- Flexible synthesis of planar chiral azoninones and optically active indolizidinones
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The flexible synthesis of defined substituted optically active indolizidinones starting from chiral pool (S)-proline and trans 4-hydroxy-(S)-proline is described. Several defined 2-vinylpyrrolidines were generated in short sequences. The aza-Claisen rearr
- Bohland, Frank,Erlin, Irina,Platte, Lukas,Schr?der, Maike,Schollmeyer, Dieter,Nubbemeyer, Udo
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- Expansion of substrate scope for nitroxyl radical/copper-catalyzed aerobic oxidation of primary alcohols: A guideline for catalyst selection
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Four distinctive sets of optimum nitroxyl radical/copper salt/additive catalyst combinations have been identified for accommodating the aerobic oxidation of various types of primary alcohols to their corresponding aldehydes. Interestingly, less nucleophilic catalysts exhibited higher catalytic activities for the oxidation of particular primary allylic and propargylic alcohols to give α,β-unsaturated aldehydes that function as competent Michael acceptors. The optimum conditions identified herein were successful in the oxidation of various types of primary alcohols, including unprotected amino alcohols and divalent-sulfur-containing alcohols in good-to-high yields. Moreover, N-protected alaninol, an inefficient substrate in the nitroxyl radical/ copper-catalyzed aerobic oxidation, was oxidized in good yield. On the basis of the optimization results, a guideline for catalyst selection has been established.
- Iwabuchi, Yoshiharu,Nagasawa, Shota,Sasaki, Ryota,Sasano, Yusuke,Yamaichi, Aoto
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p. 488 - 497
(2021/05/27)
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- Reduction of N,N-Dimethylcarboxamides to Aldehydes by Sodium Hydride–Iodide Composite
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A new and concise protocol for selective reduction of N,N-dimethylamides into aldehydes was established using sodium hydride (NaH) in the presence of sodium iodide (NaI) under mild reaction conditions. The present protocol with the NaH-NaI composite allows for reduction of not only aromatic and heteroaromatic but also aliphatic N,N-dimethylamides with wide substituent compatibility. Retention of α-chirality in the reduction of α-enantioriched amides was accomplished. Use of sodium deuteride (NaD) offers a new step-economical alternative to prepare deuterated aldehydes with high deuterium incorporation rate. The NaH-NaI composite exhibits unique chemoselectivity for reduction of N,N-dimethylamides over ketones.
- Chan, Guo Hao,Ong, Derek Yiren,Yen, Zhihao,Chiba, Shunsuke
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- Synthesis of diastereomeric pyrrolidine sulfamides via anchimerically assisted nucleophilic substitution reactions
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The Mitsunobu reaction was employed in a key step during the development of a convenient synthetic route for the enantioselective preparation of pyrrolidine-sulfamide ligands from (R)- or (S)- [(S)-1-benzylpyrrolidin-2-yl](phenyl)methanol, and employing tert-butyl pyrrolidin-1-yl-sulfonylcarbamate as a non-conventional nucleophilic source. Although it is well documented that the exposure of this type of diastereomeric amino alcohols to the above-mentioned nucleophile usually leads to the formation of piperidines via ring expansion, either through classical nucleophilic substitution or the Mitsunobu version, only the pyrrolidine derivatives were generated with retention of configuration on the exocyclic stereocenter, owing to the neighboring group participation (internal backside nucleophilic substitution, SNib). Final removal of the N-Boc protecting group from the sulfamide fragment afforded chiral compounds with significant potential as chiral ligands in asymmetric catalysis.
- Vargas-Caporali, Jorge,van der Lee, Arie,Dewynter, Georges,Juaristi, Eusebio
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p. 352 - 358
(2018/05/22)
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- METHOD FOR PRODUCING ALDEHYDE
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PROBLEM TO BE SOLVED: To provide a new method for producing aldehyde capable of evading reduction under low temperature conditions and having higher selectivity. SOLUTION: Provided is a method for producing aldehyde where activated ester is prepared from carboxylic acid such as saturated fatty acid, unsaturated fatty acid, hydroxy acid, aromatic carboxylic acid and amino acid and an activation ester agent such as halogenated carbonic acid aryl, a carbodiimide-based condensation agent, an imidazole-based condensation agent and a triazine-based condensation agent, and the activated ester is reduced, and being a method for producing aldehyde in which an environmental load is reduce, and having high yield and high selectivity. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0016; 0017-0018
(2017/05/27)
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- Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil
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A series of twenty seven acetylcholinesterase inhibitors, as potential agents for the treatment of Alzheimer's disease, were designed and synthesised based upon previously unexplored chemical space surrounding the molecular skeleton of the drug donepezil, which is currently used for the management of mild to severe Alzheimer's disease. Two series of analogues were prepared, the first looking at the replacement of the piperidine ring in donepezil with different sized saturated N-containing ring systems and the second looking at the introduction of different linkers between the indanone and piperidine rings in donepezil. The most active analogue 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (67) afforded an in vitro IC50value of 0.03 ± 0.07 μM against acetylcholinesterase with no cytotoxicity observed (IC50of >100 μM, SH-SY5Y cell line). In comparison donepezil had an IC50of 0.05 ± 0.06 μM and an observed cytotoxicity IC50of 15.54 ± 1.12 μM. Molecular modelling showed a strong correlation between activity and in silico binding in the active site of acetylcholinesterase.
- van Greunen, Divan G.,Cordier, Werner,Nell, Margo,van der Westhuyzen, Chris,Steenkamp, Vanessa,Panayides, Jenny-Lee,Riley, Darren L.
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p. 671 - 690
(2017/02/10)
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- USE OF AMINOINDANE COMPOUNDS IN TREATING OVERACTIVE BLADDER AND INTERSTITIAL CYSTITIS
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The present application provides methods of using the aminoindane compounds of formula (I) or (II) in treating an overactive bladder or interstitial cystitis by administering one or more of the compounds to a patient.
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- Highly chemoselective aerobic oxidation of amino alcohols into amino carbonyl compounds
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The direct oxidation of unprotected amino alcohols to their corresponding amino carbonyl compounds has often posed serious challenges in organic synthesis and has constrained chemists to adopting an indirect route, such as a protection/deprotection strategy, to attain their goal. Described herein is a highly chemoselective aerobic oxidation of unprotected amino alcohols to their amino carbonyl compounds in which 2-azaadamantane N-oxyl (AZADO)/copper catalysis is used. The catalytic system developed leads to the alcohol-selective oxidation of various unprotected amino alcohols, carrying a primary, secondary, or tertiary amino group, in good to high yield at ambient temperature with exposure to air, thus offering flexibility in the synthesis of nitrogen-containing compounds. Strong as an ox: The highly chemoselective aerobic oxidation of unprotected amino alcohols to their corresponding amino carbonyl compounds has been achieved by using 2-azaadamantane N-oxyl (AZADO)/copper catalysis. This catalytic system oxidizes not only alcohols with tertiary amino groups but also those with secondary and primary amines in good to high yield at ambient temperature in air. bpy=2,2-bipyridyl, DMAP=4-(N,N-dimethylamino)pyridine.
- Sasano, Yusuke,Nagasawa, Shota,Yamazaki, Mai,Shibuya, Masatoshi,Park, Jaiwook,Iwabuchi, Yoshiharu
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p. 3236 - 3240
(2014/04/03)
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- Asymmetric synthesis of (-)-(1R,7aS)-absouline
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The most efficient and concise asymmetric synthesis of (-)-(1R,7aS)- absouline to date, which was accomplished in eight steps and 20% overall yield from commercially available starting materials, is described. The doubly diastereoselective conjugate addit
- Davies, Stephen G.,Fletcher, Ai M.,Lebée, Clément,Roberts, Paul M.,Thomson, James E.,Yin, Jingda
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p. 1369 - 1377
(2013/02/23)
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- Synthesis of acyclic ketones by catalytic, bidirectional homologation of formaldehyde with nonstabilized diazoalkanes. Application of a chiral diazomethyl(pyrrolidine) in total syntheses of erythroxylon alkaloids
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This work offers a catalytic approach to convergent ketone assembly based upon formal and tandem C-H insertion of diazoalkanes in the presence of limiting amounts of monomeric formaldehyde, which is easily generated as a gas by thermolysis of the inexpensive and abundant paraformaldehyde (~30 USD/kg). The method forms di-, tri-, and even tetrasubstituted acetones with high efficiency, and it has streamlined a synthesis of (-)-dihydrocuscohygrine in which the absolute stereochemistry of a proline-based starting material is preserved. Assisted by the advent of new protocols for hydrazone oxidation, we also provide full details on handling non-carbonyl-stabilized diazo compounds.
- Wommack, Andrew J.,Kingsbury, Jason S.
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p. 10573 - 10587
(2013/11/19)
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- Aminoindane Compounds and Use Thereof in Treating Pain
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The present application provides novel aminoindane compounds and methods for preparing and using these compounds. These compounds are useful in treating pain and/or itch in patients by administering one or more of the compounds to a patient. The methods include administering a compound of formula (I) or (II) and a TRPV 1 receptor activator. In one embodiment, the TRPV 1 receptor activator is lidocaine.
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- Catalysis through temporary intramolecularity: Mechanistic investigations on aldehyde-catalyzed cope-type hydroamination lead to the discovery of a more efficient tethering catalyst
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Mechanistic investigations on the aldehyde-catalyzed intermolecular hydroamination of allylic amines using N-alkylhydroxylamines are presented. Under the reaction conditions, the presence of a specific aldehyde catalyst allows formation of a mixed aminal intermediate, which permits intramolecular Cope-type hydroamination. The reaction was determined to be first-order in both the aldehyde catalyst (α-benzyloxyacetaldehyde) and the allylic amine. However, the reaction displays an inverse order behavior in benzylhydroxylamine, which reveals a significant off-cycle pathway and highlights the importance of an aldehyde catalyst that promotes a reversible aminal formation. Kinetic isotope effect experiments suggest that hydroamination is the rate-limiting step of this catalytic cycle. Overall, these results enabled the elaboration of a more accurate catalytic cycle and led to the development of a more efficient catalytic system for alkene hydroamination. The use of 5-10 mol % of paraformaldehyde proved more effective than the use of 20 mol % of α-benzyloxyacetaldehyde, leading to high yields of intermolecular hydroamination products within 24 h at 30 °C.
- Guimond, Nicolas,MacDonald, Melissa J.,Lemieux, Valerie,Beauchemin, Andre M.
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supporting information
p. 16571 - 16577,7
(2020/09/15)
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- Synthesis of versatile bifunctional derivatives of chiral diamines obtained through anchimerically assisted nucleophilic substitution reactions on diastereomeric phenylprolinols
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Diastereomeric [(S)-1-benzylpyrrolidin-2-yl]-(R)-[(phenyl)- methanamine] and [(S)-1-benzylpyrrolidin-2-yl]-(S)-[(phenyl)methanamine], were synthesized by selective internal backside nucleophilic substitution of the corresponding activated phenylprolinols. X-Ray diffraction structures of crystalline acetamide derivatives confirmed the anticipated stereochemistry for a SNib reaction mechanism. In order to apply this reaction to the synthesis of bifunctional analogs, a series of fragments such as a thiourea moiety and sulfonamide functions were introduced for the functionalization of the primary amino group in the substrate, obtaining more stable and potentially useful derivatives.
- Vargas-Caporali, Jorge,Cruz-Hernandez, Carlos,Juaristi, Eusebio
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p. 1275 - 1300
(2013/08/23)
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- NHC-Catalyzed intramolecular redox amidation for the synthesis of functionalized lactams
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A very efficient NHC-catalyzed lactamization reaction is reported. For most cases, the ring expansion reaction proceeds to cleanly furnish five- and six-membered N-Ts and N-Bn lactams, without the need for further purification. Evidence is presented suggesting a dual role for the stoichiometric base: (1) deprotonation of the triazolium precatalyst and (2) activation of the nitrogen leaving group through hydrogen bonding.
- Thai, Karen,Wang, Li,Dudding, Travis,Bilodeau, Francois,Gravel, Michel
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supporting information; experimental part
p. 5708 - 5711
(2011/03/19)
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- Synthesis and utilization of trifluoromethylated amino alcohol ligands for the enantioselective Reformatsky reaction and addition of diethylzinc to N-(diphenylphosphinoyl)imine
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A series of trifluoromethylated amino alcohol ligands, which had been designed and conveniently prepared, were successfully applied in the enantioselective Reformatsky reaction and addition of diethylzinc to N-(diphenylphosphinoyl)imine, respectively. The influence of the substituents on C-3 position and the amino moiety on the enantioselectivity has been carefully investigated. In the best cases, ligand 1b exhibited good selectivity for the enantioselective Reformatsky reaction in 86% ee and ligand 12d provided excellent enantioselectivity in the addition of diethylzinc to N-(diphenylphosphinoyl)imine with 95% ee.
- Xu, Xiu-Hua,Qiu, Xiao-Long,Qing, Feng-Ling
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p. 7353 - 7361
(2008/12/20)
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- Stereoselective synthesis of β-hydroxy-α-amino acids β-substituted with non-aromatic heterocycles
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We have stereoselectively synthesised β-hydroxy-α-amino acids β-substituted with non-aromatic heterocycles by means of a condensation reaction between enantiomerically pure heterocyclic aldehydes and the (R)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazi
- Cremonesi, Giuseppe,Dalla Croce, Piero,Fontana, Francesco,Forni, Alessandra,La Rosa, Concetta
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p. 1667 - 1675
(2008/02/11)
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- Enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinoyl)imines catalyzed by β-aminoalcohols with the prolinol skeleton
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Several β-aminoalcohols with the prolinol framework are shown to be very efficient catalysts for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinoyl)imines. The use of 0.5 equiv of the catalyst leads to the expected addition products in good yields and with ee up to 94% in a reaction time of only 4 h at room temperature. This ee is the highest value reported so far using 0.5 equiv of an aminoalcohol as a promoter. High enantioselectivities are obtained in the addition of dialkylzincs to both aromatic and aliphatic imines. The amount of the catalyst can be reduced to 0.25 equiv with a slight decrease in the ee. A very interesting effect of the addition rate and temperature on the enantioselectivity was also observed.
- Almansa, Raquel,Guijarro, David,Yus, Miguel
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p. 2828 - 2840
(2008/03/28)
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- Synthesis of the bicyclic core of pumiliotoxins
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The bicyclic core of the pumiliotoxins was synthesized in nine to eleven steps starting from L-(-)-proline. This chiral pool starting material was initially converted into an optically active 2-vinylpyrrolidine by standard operations. The first key step allowed the generation of a nine-membered ring lactam by means of a zwitterionic aza-Claisen rearrangement. The 1,4 chirality transfer was found to be low, but the double bond of the azoninone was generated with an exclusive trans configuration in a planar-S arrangement. The mixture of diastereomers thus obtained was immediately epoxidized; the planar chiral information could be completely used to build up new stereogenic centers. Subsequent ring closure under hydrogenolytic conditions resulted in the formation of the bicyclic core with a bridgehead of defined configuration. The hydroxyl group of that material could be protected as a TBS ether, or alternatively a sequence of a Swern oxidation and subsequent methyl Grignard addition gave the complete bicyclic framework with low C8 diastereoselectivity. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.
- Sudau, Alexander,Muench, Winfried,Bats, Jan-W.,Nubbemeyer, Udo
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p. 3304 - 3314
(2007/10/03)
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- Photochemical reaction between tertiary allylic amines and chromium carbene complexes: Synthesis of lactams via a zwitterion aza cope rearrangement
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Photolysis of chromium carbene complexes in the presence of tertiary allylic amines resulted in a zwitterionic aza Cope rearrangement to produce unsaturated lactams in fair yield.
- Deur, Christopher J.,Miller, Michael W.,Hegedus, Louis S.
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p. 2871 - 2876
(2007/10/03)
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- Diastereoselective Zwitterionic Aza-Claisen Rearrangement: Synthesis of Nine-Membered Ring Lactams and Transannular Ring Contraction
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The zwitterionic aza-Claisen rearrangement of optically active 3-pyrrolidine acryl esters and various acid chlorides to generate optically active azoninones proceeds with high simple diastereoselectivity (internal asymmetric induction) and a complete 1,3-
- Diederich, Michel,Nubbemeyer, Udo
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p. 894 - 900
(2007/10/03)
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