Showing papers on "Bicyclic molecule published in 2018"
TL;DR: This work has shown that the elusive cyclic enamine intermediates were effectively generated by photoredox catalysis under mild conditions and efficiently captured by acetylene esters to form a wide array of bicyclic amino acid derivatives, thus enabling the simultaneous functionalization of two vicinal C(sp3 )-H bonds.
Abstract: Herein we describe a mild method for the dual C(sp3 )-H bond functionalization of saturated nitrogen-containing heterocycles through a sequential visible-light photocatalyzed dehydrogenation/[2+2] cycloaddition procedure. As a complementary approach to the well-established use of iminium ion and α-amino radical intermediates, the elusive cyclic enamine intermediates were effectively generated by photoredox catalysis under mild conditions and efficiently captured by acetylene esters to form a wide array of bicyclic amino acid derivatives, thus enabling the simultaneous functionalization of two vicinal C(sp3 )-H bonds.
69 citations
TL;DR: In this paper, a Ni-catalysed dehydrogenative approach for the synthesis of pyrroles, pyridines, and quinolines by the reaction of β- and γ-amino alcohols with ketones via C-N and C-C bond formations in a tandem fashion was demonstrated.
62 citations
TL;DR: In this article, the authors replaced the naphthalene C-unit of the anti-tuberculosis drug bedaquiline with a range of bicyclic heterocycles of widely differing lipophilicity.
60 citations
TL;DR: The perfluoroaryl cyclic and bicyclic peptides improved PMO activity roughly 14-fold over the unconjugated PMO and exhibited increased proteolytic stability relative to the monocycle, demonstrating that perfluorosoroaryl bicyclIC peptides are potent and stable delivery agents.
Abstract: Exon-skipping antisense oligonucleotides are effective treatments for genetic diseases, yet exon-skipping activity requires that these macromolecules reach the nucleus. While cell-penetrating peptides can improve delivery, proteolytic instability often limits efficacy. It is hypothesized that the bicyclization of arginine-rich peptides would improve their stability and their ability to deliver oligonucleotides into the nucleus. Two methods were introduced for the synthesis of arginine-rich bicyclic peptides using cysteine perfluoroarylation chemistry. Then, the bicyclic peptides were covalently linked to a phosphorodiamidate morpholino oligonucleotide (PMO) and assayed for exon skipping activity. The perfluoroaryl cyclic and bicyclic peptides improved PMO activity roughly 14-fold over the unconjugated PMO. The bicyclic peptides exhibited increased proteolytic stability relative to the monocycle, demonstrating that perfluoroaryl bicyclic peptides are potent and stable delivery agents.
55 citations
TL;DR: In this article, cyclohexadienones with a flexible ether or alkyl group linked internal enone moiety were constructed and the hydrogen-bonding interaction between thiourea and carbonyl group is crucial and facilitates the otherwise flexible backbones to undergo cyclization.
Abstract: Highly enantioselective intramolecular RC reactions via desymmetrization of cyclohexadienones have been developed. By employing cyclohexadienones with a flexible ether or alkyl group linked internal enone moiety, optically enriched bicyclic pyran and hydrindane skeletons were constructed. Bifunctional phosphine catalysts bearing a thiourea moiety were found to effectively promote the reaction, and preliminary studies suggest that the hydrogen-bonding interaction between thiourea and carbonyl group is crucial and facilitates the otherwise flexible backbones to undergo the desired cyclization.
52 citations
TL;DR: A C-C bonded amino-nitro pyrazole and its ring-expansion product have been synthesized and characterized and both structures were confirmed by single crystal X-ray diffraction.
49 citations
TL;DR: Quinazoline is a heterocyclic compound having biological activities as discussed by the authors, it is aromatic in nature having bicyclic structure containing benzene ring and pyrimidine ring.
46 citations
TL;DR: A new class of chiral C2 -symmetric bicyclic bisborane catalysts is prepared by addition reactions of internal dienes with the Piers borane and an analogue to select two diastereomeric catalysts from a single diene precursor.
Abstract: We prepared a new class of chiral C2 -symmetric bicyclic bisborane catalysts by addition reactions of internal dienes with the Piers borane, HB(C6 F5 )2 , and an analogue, HB(p-C6 F4 H)2 The dependence of the addition pattern on the reaction temperature allowed us to selectively prepare two diastereomeric catalysts from a single diene precursor The bisboranes prepared in situ exhibited excellent activity (turnover numbers up to 200 at -40 °C) and enantioselectivity (up to 95 % ee) in imine hydrogenation reactions
45 citations
TL;DR: A straightforward general method for the synthesis of cyclic carbamates from amino alcohols and carbon dioxide in the presence of an external base and a hydroxyl group activating reagent with high regio- chemo- and stereoselectivity.
42 citations
TL;DR: One bicyclic peptide was shown to inhibit the interaction between a pro-apoptotic protein (Bim) and either endogenous Bcl2A1 or Mcl-1, to induce apoptosis of SKMel28 human melanoma cells, and to sensitize them for enhanced cell death by the anticancer drug etoposide.
Abstract: A 26-residue peptide BimBH3 binds indiscriminately to multiple oncogenic Bcl2 proteins that regulate apoptosis of cancer cells. Specific inhibition of the BimBH3-Bcl2A1 protein–protein interaction was obtained in vitro and in cancer cells by shortening the peptide to 14 residues, inserting two cyclization constraints to stabilize a water-stable α-helix, and incorporating an N-terminal acrylamide electrophile for selective covalent bonding to Bcl2A1. Mass spectrometry of trypsin-digested bands on electrophoresis gels established covalent bonding of an electrophilic helix to just one of the three cysteines in Bcl2A1, the one (Cys55) at the BimBH3-Bcl2A1 protein–protein interaction interface. Optimizing the helix-inducing constraints and the sequence subsequently enabled electrophile removal without loss of inhibitor potency. The bicyclic helical peptides were potent, cell permeable, plasma-stable, dual inhibitors of Bcl2A1 and Mcl-1 with high selectivity over other Bcl2 proteins. One bicyclic peptide was sh...
40 citations
TL;DR: This review describes advances in the literature since 2000 in the area of reactions of Vinylsulfonium and vinylsulfoxonium salts, with a particular emphasis on stereoselective examples.
Abstract: This review describes advances in the literature since 2000 in the area of reactions of vinylsulfonium and vinylsulfoxonium salts, with a particular emphasis on stereoselective examples. Although the chemistry of vinylsulfonium salts was first explored back in the 1950s, and that of vinylsulfoxonium salts in the early 1970s, there has been renewed interest in these compounds since the turn of the century. This has been largely due to an increased appreciation for the many synthetic possibilities associated with these valuable electrophiles. The development of improved routes to vinylsulfonium salts allowing for their in situ generation has played a part in accelerating their study. In general, reactions of the two sulfur salt classes follow a similar mechanistic pathway: initial conjugate addition of a nucleophile to the β-position, followed by protonation of an ylide intermediate, and cyclization of tethered anion to afford monocyclic or bicyclic product (e.g., cyclopropane, aziridine, oxazole, oxazolidinone, γ-lactam or γ-lactone). Alternatively, reactions involve formation of an ylide intermediate followed by intramolecular Johnson-Corey-Chaykovsky reaction (epoxidation or cyclopropanation), and subsequent cyclization to afford the desired bicyclic product (e.g., fused bicyclic epoxide or cyclopropane).
TL;DR: A previously unreported family of P-stereogenic bicyclic chiral phosphines is prepared through straightforward syntheses starting from the natural product carvone, obtained in high yields and enantioselectivities, including a biologically active small molecule, efsevin.
Abstract: We have prepared a previously unreported family of P-stereogenic [2.2.1] bicyclic chiral phosphines through straightforward syntheses starting from the natural product carvone. This design rationale prompted the development of an unforeseen C-dealkenylation reaction. We have applied these organocatalysts in the asymmetric syntheses of a bevy of pyrrolines, obtained in high yields and enantioselectivities, including a biologically active small molecule, efsevin.
TL;DR: A bridged [2.2.1] bicyclic phosphine oxide has been created and applied successfully in halide-/base-free catalytic γ-umpolung addition–Wittig olefinations.
Abstract: A novel bridged [2.2.1] bicyclic phosphine oxide, devised to circumvent the waste generation and burdens of purification that are typical of reactions driven by the generation of phosphine oxides, has been prepared in three steps from commercially available cyclopent-3-ene-1-carboxylic acid. The performance of this novel phosphine oxide was superior to those of current best-in-class counterparts, as verified experimentally through kinetic analysis of its silane-mediated reduction. It has been applied successfully in halide-/base-free catalytic γ-umpolung addition-Wittig olefinations of allenoates and 2-amidobenzaldehydes to produce 1,2-dihydroquinolines with good efficiency. One of the 1,2-dihydroquinoline products was converted to known antitubercular furanoquinolines.
TL;DR: It is shown that a metal-free amphoteric diamination of allenes produces valuable six-, seven- and eight-membered N-heterocycles with high diversity and tolerance of functional groups on the ring.
Abstract: Saturated 1,4-diazo heterocycles including piperazines, 1,4-diazepanes, and 1,4-diazocanes, are highly important for therapeutic development, but their syntheses are often tedious. We describe here an amphoteric diamination strategy to unite readily available 1,2-, 1,3- or 1,4-diamine derivatives with electron-deficient allenes via a formal [n + 2] (n = 4, 5, 6) cyclization mode to produce the corresponding 1,4-diazo heterocycles in just one step. This strategy features mild reaction conditions, high functional group tolerance, and scalability (gram scale). The reagents used are cheap and readily available and no transition metal catalysts are needed. More sophisticated products containing trifluoromethyl group or bicyclic ring systems can be accessed via a one-pot procedure as well. Our mechanistic studies support that formation of mono-iodinated or chlorinated diamine intermediates is important for the desired transformation and the commonly proposed chloride-iodide exchange process and a radical N−C bond formation is unlikely when the combination of NCS/KI is used. Saturated N-heterocycle rings are common structural motifs of many FDA-approved drugs. Here, the authors show that a metal-free amphoteric diamination of allenes produces valuable six-, seven- and eight-membered N-heterocycles with high diversity and tolerance of functional groups on the ring.
TL;DR: The [3 + 2] annulations of γ-butyrolactone fused donor-acceptor (D-A) cyclopropanes with aromatic isothiocyanates and dialkyl carbodiimides promoted by FeCl3 is reported.
Abstract: The [3 + 2] annulations of γ-butyrolactone fused donor–acceptor (D–A) cyclopropanes with aromatic isothiocyanates and dialkyl carbodiimides promoted by FeCl3 is reported. A series of bicyclic/polycyclic γ-butyrolactone fused thioimidates and γ-butyrolactone fused amidines containing four contiguous stereogenic centers were obtained in excellent yields as single stereoisomers.
TL;DR: The umpolung of β,γ-unsaturated diketones through N-heterocyclic carbene catalysis is described, which allows access to a variety of highly functionalized bicyclic cyclohexene-β-lactones and 1,3,4-triaryl benzenes.
TL;DR: Non-catalysed addition of trifluoroacetonitrile imines to enol ethers provided fully regioselectively (3 + 2)-cycloadducts, which either spontaneously or via Brønsted acid-induced elimination of ROH molecules led to the formation of 3-trifluoromethylated pyrazoles.
Abstract: Non-catalysed addition of trifluoroacetonitrile imines to enol ethers provided fully regioselectively (3 + 2)-cycloadducts, which either spontaneously or via Bronsted acid-induced elimination of ROH molecules led to the formation of 3-trifluoromethylated pyrazoles. In the case of 2,3-dihydrofuran, the respective bicyclic intermediate was isolated and its structure was confirmed by X-ray analysis. Using the developed protocol the synthesis of a known antitumor compound SC-560 was performed in 45% yield. Subsequent functionalisations of selected 4-(ω-hydroxyalkyl)pyrazoles at C(5) through lithiation/addition, cross-coupling reactions or via intramolecular Pd-catalysed C–H arylations opened up an access to polysubstituted pyrazoles including unusual tricyclic systems comprising 7-membered rings (oxepane, thiepane and azepane) as the central unit.
TL;DR: A new strategy was devised for the total synthesis of highly oxidized ent-kauranoids using a diene embedded in a substituted bicyclo in a highly regio- and diastereoselective intermolecular Diels-Alder cycloaddition.
Abstract: A new strategy was devised for the total synthesis of highly oxidized ent-kauranoids. A highly regio- and diastereoselective intermolecular Diels-Alder cycloaddition involving a diene embedded in a substituted bicyclo[4.1.0] skeleton was used to assemble all carbon centers but C17 of the target molecule at an early stage of the synthesis. Subsequent synthetic steps, including redox manipulations, SmI2 -mediated cyclization, and isomerization reactions, afforded the antitumor natural product maoecrystal P.
TL;DR: The synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles via rhodium(III)-catalyzed C-H functionalization of C-alkenyl azoles with sulfoxonium ylides is disclosed.
TL;DR: In comparison to other established enzymatic methods such as the use of oxidases, ALDHs offer greatly improved selectivity, and shows applicability across a wide range of substrates, and retains perfect chemoselectivity.
TL;DR: The present strategy enables the double isocyanide insertion and subsequent 5-endo-dig cyclization, thus providing a quick access to structurally complex pyrrole-fused heterocycles.
TL;DR: The iron-catalyzed cycloaddition reaction of alkene-tethered oxime esters with 1,2-disubstituted alkenes afforded tetrahydropyrrolizines, the structural motif often seen in bicyclic alkaloids, is studied.
TL;DR: In this article, a divergent catalytic transformation of alkene-tethered isoxazol-5(4H)-ones by using rhodium and cobalt catalysts to afford 2H-pyrroles (with Rh catalyst) and azabicyclic cyclopropanes (with Co catalyst).
Abstract: We report the divergent catalytic transformation of alkene-tethered isoxazol-5(4H)-ones by using rhodium and cobalt catalysts to afford 2H-pyrroles (with Rh catalyst) and azabicyclic cyclopropanes (with Co catalyst). The rhodium-catalyzed 2H-pyrrole formation involving hydrogen shift is supported by deuterium-labeling experiments. The control experiments in the cobalt-catalyzed reaction indicate that the bicyclic aziridines as the primary product undergo a skeletal rearrangement assisted by metal iodide salts.
Patent•
19 Dec 2018TL;DR: In this article, the authors described compositions including the compounds and methods of using the compounds as autotaxin inhibitors as well as the methods of applying them as inhibitors as a whole.
Abstract: Compounds of formula (I)
wherein R 1 , R 2 , A, W, m, n, p and q are as described herein, compositions including the compounds and methods of using the compounds as autotaxin inhibitors.
TL;DR: Substrate-controlled reactions have been developed for the synthesis of spirocyclopropylpyrazolones and bicyclic 4,5-dihydropyrazoles from 1,2-diaza-1,3-dienes and sulfur ylides in generally moderate to good yields.
TL;DR: The flexibility and high reactivity of malononitrile dimer as a multi-functional reagent and its potential to the preparation of novel beneficial scaffolds as well as biologically active molecules signify it as a suitable building block in total synthesis, medicinal chemistry, and dyes.
Abstract: Malononitrile dimer as a precursor reactant has been extensively applied in the diversity-oriented synthesis of various heterocyclic motifs, bis-heterocyclic compounds, fused heterocycle derivatives, bicyclic bridged heterocyclic scaffolds, and highly substituted carbocyclic compounds. These remarkable products were synthesized via various types of reactions, such as cycloaddition, cyclocondensation, cascade/domino/tandem reactions along with multi-component reactions. In addition, the flexibility and high reactivity of malononitrile dimer as a multi-functional reagent and its potential to the preparation of novel beneficial scaffolds as well as biologically active molecules signify it as a suitable building block in total synthesis, medicinal chemistry, and dyes. In the present review, the advances in the chemistry of malononitrile dimer as a potent reagent in organic synthesis have been reported in the past to now.
TL;DR: The first total synthesis of chaetoglobin A, which features a chiral axis between two identical highly oxygenated bicyclic cores, was successfully completed in 12 steps from 2,6-dimethoxytoluene.
TL;DR: This transformation represents the first asymmetric [2+2] cycloaddition reaction of azabenzonorbornadienes with internal alkynes, providing a straightforward method to prepare four-membered carbocycles.
Abstract: Enantioselective [2+2] cycloaddition reaction of azabenzonorbornadienes and oxabenzonorbornadienes with internal alkynes has been enabled by a catalyst system comprising Ni(COD)2 and (R)-SIPHOS-Ph-Mor. This transformation represents the first asymmetric [2+2] cycloaddition reaction of azabenzonorbornadienes with internal alkynes, providing a straightforward method to prepare four-membered carbocycles.