- Enamine Organocatalysts for the Thiol-Michael Addition Reaction and Cross-Linking Polymerizations
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This article describes an efficient enamine organocatalyzed thiol-Michael click reaction and its broad application in cross-linking polymerizations. A series of enamines was shown to catalyze the thiol-Michael reaction via a nucleophilic pathway. By varying the amines as well as the ring size of the ketones, enamines were designed with broad ranges of nucleophilic character ranging from 11 to 17 on the Mayr nucleophilicity scale. Upon evaluating the enamines' organocatalytic effect on the kinetics of reactions involving a thiol and Michael acceptor, wherein butyl 3-mercaptopropionate and 1-hexyl acrylate were used as model reactants, enamines were shown to outperform their base analogs. The efficiency and overall reaction yields, ranging from 11 to 92% based on the thiol conversion, were highly dependent upon the nucleophilicity of the enamines employed. Interestingly, in situ formation of an enamine via photo-deprotection of an amine in the presence of cyclic ketones facilitated the thiol-Michael reaction efficiently while simultaneously enabling higher functional group conversion. This efficiency in the reaction kinetics and conversion was extended to multifunctional derivatives, which resulted in the formation of highly cross-linked polymers.
- Sinha, Jasmine,Soars, Shafer,Bowman, Christopher N.
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- Domino Synthesis of Benzo-Fused β,γ-Unsaturated Ketones from Alkenylboronic Acids and N-Tosylhydrazone-Tethered Benzonitriles
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The transition-metal-free domino reaction between alkenylboronic acids and N-tosylhydrazones from o-(2-oxoalkyl)- and o-(3-oxoalkyl)benzonitriles leads to β, γ-unsaturated indanones and tetralones featuring an α-"all-carbon" quaternary center. The employment of derivatives of α-substituted cyclopentanones and cyclohexanones led to the stereoselective preparation of β, γ-unsaturated tetrahydrocyclopenta[a]inden-8(1H)-ones, hexahydrofluorenones, and hexahydroanthracenones as cis-fused single stereoisomers. A domino sequence involving diazo compound formation/reductive alkenylation/1,3-borotropic rearrangement/intramolecular bora-aza-ene reaction is proposed to justify the formation of the products as well as the stereoselectivity.
- Plaza, Manuel,Paraja, Miguel,Florentino, Lucía,Valdés, Carlos
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- Microwave-Assisted Facile Synthesis of Imines and Enamines using Envirocat EPZGR as a Catalyst
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In a simple microwave-assisted and environmentally benign approach, aldehydes and ketones react readily with primary and secondary amines to afford imines and enamines, respectively, under solvent-free conditions using Envirocat EPZGR as a catalyst.
- Varma, Rajender S.,Dahiya, Rajender
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- Rate constants for 1,2-hydrogen migration in cyclohexylidene and in substituted cyclohexylidenes
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Laser flash photolysis (UV-LFP, 308 nm) of suitably substituted oxadiazolines leads to cyclohexylidene (14a), 4-tert-butyl-cyclohexylidene (14b), 2-trifluoromethylcyclohexylidene (14d), 8-aza-8-methyl[3.2.1]oct-3- ylidene (14e), diethylcarbene (14f), and ethyl(methyl)carbene (14h). Carbene intermediates were inferred from the products of steady state photolyses, and their pyridinium ylides were inferred from transient absorption spectra observed when pyridine was present. Yields of the pyridinium ylides 15a-h as a function of pyridine concentration gave the lifetimes (τ) for carbenes 14a-h in cyclohexane, cyclohexane-d12, and benzene solutions, at 22 °C. The intermediacy of cyclohexylidene (14a) was inferred from the observation of cyclohexene formed in both the LFP and steady state (SS) experiments. The major products from dual wavelength irradiation of the oxadiazolines (at 254 and 300 nm) were those of 1,2-migration of hydrogen (1,2-H) in the corresponding carbenes. 2-Trifluoromethylcyclohexylidene gave 3- trifluoromethylcyclohexene and 1-trifluoromethylcyclohexene in a 9.8:1 ratio. The kinetic data support the conclusion that 1,2-H in the cyclohexylidenes is accelerated, relative to 1,2-H in dimethylcarbene. A 4-tert-butyl substituent has a negligible effect on the rate constant for 1,2-H, but the CF3 group at the α-position decelerates 1,2-H by roughly 10-fold, as inferred from the distribution of products.
- Pezacki, John Paul,Couture, Philippe,Dunn, James A.,Warkentin, John,Wood, Paul D.,Lusztyk, Janusz,Ford, Francis,Platz, Matthew S.
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- 1 microwave-induced montmorillonite-mediated facile synthesis of enamines
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Montmorillonite clay-mediated simple and high yielding protocol for the synthesis of various enamines with secondary amines and ketones is developed under microwave condition. This protocol is very convenient to accesses the enamines from cyclic amines with various carbonyl compounds in high yield under mild reaction conditions with short reaction time.
- Yadav, Ram Naresh,Banik, Indrani,Srivastava, Ashok Kumar,Ramos, Katherine,Banik, Bimal Krishna
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- Nitric oxide inhibitory activity and antioxidant evaluations of 2-benzoyl-6-benzylidenecyclohexanone analogs, a novel series of curcuminoid and diarylpentanoid derivatives
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Abstract A series of twenty-four 2-benzoyl-6-benzylidenecyclohexanone analogs were synthesized and evaluated for their nitric oxide inhibition and antioxidant activity. Six compounds (3, 8, 10, 17, 18 and 19) were found to exhibit significant NO inhibitory activity in LPS/IFN-induced RAW 264.7 macrophages, of which compound 10 demonstrated the highest activity with the IC50 value of 4.2 ± 0.2 μM. Furthermore, two compounds (10 and 17) displayed antioxidant activity upon both the DPPH scavenging and FRAP analyses. However, none of the 2-benzoyl-6-benzylidenecyclohexanone analogs significantly scavenged NO radical. Structure-activity comparison suggested that 3,4-dihydroxylphenyl ring is crucial for bioactivities of the 2-benzoyl-6-benzylidenecyclohexanone analogs. The results from this study and the reports from previous studies indicated that compound 10 could be a candidate for further investigation on its potential as a new anti-inflammatory agent.
- Leong, Sze Wei,Mohd Faudzi, Siti Munirah,Abas, Faridah,Mohd Aluwi, Mohd Fadhlizil Fasihi,Rullah, Kamal,Lam, Kok Wai,Abdul Bahari, Mohd Nazri,Ahmad, Syahida,Tham, Chau Ling,Shaari, Khozirah,Lajis, Nordin H.
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- Synthesis and biological evaluation of asymmetrical diarylpentanoids as antiinflammatory, anti-α-glucosidase, and antioxidant agents
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A series of seven new (1, 3, 6, 7, 10, 12, and 13) and six (2, 4, 5, 8, 9, and 11) known diarylpentanoid analogs were synthesized and assessed for their nitric oxide (NO) and α-glucosidase inhibitory activities as well as their antioxidant capacity. Nine compounds (2, 3, 4, 5, 6, 8, 11, 12, and 13) were found to exhibit comparable activity to that of curcumin (IC50= 13.0 μM), in which compound 8 has displayed strongest NO inhibitory activity with the IC50 values of 17.5 μM. Meanwhile, four compounds (1, 7, 12, and 13) were found to possess better α-glucosidase inhibitory activity than that of curcumin (30.9 μM), with the IC50 values ranging from 19.4 to 24.9 μM. On the other hand, none of the synthesized compounds has achieved better DPPH scavenging activities than that of curcumin, indicating the relatively poor antioxidant potential of desired diarylpentanoid structure. Structure-activity relationship (SAR) study disclosed that the existence of meta-hydroxyphenyl and bromo groups is crucial for antiinflammatory and anti-α-glucosidase activities, respectively. Molecular docking study showed that bromo moiety could form additional hydrophobic contacts with α-glucosidase, thereby increased the inhibition of diarylpentanoid against α-glucosidase. The overall results suggested that diarylpentanoids with poly-meta-hydroxylated phenyl ring and multiple bromo groups may lead to the discovery of new diarylpentanoids with both antiinflammatory and anti-α-glucosidase activities.
- Leong, Sze Wei,Awin, Tahani,Mohd Faudzi, Siti Munirah,Maulidiani,Shaari, Khozirah,Abas, Faridah
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- Preparation of Hexahydrocarbazole Derivatives by Reductive Indolization
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The reductive indolization is a two-step protocol performed in one flask: First, the acid-mediated Fischer indolization of a cyclic ketone with phenylhydrazine forms an iminium ion which is subsequently reduced by a hydrido borate reagent to the indoline as the final product. We utilized this new strategy for the preparation of hexahydrocarbazole derivatives with a side chain in the quaternary C4a-position. Starting materials were several N1- and aryl-substituted phenylhydrazines and a cyclic ketone with propanoic ester moiety, which is the product of the conjugated addition of cyclohexanone to ethyl acrylate. Furthermore, benzannulated congeners as well as a pyrido[4,3-b]indole derivative were accessed. The hexahydrocarbazole defines a molecular scaffold with two points of diversification. Therefore, several derivatives at N9 and at the C4a-side chain were prepared.
- Christoffers, Jens,Dierks, Anna,Fliegel, Lukas,Schmidtmann, Marc
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- Are oxazolidinones really unproductive, parasitic species in proline catalysis? - Thoughts and experiments pointing to an alternative view
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The N,O-acetal and N,O-ketal derivatives (oxazolidinones) formed from proline, and aldehydes or ketones are well-known today, and they are detectable in reaction mixtures involving proline catalysis, where they have been considered 'parasitic dead ends'. We disclose results of experiments performed in the early 1970's, and we describe more recent findings about the isolation, characterization, and reactions of the oxazolidinone derived from proline and cyclohexanone. This oxazolidinone reacts (THF, room temperature) with the electrophiles β-nitrostyrene and chloral (=trichloroacetaldehyde), to give the Michael and aldol adduct, respectively, after aqueous workup (Scheme 5). The reactions occur even at -75° when catalyzed with bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or EtN(i-Pr)2 (DIPEA) (10%; Table 1). It is shown by NMR (Figs. 1 and 3) and IR analysis (Figs. 2 and 4) that the primarily detectable product (before hydrolysis) of the reaction with the nitro-olefin is again an oxazolidinone. When dissolved in hydroxylic solvents such as MeOH, 'hexafluoroisopropanol' ((CF3) 2CHOH; HFIP), AcOH, CF3COOH, or in LiBr-saturated THF, the ring of the oxazolidinone from cyclohexanone and proline opens up to the corresponding iminium ion (Tables 2-4), and when treated with strong bases such as DBU (in (D8)THF) the enamino-carboxylate derived from proline and cyclohexanone is formed (Scheme 8). Thus, the two hitherto putative participants (iminium ion and enamine) of the catalytic cycle (Scheme 9) have been characterized for the first time. The commonly accepted mechanism of the stereoselective C,C- or C,X-bond-forming step (i.e., A-D) of this cycle is discussed and challenged by thoughts about an alternative model with a pivotal role of oxazolidinones in the regio- and diastereoselective formation of the intermediate enamino acid (by elimination) and in the subsequent reaction with an electrophile (by trans-addition with lactonization; Schemes 11-14). The stereochemical bias between endo- and exo-space of the bicyclo[3.3.0]octane-type oxazolidinone structure (Figs. 5 and 6) is considered to possibly be decisive for the stereochemical course of events. Finally, the remarkable consistency, with which the diastereotopic Re-face of the double bond of pyrrolidino-enamines (derived from proline) is attacked by electrophiles (Schemes 1 and 15), and the likewise consistent reversal to the Si-face with bulky (Aryl) 2C-substituents on the pyrrolidine ring (Scheme 16) are discussed by invoking stereoelectronic assistance from the lone pair of pyramidalized enamine N-atoms.
- Seebach, Dieter,Beck, Albert K.,Badine, D. Michael,Limbach, Michael,Eschenmoser, Albert,Treasurywala, Adi M.,Hobi, Reinhard,Prikoszovich, Walter,Linder, Bernard
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- Chemoenzymatic route to optically active dihydroxy cyclopenta[b]naphthalenones; precursors for decalin-based bioactive natural products
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The development of an efficient chemoenzymatic route for the synthesis of optically active dihydroxy cyclopenta[b]naphthalenones; (+)-1,4a-dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta[b]naphthalen-2(4H)-one (+)-10 and (+)-1,8a-dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta[b]naphthalen-2(4H)-one (+)-11 is described. Different lipases and esterases were tested in the enzymatic hydrolysis of the corresponding acetates (±)-4a-hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-cyclopenta[b]naphthalen-1-yl acetate (±)-8, (±)-8a-hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-cyclopenta[b]naphthalen-1-yl acetate (±)-9, CRL (Candida Rugosa Lipase) and PLE (Pig Liver Esterase) were found to be the most effectual enzymes; for (?)-8 by 47% ee with the corresponding dihydroxy; (+)-10 by 98% ee in the presence of CRL; whereas, (?)-8 was obtained with 40% ee with the corresponding dihydroxy, (+)-10 with 58% ee in the PLE hydrolysis. It was concluded that CRL was the best biocatalyst for the substrate (±)-8. Moreover, enzymatic resolution in the presence of CRL yields, (?)-9 with 46% ee with the corresponding dihydroxy derivative; (+)-11 with 98% ee; however, in the presence of PLE, yields (?)-9 with 36% ee as well as the related dihydroxy derivative; (+)-11 with 49% ee respectively. The study concluded that CRL is the best biocatalyst for compounds (±)-8 and (±)-9.
- ?zdemirhan, Devrim,Sar??elik, ?zlem
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- Formation of aromatic rings through enamine annulation
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(matrix presented) Condensation of pyrrolidine enamine of ketones with 1,4-diacetoxy-2-butanone provides a new, concise synthetic route to substituted benzenes, dihydroindenes, tetrahydronaphthalenes, and di- and octahydrophenanthrenes. The reaction produced modest yields with regiocontrol of the secondary amine substituent.
- Wang, Chen,Kohn, Harold
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- Preparation of o-Fluorophenols from Nonaromatic Precursors: Mechanistic Considerations for Adaptation to Fluorine-18 Radiolabeling
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The preparation of fluorine-18 labeled o-fluorophenols at high specific activity is challenging and requires use of [18F]fluoride ion as the radioisotope source. As a novel, alternative approach, we found that treatment of α-diazocyclohexenones with Selectfluor and Et3N·3HF followed by HF elimination and tautomerization afforded o-fluorophenols regioselectively and rapidly. To adapt this chemistry to 18F radiolabeling, using bromine electrophiles in place of Selectfluor gave the o-fluorophenol via an α-bromo-α-fluoroketone intermediate in lower but still reasonable yields.
- Yasui, Norio,Mayne, Christopher G.,Katzenellenbogen, John A.
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- 2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase
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In the present study, a series of 2-benzoyl-6-benzylidenecyclohexanone analogs have been synthesized and evaluated for their anti-cholinesterase activity. Among the forty-one analogs, four compounds (38, 39, 40 and 41) have been identified as lead compounds due to their highest inhibition on both AChE and BChE activities. Compounds 39 and 40 in particular exhibited highest inhibition on both AChE and BChE with IC50values of 1.6?μM and 0.6?μM, respectively. Further structure–activity relationship study suggested that presence of a long-chain heterocyclic in one of the rings played a critical role in the dual enzymes’ inhibition. The Lineweaver–Burk plots and docking results suggest that both compounds could simultaneously bind to the PAS and CAS regions of the enzyme. ADMET analysis further confirmed the therapeutic potential of both compounds based upon their high BBB-penetrating. Thus, 2-benzoyl-6-benzylidenecyclohexanone containing long-chain heterocyclic amine analogs represent a new class of cholinesterase inhibitor, which deserve further investigation for their development into therapeutic agents for cognitive diseases such as Alzheimer.
- Leong, Sze Wei,Abas, Faridah,Lam, Kok Wai,Shaari, Khozirah,Lajis, Nordin H.
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- Why Cyclopropanation is not Involved in Photoinduced α-Alkylation of Ketones with Diazo Compounds
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Diazo compounds are widely used reagents in organic synthesis. Direct photolysis leads to singlet carbenes whereas, in the presence of a photosensitizer, carbenes in the triplet state are generated. However, their reactivity under light irradiation remains poorly understood. Herein, we report photocatalytic, direct alkylation of enamines, generated from ketones, with diazo esters in the presence of free-base porphyrins acting as photoredox catalysts. Based on the experimental and theoretical studies, we propose a plausible mechanism involving generation of an enamine radical cation that subsequently reacts with diazo compounds giving the radical thus excluding the controversial cyclopropanation–ring opening pathway.
- Rybicka-Jasińska, Katarzyna,Or?owska, Katarzyna,Karczewski, Maksymilian,Zawada, Katarzyna,Gryko, Dorota
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- Clay catalyzed synthesis of imines and enamines under solvent-free conditions using microwave irradiation
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The reactions of primary and secondary amines with aldehydes and ketones, respectively, are accelerated by microwaves under solvent-free conditions in the presence of montmorillonite K 10 clay to afford a high yield synthesis of imines and enamines.
- Varma, Rajender S.,Dahiya, Rajender,Kumar, Sudhir
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- Access to Bicyclo[4.2.0]octene Monomers to Explore the Scope of Alternating Ring-Opening Metathesis Polymerization
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Bicyclo[4.2.0]oct-1(8)-ene-8-carboxamides undergo alternating ring-opening metathesis polymerization (AROMP) with cyclohexene. Herein, a general method for the preparation of bicyclo[4.2.0]oct-(8)-ene-8-carboxy derivatives is described. The central 8-cyano intermediate provides entry to five different functional group substituents on the alkene. These monomers were tested as potential substrates for AROMP with cyclohexene. In addition to the carboxamide, the carboxynitrile and carboxaldehyde are also substrates for AROMP. In the case of the carboxaldehyde, the polymer is regioregular. However, the addition of carboxynitrile is stereoirregular and slow.
- Chen, Lei,Li, Liqiang,Sampson, Nicole S.
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- Suppression of PGE2 production via disruption of MAPK phosphorylation by unsymmetrical dicarbonyl curcumin derivatives
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Curcumin is an important molecule found in turmeric plants and has been reported to exhibit some profound anti-inflammatory activities by interacting with several important molecular targets found in the mitogen-activated protein kinase and NF-κβ pathways. As part of our continuing effort to search for new anti-inflammatory agents with better in vitro and in vivo efficacies, we have synthesized a series of new unsymmetrical dicarbonyl curcumin derivatives and tested their effects on prostaglandin E2 secretion level in interferon-γ/lipopolysaccharide-activated macrophage cells. Among those, five compounds exhibited remarkable suppression on prostaglandin E2 production with IC50 values ranging from 0.87 to 18.41 μM. The most potent compound 17f was found to down-regulate the expression of cyclooxygenase-2 mRNA suggesting that this series of compounds could possibly target the mitogen-activated protein kinase signal transduction pathway. Whilst the compound did not affect the expression of the conventional mitogen-activated protein kinases, the results suggest that it could disrupt the phosphorylation and activation of the proteins particularly the c-Jun N-terminal kinases. Finally, the binding interactions were examined using the molecular docking and dynamics simulation approaches.
- Mohd Aluwi, Mohd Fadhlizil Fasihi,Rullah, Kamal,Haque, Md. Areeful,Yamin, Bohari M.,Ahmad, Waqas,Amjad, Muhammad Wahab,Leong, Sze Wei,Fahmizar, Nurul Amira,Jalil, Juriyati,Abas, Faridah,Ismail, Nor Hadiani,Jantan, Ibrahim,Lam, Kok Wai
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- Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA
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The search of novel mPGES-1 inhibitors has recently intensified probably due to the superior safety in comparison to existing anti-inflammatory drugs. Although two mPGES-1 inhibitors have entered clinical trials, none has yet reached the market. In this study, we performed modifications guided by 3D-QSAR CoMFA on 2, which is an unsymmetrical curcumin derivative with low binding affinity towards mPGES-1. To counter the PAINS properties predicted for 2, the diketone linker was replaced with a pyrazole ring. On the other hand, both prenyl and carboxylate ester groups were introduced to improve the activity. When tested in vitro, 11 suppressed PGE2 biosynthesis in activated macrophages and showed promising human mPGES-1 inhibition in microsomes of interleukin-1β-stimulated A549 cells. Altogether, 11 has been identified as a potential mPGES-1 inhibitor and could be a promising lead for a novel class of mPGES-1 inhibitors.
- Fasihi Mohd Aluwi, Mohd Fadhlizil,Rullah, Kamal,Koeberle, Andreas,Werz, Oliver,Abdul Razak, Nur Sakinah,Wei, Leong Sze,Salim, Fatimah,Ismail, Nor Hadiani,Jantan, Ibrahim,Wai, Lam Kok
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- Neurotropic activity and safety of methylene-cycloalkylacetate (MCA) derivative 3-(3-allyl-2-methylenecyclohexyl) propanoic acid
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Polyneuropathy is a disease involving multiple peripheral nerves injuries. Axon regrowth remains the major prerequisite for plasticity, regeneration, circuit formation, and eventually functional recovery and therefore, regulation of neurite outgrowth might be a candidate for treating polyneuropathies. In a recent study, we synthesized and established the methylene-cycloalkylacetate (MCAs) pharmacophore as a lead for the development of a neurotropic drug (inducing neurite/axonal outgrowth) using the PC12 neuronal model. In the present study we extended the characterizations of the in vitro neurotropic effect of the derivative 3-(3-allyl-2-methylenecyclohexyl) propanoic acid (MCA-13) on dorsal root ganglia and spinal cord neuronal cultures and analyzed its safety properties using blood biochemistry and cell counting, acute toxicity evaluation in mice and different in vitro “off-target” pharmacological evaluations. This MCA derivative deserves further preclinical mechanistic pharmacological characterizations including therapeutic efficacy in in vivo animal models of polyneuropathies, toward development of a clinically relevant neurotropic drug.
- Lahiani, Adi,Haham-Geula, Dikla,Lankri, David,Cornell-Kennon, Susan,Schaefer, Erik M.,Tsvelikhovsky, Dmitry,Lazarovici, Philip
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- On the formation and reactivity of 2-alkylidene-benzopyrans and their 2-amino-5,6-benzo-2H-pyran precursors
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A series of 2-amino-substituted 5,6-benzo-2H-pyrans 14, 2-alkylidene-5,6-benzo-2H-pyrans 15, and their dimers 17 are obtained, depending on the condition used, by the reaction of 2-hydroxy-benzaldehydes 1 with enamines 9 derived of (cyclo)aliphatic ketones. Compounds 14, 15, and 17 can be transformed into 2-alkyl-benzopyrylium salts 16 or 2-[1-(2-hydroxyphenyl)-alken-2-yl]-benzopyrylium salts 23 by treatment with mineral acids. With aromatic aldehydes or the Vilsmeier reagent the compounds 14, 15, or 17 are transformed into deeply colored 2-(aryl-alkenyl)-benzopyrylium perchlorates 25 or 2-(2-dialkylamino)-alkenyl-benzopyrylium salts 26, respectively. Johann Ambrosius Barth 1998.
- Kanitz, Andreas,Hartmann, Horst,Czerney, Peter
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- Cascade Pd(ii)-catalyzed Wacker lactonization-Heck reaction: Rapid assembly of spiranoid lactones
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An unprecedented Pd-catalyzed cascade Wacker-Heck lactonization-cyclization sequence is reported. The process provides a facile approach to bi- and tricyclic spiranoid lactones in good yields. The reaction shows general substrate scope and a broad functional group tolerability. In addition, a rare 4-exo trig Heck-type cyclization is demonstrated.
- Albarghouti, Ghassan,Kotikalapudi, Ramesh,Lankri, David,Valerio, Viviana,Tsvelikhovsky, Dmitry
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- Synthesis of Substituted Anilines from Cyclohexanones Using Pd/C-Ethylene System and Its Application to Indole Synthesis
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The synthesis of anilines and indoles from cyclohexanones using a Pd/C-ethylene system is reported. A simple combination of NH4OAc and K2CO3 under nonaerobic conditions was found to be the most suitable to perform this reaction. Hydrogen transfer between cyclohexanone and ethylene generates the desired products. The reaction tolerates a variety of substitutions on the starting cyclohexanones.
- Maeda, Katsumi,Matsubara, Ryosuke,Hayashi, Masahiko
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supporting information
p. 1530 - 1534
(2021/03/08)
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- Synthesis of small molecules targeting paclitaxel-induced MyD88 expression in triple-negative breast cancer cell lines
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Acquired paclitaxel (PTX) chemoresistance in triple-negative breast cancer (TNBC) can be inferred from the overexpression of toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88) proteins and the activation of the TLR4/MyD88 cascading signalling pathway. Finding a new inhibitor that can attenuate the activation of this pathway is a novel strategy for reducing PTX chemoresistance. In this study, a series of small molecule compounds were synthesised and tested in combination with PTX against TNBC cells. The trimethoxy-substituted compound significantly decreased MyD88 overexpression and improved PTX activity in MDA-MB-231TLR4+ cells but not in HCCTLR4? cells. On the contrary, the trifluoromethyl-substituted compound with PTX synergistically improved the growth inhibition in both TNBC subtypes. The fluorescence titrations indicated that both compounds could bind with MD2 with good and comparable binding affinities. This was further supported by docking analysis, in which both compounds fit perfectly well and form some critical binding interactions with MD2, an essential lipid-binding accessory to TLR4 involved in activating the TLR-4/MyD88-dependent pathway.
- Poh Yen, Khor,Stanslas, Johnson,Zhang, Tianshu,Li, Hongyuan,Wang, Xiaohui,Kok Meng, Chan,Kok Wai, Lam
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- The involvement of l-arginine-nitric oxide-cgmp-atp-sensitive k+ channel pathway in antinociception of bbhc, a novel diarylpentanoid analogue, in mice model
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The present study focuses on the possible involvement of L-arginine-nitric oxide-cGMP-ATP-sensitive K+ channel pathway in the antinociceptive activity of a novel diarylpentanoid analogue, 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol (BBHC) via a chemical nociceptive model in mice. The antinociceptive action of BBHC (1 mg/kg, i.p.) was attenuated by the intraperi-toneal pre-treatment of L-arginine (a nitric oxide synthase precursor) and glibenclamide (an ATP-sensitive K+ channel blocker) in acetic acid-induced abdominal constriction tests. Interestingly, BBHC’s antinociception was significantly enhanced by the i.p. pre-treatment of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase (p + channel pathway, without any potential sedative or muscle relaxant concerns.
- Abas, Faridah,Ahmad Azmi, Ahmad Farhan,Farouk, Ahmad Akira Omar,Israf, Daud Ahmad,Leong, Sze Wei,Ong, Hui Ming,Perimal, Enoch Kumar,Sulaiman, Mohd Roslan
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- Regioselective Crossed Aldol Reactions under Mild Conditions via Synergistic Gold-Iron Catalysis
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A synergistic gold-iron (Au-Fe) catalytic system was developed for sequential alkyne hydration and vinyl Au addition to aldehydes or ketones. Fe(acac)3 was identified as an essential co-catalyst in preventing vinyl Au protodeauration and facilitating nucleophilic additions. Effective C–C bond formation was achieved under mild conditions (room temperature) with excellent regioselectivity and high efficiency (1% [Au], up to 95% yields). The intramolecular reaction was also achieved, giving successful macrocyclization (16–31 ring sizes) with excellent yields (up to 90%, gram scale) without extended dilution (0.2 M), which highlights the great potential of this new crossed aldol strategy in challenging target molecule synthesis. Effective construction of the C–C bond is one of the most important tasks in organic synthesis. Whereas aldol condensation is a classic C–C bond-forming transformation, it requires other chemical promoters, such as strong base and reactive acidic catalysts. As a result, the overall transformation is limited in terms of ideal atom economy and environmentally friendly operation. With the discovery of a gold-iron (Au-Fe) synergistic catalysis system, here we describe a new approach to facilitating alkyne hydration and sequential vinyl Au addition to carbonyls. This approach gives the C–C bond-forming products in excellent yields, wide substrate scope, and great functional-group compatibility under mild conditions. This protocol can also be applied to macrocyclization without extended dilution. This C–C bond-forming strategy could facilitate challenging molecule synthesis in chemical, biological, and medicinal research. We report a synergistic gold-iron (Au-Fe) catalytic system to access vinyl Au reactivity by avoiding frequently occurring protodeauration. Fe(acac)3 was identified as an essential co-catalyst, facilitating vinyl Au addition to aldehydes. A broad substrate scope was obtained under mild conditions (room temperature) with excellent regioselectivity and high efficiency (1% [Au], up to 95% yields). This protocol offers a practical solution for achieving macrocyclization (16–31 ring sizes, up to 90%, gram scale) without extended dilution, highlighting the synthetic utility in complex molecular synthesis.
- Chen, Hao,Jean, Jonathan,Shan, Chuan,Shi, Xiaodong,Teng, Shun,Wang, Jin,Wojtas, Lukasz,Ye, Xiaohan,Yi, Yaping,Yuan, Teng,Zhao, Pengyi
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supporting information
p. 1420 - 1431
(2020/06/19)
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- Revisiting the role of acids and hydrogen bond acceptors in enamine formation
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A systematic investigation into the effects of acids and hydrogen bond acceptors on the reaction rates and equilibria of enamine formation is reported. Acids can accelerate the reaction but do not change the reaction equilibria. In comparison, hydrogen bond acceptors facilitate the enamine formation via their strong hydrogen bonding interaction with the water generated in the reaction.
- Hammond, Gerald B.,Lu, Zhichao,Xu, Bo
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supporting information
p. 6849 - 6852
(2020/10/02)
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- Tf2O-Mediated Intermolecular Coupling of Secondary Amides with Enamines or Ketones: A Versatile and Direct Access to β-Enaminones
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Based on the Tf2O-mediated intermolecular reaction of secondary amides with enamines derived from ketones, a novel approach to β-enaminones has been developed. The reaction is widely functional group tolerant and highly chemoselective. In the presence of 4 ? molecular sieves, the method can be extended to the one-pot condensation of secondary amides with ketones for NH β-enaminones synthesis.
- Liu, Yong-Peng,Zhu, Cheng-Jie,Yu, Cun-Cun,Wang, Ai-E,Huang, Pei-Qiang
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supporting information
p. 7169 - 7174
(2019/11/16)
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- In vitro and in silico evaluations of diarylpentanoid series as α-glucosidase inhibitor
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A series of thirty-four diarylpentanoids derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity. Eleven compounds (19, 20, 21, 24, 27, 28, 29, 31, 32, 33 and 34) were found to significantly inhibit α-glucosidase in which compounds 28, 31 and 32 demonstrated the highest activity with IC50 values ranging from 14.1 to 15.1 μM. Structure-activity comparison shows that multiple hydroxy groups are essential for α-glucosidase inhibitory activity. Meanwhile, 3,4-dihydroxyphenyl and furanyl moieties were found to be crucial in improving α-glucosidase inhibition. Molecular docking analyses further confirmed the critical role of both 3,4-dihydroxyphenyl and furanyl moieties as they bound to α-glucosidase active site in different mode. Overall result suggests that diarylpentanoids with both five membered heterocyclic ring and polyhydroxyphenyl moiety could be a new lead design in the search of novel α-glucosidase inhibitor.
- Leong, Sze Wei,Abas, Faridah,Lam, Kok Wai,Yusoff, Khatijah
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p. 302 - 309
(2018/01/03)
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- Divergent pathways to isophthalates and naphthalate esters from methyl coumalate
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Methyl coumalate readily reacts with enamines at ambient temperature to give lactones, which can be further transformed into isophthalates and tetrahydronaphthoates. Both cyclic and acyclic enamines show good reactivity. Dehydrogenation of tetrahydronaphthoate 4a was achieved on a hundred-gram scale.
- Yu, Huangchao,Kraus, George A.
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supporting information
p. 4008 - 4010
(2018/10/04)
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- Pd-Catalyzed Intramolecular Aminoalkylation of Unactivated Alkenes: Access to Diverse N-Heterocycles
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A highly efficient palladium-catalyzed intramolecular aminoalkylation of unactivated alkenes in the absence of an external ligand and oxidant is described. New C-N and C(sp3)-C(sp3) bonds are formed simultaneously. This general transformation allows for construction of diverse N-heterocycles. Mechanistic studies show that the process may involve a four-membered Pd(alkyl)amido intermediate.
- Ye, Liu,Lo, Kai-Yip,Gu, Qiangshuai,Yang, Dan
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supporting information
p. 308 - 311
(2017/04/21)
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- SPIROFURANONE COMPOUNDS, DERIVATIVES THEREOF AND PROCESSES FOR THEIR PREPARATION
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The present invention provides compounds comprising fused tricyclic backbone structure and processes for their preparation. The invention further provides compounds and compositions useful in the treatment of pain and any type of disorder or symptom associated therewith.
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Page/Page column 40; 41
(2016/08/23)
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- Synthetic Processes of Carprofen
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Methods and intermediates for the synthesis of carprofen and its derivatives starting from cyclohexanone are disclosed.
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Paragraph 0066
(2016/11/24)
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- Regio- and stereoselective synthesis of chiral nitrilolactones using Baeyer–Villiger monooxygenases
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This work describes the regio- and enantioselective synthesis of nitrile-containing chiral lactones from easily accessible ketone precursors using Baeyer–Villiger monooxygenases. These biocatalysts controlled the distribution of regioisomers much more tightly than commonly used stoichiometric reagents, additionally with good to excellent optical purity of products. A surprising case of strong stereoelectronic control was also observed. We tested a library of 14 catalysts using five-to eight-membered cyclic ketones with two different tether lengths to the nitrile group. In all but the largest series we found suitable wild-type enzymes for preparative scale synthesis of the target compounds. The diverse possibilities to further functionalize lactones and nitriles make this method interesting for the generation of chiral building blocks.
- Fink, Michael J.,Snajdrova, Radka,Winninger, Alexander,Mihovilovic, Marko D.
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p. 7241 - 7248
(2016/10/26)
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- Importance of the Electron Correlation and Dispersion Corrections in Calculations Involving Enamines, Hemiaminals, and Aminals. Comparison of B3LYP, M06-2X, MP2, and CCSD Results with Experimental Data
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While B3LYP, M06-2X, and MP2 calculations predict the δG° values for exchange equilibria between enamines and ketones with similar acceptable accuracy, the M06-2X/6-311+G(d,p) and MP2/6-311+G(d,p) methods are required for enamine formation reactions (for example, for enamine 5a, arising from 3-methylbutanal and pyrrolidine). Stronger disagreement was observed when calculated energies of hemiaminals (N,O-acetals) and aminals (N,N-acetals) were compared with experimental equilibrium constants, which are reported here for the first time. Although it is known that the B3LYP method does not provide a good description of the London dispersion forces, while M06-2X and MP2 may overestimate them, it is shown here how large the gaps are and that at least single-point calculations at the CCSD(T)/6-31+G(d) level should be used for these reaction intermediates; CCSD(T)/6-31+G(d) and CCSD(T)/6-311+G(d,p) calculations afford δG° values in some cases quite close to MP2/6-311+G(d,p) while in others closer to M06-2X/6-311+G(d,p). The effect of solvents is similarly predicted by the SMD, CPCM, and IEFPCM approaches (with energy differences below 1 kcal/mol).
- Castro-Alvarez, Alejandro,Carneros, Héctor,Sánchez, Dani,Vilarrasa, Jaume
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p. 11977 - 11985
(2016/01/09)
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- Silver-free activation of ligated gold(I) chlorides: The use of [Me3NB12Cl11]- as a weakly coordinating anion in homogeneous gold catalysis
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Phosphane and N-heterocyclic carbene ligated gold(I) chlorides can be effectively activated by Na[Me3NB12Cl11] (1) under silver-free conditions. This activation method with a weakly coordinating closo-dodecaborate anion was shown to be suitable for a large variety of reactions known to be catalyzed by homogeneous gold species, ranging from carbocyclizations to heterocyclizations. Additionally, the capability of 1 in a previously unknown conversion of 5-silyloxy-1,6-allenynes was demonstrated.
- Wegener, Michael,Huber, Florian,Bolli, Christoph,Jenne, Carsten,Kirsch, Stefan F.
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supporting information
p. 1328 - 1336
(2015/02/05)
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- The hit-to-lead optimization of 1,2,3,4,4a,9a-hexahydro-1H-xanthenes as glucocorticoid receptor antagonists
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The structure-activity relationship (SAR) study of a 1,2,3,4,4a,9a- hexahydro-1H-xanthene series of selective, human glucocorticoid receptor α (hGRα) antagonists is reported. Compounds were screened using hydroxyapatite-based GR binding and MMTV-Luc co-transfection reporter gene assays. Four different regions of the scaffold were modified to assess the effects on hGRα antagonism and related potency. Compound 8d exhibits an 8-fold better bioactivity than the original hit 1a, as well as an improved chemical stability, which make it a promising lead for the subsequent optimization.
- Zhu, Yan-Hui,Zhang, Meng,Li, Qun-Yi,Liu, Qing,Zhang, Jie,Yuan, Yun-Yun,Nan, Fa-Jun,Wang, Ming-Wei
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supporting information
p. 693 - 698
(2014/06/09)
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- 2-phenylindole and arylsulphonamide: Novel scaffolds bactericidal against mycobacterium tuberculosis
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A cellular activity-based screen on Mycobacterium tuberculosis (Mtb) H37Rv using a focused library from the AstraZeneca corporate collection led to the identification of 2-phenylindoles and arylsulphonamides, novel antimycobacterial scaffolds. Both the series were bactericidal in vitro and in an intracellular macrophage infection model, active against drug sensitive and drug resistant Mtb clinical isolates, and specific to mycobacteria. The scaffolds showed promising structure-activity relationships; compounds with submicromolar cellular potency were identified during the hit to lead exploration. Furthermore, compounds from both scaffolds were tested for inhibition of known target enzymes or pathways of antimycobacterial drugs including InhA, RNA polymerase, DprE1, topoisomerases, protein synthesis, and oxidative-phosphorylation. Compounds did not inhibit any of the targets suggesting the potential of a possible novel mode of action(s). Hence, both scaffolds provide the opportunity to be developed further as leads and tool compounds to uncover novel mechanisms for tuberculosis drug discovery.
- Naik, Maruti,Ghorpade, Sandeep,Jena, Lalit Kumar,Gorai, Gopinath,Narayan, Ashwini,Guptha, Supreeth,Sharma, Sreevalli,Dinesh, Neela,Kaur, Parvinder,Nandishaiah, Radha,Bhat, Jyothi,Balakrishnan, Gayathri,Humnabadkar, Vaishali,Ramachandran, Vasanthi,Naviri, Lava Kumar,Khadtare, Pallavi,Panda, Manoranjan,Iyer, Pravin S.,Chatterji, Monalisa
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supporting information
p. 1005 - 1009
(2014/12/10)
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- A practical synthetic route to enantiopure 6-substituted cis-decahydroquinolines
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Starting from 4-substituted cyclohexanones, a practical synthetic route to enantiopure 6-substituted cis-decahydroquinolines has been developed, the key steps being a stereoselective cyclocondensation of an unsaturated δ-keto ester derivative with (R)-phenylglycinol and the stereoselective hydrogenation of the resulting tricyclic oxazoloquinolone lactams.
- Amat, Mercedes,Navio, Laura,Llor, Nuria,Molins, Elies,Bosch, Joan
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supporting information; experimental part
p. 210 - 213
(2012/03/10)
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- A new and facile synthesis of methyl 3-amino-4,5,6,7-tetrahydrobenzo[b] thiophene-2-carboxylate
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A four-step synthesis of methyl 3-amino-4,5,6,7-tetrahydrobenzo[b] thiophene-2-carboxylate from commercially available starting materials is presented.
- Tenora, Luká?,Buchlovi?, Marian,Man, Stanislav,Potá?ek, Milan
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supporting information; experimental part
p. 401 - 403
(2011/02/28)
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- Efficient palladium-catalyzed asymmetric allylic alkylation of ketones and aldehydes
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Palladium-catalyzed asymmetric allylic alkylation of ketones, via enamines generated in situ as nucleophiles, were carried out smoothly with chiral metallocene-based P,N-ligands. Under the same conditions, however, reactions of aldehydes could hardly be observed. Subsequently, this obstacle was resolved by using chiral metallocene-based P,P-ligands. Both ketones and aldehydes afforded excellent enantioselectivities with up to 98% ee and 94% ee, respectively.
- Zhao, Xiaohu,Liu, Delong,Xie, Fang,Liu, Yangang,Zhang, Wanbin
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supporting information; scheme or table
p. 1871 - 1875
(2011/05/03)
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- Synthesis of 6 H-dibenzo[ b, d ]pyran-6-ones using the inverse electron demand Diels-Alder reaction
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A set of coumarin-fused electron-deficient 1,3-dienes was synthesized, which differ in the nature of the electron-withdrawing group (EWG) at the terminus of the diene unit and (when EWG = CO2Me) the nature and position of substituents. These dienes reacted with the enamine derived from cyclopentanone and pyrrolidine to afford the corresponding cyclopenteno-fused 6H-dibenzo[b,d]pyran-6-ones, most likely via a domino inverse electron demand Diels-Alder (IEDDA)/elimination/transfer hydrogenation sequence. The parent diene (EWG = CO2Me, no substituents) was reacted with a range of electron-rich dienophiles (mostly enamines) to afford the corresponding 6H-dibenzo[b,d]pyran-6-ones or their nondehydrogenated precursors, which were aromatized upon treatment with a suitable oxidant. The enamines could either be synthesized prior to the reaction or generated in situ. The syntheses of 30 dibenzopyranones are reported.
- Pottie, Ian R.,Nandaluru, Penchal Reddy,Benoit, Wendy L.,Miller, David O.,Dawe, Louise N.,Bodwell, Graham J.
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experimental part
p. 9015 - 9030
(2011/12/03)
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- Enamines: efficient nucleophiles for the palladium-catalyzed asymmetric allylic alkylation
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Enamines were tested to be efficient nucleophiles for palladium-catalyzed asymmetric allylic alkylation, avoiding the use of unstablilized ketone enolates formed by strong bases. The influence of the chiral metallocene-based ligands upon this reaction was studied in detail. It was shown that planar chirality played an important role in enantioselectivities. Meanwhile, different kinds of enamines and allylic acetate to the reactions were also investigated. High catalytic activity and excellent enantioselectivity (up to 99% ee) were obtained with pyrrolidine enamines of both aliphatic and aromatic ketone.
- Zhao, Xiaohu,Liu, Delong,Xie, Fang,Zhang, Wanbin
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experimental part
p. 512 - 517
(2009/04/07)
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- Reaction control in synthetic organic photochemistry: Switching between [5+2] and [2+2] Modes of Cycloaddition
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Split personality: Reaction conditions that enable powerful control over the mode of photocycloaddition in maleimides have been developed. Direct irradiation favors the [5+2] mode whereas sensitized irradiation allows a complete switch to the [2+2] mode (see scheme; TBS=tertbutyldimethylsilyl).
- Roscini, Claudio,Cubbage, Kara L.,Berry, Malcolm,Orr-Ewing, Andrew J.,Booker-Milburn, Kevin I.
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supporting information; experimental part
p. 8716 - 8720
(2010/03/01)
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- Diastereoselectivity control of the radical carboazidation of substituted methylenecyclohexanes
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A systematic study of the diastereoselectivity of the radical carboazidation of methylenecyclohexane derivatives is presented. Several substitution patterns leading to a high level of stereocontrol have been identified. Axial attack is the preferred reaction pathway for cyclohexyl radicals, and excellent stereoselectivities can be obtained by introducing an axial substitutent at position 2. In this case, a second equatorial substituent at position 2 may be tolerated without a large detrimental effect on the diastereoselectivity. Finally, a high level of equatorial attack is observed with a very bulky substituent at position 2.
- Cren, Sylvaine,Schar, Pascal,Renaud, Philippe,Schenk, Kurt
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supporting information; experimental part
p. 2942 - 2946
(2009/09/06)
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- TETRAHYDROINDOLE DERIVATIVES AS NADPH OXIDASE INHIBITORS
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The present invention is related to tetrahydroindolederivatives of Formula (I), pharmaceutical composition thereof, methods of preparation thereofand to their use for the treatment and/or prophylaxis of disorders or conditions related to Nicotinamide adenine dinucleotide phosphateoxidase (NADPH Oxidase).
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Page/Page column 48
(2008/12/04)
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- COMPOUNDS FOR DISEASES AND DISORDERS
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The invention provides novel compounds useful for the treatment of disorders associated with a defect in vesicular transport (e.g., axonal transport). The compounds have a substituents chosen from -L-C(=O)OH, -L-CH=CHC(=O)OH, -L-C(=O)NH2, -L-C(=O)NH(C1-3 alkyl), -L-C(=O)N(C1-3 alkyl)2, -L-S(=O)2(C1-3alkyl), -L-S(=O)2NH2, -L-S(=O)2N(C1-3 alkyl)2, -L-S(=O)2NH(C1-3 alkyl), -L-C(=O)NHOH, -L-C(=O)CH2NH2, -L-C(=O)CH2OH, -L-C(=O)CH2SH, -L-C(=O)NHCN, -L-NHC(=O)ORo, -L-C(=O)NHRo, -L-NH(C=O)NHRo, -L-C(=O)N(Ro)2, -L-NH(C=O)N(Ro)2, -L-sulfo, -L-(2,6 difluorophenol), -L-phosphono, and -L-tetrazolyl, where L is a linker.
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Page/Page column 151
(2008/06/13)
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- Iridium catalysts with bicyclic pyridine-phosphinite ligands: Asymmetric hydrogenation of olefins and furan derivatives
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(Chemical Equation Presented) Superior bicyclics: Iridium catalysts as 1 derived from pyridine-phosphinite ligands considerably extend the scope of asymmetric hydrogenation. In addition to various unfunctionalized and functionalized olefins, furans, and benzofurans, for which no catalysts were known before, are also hydrogenated with high enantioselectivity (see scheme).
- Kaiser, Stefan,Smidt, Sebastian P.,Pfaltz, Andreas
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p. 5194 - 5197
(2007/10/03)
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- New, general, and practical enamine cyclopropanation using dichloromethane
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Dichloromethane serves as a novel electrophilic carbene equivalent which adds to an enamine double bond. The presence of other alkene moieties in the enamine partner is well tolerated. Even enamines derived from sterically hindered ketones react readily with dichloromethane promoted by TiCl 4-Mg.
- Tsai, Chia-Chung,Hsieh, I.-Lin,Cheng, Tsung-Ting,Tsai, Ping-Kuei,Lin, Kuo-Wei,Yan, Tu-Hsin
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p. 2261 - 2263
(2007/10/03)
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- Total synthesis of the marine alkaloid (±)-lepadiformine via a radical carboazidation
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The total synthesis of lepadiformine has been achieved in 10 steps and 15% overall yield from cyclohexanone. The amino-substituted quaternary carbon center is created through a radical carboazidation reaction. The tricyclic core of lepadiformine is built via an efficient hydrogenation process, involving reduction of the azide and intramolecular reductive amination of a ketone, followed by lactamization of the intermediate γ-aminoester. The hydroxymethyl side chain is introduced according to a modified Takahata procedure after conversion of the lactam into a thiolactam.
- Schaer, Pascal,Renaud, Philippe
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p. 1569 - 1571
(2007/10/03)
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- Process for the synthesis of ?2S, 3aR, 7aS|-octahydroindole-2-carboxylic acid and its conversion to trandolapril
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The present invention describes a novel method for the synthesis of (2S,3aR,7aS)-octahydroindole-2-carboxylic acid of formula III using a new intermediate of formula II and conversion of the product of formula-III to trandolapril of formula I
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Page/Page column 13
(2010/11/24)
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- A new reactivity pattern for vinyl bromides: Cine-substitution via palladium catalysed C-N coupling/Michael addition reactions
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Palladium catalysed C-N bond formation can be used to convert vinyl bromides to the corresponding enamines, which are reacted in situ with alkylidene malonates to provide Michael adducts. The overall transformation results in cine-substitution of the starting vinyl bromide. The Royal Society of Chemistry 2005.
- Willis, Michael C.,Chauhan, Jay,Whittingham, William G.
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p. 3094 - 3095
(2007/10/03)
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- A NOVEL SYNTHESIS OF 2-AZABICYCLIC-3-CARBOXYLIC ACIDS, USEFUL AS IMPORTANT DRUG INTERMEDIATES
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A novel process for the preparation of 2-azabicyclo-3-carboxylic acid hydrochloride of formula (I), by reacting the compound of formula (II) with an acylating agent in a non-polar solvent at 0-150 °C to give a compound of formula (III), which is reacted with an enamine of formula (IV) in a non-polar solvent in the presence of an organic base at 0 °C to 150 °C to yield a compound of formula (V), which is hydrolytically cyclised to give a compound of formula (VI) and further catalytically hydrogenated to give the compound of formula (I).
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Page/Page column 9
(2008/06/13)
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- Construction of fused cyclooctanoid ring systems via seven-membered ring carbonyl ylides
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A series of α-diazo carbonyl compounds tethered to cyclopentanone/cyclohexanone/1-tetralone units have been synthesized using a diazomethane solution to construct various fused cyclooctane ring systems via rhodium-generated carbonyl ylides. The reaction of rhodium(II) acetate dimer with various α-diazo carbonyl compounds generated transient cyclic seven-membered ring carbonyl ylides, which underwent facile 1,3-dipolar cycloadditions with dipolarophiles, like N-phenylmaleimide, p-benzoquinone, and DMAD to furnish a variety of fused epoxy-bridged cyclooctane ring systems in a tandem manner. Interestingly, an oxepine ring system was generated via an intramolecular proton transfer of a seven-membered ring carbonyl ylide. A tri-oxa polycyclic compound was obtained in the case of p-benzoquinone as dipolarophile. A single-crystal X-ray analysis of a fused cyclootanoid derivative is reported to decisively establish the structure and stereochemistry of the fused epoxy-bridged cyclooctane ring systems; a further analysis revealed the existence of a unique intermolecular C-H ···π interaction motif in the solid-state architecture.
- Muthusamy, Sengodagounder,Babu, Srinivasarao Arulananda,Gunanathan, Chidambaram,Suresh, Eringathodi,Dastidar, Parthasarathi
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p. 801 - 811
(2007/10/03)
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- Substituted pyridine or piperidine compounds
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The invention relates to a compound of formula (I): wherein:A represents pyridine, pyridinium or piperidineR1, R2, R3 and R4 are as defined in the descriptionR5 represents hydrogen, a nitrogen-containing heterocycle or a group of R6 represents hydrogen or linear or branched (C1-C6)alkyl.and medicinal products containing the same which are useful in treating pain or deficiencies in memory.
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- Effect of C-ring modifications in benzo[c]quinolizin-3-ones, new selective inhibitors of human 5α-reductase 1
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The synthesis and the inhibition potency of ocatahydro- and decahydrobenzo[c]quinolizin-3-one derivatives 3-7, as new non-steroidal selective inhibitors of human enzyme 5α-reductase type 1, are reported. These compounds differ from the recently reported enzo[c]quinolizin-3-one inhibitors 2 by the presence of a fully or partially saturated C-ring. Compounds 3 and 4, with a double bond in the C-ring, were prepared by sequential rearrangement-annulation of isoxazolines 19 and 20. C-ring saturated compounds 5-7 were prepared by the lewis acid-promoted. Mannich-Michael tandem reaction of Danishefsky diene with the appropriate N-t-Boc iminium ion. Inhibition experiments were carried out in 5αR-1 and 5αR-2 expressed by CHO cells. Among the prepared compounds, octahydrobenzo9c0quinolizin-3-one3, with a double bond at the position 6a-10a, was a potent and selective inhibitor of human 5αR-1 IC50 = 58 nM). The introduction of a tert-butylcarboxyamide at the position 8 compounds 5-7. The extended planarity of the most potent benzo[c]quinolizin-3-ones as well as favorable interactions of the C-ring unsaturation with the enzyme active site could account for the inhibition activity of these compounds. Copyright
- Guarna, Antonio,Occhiato, Ernesto G.,Machetti, Fabrizio,Trabocchi, Andrea,Scarpi, Dina,Danza, Giovanna,Mancina, Rosa,Comerci, Alessandra,Serio, Mario
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p. 1385 - 1393
(2007/10/03)
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