Bicyclic Ring Research Articles

A base-promoted tandem approach to bicyclic 8-membered ring ketones.

A base-promoted tandem route toward unprecedented bicyclic 8-membered ring ketones is reported. Under our approach, the targeted products are delivered in high yields from phenylacetylenes and 1,3-diketones. The method has a good scope and gives access to a complex structure that offers a wealth of opportunities for further functionalization.

Stereochemistry of tropane alkaloid of convolvine and their derivatives

Structures of alkaloid convolvine (1) isolated from Convolvulus subhirsutus and its derivatives-convolamine(N-methylconvolvine) (2) and hydrochloride of N-benzylconvolvine (3) have been determined by single crystal X-ray diffraction technique. Compounds were crystallized in monoclinic space groups having four molecules in unit cell. All compounds contain a bicyclic ring system of tropane, where piperidine rings in all case adopt chair conformation. Hydrogen atom and methyl- and benzyl-substituents located in nitrogen atom of studied compounds occupy equatorial positions. The substituent of tropane core- the veratroyloxy group containing in all compound molecules is an α-axial oriented relative to the tropane core. In crystal structures of compound 1 and 2, the molecules are located in the distance of van der Waals interactions. The H-bond between the anion Cl and the proton of the N atom is observed in the crystal of N-benzylconvolvine hydrochloride (Cl···N 3.337 Å, Cl···H 2.42 Å and Cl-H-N 175°).

Complete synthesis of the bicyclic ring of a mutacin analog with orthogonally protected lanthionine via solid-phase intracyclization.

Mutacin 1140 (MU1140) is a naturally occurring lantibiotic derived from posttranslational modifications of a ribosomally synthesized peptide during the fermentation of a bacterium called Streptococcus mutans, the etiological agent of dental cavities. A practical approach for chemically synthesizing lantibiotics would be a valuable tool to expand the MU1140 library with additional semisynthetic analogs. In turn, an expanded library may prove useful to explore additional therapeutic indications for this pipeline of novel compounds. In this work, orthogonally protected lanthionine analogs were synthesized via an aziridine ring opening strategy. This lanthionine was utilized to synthesize a cysteamine (Cya) instead of the (S)-aminovinyl-D-cysteine (AviCys) that is naturally found in MU1140. The Cya containing bicyclic C/D ring of MU1140 was synthesized by Fmoc solid-phase peptide synthesis (SPPS). The linear peptides were synthesized using OPfp ester derivatives and using various common coupling reagents such as COMU and TCTU. The linear peptide was intracyclized with DEPBT to construct the so-called bicyclic ring C/D. This is the first report on the complete chemical synthesis of the bicyclic C/D ring of a MU1140 analog using orthogonally protected lanthionines using SPPS.

Nitrosoalkenes: Underappreciated Reactive Intermediates for Formation of Carbon–Carbon Bonds

This Account describes studies carried out by my group during the past decade on both intra- and intermolecular conjugate additions of carbon nucleophiles to nitrosoalkenes. Using the Denmark protocol for the generation of nitrosoalkenes from α-chloro-O-silyloximes, a number of bridged and fused bicyclic ring systems can be prepared via the intramolecular version of this process. Intermolecular conjugate addition reactions of nitrosoalkenes with a wide variety of ester enolates as coupling partners can also be achieved efficiently using a similar procedure. Some stereochemical aspects of these nucleophilic additions have been studied with both acyclic and cyclic nitrosoalkenes. This methodology has been applied as key steps in synthetic approaches to some complex indole and Myrioneuron alkaloids.1 Introduction2 Conjugate Additions of Nitrosoalkenes2.1 Background2.2 Intramolecular Reactions2.3 Intermolecular Reactions2.4 Stereochemical Aspects3 Applications to Natural Product Synthesis3.1 Angustilodine and Related Alkaloids3.2 Approach to Apparicine-Type Alkaloids3.3 Myrioneurinol4 Summary and Outlook

Sustainable and recyclable super engineering thermoplastic from biorenewable monomer

Environmental and health concerns force the search for sustainable super engineering plastics (SEPs) that utilise bio-derived cyclic monomers, e.g. isosorbide instead of restricted petrochemicals. However, previously reported bio-derived thermosets or thermoplastics rarely offer thermal/mechanical properties, scalability, or recycling that match those of petrochemical SEPs. Here we use a phase transfer catalyst to synthesise an isosorbide-based polymer with a high molecular weight >100 kg mol−1, which is reproducible at a 1-kg-scale production. It is transparent and solvent/melt-processible for recycling, with a glass transition temperature of 212 °C, a tensile strength of 78 MPa, and a thermal expansion coefficient of 23.8 ppm K−1. Such a performance combination has not been reported before for bio-based thermoplastics, petrochemical SEPs, or thermosets. Interestingly, quantum chemical simulations show the alicyclic bicyclic ring structure of isosorbide imposes stronger geometric restraint to polymer chain than the aromatic group of bisphenol-A.

Fused vs. spiro: Kinetic, not thermodynamic preference may direct the reaction of α-carbonyl oxonium ylides

Rh(II)-catalyzed decomposition of certain cyclic α-diazocarbonyl compounds in the presence of cyclic ethers has been shown to give bicyclic ring expansion products. These are thought to arise from a [1,4]-alkyl shift toward the carbonyl oxygen atom and are in contrast with the recently observed spirocyclic products of a Stevens-type [1,2]-alkyl shift within the postulated oxonium ylide intermediate. Quantum chemical calculations performed at the B3LYP/6-31G* level of theory showed that the former reaction pathway (toward fused bicycles) is kinetically preferred.

Iridium-Catalyzed C-H Amination/Cyclization for Medium to Large N-Heterocycle-Fused Dihydroquinazolinones.

A practical iridium-catalyzed cascade/stepwise synthesis of dihydroquinazolinones (DHQs) and bis-DHQs fused to medium to large N-heterocyclic rings is developed. The reaction undergoes benzamide-directed intermolecular C-H amination with an aldehyde-tethered alkyl azide, and then the newly installed amino group undergoes intramolecular cyclization with a remote aldehyde group present in azide and amidyl group of benzamide either intrinsically or catalyzed by phosphoric acid, facilitating the formation of bicyclic and/or tricyclic rings in a very efficient manner.

Synthesis of potent neuroprotective butenolides based on plant smoke derived 3,4,5-Trimethylfuran-2(5H)-one and 3-methyl-2H-furo[2,3-c]pyrone-2-one

Smoke derived karrikinolide and trimethylbutenolide exerted neuroprotective effects against monoamine oxidase and acetylcholinesterase. Synthesis of potent analogs was achieved. Sulphur substitution in the bicyclic ring structure of KAR1 displayed the most encouraging activity returning IC50 values of 13.75 ± 0.001 μM and 0.03 ± 0.02 μM for monoamine oxidase A and B and 0.08 ± 0.006 μM for acetylcholinesterase. Neuroprotective butenolides may be particularly useful in the treatment of depressive disorders, Alzheimer's and Parkinson's diseases.

Computational design, Synthesis of 4,6-dihydroxy-2-phenyl-1-benzofuran-3(2H)-one derivatives as new leads for anti-cancer activity

Benzofuranone is a bicyclic ring where a benzene ring fused with a furanone. Computation chemistry plays a major role in the development of new lead molecules. Computational tools docking, virtual screening, ADMET prediction are utilised in the identification of new lead molecules. Synthetic chemistry plays a major in developing a series of potent anti-cancer agents. Benzofuranone was synthesized by reacting benzene diols, and triols with bromo phenyl acetonitrile yielded an imine derivative are converted to a ketone with treatment with hydrochloric acid then cyclised with sodium acetate. The compounds identity and purity were confirmed by spectral and analytical methods. Benzofuranone derivatives are screened antineoplastic activity was performed against human skin cancer cell line G361 at micro molecular concentrations. The compounds IA, IB, ID, IE, IF, was found to be with potent activity.

Docking, Screening, Synthesis of 4-hydroxy-6-methyl-2-phenyl-1-benzofuran-3(2H)-one derivatives as new leads for anti-cancer activity

Auroneis a bicyclic ring where a benzene ring fused with a furanone. Docking is an efficient tool in the development of new lead molecules. Docking, virtual screening, ADMET prediction are prominent devices in the identification of new lead molecules. Synthetic chemistry plays a major in developing a series of potent anti-cancer agents. Benzofuranone was synthesized by reacting benzene diols, and triols with bromo phenyl acetonitrile yielded an imine derivative are converted to a ketone with treatment with hydrochloric acid then cyclised with sodium acetate. The compounds identity and purity were confirmed by spectral and analytical methods. Benzofuranone derivatives are screened antineoplastic activity was performed against human skin cancer cell line G361 at micro molecular concentrations. The compound IIIA was found to be with potent activity.

Structure of Sesquisabinene Synthase 1, a Terpenoid Cyclase That Generates a Strained [3.1.0] Bridged-Bicyclic Product.

The natural product sesquisabinene is a key component of the fragrant essential oil of the sandalwood tree, currently valued at $5,000/L. Sesquisabinene contains a highly strained [3.1.0] bicyclic ring system and is generated from farnesyl diphosphate in a reaction catalyzed by a class I terpenoid cyclase. To understand how the enzyme directs the formation of a strained hydrocarbon ring system, we now report the X-ray crystal structure of sesquisabinene synthase 1 (SQS1) from the Indian sandalwood tree ( Santalum album). Specifically, we report the structure of unliganded SQS1 at 1.90 Å resolution and the structure of its complex with three Mg2+ ions and the inhibitor ibandronate at 2.10 Å resolution. The bisphosphonate group of ibandronate coordinates to all three metal ions and makes hydrogen bond interactions with basic residues at the mouth of the active site. These interactions are similarly required for activation of the substrate diphosphate group to initiate catalysis, although partial occupancy binding of the Mg2+B ion suggests that this structure represents the penultimate metal coordination complex just prior to substrate activation. The structure of the liganded enzyme enables a precise definition of the enclosed active site contour that serves as a template for the cyclization reaction. This contour is very product-like in shape and readily fits an extended conformation of sesquisabinene and its precursor, the homobisabolyl cation. Structural comparisons of SQS1 with epi-isozizaene synthase mutants that also generate sesquisabinene suggest that [3.1.0] ring formation is not dependent on the isoprenoid tail conformation of the homobisabolyl cation.

Structure-Activity Relationships of 1-Benzoylazulenes at the OX1 and OX2 Orexin Receptors.

We previously demonstrated the potential of di- or trisubstituted azulenes as ligands (potentiators, weak agonists, and antagonists) of the orexin receptors. In this study we investigated 27 1-benzoylazulene derivatives, uncovering seven potentiators of the orexin response on OX1 and two weak dual orexin receptor agonists. For potentiators, replacement of the azulene scaffold by indole retained the activity of four out of six compounds. The structure-activity relationships for agonism and potentiation can be summarized into a bicyclic aromatic ring system substituted with two hydrogen-bond acceptors (1-position, benzoyl; 6-position, carboxyl/ester) within 7-8 Å of each other; a third acceptor at the 3-position is also well tolerated. The same pharmacophoric signature is found in the preferred conformations of the orexin receptor agonist Nag26 from molecular dynamics simulations. Subtle changes switch the activity between weak agonism and potentiation, suggesting overlapping binding sites.

The Intrinsic Mechanochemical Reactivity of Vinyl‐Addition Polynorbornene

AbstractHerein we report the discovery of the intrinsic mechanochemical reactivity of vinyl‐addition polynorbornene (VA‐PNB), which has strained bicyclic ring repeat units along the polymer backbone. VA‐PNBs with three different side chains were found to undergo ring‐opening olefination upon sonication in dilute solutions. The sonicated polymers exhibited spectroscopic signatures consistent with conversion of the bicyclic norbornane repeat units into the ring‐open isomer typical of polynorbornene made by ring‐opening metathesis polymerization (ROMP‐PNB). Thermal analysis and evaluation of chain‐scission kinetics suggest that sonication of VA‐PNB results in chain segments containing a statistical mixture of vinyl‐added and ROMP‐type repeat units.

The Intrinsic Mechanochemical Reactivity of Vinyl-Addition Polynorbornene.

Herein we report the discovery of the intrinsic mechanochemical reactivity of vinyl-addition polynorbornene (VA-PNB), which has strained bicyclic ring repeat units along the polymer backbone. VA-PNBs with three different side chains were found to undergo ring-opening olefination upon sonication in dilute solutions. The sonicated polymers exhibited spectroscopic signatures consistent with conversion of the bicyclic norbornane repeat units into the ring-open isomer typical of polynorbornene made by ring-opening metathesis polymerization (ROMP-PNB). Thermal analysis and evaluation of chain-scission kinetics suggest that sonication of VA-PNB results in chain segments containing a statistical mixture of vinyl-added and ROMP-type repeat units.

Noncanonical Cation-π Cyclizations of Alkylidene β-Ketoesters: Synthesis of Spiro-fused and Bridged Bicyclic Ring Systems.

Three cation-π cyclization cascades initiated at alkylidene β-ketoesters bearing pendent alkenes are described. Depending upon the alkene substitution pattern and the reaction conditions employed, it is possible to achieve selective synthesis of the three different types of products, including 1-halo-3-carbomethoxycyclohexanes, spiro-fused tricyclic systems, and [4.3.1] bridged bicyclic ring systems. All three reactions begin with 6- endo addition of an olefin to the alkylidene β-ketoester electrophile, followed by one of three different cation capture events.

New-generation azaindole-adamantyl-derived synthetic cannabinoids

PurposeThis work reports the synthesis and pharmacological and analytical data for a new series of recently identified azaindole-adamantyl-derived synthetic cannabinoids (SCs).MethodsEach SC was synthesised using an efficient and divergent synthesis, and assessed by electron ionisation mass spectrometry (EIMS). The cannabimimetic activity of each compound was conducted using a fluorometric imaging plate reader (FLIPR) assay.ResultsThe described EIMS method and retention time by gas chromatography were able to effectively differentiate each of the analogues regardless of the bicyclic core. For the first time in these SC structures, the bicyclic ring system was shown to have an impact on the cannabimimetic activities in the fluorometric assay of membrane potential. Analogues ranged from moderately potent at both CB1 and CB2 (e.g., AP4AIC EC50 = 160 nM and EC50 = 64 nM, respectively) to not active at either cannabinoid receptor (AP4AICA, AP5AICA, and APIC).ConclusionsFurther investigation into receptor selectivity surrounding these bicyclic cores could prove useful for future therapeutic applications.

Tropane Alkaloids: Chemistry, Pharmacology, Biosynthesis and Production.

Tropane alkaloids (TA) are valuable secondary plant metabolites which are mostly found in high concentrations in the Solanaceae and Erythroxylaceae families. The TAs, which are characterized by their unique bicyclic tropane ring system, can be divided into three major groups: hyoscyamine and scopolamine, cocaine and calystegines. Although all TAs have the same basic structure, they differ immensely in their biological, chemical and pharmacological properties. Scopolamine, also known as hyoscine, has the largest legitimate market as a pharmacological agent due to its treatment of nausea, vomiting, motion sickness, as well as smooth muscle spasms while cocaine is the 2nd most frequently consumed illicit drug globally. This review provides a comprehensive overview of TAs, highlighting their structural diversity, use in pharmaceutical therapy from both historical and modern perspectives, natural biosynthesis in planta and emerging production possibilities using tissue culture and microbial biosynthesis of these compounds.

Synthesis of Cytospolide Analogues and Late-State Diversification Thereof.

The cytospolides are a novel group of fungal secondary metabolites first described in 2011. Although all 17 natural derivatives share the same C-14 polyketide backbone, they exhibit a fairly broad structural diversity regarding their oxygenation and acetylation pattern as well as macrolide structure, e.g., monocyclic nonanolide core or bicyclic ring systems with a bridging THF ring. In the present work, the prospects for an extension of the structural diversity of cytospolides have been investigated. On the basis of a previously established synthesis of cytospolide D, a modified route to a truncated analogue carrying an alkyne instead of the natural n-pentyl side chain has been developed. In a bioinspired approach the so-derived cytospolide D alkyne analogue has been further converted to bicyclic and THF ring containing derivatives with a different backbone architecture. Finally, Sonogashira couplings or Huisgen-Sharpless click reactions have been used for late-stage diversifications. Thus, a set of 15 novel and structurally diverse natural product derivatives has been synthesized in a highly efficient manner.

A Stepwise Annulation for the Transformation of Cyclic Ketones to Fused 6 and 7‐Membered Cyclic Enimines and Enones

Summary of main observation and conclusionThe efficient construction of functionalized polycyclic structures is an important objective in organic synthesis. Herein, we disclose a three‐step “[2 + n]” annulation method for the transformation of cyclic ketones to fused enimines and enones. The method relies on the Suzuki coupling reaction and the amide reductive alkenylation reaction. A series of fused bicyclic (6/6, 6/7, 8/7) and tricyclic (6/6/6; 6/6/7, 6/5/7) ring systems bearing an α,β‐enimine or an α,β‐enone functionality have been synthetized in good overall yields.

Copper-Catalyzed Synthesis of Fused Imidazopyrazine N-Oxide Skeletons

N-Propargyl-2-aroylimidazoles synthesized and converted into the corresponding ketoximes. Under various conditions, several mono- and diketoxime imidazole derivatives were formed by converting the carbonyl or carbonyl and propargyl groups into oxime groups. N-Propargyl monooxime imidazole derivatives were cyclized by treatment with CuI to give various imidazopyrazine N-­oxides. Several copper salts, such as CuOAc, CuSO4, and CuOTf, formed the same cyclization product. This cyclization reaction occurred only in the presence of Cu(I) or Cu(II) salts; other transition metals such as Au, Ag, In, and Fe did not yield cyclic products. The nucleus-independent chemical shift method was used to calculate the aromaticity of the bicyclic rings.