Showing papers on "Bicyclic molecule published in 2016"
TL;DR: Oxidation of DPX-26 using hypofluorous acid produces 4-amino-3,7-dinitrotriazolo-[5,1-c][1,2,4] triazine 4-oxide (DPX-27), which is predicted to be a high-performance material with enhanced safety properties.
Abstract: The reaction of 3-amino-5-nitro-1,2,4-triazole with nitrous acid produces the corresponding diazonium salt. When the diazonium salt is treated with nitroacetonitrile, a subsequent condensation and cyclization reaction occurres to produced 4-amino-3,7-dinitrotriazolo-[5,1-c][1,2,4] triazine (DPX-26). X-ray crystallographic analysis shows that the DPX-26 has a density of 1.86 g cm−3, while it is calculated to have a heat of formation of 398.3 kJ mol−1. DPX-26 is predicted to approach the explosive performance of RDX but displays significantly better safety properties. Oxidation of DPX-26 using hypofluorous acid produces 4-amino-3,7-dinitrotriazolo-[5,1-c][1,2,4] triazine 4-oxide (DPX-27), which is also predicted to be a high-performance material with enhanced safety properties.
152 citations
TL;DR: A highly diastereoselective method for the synthesis of dihydroepoxybenzofluorenone derivatives from aromatic/vinylic amides and bicyclic alkenes is described, for the first time that a [3+2] cycloaddition is described in this context.
Abstract: A highly diastereoselective method for the synthesis of dihydroepoxybenzofluorenone derivatives from aromatic/vinylic amides and bicyclic alkenes is described. This new transformation proceeds through cobalt-catalyzed C-H activation and intramolecular nucleophilic addition to the amide functional group. Transition-metal-catalyzed C-H activation reactions of secondary amides with alkenes usually lead to [4+2] or [4+1] annulation; to the best of our knowledge, this is the first time that a [3+2] cycloaddition is described in this context. The reaction proceeds under mild conditions and tolerates a wide range of functional groups. Mechanistic studies imply that the C-H bond cleavage may be the rate-limiting step.
131 citations
TL;DR: The generality of the bicyclic approach is tested by synthesizing a combinatorial library of 5.7 × 106 bicyclic peptides featuring a degenerate sequence in the first ring and an invariant cell-penetrating peptide in the second ring that produced a moderately potent and cell-permeable K-Ras inhibitor.
Abstract: Cyclic peptides have great potential as therapeutic agents and research tools. However, their applications against intracellular targets have been limited, because cyclic peptides are generally impermeable to the cell membrane. It was previously shown that fusion of cyclic peptides with a cyclic cell-penetrating peptide resulted in cell-permeable bicyclic peptides that are proteolytically stable and biologically active in cellular assays. In this work, we tested the generality of the bicyclic approach by synthesizing a combinatorial library of 5.7 × 106 bicyclic peptides featuring a degenerate sequence in the first ring and an invariant cell-penetrating peptide in the second ring. Screening of the library against oncoprotein K-Ras G12V followed by hit optimization produced a moderately potent and cell-permeable K-Ras inhibitor, which physically blocks the Ras-effector interactions in vitro, inhibits the signaling events downstream of Ras in cancer cells, and induces apoptosis of the cancer cells. Our appr...
104 citations
Patent•
03 Mar 2016TL;DR: In this article, the compounds of Formula 1, including all geometric and stereoisomers, N -oxides, and salts thereof, were disclosed, and methods for controlling an invertebrate pest comprising contacting the pest or its environment with a biologically effective amount of a compound or a composition of the invention.
Abstract: Disclosed are compounds of Formula 1, including all geometric and stereoisomers, N -oxides, and salts thereof, wherein Q is Q-1, Q-2, Q-3 or Q-4 and A, R 1 , m, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 and Y 3 are as defined in the disclosure. Also disclosed are compositions containing the compounds of Formula 1 and methods for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound or a composition of the invention.
81 citations
TL;DR: Chemically orthogonal ring-closing olefin (RCM) and alkyne metathesis (RCAM) enable an efficient chemo- and regioselective synthesis of complex bicyclic peptide scaffolds with variable macrocycle geometries.
Abstract: Bicyclic peptides are promising scaffolds for the development of inhibitors of biological targets that proved intractable by typical small molecules. So far, access to bioactive bicyclic peptide architectures is limited due to a lack of appropriate orthogonal ring-closing reactions. Here, we report chemically orthogonal ring-closing olefin (RCM) and alkyne metathesis (RCAM), which enable an efficient chemo- and regioselective synthesis of complex bicyclic peptide scaffolds with variable macrocycle geometries. We also demonstrate that the formed alkyne macrocycle can be functionalized subsequently. The orthogonal RCM/RCAM system was successfully used to evolve a monocyclic peptide inhibitor of the small GTPase Rab8 into a bicyclic ligand. This modified peptide shows the highest affinity for an activated Rab GTPase that has been reported so far. The RCM/RCAM-based formation of bicyclic peptides provides novel opportunities for the design of bioactive scaffolds suitable for the modulation of challenging protein targets.
74 citations
TL;DR: Using a combination of quantitative proteomics and whole genome sequencing of susceptible and drug-resistant parasites, a putative NAD(P)H oxidase is identified as the activating nitroreductase (NTR2) and NTR2 is necessary and sufficient for activation of these bicyclic nitro- drugs.
Abstract: Drug discovery pipelines for the "neglected diseases" are now heavily populated with nitroheterocyclic compounds. Recently, the bicyclic nitro-compounds (R)-PA-824, DNDI-VL-2098 and delamanid have been identified as potential candidates for the treatment of visceral leishmaniasis. Using a combination of quantitative proteomics and whole genome sequencing of susceptible and drug-resistant parasites we identified a putative NAD(P)H oxidase as the activating nitroreductase (NTR2). Whole genome sequencing revealed that deletion of a single cytosine in the gene for NTR2 that is likely to result in the expression of a non-functional truncated protein. Susceptibility of leishmania was restored by reintroduction of the wild-type gene into the resistant line, which was accompanied by the ability to metabolise these compounds. Overexpression of NTR2 in wild-type parasites rendered cells hyper-sensitive to bicyclic nitro-compounds, but only marginally to the monocyclic nitro-drugs, nifurtimox and fexinidazole sulfone, known to be activated by a mitochondrial oxygen-insensitive nitroreductase (NTR1). Conversely, a double knockout NTR2 null cell line was completely resistant to bicyclic nitro-compounds and only marginally resistant to nifurtimox. Sensitivity was fully restored on expression of NTR2 in the null background. Thus, NTR2 is necessary and sufficient for activation of these bicyclic nitro-drugs. Recombinant NTR2 was capable of reducing bicyclic nitro-compounds in the same rank order as drug sensitivity in vitro. These findings may aid the future development of better, novel anti-leishmanial drugs. Moreover, the discovery of anti-leishmanial nitro-drugs with independent modes of activation and independent mechanisms of resistance alleviates many of the concerns over the continued development of these compound series.
74 citations
TL;DR: A manganese-catalyzed bicyclic annulation of imines with α,β-unsaturated esters via C-H activation via C–H activation is described, which provides an expedient access to fused β-lactams in one-step operation with high efficiency and good functional group tolerance.
Abstract: A manganese-catalyzed bicyclic annulation of imines with α,β-unsaturated esters via C–H activation is described, which provides an expedient access to fused β-lactams in one-step operation with high efficiency and good functional group tolerance. Of note, both ketimines and aldimines are amenable to this transformation. Mechanistic studies have identified a five-membered azamanganacycle as the key reaction intermediate.
69 citations
TL;DR: It is shown that by applying a Rh catalyst and JoSPOphos ligand, either the anti or syn bicyclic γ-lactones can be accessed with high enantio- and diastereoselectivities, depending on the choice of solvent, temperature, and counterion.
Abstract: We present a diastereodivergent strategy for constructing bicyclic γ-lactones bearing quaternary carbon centers via ketone hydroacylation. By applying a Rh catalyst and JoSPOphos ligand, either the anti or syn bicyclic γ-lactones can be accessed with high enantio- and diastereoselectivities, depending on the choice of solvent, temperature, and counterion.
66 citations
TL;DR: Asymmetric conjugate alkynylation of cyclic α,β-unsaturated carbonyl compounds (ketones, esters, and amides) was realized by use of diphenyl[(triisopropylsilyl)ethynyl]methanol as an alkynyating reagent in the presence of a rhodium catalyst coordinated with a new chiral diene ligand.
Abstract: Asymmetric conjugate alkynylation of cyclic α,β-unsaturated carbonyl compounds (ketones, esters, and amides) was realized by use of diphenyl[(triisopropylsilyl)ethynyl]methanol as an alkynylating reagent in the presence of a rhodium catalyst coordinated with a new chiral diene ligand (Fc-bod; bod=bicyclo[2.2.2]octa-2,5-diene, Fc=ferrocenyl) to give high yields of the corresponding β-alkynyl-substituted carbonyl compounds with 95-98% ee.
56 citations
TL;DR: Strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp3 character are described, leading to a fragment collection featuring regio‐ and stereo‐controlled introduction of substituents on the saturated ring system.
Abstract: Fragment-based lead generation has proven to be an effective means of identifying high-quality lead compounds for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp(2) -rich aromatic compounds, which limits the structural (and hence biological) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp(3) character. Subsequent derivatization led to a fragment collection featuring regio- and stereo-controlled introduction of substituents on the saturated ring system, often with formation of new stereocenters.
53 citations
TL;DR: Derivatives of the fully twisted bicyclic amide 7-hypoquinuclidone are synthesized using a Schmidt-Aubé reaction and their structures were unambiguously confirmed by X-ray diffraction analysis and extensive spectroscopic characterization.
Abstract: Derivatives of the fully twisted bicyclic amide 7-hypoquinuclidone are synthesized using a Schmidt–Aube reaction. Their structures were unambiguously confirmed by X-ray diffraction analysis and extensive spectroscopic characterization. Furthermore, the stability and chemical reactivity of these anti-Bredt amides are investigated. 7-Hypoquinuclidonium tetrafluoroborate is shown to decompose to a unique nitrogen bound amide–BF3 complex of 7-hypoquinuclidone under anhydrous conditions and to react instantaneously with water making it one of the most reactive amides known to date.
Patent•
02 Feb 2016TL;DR: In this article, the authors describe novel compounds of formula (I), wherein R 1, R 2a, R 2b, R 3, R 4, A 1, A 2, A 3, A 4 and n have the meanings indicated in the description, to the use thereof as acaricides and/or insecticides for controlling animal pests.
Abstract: The invention relates to novel compounds of formula (I), wherein R 1 , R 2a , R 2b , R 3 , A 1 , A 2 , A 3 , A 4 and n have the meanings indicated in the description, to the use thereof as acaricides and/or insecticides for controlling animal pests, and to methods and intermediate products for the production thereof.
TL;DR: An intramolecular nickel-catalyzed (4+2) coupling between cyclobutanones and allenes, by C-C cleavage, is reported, which provides a distinct approach for accessing [3.2.2] bicyclic scaffolds which are challenging to prepare through conventional approaches.
Abstract: Herein an intramolecular nickel-catalyzed (4+2) coupling between cyclobutanones and allenes, by C-C cleavage, is reported. The reaction provides a distinct approach for accessing [3.2.2] bicyclic scaffolds which are challenging to prepare through conventional approaches. The reaction is efficient, chemoselective, and pH/redox neutral. Room temperature conditions and low catalyst loadings can be adopted. Excellent enantioselectivity is also achieved.
TL;DR: The selectivity against fungal cells was investigated by testing the compounds endowed with the best MICs on Hep2 cells in order to assess their cell toxicity and it was noticed that two derivatives were less cytotoxic than the reference drug clotrimazole.
TL;DR: Protein engineering combining rational design and directed evolution enabled the identification of an ATA variant which catalyzes the specific synthesis of the target exo-amine with >99.5% selectivity.
Abstract: Application of amine transaminases (ATAs) for stereoselective amination of prochiral ketones represents an environmentally benign and economically attractive alternative to transition metal catalyzed asymmetric synthesis. However, the restrictive substrate scope has limited the conversion typically to non-sterically demanding scaffolds. Recently, we reported on the identification and design of fold class I ATAs that effect a highly selective asymmetric synthesis of a set of chiral aromatic bulky amines from the corresponding ketone precursors in high yield. However, for the specific amine synthetic approach extension targeted here, the selective formation of an exo- vs. endo-isomer, these biocatalysts required additional refinement. The chosen substrate (exo-3-amino-8-aza-bicyclo[3.2.1]oct-8-yl-phenyl-methanone), apart from its pharmacological relevance, is a demanding target for ATAs as the bridged bicyclic ring provides substantial steric challenges. Protein engineering combining rational design and directed evolution enabled the identification of an ATA variant which catalyzes the specific synthesis of the target exo-amine with >99.5% selectivity.
TL;DR: The reactions of isothiocyanates with the antiaromatic pentaphenylborole were investigated, revealing significantly different outcomes than the analogous reactions with isocyanate, and rational pathways for these unusual transformations are presented.
Abstract: The reactions of isothiocyanates with the antiaromatic pentaphenylborole were investigated, revealing significantly different outcomes than the analogous reactions with isocyanates. The 1:1 stoichiometric reaction products isolated include a seven-membered BNC5 heterocycle and a fused bicyclic 4/5-ring system. Studies suggest that the seven-membered ring undergoes an intramolecular [2 + 2] electrocyclic ring closure to produce the bicyclic system. The only derivative for which stoichiometry influenced the reaction outcome was 4-methoxyphenylisothiocyanate. The reaction of borole with an excess of 4-methoxyphenylisothiocyanate resulted in the formation of a fused tetracyclic species with two equivalents of isothiocyanate incorporated into the product. Rational pathways for these unusual transformations are presented.
TL;DR: A novel [3 + 2]-cycloaddition between azomethine imines and lithium ynolates is described to synthesize bicyclic pyrazolidinones, which are versatile intermediates to form β-amino acids and monocyclicpyrazolid inones.
TL;DR: In this article, the driving forces of association between three different families of macrocycles as hosts, namely cyclodextrins (α, β-, and γ-), p-sulfonatocalix[n]arenes (n = 4-6), and cucurbit[n]-urils (n= 6-8), and three different bicyclic azoalkane homologues as guests, namely 2,3-diazabicyclo[2.2.1]hept-2-ene (DBH), 2,
Abstract: The driving forces of association between three different families of macrocycles as hosts, namely cyclodextrins (α-, β-, and γ-), p-sulfonatocalix[n]arenes (n = 4–6) as well as cucurbit[n]urils (n = 6–8), and three different bicyclic azoalkane homologues as guests, namely 2,3-diazabicyclo[2.2.1]hept-2-ene (DBH), 2,3-diazabicyclo[2.2.2]oct-2-ene (DBO) as well as 2,3-diazabicyclo[2.2.3]non-2-ene (DBN), were examined by means of calorimetric titrations, NMR spectroscopy and molecular dynamics simulation, all in aqueous solution. The small, spherical and uncharged guests preferably bind inside the cavities of the medium sized hosts. The inclusion complexation by β-cyclodextrin and p-sulfonatocalix[4]arene shows medium binding affinities (millimolar), while cucurbit[7]uril macrocycle shows very strong binding (micromolar). For all types of macrocycles, the complex formation is enthalpically driven (ΔH° < 0), accompanied by slightly unfavourable entropy changes (ΔS° < 0). The results are discussed in t...
TL;DR: Facile and effective access for the asymmetric construction of the useful and important skeleton of the bicyclic N,O-acetals is described and the single-crystal structures of the copper complexes lead to a good understanding of the stereo-synergy effects of the sidearm.
Abstract: Facile and effective access for the asymmetric construction of the useful and important skeleton of the bicyclic N,O-acetals is described. CuII/SaBOX could catalyze the reaction of β,γ-unsaturated α-ketoesters with cyclic enamines efficiently, thus affording the desired products in excellent yields with excellent stereoselectivities (21 examples; up to 99 % yields; up to >95:5 d.r.; and 95–99 % ee). This reaction can be well performed on gram scale, even with only 1 mol % catalyst loading. The single-crystal structures of the copper complexes lead to a good understanding of the stereo-synergistic effects of the sidearm.
TL;DR: In this article, a microreview of the preparation of TzTz-containing materials and their application in the field of organic and hybrid photovoltaics is presented. But the authors focus on the preparation and application of such materials and do not provide a detailed analysis of their applications.
TL;DR: A highly enantioselective organocatalytic inverse-electron-demand oxo-Diels-Alder reaction involving aqueous acetaldehyde has been discovered, which allows facile construction of optically active bicyclic dihydropyrans.
TL;DR: This method provides direct access to 12–18 membered bicyclic macrocycles, which have been transformed easily in to a wide range of highly functionalized heterocyclic scaffolds including lactones and lactams that could serve the synthesis of complex macrocyclic natural products and pharmaceuticals.
Abstract: The intramolecular aza-(4 + 3) cycloaddition reactions of in situ generated aza-oxyallylic cations and furans have been reported for the construction of medium sized hydroxamate macrocycles. This method provides direct access to 12–18 membered bicyclic macrocycles. The highly functionalized macrocycles have been transformed easily in to a wide range of highly functionalized heterocyclic scaffolds including lactones and lactams that could serve the synthesis of complex macrocyclic natural products and pharmaceuticals.
TL;DR: A gold-catalyzed rearrangement of propargyl esters followed by allene-ene cyclization to afford substituted bicyclic [4.4.0] dihydronaphthalene compounds in moderate to excellent yields.
TL;DR: Two amino acids play a key role in the first total synthesis of lycopalhine A, and l-proline promotes an unusual 5-endo-trig Mannich cyclization that generates the central pyrrolidine ring of the Lycopodium alkaloid.
Abstract: Two amino acids play a key role in the first total synthesis of lycopalhine A. l-glutamic acid serves as a convenient chiral starting material for the 13-step synthesis, and l-proline promotes an unusual 5-endo-trig Mannich cyclization that generates the central pyrrolidine ring of the Lycopodium alkaloid. The bicyclo[3.3.0]octanol moiety of the molecule is formed through an intramolecular aldol addition that may occur spontaneously in nature.
TL;DR: A comprehensive survey of all pathways leading to the generation of 1-azoniabicyclo[n.1.0]alkanes is provided, as well as a discussion on their subsequent ring expansions to relevant azaheterocycles governed by ring size, substitution pattern, and/or nature of applied nucleophiles as mentioned in this paper.
Abstract: Recent advances in the field of ring-expansion chemistry, involving 1-azoniabicyclo[n.1.0]alkane scaffolds (bicyclic aziridinium ions) as key transient intermediates, have made it possible to efficiently construct a broad variety of medium- and large-sized functionalized nitrogen-containing heterocycles. In this tutorial review, a comprehensive survey of all pathways leading to the generation of 1-azoniabicyclo[n.1.0]alkanes is provided, as well as a discussion on their subsequent ring expansions to relevant azaheterocycles governed by ring size, substitution pattern, and/or nature of applied nucleophiles.
TL;DR: B3LYP/6-31++G(d) calculations indicated that the reaction of (2E)-3-phenyl- 2-nitroprop-2-enenitrile with cyclopentadiene catalyzed by cations of 1,3-dialkylimidazolium ionic liquid shall not take place according to the classical scheme of one-step [2+4] Diels–Alder cycloaddition.
Abstract: B3LYP/6-31++G(d) calculations indicated that the reaction of (2E)-3-phenyl-2-nitroprop-2-enenitrile with cyclopentadiene catalyzed by cations of 1,3-dialkylimidazolium ionic liquid shall not take place according to the classical scheme of one-step [2+4] Diels–Alder cycloaddition. Along the path finally leading to bicyclo[2.2.1]hept-5-ene (norbornene) with a nitro group in endo orientation, the process of bicarbocyclic skeleton formation shall take place according to the domino mechanism, via [2+4] heterocycloadduct. On the other hand, along the path leading finally to bicyclo[2.2.1]hept-5-ene with a nitro group in exo orientation, acyclic adduct with a zwitterionic nature is formed in the first reaction, which undergoes cyclisation next in the second step of the reaction.
TL;DR: The results provide evidence that linking hpp groups with the pyridyl group stabilizes the protonation center, thereby increasing the intrinsic basicity in the gas phase, while the bulk prevents efficient cation solvation, resulting in diminished pKa(MeCN) values.
Abstract: Pyridine substituted with one and two bicyclic guanidine groups has been studied as a potential source of superbases. 2-{hpp}C5H4N (I) and 2,6-{hpp}2C5H3N (II) (hppH = 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine) were protonated using [HNEt3][BPh4] to afford [I-H][BPh4] (1a), [II-H][BPh4] (2), and [II-H2][BPh4]2 (3). Solution-state (1)H and (15)N NMR spectroscopy shows a symmetrical cation in 2, indicating a facile proton-exchange process in solution. Solid-state (15)N NMR data differentiates between the two groups, indicating a mixed guanidine/guanidinium. X-ray diffraction data are consistent with protonation at the imine nitrogen, confirmed for 1a by single-crystal neutron diffraction. The crystal structure of 1a shows association of two [I-H](+) cations within a cage of [BPh4](-) anions. Computational analysis performed in the gas phase and in MeCN solution shows that the free energy barrier to transfer a proton between imino centers in [II-H](+) is 1 order of magnitude lower in MeCN than in the gas phase. The results provide evidence that linking hpp groups with the pyridyl group stabilizes the protonation center, thereby increasing the intrinsic basicity in the gas phase, while the bulk prevents efficient cation solvation, resulting in diminished pKa(MeCN) values. Spectrophotometrically measured pKa values are in excellent agreement with calculated values and confirm that I and II are superbases in solution.
TL;DR: For α,β-unsaturated N-tosyl ketimines, the briphos derived from 1-aminoindane was found to selectively provide γ,γ-diaryl N-Tosyl enamines with high yields and stereoselectivities.
Abstract: A complementary solution for Rh-catalyzed enantioselective 1,2- and 1,4-arylation with two structurally related chiral ligands is reported. A chiral bicyclic bridgehead phosphoramidite (briphos) ligand derived from 1-aminoindane was efficient for the 1,2-arylation of N-sulfonyl imines, while that derived from 1,2,3,4-tetrahydro-1-naphthylamine was efficient for 1,4-arylation of α,β-unsaturated cyclic ketones. For α,β-unsaturated N-tosyl ketimines, the briphos derived from 1-aminoindane was found to selectively provide γ,γ-diaryl N-tosyl enamines with high yields and stereoselectivities.
TL;DR: In the presence of CuI, 1,3-dipolar cycloadditions of N,N'-cyclic azomethine imines with iminooxindoles proceeded readily and furnished novel oxindole spiro-N,N-bicyclic heterocycles in moderate to excellent chemical yields with excellent diastereoselectivities.
TL;DR: The first example of metal-mediated acetylene bicyclopentamerization to form naphthalene in the gas phase is reported, and three intermediates in the reaction have been identified: lanthanacyclopropene, La, and La(benzyne).
Abstract: We report the first example of metal-mediated acetylene bicyclopentamerization to form naphthalene in the gas phase. The bicyclic aromatic compound was observed in a complex with La. The La(naphthalene) complex was formed by the reaction of laser-ablated La atoms with acetylene molecules in a molecular beam source and was characterized by mass-analyzed threshold ionization spectroscopy. The bicyclo-oligomerization reaction occurs through sequential acetylene additions coupled with dehydrogenation. Three intermediates in the reaction have been identified: lanthanacyclopropene [La(C2H2)], La(cyclobut-1-en-3-yne) [La(C4H2)], and La(benzyne) [(La(C6H4)]. The metal-ligand bonding in the three intermediates is considerably different from that in the La(naphthalene) complex, as suggested by accurately measured adiabatic ionization energies.