Showing papers on "Bicyclic molecule published in 2017"
TL;DR: Bioisosteres of tazarotene and the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethynyl)pyridine were prepared and their physicochemical properties were evaluated.
Abstract: We report a general preparation of arylated bicyclo[1.1.1]pentanes through the opening of [1.1.1]propellane with various arylmagnesium halides. After transmetalation with ZnCl2 and Negishi cross-coupling with aryl and heteroaryl halides, bis-arylated bicyclo[1.1.1]pentanes are obtained. These bis-arylated bicyclo[1.1.1]pentanes may be considered as bioisosteres of internal alkynes. Bioisosteres of tazarotene and the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethynyl)pyridine were prepared and their physicochemical properties were evaluated.
123 citations
TL;DR: A decarboxylative ring-opening of the products led to the facile synthesis of vicinal biheteroaryls and a series of structurally diverse bicyclic or tricyclic compounds bearing an exocyclic double bond were constructed in good to excellent efficiency.
Abstract: Heteroarenes are important structural motif in functional molecules. Reported herein is a Mn(I)-catalyzed 1,2-diheteroarylation of allenes via a C-H activation/Smiles rearrangement cascade. The reaction occurred under additive-free or even solvent-free conditions which allowed the creation of two C-C and one C-N bonds in a single operation. A series of structurally diverse bicyclic or tricyclic compounds bearing an exocyclic double bond were constructed in good to excellent efficiency. The decarboxylative ring-opening of the products led to the facile synthesis of vicinal biheteroaryls. Synthetic applications were demonstrated and preliminary mechanistic studies were conducted.
114 citations
TL;DR: It is proposed that the olefin promotes a Rh(III) intermediate to undergo oxidative addition into the O-N bond to form aRh(V) nitrenoid species and subsequently direct the nitrenoids to add to the ortho position.
Abstract: A bicyclic olefin was discovered as a cocatalyst in a Cp*Rh(III)-catalyzed C–H bond amidation proceeding by an intramolecular amide transfer in N-phenoxyacetamide derivatives. Combining experimental and theoretical studies, we propose that the olefin promotes a Rh(III) intermediate to undergo oxidative addition into the O–N bond to form a Rh(V) nitrenoid species and subsequently direct the nitrenoid to add to the ortho position. The amide directing group plays a dual role as a cleavable coordinating moiety as well as an essential coupling partner for the C–H amidation. This methodology was successfully applied to the late-stage diversification of natural products and a marketed drug under mild conditions.
97 citations
TL;DR: This Minireview provides a summary of the recent progresses on the synthesis and applications of bicyclic peptides.
Abstract: Bicyclic peptides have greater conformational rigidity and metabolic stability than linear and monocyclic peptides and are capable of binding to challenging drug targets with antibody-like affinity and specificity. Powerful combinatorial library technologies have recently been developed to rapidly synthesize and screen large bicyclic peptide libraries for ligands against enzymes, receptors, and protein-protein interaction targets. Bicyclic peptides have been developed as potential therapeutics against a wide range of diseases, drug targeting agents, imaging/diagnostic probes, and research tools. In this Minireview, we provide a summary of the recent progresses on the synthesis and applications of bicyclic peptides.
90 citations
TL;DR: Highly substituted tetrahydrothiophenes with two adjacent quaternary carbon atoms were obtained in a stereospecific manner under mild conditions and in high yield when using AlCl3 as Lewis acid.
Abstract: Lewis-acid-catalyzed reactions of 2-substituted cyclopropane 1,1-dicarboxylates with thioketones are described. Highly substituted tetrahydrothiophenes with two adjacent quaternary carbon atoms were obtained in a stereospecific manner under mild conditions and in high yield when using AlCl3 as Lewis acid. Moreover, an intramolecular approach was successfully implemented to gain access to sulfur-bridged [n.2.1] bicyclic ring systems. Conversion of selenoketones, the heavier analogues, under similar conditions resulted in the formation of various tetrahydroselenophenes.
90 citations
TL;DR: Liu et al. as discussed by the authors showed that Cd(NO3)2·4H2O with 4-pyrpoly-poly-2-ene (ppene) in the presence of benzene-1,2-dicarboxylic acid (1, 2-H2BDC), benzene -1, 3-Dicaroxidibenzoic acid (4, 4′-OBA), or 4-4′-oxidin-4-yl)bicyclo[2.2.
Abstract: Solvothermal reactions of Cd(NO3)2·4H2O with 4-pyr-poly-2-ene (ppene) in the presence of benzene-1,2-dicarboxylic acid (1,2-H2BDC), benzene-1,3-dicarboxylic acid (1,3-H2BDC), benzene-1,4-dicarboxylic acid (1,4-H2BDC), benzene-1,3,5-tricarboxylic acid (1,3,5-H3BTC), or 4,4′-oxidibenzoic acid (4,4′-H2OBA) afforded five Cd(II) coordination polymers [Cd(ppene)(1,2-BDC)]n (1), [Cd(ppene)(1,3-BDC)]n (2), [{Cd(ppene)(1,4-BDC)}·MeCN]n (3) (Liu et al. Inorg. Chem. Commun. 2015, 58, 1−4), [{Cd(ppene)(1,3,5-HBTC)}·0.5(ppene)]n (4), and [Cd(ppene)(4,4′-OBA)]n (5), respectively. Upon UV light irradiation, 1, 3, and 4 can undergo a double [2 + 2] cycloaddition reaction to yield their corresponding photoproducts including [Cd2(4-tp-3-lad)(1,2-BDC)2]n (1a, 4-tp-3-lad = 2,3,5,6-tetra(pyridin-4-yl)bicyclo[2.2.0]hexane), [{Cd2(4-tp-3-lad)(1,4-BDC)2}·2MeCN]n (3a), and [{Cd2(4-tp-3-lad)(1,3,5-HBTC)2}·(ppene)]n (4a) in a single-crystal-to-single-crystal manner. Compounds 1, 2, 4, 5, 1a, 3a, and 4a have been structurally charac...
82 citations
TL;DR: The different electronic properties of BICAACs as compared to CAACs allow for ligand exchange reactions not only at a metal center, but also at main group elements.
Abstract: A straightforward strategy allows for the synthesis of storable bicyclic (alkyl)(amino)carbenes (BICAACs), which feature enhanced σ-donating and π-accepting properties compared to monocyclic (alkyl)(amino)carbenes (CAACs) Due to the bicyclo[222]octane skeleton, the steric environment around the carbene center is different from that of CAACs and similar to that observed in classical N-heterocyclic carbenes The different electronic properties of BICAACs as compared to CAACs allow for ligand exchange reactions not only at a metal center, but also at main group elements
79 citations
TL;DR: A mechanistic investigation reveals that the sequential annulations involved an unprecedented stepwise [3+2+2]-cycloaddition.
71 citations
TL;DR: The synthesis and characterization of two purely organic non-planar dithienothiophene-bridged [34]octaphyrins that permit access to two different aromatic forms as a function of the oxidation state are detailed.
Abstract: Classic formulations of aromaticity have long been associated with topologically planar conjugated macrocyclic systems. The theoretical possibility of so-called bicycloaromaticity was noted early on. However, it has yet to be demonstrated by experiment in a simple synthetic organic molecule. Conjugated organic systems are attractive for studying the effect of structure on electronic features. This is because, in principle, they can be modified readily through dedicated synthesis. As such, they can provide useful frameworks for testing by experiment with fundamental insights provided by theory. Here we detail the synthesis and characterization of two purely organic non-planar dithienothiophene-bridged [34]octaphyrins that permit access to two different aromatic forms as a function of the oxidation state. In their neutral forms, these congeneric systems contain competing 26 and 34 π-electronic circuits. When subject to two-electron oxidation, electronically mixed [4n+1]/[4n+1] triplet biradical species in the ground state are obtained that display global aromaticity in accord with Baird's rule.
63 citations
TL;DR: The key role of tert-butylamine was accounted for by its reaction with in situ generated carbon dioxide to form the carbamic acid, which in turn served as a nucleophile to trap the nitrilium intermediate.
60 citations
TL;DR: The first syntheses of privileged [5,6]-bicyclic heterocycles, with ring-junction nitrogen atoms, by transition metal catalyzed C-H functionalization of C-alkenyl azoles is disclosed.
Abstract: The first syntheses of privileged [5,6]-bicyclic heterocycles, with ring-junction nitrogen atoms, by transition metal catalyzed C-H functionalization of C-alkenyl azoles is disclosed. Several reactions are applied to alkenyl imidazoles, pyrazoles, and triazoles to provide products with nitrogen incorporated at different sites. Alkyne and diazoketone coupling partners give azolopyridines with various substitution patterns. In addition, 1,4,2-dioxazolone coupling partners yield azolopyrimidines. Furthermore, the mechanisms for the reactions are discussed and the utility of the developed approach is demonstrated by iterative application of C-H functionalization for the rapid synthesis of a patented drug candidate.
TL;DR: A novel method for the production of enantiomerically enriched cycloheptatrienes fused to a pyrrolidone ring on the basis of an isothiourea-catalyzed periselective [8+2] cycloaddition reaction between chiral ammonium enolates and azaheptafulvenes is reported.
Abstract: Higher-order cycloaddition reactions constitute an efficient approach towards the construction of medium to large ring systems. However, enantioselective versions of these transformations remain scarce, which hampers their deployment in medicinal chemistry, or any other discipline in which homochirality is deemed crucial. Herein, we report a novel method for the production of enantiomerically enriched cycloheptatrienes fused to a pyrrolidone ring on the basis of an isothiourea-catalyzed periselective [8+2] cycloaddition reaction between chiral ammonium enolates (generated in situ from carboxylic acids) and azaheptafulvenes. The resulting bicyclic compounds can be hydrogenated, but, most remarkably, they can also undergo completely regioselective [4+2] cycloaddition with active dienophiles to give architecturally complex polycyclic compounds in a straightforward manner.
TL;DR: The reaction of rhodium-bound carbenes with strained bicyclicmethylene aziridines results in a formal [3+1] ring expansion to yield highly substituted methylene azetidines with excellent regio- and stereoselectivity.
Abstract: The reaction of rhodium-bound carbenes with strained bicyclic methylene aziridines results in a formal [3+1] ring expansion to yield highly substituted methylene azetidines with excellent regio- and stereoselectivity. The reaction appears to proceed through an ylide-type mechanism, where the unique strain and structure of the methylene aziridine promotes a ring-opening/ring-closing cascade that efficiently transfers chirality from substrate to product. The resultant products can be elaborated into new azetidine scaffolds containing vicinal tertiary-quaternary and even quaternary-quaternary stereocenters.
TL;DR: In this paper, a catholyte molecule, 9,10-bis(2-methoxyethoxy)-1,2,3,4,5,6,7,8,octahydro-1,4:5,8-dimethanenoanthracene (BODMA), is obtained and exhibits greater solubility and superior chemical stability in the charged state.
Abstract: 1,4-Dimethoxybenzene derivatives are materials of choice for use as catholytes in non-aqueous redox flow batteries, as they exhibit high open-circuit potentials and excellent electrochemical reversibility. However, chemical stability of these materials in their oxidized form needs to be improved. Disubstitution in the arene ring is used to suppress parasitic reactions of their radical cations, but this does not fully prevent ring-addition reactions. By incorporating bicyclic substitutions and ether chains into the dialkoxybenzenes, a novel catholyte molecule, 9,10-bis(2-methoxyethoxy)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimethanenoanthracene (BODMA), is obtained and exhibits greater solubility and superior chemical stability in the charged state. A hybrid flow cell containing BODMA is operated for 150 charge–discharge cycles with a minimal loss of capacity.
TL;DR: Simple, inexpensive linear aldehydes such as n-propanal can be used directly in asymmetric cycloadditions via oxidative N-heterocyclic carbene organocatalysis with low catalyst loading, and may provide an economical and practical approach for the asymmetric synthesis of medicinally relevant molecules.
TL;DR: DFT calculations were applied to understand why the challenging bicyclo[4.3.1]decane skeleton was obtained via an unprecedented bridged [5+2] cycloaddition.
Abstract: Previously reported was that cis-ene-vinylcyclopropanes (cis-ene-VCPs) underwent Rh-catalyzed [5+2] reaction to give 5,7-fused bicyclic products, where vinylcyclopropane (VCP) acts as five-carbon synthon. Unfortunately, this reaction had very limited scope. Replacing the 2π component of cis-ene-VCPs to allene moiety, the corresponding cis-allene-VCPs did not undergo the expected normal [5+2] cycloaddition to give 5,7-fused bicyclic products. Instead, the challenging bicyclo[4.3.1]decane skeleton was obtained via an unprecedented bridged [5+2] cycloaddition. DFT calculations were applied to understand why this bridged [5+2] reaction is favored over the anticipated but not realized normal [5+2] reaction.
TL;DR: A general, reversible bicyclization strategy is now reported to increase both the proteolytic stability and cell permeability of peptidyl drugs.
Abstract: Therapeutic applications of peptides are currently limited by their proteolytic instability and impermeability to the cell membrane. A general, reversible bicyclization strategy is now reported to increase both the proteolytic stability and cell permeability of peptidyl drugs. A peptide drug is fused with a short cell-penetrating motif and converted into a conformationally constrained bicyclic structure through the formation of a pair of disulfide bonds. The resulting bicyclic peptide has greatly enhanced proteolytic stability as well as cell-permeability. Once inside the cell, the disulfide bonds are reduced to produce a linear, biologically active peptide. This strategy was applied to generate a cell-permeable bicyclic peptidyl inhibitor against the NEMO-IKK interaction.
TL;DR: Vinyl triazenes were obtained by enantioselective [2+2] cycloaddition reactions of bicyclic alkenes with 1-alkynyl triazene in the presence of a RuII catalyst with a chiral cyclopentadienyl ligand, providing efficient access to a pool of chiral polycyclic compounds.
Abstract: Vinyl triazenes were obtained by enantioselective [2+2] cycloaddition reactions of bicyclic alkenes with 1-alkynyl triazenes in the presence of a RuII catalyst with a chiral cyclopentadienyl ligand. These triazenes serve as unique vinyl cation surrogates. Under acidic conditions, the triazene functionality can be replaced with a variety of groups, including halides, alkoxides, sulfoxides, amides, arenes, and heteroarenes, thus providing efficient access to a pool of chiral polycyclic compounds.
TL;DR: A general and unprecedented gold-catalyzed tandem dual heterocyclization reaction of enynones with 1,3,5-triazines has been developed, which provides bicyclic fused furans in high to excellent yields under mild reaction conditions.
Abstract: A general and unprecedented gold-catalyzed tandem dual heterocyclization reaction of enynones with 1,3,5-triazines has been developed, which provides bicyclic fused furans in high to excellent yields under mild reaction conditions. In addition, mechanistic studies indicate that the reaction goes through a stepwise [3+2+2]-cycloaddition of furanyl gold intermediate, which is generated from gold-catalyzed cyclization of enynone, with two molecules of formaldimines derived in situ from 1,3,5-triazine, instead of formal [4+3]-cycloaddition.
TL;DR: A method is presented which utilizes two robust, orthogonal chemical steps to create highly constrained bicyclic peptide libraries and was optimized to be compatible with in vitro selections by mRNA display.
Abstract: Highly constrained peptides such as the knotted peptide natural products are promising medicinal agents because of their impressive biostability and potent activity. Yet, libraries of highly constrained peptides are challenging to prepare. Here, we present a method which utilizes two robust, orthogonal chemical steps to create highly constrained bicyclic peptide libraries. This technology was optimized to be compatible with in vitro selections by mRNA display. We performed side-by-side monocyclic and bicyclic selections against a model protein (streptavidin). Both selections resulted in peptides with mid-nanomolar affinity, and the bicyclic selection yielded a peptide with remarkable protease resistance.
TL;DR: In this paper, the authors developed a greener and efficient protocol for chalcogenylation of bicyclic arenes using the I2/DMSO catalytic system under solvent and metal-free conditions.
TL;DR: A novel multicomponent self-assembly approach that has the prospect of furnishing unprecedented heterometallic bicyclic architectures with a high level of constitutional control is described.
Abstract: Herein, we describe a novel multicomponent self-assembly approach that has the prospect of furnishing unprecedented heterometallic bicyclic architectures with a high level of constitutional control. The methodology relies on the coordination directionality, and the stoichiometry of the individual precursor units, as well as on the difference of the coordination preference of the associated metal ions. As a proof-of-concept example, two aesthetically pleasing Fe–Pt heterometallic bicyclic metallacycles 6a and 6b, consisting of nine communicative components from four unique species, were prepared in ca. 70% isolated yields and fully characterized by multinuclear NMR, 2D NMR, electrospray ionization time-of-flight mass, and UV–vis spectroscopies. Furthermore, density functional theory based computations suggest that each of these supramolecular constructs encompasses two twisted [organo–Pt(II)←pyridine] coordination based irregular hexagons that are joined via a robust [terpyridine→Fe(II)←terpyridine] hinge.
TL;DR: A cobalt-catalyzed dual C(sp3 )-H activation strategy has been developed and it provides a novel strategy for the synthesis of bicyclo[4.1.0]heptanes and bicyclo [3.n.1]hexanes.
Abstract: A cobalt-catalyzed dual C(sp3 )-H activation strategy has been developed and it provides a novel strategy for the synthesis of bicyclo[4.1.0]heptanes and bicyclo[3.1.0]hexanes. A key to the success of this reaction is the conformation-induced methylene C(sp3 )-H activation of the resulting cobaltabicyclo[4.n.1] intermediate. In addition, the synthesis of bicyclo[3.1.0]hexane from pivalamide, by a triple C(sp3 )-H activation, has also been demonstrated.
TL;DR: This direct α-carbon functionalization reaction of aldehyde can be readily performed on gram scale under mild conditions, and a five-membered transition state is proposed to rationalize the stereochemical outcome.
TL;DR: Mechanistically, this study provides insights into modulating the reactivities of heteroatoms, such as nitrogen atoms, in challenging carbene-catalyzed asymmetric carbon-heteroatom bond-forming reactions.
Abstract: A carbene-catalyzed intermolecular C-N bond formation, which initiates a highly selective cascade reaction for the synthesis of pyrrolidine fused β-lactones, is disclosed. The nitrogen-containing bicyclic β-lactone products are obtained with good yields and excellent stereoselectivities. Synthetic transformations of the reaction products into useful functional molecules, such as amino catalysts, can be efficiently realized under mild reaction conditions. Mechanistically, this study provides insights into modulating the reactivities of heteroatoms, such as nitrogen atoms, in challenging carbene-catalyzed asymmetric carbon-heteroatom bond-forming reactions.
TL;DR: 1, 2 and 3 were characterized by 1 H and 13 C NMR spectroscopy, elemental analysis, and single crystal X-ray diffraction, and their bonding situation was analyzed by quantum chemical calculations.
Abstract: Monovalent gallanediyl LGa {L=HC[C(Me)N(2,6‐iPr2C6H3)]2} reacts with SbX3 to form the Ga‐substituted distibenes [(LGaX)2Sb2] (X=NMeEt 1, Cl 2). Upon heating, 2 reacts to the bicyclo[1.1.0]butane analogue [(LGaCl)2(μ,η1:1‐Sb4)] 3 containing a [Sb4]2− dianion. Moreover, 2 reacts with Li amides LiNR2 in salt elimination reactions that form the corresponding amido‐substituted compounds 1 and [(LGaNMe2)2Sb2] 4, whereas reactions of 4 and [(LGaNMe2)2(μ,η1:1‐Sb4)] 5 with two equivalents of GaCl3 resulted in the formation of 2 and 3, respectively. 1, 2 and 3 were characterized by 1H and 13C NMR spectroscopy, elemental analysis, and single crystal X‐ray diffraction. In addition, their bonding situation was analyzed by quantum chemical calculations. Dedication to Prof. D. Naumann on the occasion of his 75th birthday.
TL;DR: The synergetic use of bonding evolution theory (BET) and noncovalent interaction (NCI) analysis allows to obtain new insight into the bond breaking/forming processes and electron redistribution along the reaction path to understand the molecular mechanism of a reaction and recognize regions of strong and weak electron pairing.
Abstract: The synergetic use of bonding evolution theory (BET) and noncovalent interaction (NCI) analysis allows to obtain new insight into the bond breaking/forming processes and electron redistribution along the reaction path to understand the molecular mechanism of a reaction and recognize regions of strong and weak electron pairing. This viewpoint has been considered for cheletropic extrusion of CO from unsaturated cyclic ketones cyclohepta-3,5-dien-1-one CHD, cyclopent–3-en-1-one CPE, and bicyclo[2.2.1]hept-2-en-7-one BCH by using hybrid functional MPWB1K in conjugation with aug-cc-pVTZ basis set. Decarbonylation of CHD, CPE, and BCH are nonpolar cyclo-elimination reactions that are characterized by the sequence of turning points (TPs) as CHD, 1–11-C[CC]C†C†FFFTSC†C†C†–0:HT + CO; CPE, 1–8-CC[C†C†F†][FF][FF]FTS[C†C†]–0:BD + CO; and BCH, 1–8-CC[C†C†]F[FF]FTS[C†C†]–0:CD + CO. Breaking of C–C bond between the terminal carbon atoms of diene/triene framework and carbon atom of CO fragment starts at a distance of ca....
TL;DR: Enantioselective total synthesis of estradiol methyl ether has been accomplished in a pot-economical manner using five reaction vessels and four purifications using a diphenylprolinol silyl ether mediated domino Michael/aldol reaction to afford bicyclo[4.3.0]nonane derivatives as a single isomer with excellent enantioselectedivity.
Abstract: Enantioselective total synthesis of estradiol methyl ether has been accomplished in a pot-economical manner using five reaction vessels and four purifications. The key reaction is a diphenylprolinol silyl ether mediated domino Michael/aldol reaction to afford bicyclo[4.3.0]nonane derivatives, containing the A, C, and D rings of steroids, as a single isomer with excellent enantioselectivity. Six reactions such as oxidation, hydrogenation, formation of acid chloride, Friedel–Crafts reaction, deprotection, and reduction can be carried out in the last one-pot sequence.
TL;DR: High enantioselectivity (up to 96 % ee) was achieved by exploiting a significant matching effect between the chirality of a cinchona alkaloid-derived aminophosphine ligand for the silver(I) salt and the 2-bis(aryl)methylpyrrolidine catalyst which was rationalized by DFT calculations.
Abstract: A silver(I) and amine co-catalyzed desymmetrization of 4-propargylamino cyclohexanones for the direct enantioselective synthesis of 2-azabicyclo[3.3.1]nonanes is described. Exploiting reactivity arising from dual activation of the pendant terminal alkyne by silver(I) and the ketone moiety through transient enamine formation, this synthetically relevant transformation is easy to perform, efficient and broad in scope. High enantioselectivity (up to 96 % ee) was achieved by exploiting a significant matching effect between the chirality of a cinchona alkaloid-derived aminophosphine ligand for the silver(I) salt and the 2-bis(aryl)methylpyrrolidine catalyst which was rationalized by DFT calculations. This allowed for the preparation of both enantiomers of the bicyclic product with near-identical stereocontrol.
TL;DR: A cascade vinylogous 1,6-Michael addition/1,4-proton shift/aza-Michael added/hemiaminal formation sequence of 1,2-diaza-1,3-dienes and β-substituted 2-butenals has been developed under the influence of dienamine activation of a chiral secondary amine.