- Building polyfunctional piperidines: A stereoselective strategy of a three-component Mannich reaction inspired by biosynthesis and applications in the synthesis of natural alkaloids (+)-241D; (-)-241D; isosolenopsin A and (-)-epimyrtine
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A general method to assemble multi-substituted chiral piperidines was developed, inspired by the biosynthesis of piperidine natural products. In biosynthesis, Δ1-piperideine 4 plays a key role as a common intermediate giving rise to a variety of piperidine-based natural alkaloids. Nature uses l-lysine as a building block, enzymatically transforming it into a δ-amino carbonyl intermediate 3 as the precursor to cyclize into Δ1-piperideine 4. We envisioned that such a process could be accomplished by a vinylogous type Mannich reaction if a functionalized dienolate was employed. A stereoselective three-component vinylogous Mannich-type reaction (VMR) of 1,3-bis-trimethylsily enol ether 7 was therefore investigated and was found to give cyclized chiral dihydropyridinone compound 9 as an adduct. Like Δ1-piperideine in biosynthesis, the chiral 2,3-dihydropyridinone compound 9 from VMR is a versatile intermediate for building a variety of new chiral piperidine compounds. The method was showcased by concise two-step approaches in the synthesis of the bioactive natural alkaloids (+)-241D; (-)-241D and isosolenopsin A. Furthermore, when properly functionalized substrate aldehyde 24 was employed, the corresponding dihydropyridinone adduct 25 cyclized to form a second piperidine ring, leading to a chiral polyfunctional quinolizidine enaminone 27. This versatile intermediate was used to prepare a variety of new chiral quinolizidine compounds, including natural alkaloid (-)-epimyrtine.
- Yang, Yang
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Read Online
- Palladium/Copper-catalyzed Oxidation of Aliphatic Terminal Alkenes to Aldehydes Assisted by p-Benzoquinone
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The development of an anti-Markovnikov Wacker-type oxidation for simple aliphatic alkenes is a significant challenge. Herein, a variety of aldehydes can be selectively obtained from various unbiased aliphatic terminal alkenes using PdCl2(MeCN)2/CuCl in the presence of p-benzoquinone (BQ) under mild reaction conditions. Isomerization of the terminal alkene to the internal alkene was suppressed via slow addition of the starting material to the reaction mixture. In addition to the Pd catalyst, CuCl and BQ were essential in order to obtain the anti-Markovnikov product with high selectivity. Terminal alkenes bearing a halogen substituent afforded their corresponding aldehydes with high anti-Markovnikov selectivity. The halogen acts as a directing group in the reaction. DFT calculations indicate that a μ-chloro Pd(II)?Cu(I) bimetallic species with BQ coordinated to Cu is the catalytically active species in the case of a terminal alkene without a directing group.
- Komori, Saki,Yamaguchi, Yoshiko,Murakami, Yuka,Kataoka, Yasutaka,Ura, Yasuyuki
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p. 3946 - 3955
(2020/07/06)
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- A Two-Directional Synthesis of (+)-β-Isosparteine
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A two-directional synthesis of (+)-β-isosparteine is described in five steps from glutaric acid, where the entire carbon and nitrogen backbone of the alkaloid, possessing the requisite relative and absolute stereochemistry at its four stereogenic centers, is assembled using a double imino-aldol reaction.
- Al-Saffar, Firas M.,Brown, Richard C. D.
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supporting information
p. 3502 - 3504
(2017/07/15)
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- Cascade oxime formation, cyclization to a nitrone, and intermolecular dipolar cycloaddition
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Simple haloaldehydes, including enolisable aldehydes, were found to be suitable for the formation of cyclic products by cascade (domino) condensation, cyclisation, dipolar cycloaddition chemistry. This multi-component reaction approach to heterocyclic compounds was explored by using hydroxylamine, a selection of aldehydes, and a selection of activated dipolarophiles. Initial condensation gives intermediate oximes that undergo cyclisation with displacement of halide to give intermediate nitrones; these nitrones undergo in situ intermolecular dipolar cycloaddition reactions to give isoxazolidines. The cycloadducts from using dimethyl fumarate were treated with zinc/acetic acid to give lactam products and this provides an easy way to prepare pyrrolizinones, indolizinones, and pyrrolo[2,1-a]isoquinolinones. The chemistry is illustrated with a very short synthesis of the pyrrolizidine alkaloid macronecine and a formal synthesis of petasinecine.
- Furnival, Rachel C.,Saruengkhanphasit, Rungroj,Holberry, Heather E.,Shewring, Jonathan R.,Guerrand, Hélène D. S.,Adams, Harry,Coldham, Iain
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p. 10953 - 10962
(2016/12/06)
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- Bioinspired aerobic oxidation of alcohols with a bifunctional ligand based on bipyridine and TEMPO
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A novel bioinspired bifunctional ligand incorporating metal-binding site and stable free radical has been synthesized. The catalytic system obtained from the bifunctional ligand with copper(i) iodide in the presence of N-methylimidazole is highly efficient for the oxidation of a broad range of primary benzylic, allylic, alkynyl, aliphatic alcohols and secondary benzylic alcohols to the corresponding aldehydes and ketones in good to excellent yields. The catalyst system exhibits broad functional-group compatibility. The reaction is carried out in acetonitrile as solvent under air balloon at room temperature. The catalyst system features excellent activity for primary aliphatic alcohol oxidation and a high chemoselective oxidation of primary alcohols over the secondary alcohols. This oxidation process is readily amenable to larger-scale application. The interaction of the different components in the reaction mixtures was studied by UV-visible spectroscopy. The data indicated that Cu(i) existed throughout the reaction. A plausible mechanism of the catalytic cycle is proposed.
- Wang, Lianyue,Bie, Zhixing,Shang, Sensen,Lv, Ying,Li, Guosong,Niu, Jingyang,Gao, Shuang
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p. 35008 - 35013
(2016/05/19)
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- Stereoconvergent negishi arylations of racemic secondary alkyl electrophiles: Differentiating between a CF3 and an alkyl group
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In this report, we establish that a readily available nickel/bis(oxazoline) catalyst accomplishes a wide array of enantioconvergent cross-couplings of arylzinc reagents with CF3-substituted racemic secondary alkyl halides, a process that necessitates that the chiral catalyst be able to effectively distinguish between a CF3 and an alkyl group in order to provide good ee. We further demonstrate that this method can be applied without modification to the catalytic asymmetric synthesis of other families of fluorinated organic compounds.
- Liang, Yufan,Fu, Gregory C.
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supporting information
p. 9523 - 9526
(2015/08/18)
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- Chemoenzymatic synthesis of phosphonic acid analogues of L-lysine, L-proline, L-ornithine, and L-pipecolic acid of 99 % ee - Assignment of absolute configuration to (-)-proline
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(±)-ω-Halo-α-(chloroacetoxy)phosphonates were kinetically resolved by use of a protease (Chirazyme P-2). The esters recovered at levels of conversion between 56 and 72 % furnished (S)-alcohols of 99 % ee. These were converted via azides into the phosphonic acid analogues of L-lysine, L-proline, L-ornithine and L-pipecolic acid. (-)-Phosphaproline was transformed into crystalline ureas derived from (R)- and (S)-1-phenylethyl isocyanate. X-ray structure analyses revealed that the levorotary phosphaproline has the R configuration, contrary to earlier reports. Copyright
- Wuggenig, Frank,Schweifer, Anna,Mereiter, Kurt,Hammerschmidt, Friedrich
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scheme or table
p. 1870 - 1879
(2011/05/05)
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- Total syntheses of (-) epilupinine and (-)-tashiromine using imino-aldol reactions
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Short routes to enantiomerically pure indolizidine and quinolizidine alkaloids have been developed using imino-aldol reactions of enolates derived from phenyl 5-chlorovalerate. High levels of syn selectivity (dr ~13-16:1) were obtained using lithium enolates of phenyl esters in combination with tert-butylsulfinyl imines. The imino-aldol adducts were deprotected and cyclized to afford (-)-epilupinine ((-)-2) and (-)-tashiromine ((-)-1) in two further steps.
- Cutter, Amanda C.,Miller, Iain R.,Keily, John F.,Bellingham, Richard K.,Light, Mark E.,Brown, Richard C. D.
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supporting information; experimental part
p. 3988 - 3991
(2011/09/16)
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- Design and synthesis of resin-conjugated Tamiflu analogs for affinity chromatography
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Two types of resin-conjugated Tamiflu analogs were synthesized by modifying our original synthetic route of oseltamivir phosphate (Tamiflu). The prepared resins bound to influenza virus neuraminidase, the main target of Tamiflu. The resins will be useful for isolating and identifying presumed endogenous vertebrate proteins that interact with Tamiflu, which might relate to the rarely observed abnormal behavior exhibited by some influenza patients treated with Tamiflu.
- Kimura, Yasuaki,Yamatsugu, Kenzo,Kanai, Motomu,Echigo, Noriko,Kuzuhara, Takashi,Shibasaki, Masakatsu
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experimental part
p. 588 - 594
(2010/08/07)
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- NOVEL MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS REPLICATION
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The embodiments provide compounds of the general Formula I, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.
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Page/Page column 271
(2009/01/20)
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- Stereocontrolled synthesis and alkylation of cyclic β-amino esters: Asymmetric synthesis of a (-)-sparteine surrogate
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A convenient method for the stereoselective synthesis of cyclic β-amino esters from an iodo αβ-unsaturated ester and α-methylbenzylamine is described. Subsequent enolate generation and alkylation proceeds with complete stereocontrol, with the two stereogenic centres working together. In this way, a functionalised piperidine suitable for alkaloid natural product synthesis was prepared. The usefulness of the methodology is exemplified with the concise synthesis of a (-)-sparteine surrogate. The Royal Society of Chemistry.
- Hermet, Jean-Paul R.,Viterisi, Aurelien,Wright, Jonathan M.,McGrath, Matthew J.,O'Brien, Peter,Whitwood, Adrian C.,Gilday, John
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p. 3614 - 3622
(2008/09/21)
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- Umpolung of Michael acceptors catalyzed by N-heterocyclic carbenes
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N-Heterocyclic carbenes can catalyze β-alkylations of a range of α,β-unsaturated esters, amides, and nitriles that bear pendant leaving groups to form a variety of ring sizes. In this process, the nucleophilic catalyst transiently transforms the normally electrophilic β carbon into a nucleophilic site through an unanticipated addition-tautomerization sequence. Copyright
- Fischer, Christian,Smith, Sean W.,Powell, David A.,Fu, Gregory C.
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p. 1472 - 1473
(2007/10/03)
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- Quick access to optically pure 2-(1-hydroxybenzyl)piperidine and pyrrolidine
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Optically pure 2-(1-hydroxybenzyl)piperidine and pyrrolidine were prepared by reaction of oxygenated 2-(p-tolylsulfinyl)benzyl carbanions with the appropriate chlorinated N-sulfinylimines followed by subsequent elimination of the sulfinyl groups. The main reaction is a tandem process involving nucleophilic addition of the sulfinylbenzyl carbanion to the C=N bond followed by intramolecular elimination of the chlorine by the resulting amide. The matched pair of the reagents (exhibiting the same configuration at their respective sulfinyl moieties) evolves with a complete control of the stereoselectivity at the two newly created chiral carbons. Georg Thieme Verlag Stuttgart.
- Ruano, Jose Luis Garcia,Aleman, Jose,Cid, M. Belen
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p. 687 - 691
(2007/10/03)
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- PYRAZOLE DERIVATIVES AS CANNABINOID RECEPTOR ANTAGONISTS
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Novel cannabimimetic pyrazole derivatives are presented which have preferentially high affinities for both of the cannabinoid CB1 or CB2 receptor sites. The improved receptor affinity makes these analogs useful as experimental tools for cannabinoid receptor studies as well as clinically useful agents in individuals and animals for treatment of memory deficits associated with aging or neurological diseases, as anti-obesity agents, as medications for schizophrenia and treatment of septic shock syndrome.
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Page/Page column 8
(2010/02/14)
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- The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: The southern hemisphere EF segment
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The fully functionalised C29-C51 southern hemisphere of altohyrtin A/spongistatin 1 (1), incorporating the E- and F-ring tetrahydropyran rings and the unsaturated side chain, has been synthesised in a highly convergent and stereocontrolled manner. Key steps in the synthesis of this phosphonium salt include four highly diastereoselective, substrate-controlled, boron aldol reactions to establish key C-C bonds and accompanying stereocentres, where the introduction of the chlorodiene side chain and the C47 hydroxyl-bearing centre were realised by exploiting remote stereoinduction from the F-ring tetrahydropyran. The Royal Society of Chemistry 2005.
- Paterson, Ian,Coster, Mark J.,Chen, David Y.-K.,Acena, Jose L.,Bach, Jordi,Keown, Linda E.,Trieselmann, Thomas
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p. 2420 - 2430
(2007/10/03)
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- Concise asymmetric synthesis of (-)-sparteine
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A six-step asymmetric synthesis of natural (-)-sparteine from ethyl 7-iodohept-2-enoate is reported, involving a connective Michael addition of an amino ester-derived enolate to an α,β-unsaturated amino ester.
- Hermet, Jean-Paul R.,McGrath, Matthew J.,O'Brien, Peter,Porter, David W.,Gilday, John
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p. 1830 - 1831
(2007/10/03)
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- Biphenyl derivatives
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This invention provides biphenyl derivatives of formula I: wherein R1, R2, R3, R4, R5, R6, R7, W, a, b and c are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The biphenyl derivatives of this invention possess both β2 adrenergic receptor agonist and muscarinic receptor antagonist activity and therefore, such biphenyl derivatives are useful for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.
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Page/Page column 38
(2008/06/13)
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- Asymmetric synthesis of cyclic β-amino acids
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A convenient synthesis of cyclic β-amino acid derivatives (5-, 6- and 7-rings) is achieved via a four step sequence: (i) stereoselective Michael addition of substituted α-methylbenzylamines to α,β-unsaturated chloroesters; (ii) CAN-mediated deprotection; (iii) cyclisation and (iv) α-chloroethyl chloroformate-mediated α-methylbenzylamine deprotection.
- O'Brien,Porter,Smith
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p. 1336 - 1338
(2007/10/03)
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- Dienediolates of unsaturated carboxylic acids in synthesis. Aldehydes and ketones from alkyl halides, by ozonolysis of β,γ-unsaturated α-alkyl carboxylic acids. The role of a tertiary amine in the cleavage of ozonides
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A convenient two-step procedure for a two carbon homologative conversion of alkyl halides into aldehydes and methyl ketones by α-alkylation of unsaturated carboxylic acids, followed by ozonolysis is developed and applied to the synthesis of ω-chloro aldehydes. Triethylamine is superior to dimethyl sulfide or triphenylphosphine for cleavage of the ozonides, except when aldol condensation side reactions require use of protic solvents and iodide salts. Cleavage of the ozonides by triethylamine is shown to occur mainly through a reductive process.
- Aurell, Maria Jose,Ceita, Luisa,Mestres, Ramon,Tortajada, Amparo
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p. 10883 - 10898
(2007/10/03)
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- An efficient Fischer indole synthesis of avitriptan, a potent 5-HT(1D) receptor agonist
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An efficient synthesis of antimigraine drug candidate avitriptan (1, BMS 180048) is reported. The key step is a two-phase Fischer indolization reaction between hydrazine 6 and 5-chlorovaler-aldehyde, 20, to give the chloropropylindole 35, which is susceptible to acid-catalyzed degradation under the reaction conditions required for its formation. Sequential coupling of 35 with piperazine, 26, and 4-chloro-5-methoxypyrimidine, 24, gives the title compound in 40-45% overall yield. Significant improvements in the syntheses of the known starting materials, hydrazine 6, 5- chlorovaleraldehyde, 20, and 4-chloro-5-methoxypyrimidine, 24, were also achieved.
- Brodfuehrer,Chen,Sattelberg T.R.,Smith,Reddy,Stark,Quinlan,Reid
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p. 9192 - 9202
(2007/10/03)
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- Stereoselective Synthesis of Alcohols, XLII. Stereoselective Cyclization of (8-Oxo-2-octenyl)boronates to cis- or trans-Vinylcyclohexanol
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Intramolecular allylboration reactions of (8-oxo-2-octenyl)boronates proceed with excellent diastereoselectivity: the E-isomer 1d leads to the trans-2-vinylcyclohexanol (2) with 99.5percent d.s., the corresponding Z-isomer 3d cyclizes to give the cis-isomer with a diastereoselectivity exceeding 99.8percent.Key Words: Cylization, stereoselective / Allylboration, intramolecular
- Hoffmann, Reinhard W.,Sander, Thomas,Hense, Achim
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p. 771 - 776
(2007/10/02)
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- Pesticidal polyhalo alkenoic acid esters
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The present invention discloses and exemplifies alcohol, ether and ester derivatives of difluoroalkanes and difluoroalkenylalkanes having the general formula R--(CH2)m --CR2 R3 --OR1, in which R is a 1,1-difluoroalkyl or a 1,1-difluoroalkenyl group, composition thereof, and use thereof to control agricultural crop pests.
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