Showing papers on "Bicyclic molecule published in 2014"

Conformation-induced remote meta -C–H activation of amines

Abstract: Achieving site selectivity in carbon-hydrogen (C-H) functionalization reactions is a long-standing challenge in organic chemistry. The small differences in intrinsic reactivity of C-H bonds in any given organic molecule can lead to the activation of undesired C-H bonds by a non-selective catalyst. One solution to this problem is to distinguish C-H bonds on the basis of their location in the molecule relative to a specific functional group. In this context, the activation of C-H bonds five or six bonds away from a functional group by cyclometallation has been extensively studied. However, the directed activation of C-H bonds that are distal to (more than six bonds away) functional groups has remained challenging, especially when the target C-H bond is geometrically inaccessible to directed metallation owing to the ring strain encountered in cyclometallation. Here we report a recyclable template that directs the olefination and acetoxylation of distal meta-C-H bonds--as far as 11 bonds away--of anilines and benzylic amines. This template is able to direct the meta-selective C-H functionalization of bicyclic heterocycles via a highly strained, tricyclic-cyclophane-like palladated intermediate. X-ray and nuclear magnetic resonance studies reveal that the conformational biases induced by a single fluorine substitution in the template can be enhanced by using a ligand to switch from ortho- to meta-selectivity.

Homogeneous perdehydrogenation and perhydrogenation of fused bicyclic N-heterocycles catalyzed by iridium complexes bearing a functional bipyridonate ligand.

Abstract: Homogeneous perdehydrogenation of saturated bicyclic 2,6-dimethyldecahydro-1,5-naphthyridine and perhydrogenation of aromatic 2,6-dimethyl-1,5-naphthyridine with release and uptake of five molecules of H2 are efficiently achieved by iridium complexes bearing a functional bipyridonate ligand. Successive perhydrogenation and perdehydrogenation of 2,6-dimethyl-1,5-naphthryridine using a single iridium complex also proceed with the reversible interconversion of the catalytic species, depending on the presence or absence of H2.

Hydroxyproline-Derived Pseudoenantiomeric [2.2.1] Bicyclic Phosphines: Asymmetric Synthesis of (+)- and (−)-Pyrrolines

Abstract: We have prepared two new diastereoisomeric 2-aza-5-phosphabicyclo[2.2.1]heptanes from naturally occurring trans-4-hydroxy-l-proline in six chemical operations. These syntheses are concise and highly efficient, with straightforward purification. When we used these chiral phosphines as catalysts for reactions of γ-substituted allenoates with imines, we obtained enantiomerically enriched pyrrolines in good yields with excellent enantioselectivities. These two diastereoisomeric phosphines functioned as pseudoenantiomers, providing their chiral pyrrolines with opposite absolute configurations.

Complete Biosynthetic Pathway of Anditomin: Nature’s Sophisticated Synthetic Route to a Complex Fungal Meroterpenoid

Abstract: Anditomin and its precursors, andilesins, are fungal meroterpenoids isolated from Aspergillus variecolor and have unique, highly oxygenated chemical structures with a complex bridged-ring system. Previous isotope-feeding studies revealed their origins as 3,5-dimethylorsellinic acid and farnesyl pyrophosphate and suggested the possible involvement of a Diels–Alder reaction to afford the congested bicyclo[2.2.2]octane core structure of andilesins. Here we report the first identification of the biosynthetic gene cluster of anditomin and the determination of the complete biosynthetic pathway by characterizing the functions of 12 dedicated enzymes. The anditomin pathway actually does not employ a Diels–Alder reaction, but involves the nonheme iron-dependent dioxygenase AndA to synthesize the bridged-ring by an unprecedented skeletal reconstruction. Another dioxygenase, AndF, is also responsible for the structural complexification, generating the end product anditomin by an oxidative rearrangement.

Total synthesis and isolation of citrinalin and cyclopiamine congeners

Abstract: Many natural products that contain basic nitrogen atoms—for example alkaloids like morphine and quinine—have the potential to treat a broad range of human diseases. However, the presence of a nitrogen atom in a target molecule can complicate its chemical synthesis because of the basicity of nitrogen atoms and their susceptibility to oxidation. Obtaining such compounds by chemical synthesis can be further complicated by the presence of multiple nitrogen atoms, but it can be done by the selective introduction and removal of functional groups that mitigate basicity. Here we use such a strategy to complete the chemical syntheses of citrinalin B and cyclopiamine B. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalin B and citrinalin C (which contains a bicyclo[2.2.2]diazaoctane structural unit) through carbon-13 feeding studies, support the existence of a common bicyclo[2.2.2]diazaoctane-containing biogenetic precursor to these compounds, as has been proposed previously. Natural products citrinalin B and cyclopiamine B, which contain basic nitrogen atoms that are susceptible to oxidation during synthesis, can be synthesized by the selective introduction and removal of functional groups. This paper reports the first syntheses of the natural products citrinalin B and cyclopiamine B. And as a by-product of this work, the authors propose a revision of the structure initially assigned to citrinalin B. The presence of nitrogen atoms in a target molecule can complicate its synthesis because of nitrogen's basicity and susceptibility to oxidation. This can be circumvented by the selective introduction and removal of functional groups that mitigate basicity. The prenylated indole alkaloids citrinalin B and cyclopiamine B were produced using a refinement of the technique, opening up a class of compounds that includes therapeutics such as quinine and morphine to synthetic chemistry.

Expedient Synthesis of Fused Azepine Derivatives Using a Sequential Rhodium(II)-Catalyzed Cyclopropanation/1-Aza-Cope Rearrangement of Dienyltriazoles

Abstract: A general method for the formation of fused dihydroazepine derivatives from 1-sulfonyl-1,2,3-triazoles bearing a tethered diene is reported. The process involves an intramolecular cyclopropanation of an α-imino rhodium(II) carbenoid, leading to a transient 1-imino-2-vinylcyclopropane intermediate which rapidly undergoes a 1-aza-Cope rearrangement to generate fused dihydroazepine derivatives in moderate to excellent yields. The reaction proceeds with similar efficiency on gram scale. The use of catalyst-free conditions leads to the formation of a novel [4.4.0] bicyclic heterocycle.

Highly enantioselective rhodium(I)-catalyzed carbonyl carboacylations initiated by C-C bond activation.

Abstract: The lactone motif is ubiquitous in natural products and pharmaceuticals. The Tishchenko disproportionation of two aldehydes, a carbonyl hydroacylation, is an efficient and atom-economic access to lactones. However, these reaction types are limited to the transfer of a hydride to the accepting carbonyl group. The transfer of alkyl groups enabling the formation of C-C bonds during the ester formation would be of significant interest. Reported herein is such asymmetric carbonyl carboacylation of aldehydes and ketones, thus affording complex bicyclic lactones in excellent enantioselectivities. The rhodium(I)-catalyzed transformation is induced by an enantiotopic C-C bond activation of a cyclobutanone and the formed rhodacyclic intermediate reacts with aldehyde or ketone groups to give highly functionalized lactones.

Transamidation of Carboxamides Catalyzed by Fe(III) and Water

Abstract: The highly efficient transamidation of several primary, secondary, and tertiary amides with aliphatic and aromatic amines (primary and secondary) is described. The reaction is performed in the presence of a 5 mol % concentration of different hydrated salts of Fe(III), and the results show that the presence of water is crucial. The methodology was also applied to urea and phthalimide to demonstrate its versatility and wide substrate scope. An example of its use is an intramolecular application in the synthesis of 2,3-dihydro-5H-benzo[b]-1,4-thiazepin-4-one, which is the bicyclic core of diltiazem and structurally related drugs (Budriesi, R.; Cosimelli, B.; Ioan, P.; Carosati, E.; Ugenti, M. P.; Spisani, R. Curr. Med. Chem. 2007, 14, 279-287). A plausible mechanism that explains the role of water is proposed on the basis of experimental observations and previous mechanistic suggestions for transamidation reactions catalyzed by transition metals such as copper and aluminum. This methodology represents a significant improvement over other existing methods; it can be performed in air and with wet or technical grade solvents.

Double C(sp3)–H Bond Functionalization Mediated by Sequential Hydride Shift/Cyclization Process: Diastereoselective Construction of Polyheterocycles

Abstract: Described herein are two novel types of double C(sp3)–H bond functionalizations triggered by a sequential hydride shift/cyclization process: (1) construction of a bicyclo[3.2.2]nonane skeleton by a [1,6]- and [1,5]-hydride shift sequence and (2) sequential [1,4]- and [1,5]-hydride shift mediated construction of a linear tricyclic skeleton.

Metal-Catalyzed [6 + 3] Cycloaddition of Tropone with Azomethine Ylides: A Practical Access to Piperidine-Fused Bicyclic Heterocycles

Abstract: The first metal-catalyzed [6 + 3] cycloaddition of tropone with azomethine ylides has been developed. With the use of a chiral ferrocenylphosphine–copper(I) complex as the catalyst, the asymmetric variant of the [6 + 3] cycloaddition has also been successfully achieved. The reactions proceeded smoothly under mild conditions, affording piperidine-fused bicyclic heterocycles in moderate to high yields with good to excellent diastereo- and enantioselectivies. The procedures are operationally simple and the catalysts are cheap and readily accessible, thus providing a practical approach to piperidine-fused bicyclic heterocycles.

Hydroarylations of heterobicyclic alkenes through rhodium-catalyzed directed C-H functionalizations of S-aryl sulfoximines.

Abstract: Rhodium-catalyzed directed CH-functionalizations have been used in hydroarylations of heterobicyclic alkenes with NH-sulfoximines. Unexpectedly, the bicyclic framework is retained, resulting in the formation of addition products being attractive intermediates for functionalized molecules that are difficult to prepare by other means.

All-benzene carbon nanocages: size-selective synthesis, photophysical properties, and crystal structure.

Abstract: The design and synthesis of a series of carbon nanocages consisting solely of benzene rings are described. Carbon nanocages are appealing molecules not only because they represent junction unit structures of branched carbon nanotubes, but also because of their potential utilities as unique optoelectronic π-conjugated materials and guest-encapsulating hosts. Three sizes of strained, conjugated [n.n.n]carbon nanocages (1, n = 4; 2, n = 5; 3, n = 6) were synthesized with perfect size-selectivity. Cyclohexane-containing units and 1,3,5-trisubstituted benzene-containing units were assembled to yield the minimally strained bicyclic precursors, which were successfully converted into the corresponding carbon nanocages via acid-mediated aromatization. X-ray crystallography of 1 confirmed the cage-shaped structure with an approximately spherical void inside the cage molecule. The present studies revealed the unique properties of carbon nanocages, including strain energies, size-dependent absorption and fluorescence...

Metal-free coupling of saturated heterocyclic sulfonylhydrazones with boronic acids

Abstract: The coupling of aromatic moieties with saturated heterocyclic partners is currently an area of significant interest for the pharmaceutical industry. Herein, we present a procedure for the metal-free coupling of 4-, 5-, and 6-membered saturated heterocyclic p-methoxyphenyl (PMP) sulfonylhydrazones with aryl and heteroaromatic boronic acids. This procedure enables a simple, two-step synthesis of a range of functionalized sp2–sp3 linked bicyclic building blocks, including oxetanes, piperidines, and azetidines, from their parent ketones.

Substituted 6,5-fused bicyclic heteroaryl compounds

Abstract: The present invention relates to substituted 6,5-fused bicyclic heteroaryl compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof.

Asymmetric total synthesis of (−)-lingzhiol via a Rh-catalysed [3+2] cycloaddition

Abstract: Bicyclic rings with quaternary bridgehead positions are difficult targets, yet are frequently observed in nature. Here, the authors report a cycloaddition reaction giving access to these structures in a stereoselective manner and employ it as the key step in a natural product total synthesis.

Copper-Catalyzed Stereoselective Aminoboration of Bicyclic Alkenes

Abstract: A copper-catalyzed aminoboration of bicyclic alkenes, including oxa- and azabenzonorbornadienes, has been developed. With this method, amine and boron moieties are simultaneously introduced at an olefin with exo selectivity. Subsequent stereospecific transformations of the boryl group can provide oxygen- and nitrogen-rich cyclic molecules with motifs that may be found in natural products or pharmaceutically active compounds. Moreover, a catalytic asymmetric variant of this transformation was realized by using a copper complex with a chiral bisphosphine ligand, namely (R,R)-Ph-BPE.

Phosphoric Acid Catalyzed Desymmetrization of Bicyclic Bislactones Bearing an All-Carbon Stereogenic Center: Total Syntheses of (−)-Rhazinilam and (−)-Leucomidine B

Abstract: In the presence of a catalytic amount of an imidodiphosphoric acid, enantioselective desymmetrization of bicyclic bislactones by reaction with alcohols took place smoothly to afford enantiomerically enriched mono acids having an all-carbon stereogenic center. Concise catalytic enantioselective syntheses of both (-)-rhazinilam and (-)-leucomidine B were subsequently developed using (S)-methyl 4-ethyl-4-formylpimelate monoacid as a common starting material.

A Metal‐Bridged Tricyclic Aromatic System: Synthesis of Osmium Polycyclic Aromatic Complexes

Abstract: Aromaticity is one of the most important concepts in organic chemistry. A variety of metalla-aromatic compounds have been recently prepared and in most of those examples, the metal participates only in a monocyclic ring. In contrast, metal-bridged bicyclic aromatic molecules, in which a metal is shared between two aromatic rings, have been less developed. Herein, we report the first metal-bridged tricyclic aromatic system, in which the metal center is shared by three aromatic five-membered rings. These metalla-aromatics are formed by reaction between osmapentalyne and arene nucleophiles. Experimental results and theoretical calculations reveal that the three five-membered rings around the osmium center are aromatic. In addition, the broad absorption bands in the UV/Vis absorption spectra of these novel aromatic systems cover almost the entire visible region. This straightforward synthetic strategy may be extended to the synthesis of other metal-bridged polycyclic aromatics.

Functionalization of P4 Using a Lewis Acid Stabilized Bicyclo[1.1.0]tetraphosphabutane Anion

Abstract: Reacting white phosphorus (P4) with sterically encumbered aryl lithium reagents (aryl=2,6-dimesitylphenyl or 2,4,6-tBu3C6H2) and B(C6F5)3 gives the unique, isolable Lewis acid stabilized bicyclo[1.1.0]tetraphosphabutane anion. Subsequent alkylation of the nucleophilic site of the RP4 anion gives access to non-symmetrical disubstituted bicyclic tetraphosphorus compounds. This novel method enables PC bond formation in a controlled fashion using white phosphorus as starting material.

Phosphine-Catalyzed Sequential [2 +3] and [3 + 2] Annulation Domino Reaction of γ-Benzyl-Substituted Allenoates with α,β-Unsaturated Ketimines To Construct aza-Bicyclo[3,3,0]octane Derivatives

Abstract: A novel phosphine-catalyzed sequential [2 + 3] and [3 + 2] annulation domino reaction of γ-benzyl-substituted allenoates has been developed. The reaction can proceed smoothly to produce the corresponding aza-bicyclo[3,3,0]octane derivatives in good yields and excellent diastereoselectivity (only one isomer).

Enantioselective N-heterocyclic carbene-catalyzed annulation reactions with imidazolidinones

Abstract: Enantiomeric bicyclic lactone compounds as can be prepared via an N-heterocyclic carbene-catalyzed annulation reaction

Diastereoselective construction of tetrahydropyridine fused bicyclic structures via three-component domino reaction.

Abstract: The three-component reactions of enals, electron-deficient alkynes, and hydroxyl-functionalized primary amines for the highly diastereoselective construction of dihydro-3H-benzo[4,5]oxazolo[3,2-a]pyridines, hexahydropyrido[2,1-b][1,3]oxazines, and tetrahydro-2H-oxazolo[3,2-a]pyridines have been achieved. Domino formation of one C–C, two C–N, and one C–O bonds are furnished in these reactions. This bis-annulation protocol allows for the synthesis of fused heterocyclic products of high structural diversity with variation not only of appended fragments but also the ring size of the central backbone.

Novel bicyclic bromodomain inhibitors

Abstract: The invention provides novel substituted, bicyclic compounds which are useful as inhibitors of extra terminal domain BET protein function by binding to bromodomains. The pharmaceutical compositions comprising such compounds are for the prevention and treatment of diseases and conditions that are associated with bromodornain and extra terminal domain (BET) proteins.

Carbamoyl Radical‐Mediated Synthesis and Semipinacol Rearrangement of β‐Lactam Diols

Abstract: In an approach to the biologically important 6-azabicyclo[3.2.1]octane ring system, the scope of the tandem 4-exo-trig carbamoyl radical cyclization—dithiocarbamate group transfer reaction to ring-fused β-lactams is evaluated. β-Lactams fused to five-, six-, and seven-membered rings are prepared in good to excellent yield, and with moderate to complete control at the newly formed dithiocarbamate stereocentre. No cyclization is observed with an additional methyl substituent on the terminus of the double bond. Elimination of the dithiocarbamate group gives α,β- or β,γ-unsaturated lactams depending on both the methodology employed (base-mediated or thermal) and the nature of the carbocycle fused to the β-lactam. Fused β-lactam diols, obtained from catalytic OsO4-mediated dihydroxylation of α,β-unsaturated β-lactams, undergo semipinacol rearrangement via the corresponding cyclic sulfite or phosphorane to give keto-bridged bicyclic amides by exclusive N-acyl group migration. A monocyclic β-lactam diol undergoes Appel reaction at a primary alcohol in preference to semipinacol rearrangement. Preliminary investigations into the chemo- and stereoselective manipulation of the two carbonyl groups present in a representative 7,8-dioxo-6-azabicyclo[3.2.1]octane rearrangement product are also reported.