- Bicyclic Piperidines via [2 + 2] Photocycloaddition
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A synthetic strategy to fused bicyclic piperidines - building blocks for medicinal chemistry - is developed. The key step was an intramolecular [2 + 2]-photocyclization. The photochemical step was performed on a gram scale. Crystallographic analysis of the obtained compounds revealed that they occupy a novel chemical space and can be considered as elongated analogues of 3-substituted piperidines.
- Shcherbakova, Valeriya,Dibchak, Dmitry,Snisarenko, Mariya,Skalenko, Yevhen,Denisenko, Aleksandr V.,Kuznetsova, Anastasiia S.,Mykhailiuk, Pavel K.
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- Bisubstrate inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: Transition state analogs for high affinity binding
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6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a key enzyme in the folate biosynthesis pathway. It catalyzes pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). HPPK is essential for microorganisms but absent in mammals; therefore, it is an attractive target for developing novel antimicrobial agents. Previously, based on our studies of the structure and mechanism of HPPK, we created first-generation bisubstrate inhibitors by linking 6-hydroxymethylpterin to adenosine through phosphate groups, and developed second-generation inhibitors by replacing the phosphate bridge with a linkage that contains a piperidine moiety. Here, we report third-generation inhibitors designed based on the piperidine-containing inhibitor, mimicking the transition state. We synthesized two such inhibitors, characterized their protein-binding and enzyme inhibition properties, and determined their crystal structures in complex with HPPK, advancing the development of such bisubstrate analog inhibitors.
- Shi, Genbin,Shaw, Gary X.,Zhu, Fengxia,Tarasov, Sergey G.,Ji, Xinhua
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- Discovery and Development of 3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane Hydrochloride (SUVN-911): A Novel, Potent, Selective, and Orally Active Neuronal Nicotinic Acetylcholine α4β2 Receptor Antagonist for the Treatment of Depression
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A series of chemical optimizations guided by in vitro affinity at the α4β2 receptor in combination with selectivity against the α3β4 receptor, pharmacokinetic evaluation, and in vivo efficacy in a forced swim test resulted in identification of 3-(6-chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane hydrochloride (9h, SUVN-911) as a clinical candidate. Compound 9h is a potent α4β2 receptor ligand with a Ki value of 1.5 nM. It showed >10 μM binding affinity toward the ganglionic α3β4 receptor apart from showing selectivity over 70 other targets. It is orally bioavailable and showed good brain penetration in rats. Marked antidepressant activity and dose-dependent receptor occupancy in rats support its potential therapeutic utility in the treatment of depression. It does not affect the locomotor activity at doses several folds higher than its efficacy dose. It is devoid of cardiovascular and gastrointestinal side effects. Successful long-term safety studies in animals and phase-1 evaluation in healthy humans for safety, tolerability, and pharmacokinetics paved the way for its further development.
- Nirogi, Ramakrishna,Mohammed, Abdul Rasheed,Shinde, Anil K.,Ravella, Srinivasa Rao,Bogaraju, Narsimha,Subramanian, Ramkumar,Mekala, Venkat Reddy,Palacharla, Raghava Choudary,Muddana, Nageswararao,Thentu, Jagadeesh Babu,Bhyrapuneni, Gopinadh,Abraham, Renny,Jasti, Venkat
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p. 2833 - 2853
(2020/03/05)
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- A practical catalytic reductive amination of carboxylic acids
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We report reductive alkylation reactions of amines using carboxylic acids as nominal electrophiles. The two-step reaction exploits the dual reactivity of phenylsilane and involves a silane-mediated amidation followed by a Zn(OAc)2-catalyzed amide reduction. The reaction is applicable to a wide range of amines and carboxylic acids and has been demonstrated on a large scale (305 mmol of amine). The rate differential between the reduction of tertiary and secondary amide intermediates is exemplified in a convergent synthesis of the antiretroviral medicine maraviroc. Mechanistic studies demonstrate that a residual 0.5 equivalents of carboxylic acid from the amidation step is responsible for the generation of silane reductants with augmented reactivity, which allow secondary amides, previously unreactive in zinc/phenylsilane systems, to be reduced.
- Andrews, Keith G.,Denton, Ross M.,Hirst, David J.,Stoll, Emma L.,Tongue, Thomas,Valette, Damien
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p. 9494 - 9500
(2020/10/02)
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- Carbamoyl Fluoride-Enabled Enantioselective Ni-Catalyzed Carbocarbamoylation of Unactivated Alkenes
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A carbamoyl fluoride-enabled enantioselective Ni-catalyzed carbocarbamoylation of unactivated alkenes was developed, providing a broad range of chiral γ-lactams bearing an all-carbon quaternary center in 45-96% yield and 38-97% ee.
- Li, Yue,Luan, Yu-Xin,Qi, Shao-Long,Wang, Rong-Hua,Ye, Mengchun,Zhang, Feng-Ping
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supporting information
p. 19844 - 19849
(2021/01/01)
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- A 5 + 1 Protic Acid Assisted Aza-Pummerer Approach for Synthesis of 4-Chloropiperidines from Homoallylic Amines
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We report that HCl·DMPU induces the formation of (thiomethyl)methyl carbenium ion from DMSO under mild conditions. Homoallylic amines react with this electrophile to generate 4-chloropiperidines in good yields. The method applies to both aromatic and aliphatic amines. The use of HCl·DMPU as both non-nucleophilic base and chloride source constitutes an environmentally benign alternative for piperidine formation. The reaction has a broad substrate scope, and the conditions offer good chemical yields with high functional group tolerance and scalability.
- Ebule, Rene,Mudshinge, Sagar,Nantz, Michael H.,Mashuta, Mark S.,Hammond, Gerald B.,Xu, Bo
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p. 3249 - 3259
(2019/03/20)
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- Catalytic, Enantioselective Synthesis of Cyclic Carbamates from Dialkyl Amines by CO2-Capture: Discovery, Development, and Mechanism
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Cyclic carbamates are a common feature of small-molecule therapeutics, offering a constrained hydrogen bond acceptor that is both polar and sterically small. Methods for their preparation most often focus first on amino alcohol synthesis and then reaction with phosgene or its equivalent. This report describes an enantioselective synthesis of cyclic carbamates in which carbon dioxide engages an unsaturated basic amine, facilitated by a bifunctional organocatalyst designed to stabilize a carbamic acid intermediate while activating it toward subsequent enantioselective carbon-oxygen bond formation. Six-membered cyclic carbamates are prepared in good yield with high levels of enantioselection, as constrained 1,3-amino alcohols featuring a chiral tertiary alcohol carbon. Spectroscopic analysis (NMR, DOSY) of various substrate-reagent combinations provides insight into the dominant species under the reaction conditions. Two peculiar requirements were identified to achieve highest consistency: a "Goldilocks" amount of water and the use of a noncrystalline form of the ligand. These atypical features of the final protocol notwithstanding, a diverse range of products could be prepared. Their functionalizations illustrate the versatility of the carbamates as precursors to enantioenriched small molecules.
- Yousefi, Roozbeh,Struble, Thomas J.,Payne, Jenna L.,Vishe, Mahesh,Schley, Nathan D.,Johnston, Jeffrey N.
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supporting information
p. 618 - 625
(2019/01/11)
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- Reductive C-O, C-N, and C-S Cleavage by a Zirconium Catalyzed Hydrometalation/β-Elimination Approach
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A zirconium catalyzed reductive cleavage of Csp3 and Csp2 carbon-heteroatom bonds is reported that makes use of a tethered alkene functionality as a traceless directing group. The reaction is successfully demonstrated on C-O, C-N, and C-S bonds and proposed to proceed via a hydrozirconation/β-heteroatom elimination sequence of an in situ formed zirconium hydride catalyst. The positional isomerization of the catalyst further enables the cleavage of homoallylic ethers and the removal of terminal allyl and propargyl groups.
- Matt, Christof,K?lblin, Frederic,Streuff, Jan
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p. 6983 - 6988
(2019/09/09)
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- HPPK INHIBITORS USEFUL AS ANTIBACTERIAL AGENTS
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The disclosure provides linked purine pterin compounds of Formula I that are novel inhibitors of HPPK, a kinase responsible for an essential step in the biosynthesis of folic acid. (Formula I) The variables, e.g., A1-A3, R1-R4, B1-B2, and L1 are defined in the disclosure. These linked purine pterin inhibitors bind to HPPK with high affinity and specificity. Pharmaceutical compositions containing the HPPK inhibitors and methods of treating a bacterial infection in a patient with one or more of the HPPK inhibitors of the disclosure are also provided.
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Paragraph 0118; 0119
(2018/04/27)
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- A Simple, Broad-Scope Nickel(0) Precatalyst System for the Direct Amination of Allyl Alcohols
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The preparation of allylic amines is traditionally accomplished by reactions of amines with reactive electrophiles, such as allylic halides, sulfonates, or oxyphosphonium species; such methods involve hazardous reagents, generate stoichiometric waste streams, and often suffer from side reactions (such as overalkylation). We report here the first broad-scope nickel-catalysed direct amination of allyl alcohols: An inexpensive NiII/Zn couple enables the allylation of primary, secondary, and electron-deficient amines without the need for glove-box techniques. Under mild conditions, primary and secondary aliphatic amines react smoothly with a range of allyl alcohols, giving secondary and tertiary amines efficiently. This “totally catalytic” method can also be applied to electron-deficient nitrogen nucleophiles; the practicality of the process was demonstrated in an efficient, gram-scale preparation of the calcium antagonist drug substance flunarizine (Sibelium).
- Sweeney, Joseph B.,Ball, Anthony K.,Lawrence, Philippa A.,Sinclair, Mackenzie C.,Smith, Luke J.
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supporting information
p. 10202 - 10206
(2018/08/06)
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- Synergistic effect of the TiCl4/p-TsOH promoter system on the aza-Prins cyclization
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A novel aza-Prins cyclization promoted by a synergistic combination between a Lewis acid and a Br?nsted acid to efficiently afford piperidines is described. Contrary to what has been previously reported in the literature, the generality of the reaction employing N-alkyl, N-aryl, and nonprotected homoallylamines has been demonstrated. The reaction is highly diastereoselective depending on the homoallylic amine used, N-PMP homoallyl amine leading preferentially to the trans diastereomer, and free homoallylamine affording the deprotected piperidine as single cis diastereomer.
- Durel, Vianney,Lalli, Claudia,Roisnel, Thierry,Weghe, Pierre Van De
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p. 849 - 859
(2016/02/18)
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- Multicomponent Diene-Transmissive Diels-Alder Sequences Featuring Aminodendralenes
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1-Aminodecalins were prepared from acyclic precursors by combining the powerful twofold diene-transmissive Diels-Alder chemistry of [3]dendralenes with the simplicity of enamine formation. On mixing at ambient temperature, a simple dienal condenses with a primary or secondary amine to generate the enamine, a 1-amino-[3]dendralene in situ, and this participates as a double diene in a sequence of two Diels-Alder events with separate dienophiles. Overall, four C-C bonds and one C-N bond are formed. Mechanistic insights into these reactions are provided by means of density functional theory calculations.
- Tan, Siu Min,Willis, Anthony C.,Paddon-Row, Michael N.,Sherburn, Michael S.
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p. 3081 - 3085
(2016/03/12)
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- Cs2CO3-Promoted Direct N-Alkylation: Highly Chemoselective Synthesis of N-Alkylated Benzylamines and Anilines
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Herein is described an efficient and chemoselective method for the synthesis of diversely substituted secondary amines in yields up to 98 %. Direct mono-N-alkylation of primary benzylamines and anilines with a wide range of alkyl halides is promoted by a cesium base in the absence of any additive or catalyst. The basicity and solubility of cesium carbonate in anhydrous N,N-dimethylformamide not only enables mono-N-alkylation of primary amines but also suppresses undesired dialkylation of the desired amines.
- Castillo, Juan-Carlos,Orrego-Hernández, Jessica,Portilla, Jaime
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p. 3824 - 3835
(2016/08/20)
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- (Indazol-4-YL) Hexahydropyrrolopyrrolones and Methods of Use
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Compounds of formula (I) and pharmaceutically acceptable salts, esters, amides, or radiolabelled forms thereof, wherein GAr, L1, Z1 and Z2 are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by voltage-gated sodium channels, e.g., Nav 1.7 and/or Nav 1.8. Methods for making the compounds are disclosed. Also disclosed are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.
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Paragraph 0285
(2016/10/04)
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- Ring-closing metathesis of vinyl fluorides towards α-fluorinated α,β-unsaturated lactams and lactones
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Ring-closing olefin metathesis reactions (RCM) using Grubbs II or Hoveyda's catalysts have been applied to a series of N-alkenyl-N-benzyl-α-fluoroacrylamides. α-Fluoro-α,β-unsaturated γ- or δ-lactams incorporating a fluorinated double bond were obtained in moderate to good yields, depending on the nature of substituents on the benzyl ring. The corresponding seven- and eight-membered lactams were not formed under similar conditions. When the N-benzyl group was replaced by an N-tosyl group, the corresponding ε-lactam was also formed in 38% yield. When N-(2-fluoroallyl) derivatives were used instead of fluoroacryloyl derivatives, six-, seven-, and eight-membered N-heterocycles were obtained in low yields. This method was also used to synthesize fluorinated α,β-unsaturated analogues of pyrrolizidine and indolizidine alkaloids from prolinol, and also to synthesize N-benzyl-3-fluoroquinolone in three steps from commercially available 2-vinylaniline in 44% overall yield. Also 3-fluorocoumarin and 3-fluorochromene were prepared from ovinylphenol, and 3-fluoro-benzoxepine was available from o-allylphenol.
- Marhold, Michael,Stillig, Christian,Fr?hlich, Roland,Haufe, Günter
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supporting information
p. 5777 - 5785
(2014/10/15)
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- Reductive alkylation of thioamides with Grignard reagents in the presence of Ti(O i Pr)4: Insight and extension
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The reductive alkylation of thioamides by Grignard reagents in the presence of Ti(OiPr)4 is the subject of a study involving 20 different substrates. The influence of various parameters has been evaluated, showing notably that the yields of this moderately efficient process can be improved in several cases by applying a slow addition of the Grignard reagent. The results presented in this contribution also provide new insight into the reactivity of the proposed key intermediates, namely, a metalated iminium species and, ultimately, an α-metalated amine. Interestingly, by control of the temperature and the amount of Grignard reagent engaged, the reaction can be directed toward the selective formation of the former titanium intermediate complex. This represents an extension of the original method, allowing the synthesis of various previously inaccessible substituted amines by subsequent addition of a nucleophilic reagent. This role can be played not only by organomagnesium compounds but also by alkyllithium reagents, alkyltitanium(IV) complexes, and lithium aluminum hydride. The properties of the α-metalated amine final intermediate have also been explored, demonstrating that this complex is a poor nucleophile but can act as a radical precursor, which is especially evidenced when the resulting radical species are stabilized. Overall, this chemistry thus proves unexpectedly rich and can plausibly lay the basis for the development of new applications in the future.
- Hermant, Fabien,Urbaska, Ewelina,Seizilles De Mazancourt, Sarah,Maubert, Thomas,Nicolas, Emmanuel,Six, Yvan
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supporting information
p. 5643 - 5653
(2015/02/19)
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- BENZOFURO[3,2-c] PYRIDINES AND RELATED ANALOGS AS SEROTONIN SUB-TYPE 6 (5-HT6) MODULATORS FOR THE TREATMENT OF OBESITY, METABOLIC SYNDROME, COGNITION AND SCHIZOPHRENIA
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The present invention relates to benzofuro[3,2-c]pyridine and azepine analogs as serotonin sub-type 6 (5-HT6) modulators, pharmaceutical compositions including these compounds, methods of preparation, and use thereof. These compounds are useful in the treatment of central nervous system disorders including obesity, metabolic syndrome, cognition, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, rare and orphan diseases, and sleep disorders. The subject compounds have the structure of formula (I) with the substituents being described herein.
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Page/Page column 61-62
(2012/07/28)
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- COMPOUND HAVING SPIRO-BONDED CYCLIC GROUP AND USE THEREOF
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The invention relates to a compound represented by formula (I): a salt thereof, an N-oxide thereof, or a solvate thereof (symbols in the formula are as described in the specification). The compound of the present invention exhibits very low risk of side effects and also has persistent and strong antagonistic activity against CXCR4, and is therefore useful as for example, preventive and/or therapeutic agent for inflammatory and immune diseases, infections (for example, HIV infection), diseases associated with HIV infection (for example, acquired immunodeficiency syndrome (AIDS)), cancer, cancer metastasis, psychoneurotic diseases and cardiovascular diseases (for example, retinopathy), metabolic diseases, cancerous diseases, or an agent for regeneration therapy.
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Page/Page column 48
(2012/05/04)
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- SUBSTITUTED ADIPIC ACID AMIDES AND USES THEREOF
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The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein A is a five to eight membered monocyclic or a nine to twelve membered bicyclic heterocyclic ring, as further defined herein; Y is S, CH2, or CH; Z is CH or N; R7 and R9 are hydrogen or (C1-C6)alkyl; R2 is (C1 C6)alkoxy, OH, CN, (C1-C6)alkyl, halogen, or CF3; r and s are 0, 1, or 2; and R1 and R3 are as further defined herein. These compounds are agonists, partial agonists and/or modulators of the NPY4 receptor and may be used for the treatment and prophylaxis of obesity, food intake, and other diseases and conditions modulated by the NPY4 receptor.
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Page/Page column 115
(2012/10/07)
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- γ- and δ-lactams through palladium-catalyzed intramolecular allylic alkylation: Enantioselective synthesis, NMR investigation, and DFT rationalization
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The Pd-catalyzed intramolecular allylic alkylation of unsaturated amides to give γ- and δ-lactams has been studied in the presence of chiral ligands. Ligand (R)-3,5-tBu-MeOBIPHEP (MeOBIPHEP=6,6'-dimethoxybiphenyl-2,2- diyl)bis(diphenylphosphine)) afforded the best results and allowed the cyclization reactions to take place in up to 94:6 enantiomeric ratio. A model Pd-allyl complex has been prepared and studied through NMR spectroscopic analysis, which provided insight into the processes responsible for the observed enantiomeric ratios. DFT studies were used to characterize the diastereomeric reaction pathways. The calculated energy differences were in good agreement with the experimentally observed enantiomeric ratios. A transient existence: The Pd-catalyzed intramolecular allylic alkylation of unsaturated amides to give γ- and δ-lactams in the presence of (R)-3,5-tBu-MeOBIPHEP takes place in up to 94:6 enantiomeric ratio (e.r.; see scheme). The energies of the diastereomeric transition states are in good agreement with the experimentally observed enantiomeric ratios.
- Bantreil, Xavier,Prestat, Guillaume,Moreno, Aitor,Madec, David,Fristrup, Peter,Norrby, Per-Ola,Pregosin, Paul S.,Poli, Giovanni
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supporting information; experimental part
p. 2885 - 2896
(2011/04/24)
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- Palladium-catalysed cyclisation of N-alkynyl aminomalonates
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Go around in (hetero)cycles! The palladium-catalysed tandem cyclisation/coupling reaction of alkynyl- and alkenyl-substituted aminomalonates leads to highly functionalised pyrrolidines and piperidines in good yield (see scheme). The reaction allows efficient access to a broad range of synthetically valuable building blocks.
- Hess, Wilfried,Burton, Jonathan W.
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supporting information; experimental part
p. 12303 - 12306
(2011/02/23)
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- Asymmetric synthesis of Sedum alkaloids via lithium amide conjugate addition
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Conjugate addition of lithium (R)-N-allyl-N-(α-methylbenzyl)amide or lithium (R)-N-but-3-enyl-N-(α-methylbenzyl)amide to an alkyl hexa-2,4-dienoate or alkyl hepta-2,6-dienoate, followed by ring-closing metathesis of the olefin functionalities within the resultant β-amino ester, generates a range of diastereoisomerically pure azacycles in good yield. These homochiral templates are readily transformed to a range of piperidine alkaloids of the Sedum family, and the corresponding five-, seven- and eight-membered ring homologues.
- Davies, Stephen G.,Fletcher, Ai M.,Roberts, Paul M.,Smith, Andrew D.
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supporting information; experimental part
p. 10192 - 10213
(2010/02/28)
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- An oxidatively-activated safety catch linker for solid phase synthesis
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A N-benzyl-4-amino-2,2-dimethylbutanoic acid-based system has been developed as a new oxidatively activated safety catch linker for reaction monitoring and optimisation on solid support. The CAN promoted oxidative debenzylation of the tertiary N-benzylamine moiety, followed by concomitant cyclisation and release of alcohols and amines has been demonstrated both in solution phase model studies and on the solid phase. The linker system has been applied to the solid phase synthesis of a collection of phenol derivatives, and to the demonstration of the attachment and release of a chiral auxiliary from a solid support. The Royal Society of Chemistry 2008.
- Davies, Stephen G.,Mortimer, Duncan A. B.,Mulvaney, Andrew W.,Russell, Angela J.,Skarphedinsson, Hjalmar,Smith, Andrew D.,Vickers, Richard J.
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supporting information; experimental part
p. 1625 - 1634
(2008/10/09)
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- Constraining the amide bond in N-Sulfonylated dipeptide VLA-4 antagonists
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The integrin VLA-4 is implicated in several inflammatory disease states. In search of non-peptidic antagonists of VLA-4, rotational constraints were imposed on the amide bond of prototypical N-sulfonylated dipeptide VLA-4 antagonists. By judicious structural modification of the side chains, trisubstituted imidazoles with moderate binding potencies were obtained, for example, 19, VLA-4 IC50 = 237 nM.
- Chang, Linda L.,Yang, Ginger X.,McCauley, Ermengilda,Mumford, Richard A.,Schmidt, John A.,Hagmann, William K.
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p. 1688 - 1691
(2008/09/20)
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- Synthesis of 3-oxooxa- and 3-oxoazacycloalk-4-enes by ring-closing metathesis. Application to the synthesis of an inhibitor of cathepsin K
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3-Oxooxa- and 3-oxoazacycloalk-4-enes were obtained with good yield from 1-(ω-alkenyloxy)- and 1-(ω-alkenylamino)-but-3-en-2-ones by using a ring-closing metathesis. This methodology has been used to synthesize an inhibitor of cathepsin K.
- Taillier, Catherine,Hameury, Thomas,Bellosta, Véronique,Cossy, Janine
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p. 4472 - 4490
(2008/02/01)
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- Structure-activity relationship studies of a series of novel δ-lactam-based histone deacetylase inhibitors
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We synthesized a series of δ-lactam-based HDAC inhibitors that were identified with various degrees of anti-inflammatory and cell growth inhibitory activities. Compounds possessing significant HDAC inhibitory activity exhibited both anti-inflammatory and cell growth inhibitory activities as well as significant tumor growth inhibition in the in vivo tumor xenograft experiments. Besides, these compounds demonstrated antiinflammatory properties in vitro via suppression of the production of the proinflammatory cytokine TNF-α and nitric oxide by LPS-stimulated RAW264.7 cells.
- Hwan, Mook Kim,Ryu, Dong-Kyu,Choi, Yongseok,Bum, Woo Park,Lee, Kiho,Sang, Bae Han,Lee, Chang-Woo,Kang, Moo-Rim,Jong, Soon Kang,Boovanahalli, Shanthaveerappa K.,Park, Song-Kyu,Jung, Whan Han,Chun, Tae-Gyu,Lee, Hee-Yoon,Nam, Ky-Youb,Eun, Hyun Choi,Han, Gyoonhee
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p. 2737 - 2741
(2008/02/04)
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- [1,3]-Transfer of chirality during the nicholas reaction in γ-benzyloxy propargylic alcohols
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A highly regio- and stereoselective intramolecular [1.5]-hydrogentransfer process is described. Treatment of γ-benzyl-protccted Co 2(CO)6-α,γ-acetylenic diols with BF 3·OEt2 provides bis-homopropargylic alcohols. The reaction occurs within seconds, tolerates a wide range of functionalities, and provides good yields. When the ether group is located at a stereochemically defined carbon atom, the rearrangement occurs with high stereoselectivity, transferring the chirality of the carbinol center to the newly created stereocenter. The cleavage of the benzyloxy group is totally regioselective when additional benzyl ethers are present. The scope and limitations of this novel process in densely substituted substrates are evaluated, and possible competitive reactions and/or stereochemical influences are also described. A mechanism based on a highly ordered chair-like transition state substantiated by a theoretical study is also included.
- Diaz, David D.,Ramirez, Miguel A.,Martin, Victor S.
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p. 2593 - 2606
(2008/02/07)
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- Synthesis, enzymatic inhibition, and cancer cell growth inhibition of novel δ-lactam-based histone deacetylase (HDAC) inhibitors
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δ-Lactam-based hydroxamic acids, inhibitors of histone deacetylase (HDAC), have been synthesized via ring closure metathesis of key diene intermediates followed by conversion to hydroxamic acid analogues. The hydroxamic acids 12a, 12b, and 17c showed potent inhibitory activity in HDAC enzyme assay. The hydroxamic acid 12b exhibited growth inhibitory activity on five human tumor cell lines, showing good sensitivity on the MDA-MB-231 breast tumor cell.
- Kim, Hwan Mook,Lee, Kiho,Park, Bum Woo,Ryu, Dong Kyu,Kim, Kangjeon,Lee, Chang Woo,Park, Song-Kyu,Han, Jung Whan,Lee, Hee Yoon,Lee, Hyun Yong,Han, Gyoonhee
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p. 4068 - 4070
(2007/10/03)
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- NEW COMPOUNDS
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The present invention relates to new compounds of formula I, wherein P Q X1 X2 X3 X4 X5 R R1 R2 R3 R4R5 G M1 M2 M3 m and n are defined as in formula I, a process for their preparation and new intermediates prepared therein, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
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- 1,2,3,5-tetrahydrobenzo'c!azepin-4-one derivatives having muscarinic antagonist activity
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There is disclosed a compound having the formula or a pharmaceutically acceptable salt thereof, wherein: R1a, R1b and R1c are independently fluorine or hydrogen; R2 is C1 to C12 alkyl being
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- Generation of aminoacyl radicals from 1-carbamoyl-1-methylcyclohexa-2,5-dienes: A new tin-free homolytic route to β- and γ-lactams
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Radical induced homolyses of 1-carbamoyl-1-methylcyclo-hexa-2,5-dienes took place cleanly to yield aminoacyl radicals, with no competition from the alternative dissociation to methyl radicals: β- and γ-lactams were obtained from ring closures of suitably
- Jackson,Walton
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p. 2327 - 2328
(2007/10/03)
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- Zinca-ene-allene cyclizations: A way to substituted tetrahydrofurans or pyrrolidines
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Polysubstituted enynes have been lithiated on the propargylic position, and transmetalation to the corresponding zinc reagents promotes an easy cyclization reaction leading to polysubstituted tetrahydrofurans and pyrrolidines of definite geometry via the zinca-ene-allene reaction.Keywords: carbocyclization; allenyl zinc; tetrahydrofuran; pyrrolidine; zinca-ene-allene
- Lorthiois, Edwige,Marek, Ilane,Normant, Jean-Francois
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p. 333 - 342
(2007/10/03)
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- Facile preparation of homoallyl amines via reaction of N-aminoalkylbenzotriazoles with allylsamarium bromide
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Homoallyl amines can be readily prepared in good to excellent yields via reaction of N-aminoalkylbenzotriazoles with allylsamarium bromide in THF at room temperature.
- Wang, Junquan,Zhou, Jianqin,Zhang, Yongmin
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p. 3395 - 3399
(2007/10/03)
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- An intramolecular 1,3-dipolar cycloaddition approach to a pyrimidoazepinone derivative. A potentially useful intermediate towards the synthesis of pyrimidoazepine based folic acid derivatives
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An intramolecular nitrile oxide cycloaddition route to the isoxazolinopyrimidoazepine derivative 21 is described. This was transformed to the pyrimidoazepinone derivative 22, a potentially useful intermediate for the synthesis of pyrimidoazepine based fol
- Miller, Michael L.,Ray, Partha S.
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p. 5739 - 5744
(2007/10/03)
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- Radical Cyclisation in Heterocycle Synthesis. Part 1. Sulfanyl Radical Addition-Cyclisation of Dienylamides for Lactam Synthesis
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A new method for the synthesis of five- to eight-membered lactams by sulfanyl radical mediated-cyclisation of dienylamides is described.The sulfanyl radical addition-cyclisation of the dienylamide 1 was systematically investigated under four different conditions and was found to give the cyclised lactams 2-6 in 54-79percent yield.The stereo- and regio-selectivity of sulfanyl radical addition-cyclisation was established from the preferential formation of the trans-cyclised lactam 3 and also from the substituent effects in the cyclisation of the dienylamides 11-18.The sulfanyl radical mediated addition-cyclisation was successfully applied to the construction of the six- and eight-membered lactams 28a, b.
- Naito, Takeaki,Honda, Yuko,Miyata, Okiko,Ninomiya, Ichiya
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- Aza-Wittig Rearrangements and Cyclizations by Transmetallation of N-Benzylaminomethylstannanes
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Transmetallation of N-allyl-N-benzylaminomethylstannanes with butyllithium or methyllithium allows carbon-carbon bond formation by a -rearrangement.Substantial amounts of the protodestannylated product are also produced.Transmetallation of the corresponding α-methyl substituted allylic amine or homoallylic amine gives an overall rearrangement by cyclization onto the olefin followed by recapture of the new carbanion by tetramethyltin.
- Coldham, Iain
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p. 1275 - 1276
(2007/10/02)
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- SYNTHESIS OF THE HOMOCHIRAL "TRICYCLIC HEART" OF MANZAMINE A
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An expedient and enantiospecific synthesis of a strategically functionalized tricyclic intermediate for the construction of manzamine A is described.
- Brands, Karel M. J.,Meekel, Arthur A. P.,Pandit, Upendra K.
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p. 2005 - 2026
(2007/10/02)
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- APPLICATION OF TiCl4 INDUCED IMINIUM ION CYCLIZATIONS TO THE PREPARATIONS OF PIPERIDINE ALKALOIDS: TOTAL SYNTHESES OF (+/-)-CONIINE
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Syntheses of (+/-)-coniine via TiCl4 induced iminium ion cyclizations of α-cyanoamines are described.Moreover, (α-cyanoalkyl)amine could lead to the cyclic piperidine system in good yields.
- Teng, Tsung-Fan,Lin, Jyh-Hwa,Yang, Teng-Kuei
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p. 1201 - 1204
(2007/10/02)
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- Utilization of Phenylthio Substituted Amines for the Synthesis of Pyrrolidines
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α-Phenylthio substituted amines have been found to be convenient reagents for the preparation of the pyrrolidine ring.Benzylamine (2) undergoes 1,3-dipolar cycloaddition with several dipolarophiles in the presence of silver fluoride.The reaction is believed to proceed via the intermediacy of an azomethine ylide.Treatment of α-(phenylthio)cyanoamines 10 and 17 with strong base results in the loss of the phenylthio group, and formation of substituted trans-piperazines 21, 22 in the case of 17.The mechanism of the reaction involves dimerization of the initially formed cyano substituted azomethine ylide intermediate, which behaves as a captodative diradical.Finally, the reaction of several alkenylamines with tributyltin hydride was studied as a method for generating the pyrrolidine ring via a radical cyclization reaction.
- Padwa, Albert,Dent, William,Nimmesgern, Hildegard,Venkatramanan, M. K.,Wong, George S. K.
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p. 813 - 828
(2007/10/02)
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- Synthesis of the Pyrrolidine Ring System by Radical Cyclization
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A series of bromo-substituted allyl- and diallyl-substituted sulfonamides have been found to undergo free radical cyclization when treated with tri-n-butyltin hydride in the presence of AIBN.The regiochemical course of the cyclization depends on the nature of the substituent groups attached to the ?-bond.The stereoelectronic factors governing the cyclization reaction of these N-allylsulfonamides are even more stringent than those which occur with the simple 5-hexenyl system.This is probably related to the shorter C-N bond distance which promotes the 5-exo trigcyclization pathway.The present method provides an attractive entry to the preparation of pyrrolidines from easily available N-(2-bromoethyl)-N-allyl- and N-(2-bromopropenyl)-N-allylsulfonamides.The method represents a clear-cut example of the use of hetero-substituted radicals in C-C bond-forming processes.
- Padwa, Albert,Nimmesgern, Hildegard,Wong, George S. K.
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p. 5620 - 5627
(2007/10/02)
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