centers. Nickel-catalyzed asymmetric hydrovinylation (AHV) of vinylarenes and 1,3-dienes such as 1-vinylcycloalkenes provides an exceptionally facile way of introducing these chiral centers. This Article documents our efforts to demonstrate the generality of AHV to access not only the natural products but also their various diastereoisomeric derivatives. Key to success here is the availability of highly tunable phosphoramidite Ni(II) complexes useful for overcoming the inherent selectivity of the chiral intermediates. The yields for hydrovinylation (HV) reactions are excellent, and selectivities are in the range of 92-99% for the desired isomers. Discovery of novel, configurationally fluxional, yet sterically less demanding 2,2'-biphenol-derived phosphoramidite Ni complexes (fully characterized by X-ray) turned out to be critical for success in several HV reactions. We also report a less spectacular yet equally important role of solvents in a metal-ammonia reduction for the installation of a key benzylic chiral center. Starting with simple oxygenated styrene derivatives, we iteratively install the various exocyclic chiral centers present in typical serrulatane [e.g., a (+)- p-benzoquinone natural product, elisabethadione, nor-elisabethadione, helioporin D, a known advanced intermediate for the synthesis of colombiasin and elisapterosin] and amphilectane [e.g., A-F, G-J, and K,L pseudopterosins] derivatives. A concise table showing various synthetic approaches to these molecules is included in the Supporting Information. Our attempts to synthesize a hitherto elusive target, elisabethin A, led to a stereoselective, biomimetic route to pseudopterosin A-F aglycones.

One-pot sequential synthesis of tetrasubstituted thiophenes via sulfur ylide-like intermediates.

Herein, we describe a novel approach for the practical synthesis of tetrasubstituted thiophenes 8. The developed method was particularly used for the facile preparation of thienyl heterocycles 8. The mechanism for this reaction is based on the formation of a sulfur ylide-like intermediate. It was clearly suggested by (i) the intramolecular cyclization of ketene N,S-acetals 7 to the corresponding thiophenes 8, (ii) 1H NMR studies of Meldrum's acid-substituted aminothioacetals 9, and (iii) substitution studies of the methoxy group on Meldrum's acid containing N,S-acetals 9b. Notably, in terms of structural effects on the reactivity and stability of sulfur ylide-like intermediates, 2-pyridyl substituted compound 7a exhibited superior properties over those of others.

Small molecule inhibitors of the Dishevelled-CXXC5 interaction are new drug candidates for bone anabolic osteoporosis therapy.

Bone anabolic agents promoting bone formation and rebuilding damaged bones would ideally overcome the limitations of anti-resorptive therapy, the current standard prescription for osteoporosis. However, the currently prescribed parathyroid hormone (PTH)-based anabolic drugs present limitations and adverse effects including osteosarcoma during long-term use. Also, the antibody-based anabolic drugs that are currently being developed present the potential limits in clinical application typical of macromolecule drugs. We previously identified that CXXC5 is a negative feedback regulator of the Wnt/ß-catenin pathway via its interaction with Dishevelled (Dvl) and suggested the Dvl-CXXC5 interaction as a potential target for anabolic therapy of osteoporosis. Here, we screened small-molecule inhibitors of the Dvl-CXXC5 interaction via a newly established in vitro assay system. The screened compounds were found to activate the Wnt/ß-catenin pathway and enhance osteoblast differentiation in primary osteoblasts. The bone anabolic effects of the compounds were shown using ex vivo-cultured calvaria. Nuclear magnetic resonance (NMR) titration analysis confirmed interaction between Dvl PDZ domain and KY-02061, a representative of the screened compounds. Oral administration of KY-02327, one of 55 newly synthesized KY-02061 analogs, successfully rescued bone loss in the ovariectomized (OVX) mouse model. In conclusion, small-molecule inhibitors of the Dvl-CXXC5 interaction that block negative feedback regulation of Wnt/ß-catenin signaling are potential candidates for the development of bone anabolic anti-osteoporosis drugs.

Mild one-pot Horner-Wadsworth-Emmons olefination and intramolecular N-arylation for the syntheses of indoles, all regio-isomeric azaindoles, and thienopyrroles.

The syntheses of various N-protected aromatic-ring fused pyrrole-2-carboxylate derivatives have been accomplished using mild one-pot Horner-Wadsworth-Emmons olefination and Cu-catalyzed intramolecular N-arylation reactions. The optimized mild one-pot reaction conditions of various 2-bromo arylcarboxaldehydes with commercially available N-protected phosphonoglycine trimethylesters gave the desired aromatic-ring fused pyrrole-2-carboxylates, such as substituted indole-, all regio-isomeric azaindole-, and thienopyrrole-2-carboxylates, in good to excellent yields. These conditions showed broad substrate compatibility, without the loss of the protecting group.

Probes for narcotic receptor mediated phenomena. 48. C7- and C8-substituted 5-phenylmorphan opioids from diastereoselective alkylation.

The exploration of the effect of substituents at C7 and C8 of the 5-phenylmorphans on their affinity for opioid receptors was enabled by our recently introduced "one pot" diastereoselective synthesis that provided C7-oxo, hydroxy and alkyl substituents, C8-alkyl substituted 5-phenylmorphans, and compounds that had a new cyclohexane ring that includes the C7 and C8 carbon atoms of the 5-phenylmorphan. The affinity of the 5-phenylmorphans for opioid receptors is increased by a C8-methyl substituent, compared with its C7 analog. The affinity of the newly synthesized compounds is generally for the µ-opioid receptor, rather than the δ- or κ-receptors. Addition of a new cyclohexane ring to the C7 and C8 positions on the cyclohexane ring of the 5-phenylmorphans enhances µ-receptor affinity, bringing the Ki to the subnanomolar level. Unexpectedly, the N-methyl substituted compounds generally had higher affinity than comparable N-phenethyl-substituted relatives. The configurations of two compounds were determined by single-crystal X-ray crystallographic analyses.

One-pot transition-metal-free synthesis of dibenzo[b,f]oxepins from 2-halobenzaldehydes.

A one-pot transition-metal-free, base-mediated synthesis of dibenzo[b,f]oxepins was developed. The reaction of 2-halobenzaldehydes with (2-hydroxyphenyl)acetonitriles proceeds via a sequential aldol condensation and intramolecular ether formation reaction in the presence of Cs(2)CO(3) and molecular sieves in toluene.

Asymmetric hydrovinylation of vinylindoles. A facile route to cyclopenta[g]indole natural products (+)-cis-trikentrin A and (+)-cis-trikentrin B.

Vinylindoles undergo Ni(II)-catalyzed asymmetric hydrovinylation under very mild conditions (-78 °C, 1 atm ethylene, 4 mol % catalyst) to give the corresponding 2-but-3-enyl derivatives in excellent yields and enantioselectivities. Hydroboration of the alkene and oxidation to an acid, followed by Friedel-Crafts annulation, gives an indole-annulated cyclopentanone that is a suitable precursor for the syntheses of cis-trikentrins and all known herbindoles. For example, the cyclopentanone from 4-ethyl-7-vinylindole is converted into (+)-cis-trikentin A in four steps (Wittig reaction, alkene isomerization, diastereoselective hydrogenation, and nitrogen deprotection). The previous synthesis of this molecule from (S)-(-)-malic acid involved more than 20 steps and a preparative HPLC separation of diastereomeric intermediates.

Ethylene in organic synthesis: a new route to anticholenergic pyrrolidinoindolines, and other molecules with all carbon-quaternary centers via asymmetric hydrovinylation.

The asymmetric hydrovinylation (1 mol % Ni-cat., 1 atm, ethylene, >98% ee) products from 1-methylenetetralines are readily converted into 3,3-disubstituted oxindoles and subsequently to pyrrolidinoindolines. These hydrovinylation products are also useful for the syntheses of enantiopure benzomorphans.

Diastereoselective one-pot synthesis of 7- and 8-substituted 5-phenylmorphans.

Novel 7- and 8-alkyl and aryl substituted 5-phenylmorphans were synthesized from substituted allyl halides and N-benzyl-4-aryl-1,2,3,6-tetrahydropyridine by a highly efficient and diastereoselective reaction series, "one-pot" alkylation and ene-imine cyclization followed by sodium borohydride reduction. Mild cyclization conditions gave the desired substituted 5-phenylmorphans in good yield as a single diastereomer.

Annulated diketopiperazines from dipeptides or Schöllkopf reagents via tandem cyclization-intramolecular N-arylation.

Facile CuI-mediated N-arylation of diketopiperazine using the Fukuyama modification of the Ullmann-Goldberg reaction can be exploited in new approaches to enantiopure polycyclic diketopiperazines from easily assembled dipeptides or functionalized Schöllkopf reagents.

Tunable Phosphoramidite Ligands for Asymmetric Hydrovinylation: Ligands par excellence for Generation of All-Carbon Quaternary Centers.

1-Alkylstyrenes undergo efficient hydrovinylation (addition of ethylene) in the presence of a Ni-catalyst prepared from [(allyl)NiBr](2), Na(+) [BAr(4)](-) (Ar = 3,5-bis-trifluromethylphenyl), and a phosphoramidite ligand giving products in excellent yields and enantioselectivities. In many cases phosphoramidites derived from achiral 2,2'-biphenol are almost as good as ligands derived from the more expensive enantiopure 2,2'-binaphthols. The hydrovinylation products, which carry two versatile latent functionalities, an aryl and a vinyl group, are potentially useful for the synthesis of several important natural products containing benzylic all-carbon quaternary centers.

Seleniranium ion-triggered reactions: new aspects of Friedel-Crafts and N-detosylative cyclizations.

Seleniranium ions at low temperatures (-90 to -78 degrees C) will initiate effective Friedel-Crafts cyclization if a suitably placed arene is allowed to react even when the arene is unactivated. These intermediates generated from N-aryl-N-tosylamides undergo a novel, surprisingly efficient, detosylative cyclization to form 5- or 6-membered nitrogen heterocycles. A debenzylation route is preferred if both benzyl and tosyl groups are present in the substrate.

Facile Pd(II)- and Ni(II)-catalyzed isomerization of terminal alkenes into 2-alkenes.

Mono- and 2,2'-disubstituted terminal alkenes can be isomerized into the more stable internal (Z)- and (E)-alkenes by treating them with catalytic amounts of [(allyl)PdCl](2) or [(allyl)NiBr](2), a triarylphosphine, and silver triflate at room temperature. The isomeric ratio (E:Z) depends on the alkenes, the E-isomer being the major one. The reaction is tolerant to a wide variety of functional groups including other reactive olefins. Unlike the more reactive Ir catalysts, monosubstituted alkenes give almost exclusively the 2-alkenes. Direct comparison to two of the best-known catalysts for this process {[Ir(PCy(3))(3)](+)[BPh(4)](-) and Grubbs generation II metathesis catalyst} is also described.