- Visible Light-Mediated Synthesis of Enantiopure γ-Cyclobutane Amino and 3-(Aminomethyl)-5-phenylpentanoic Acids
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A visible light-mediated [2+2] photocycloaddition of amide-linked dienes using [Ir(dtb-bpy)(dF(CF3)ppy)2]PF6 as triplet sensitizer was applied to generate a variety of N-tert-butyl, N-benzyl- and N-tert-butoxycarbonyl-protected 3-azabicyclo[3.2.0]heptan-2-ones in good yields and with good diastereoselectivity. Density functional theory calculations shed light on the conformational prerequisites for the [2+2] photocycloaddition. The bicyclic key structures could be readily transformed into γ-cyclobutane amino acids. For the obtained racemic 3-phenyl-2-aminocyclobutane-1-carboxylic acid the resolution with chiral oxazolidin-2-one is demonstrated to allow access to both enantiomers. Alternatively, a chiral auxiliary approach led as well to the enantiomerically pure target compound. Finally, the synthesis of either enantiomer of 3-(aminomethyl)-5-phenylpentanoic acid, the racemate being described as an anticonvulsant, is described.
- Kerres, Sabine,Plut, Eva,Malcherek, Simon,Rehbein, Julia,Reiser, Oliver
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supporting information
(2019/02/07)
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- Visible Light-Mediated Synthesis of Enantiopure g-Cyclobutane Amino and 3-(Aminomethyl)-5-phenylpentanoic Acids
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A visible light-mediated [2+2] photocycloaddition of amide-linked dienes using [Ir(dtb-bpy)(dF(CF3)ppy)2]PF6 as triplet sensitizer was applied to generate a variety of N-tert-butyl, N-benzyl- and N-tert-butoxycarbonyl-protected 3-aza-bicyclo[3.2.0]heptan-2-ones in good yields and with good diastereoselectivity. Density functional theory calculations shed light on the conformational prerequisites for the [2+2] photocycloaddition. The bicyclic key structures could be readily transformed into g-cyclobutane amino acids. For the obtained racemic 3-phenyl-2-aminocyclobu-tane-1-carboxylic acid the resolution with chiral oxazolidin-2-one is demonstrated to allow access to both enantiomers. Alternatively, a chiral auxiliary approach led as well to the enantiomerically pure target compound. Finally, the synthesis of either enantiomer of 3-(aminomethyl)-5-phenylpentanoic acid, the racemate being described as an anticonvulsant is described.
- Kerres, Sabine,Plut, Eva,Malcherek, Simon,Rehbein, Julia,Reiser, Oliver
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supporting information
p. 1400 - 1407
(2019/10/28)
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- Metal-free, mild, nonepimerizing, chemo- and enantio- or diastereoselective N-alkylation of amines by alcohols via oxidation/imine-iminium formation/reductive amination: A pragmatic synthesis of octahydropyrazinopyridoindoles and higher ring analogues
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A mild step and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure has been developed via oxidation/imine-iminium formation/reduction cascade using TEMPO-BAIB-HEH-Bronsted acid catalysis in DMPU as solvent and a stoichiometric amount of amine. The optimized conditions were further extended for the nonenzymatic kinetic resolution of the chiral amine thus formed under nonenzymatic in situ hydrogen-transfer conditions using VAPOL-derived phosphoric acid (VAPOL-PA) as the Bronsted acid catalyst. The enantioselective cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring analogues.
- Khan, Imran A.,Saxena, Anil K.
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p. 11656 - 11669
(2014/01/06)
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- 1,1′-Binaphthyldiamine-based lewis bases as readily available and efficient grganocatalysts for the reduction of N-Aryl and N-Alkyl ketimines
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The development of simple, low-cost, efficient, and sustainable routes to enantiomerically pure amines is a topic of extraordinary interest, specially in view of future industrial applications. In this context, we wish to report a chemical and stereochemical efficient synthesis of chiral amines through the Lewis base activated trichlorosilane reduction of ketimines. An organocatalyst, easily prepared in a single step through the condensation of picolinic acid and commercially available 1,1′-binaphthyldiamine, is the key element of this metal-free methodology, that allowed the synthesis of chiral secondary and primary amines in high yields and stereose-lectivity. Noteworthy, such catalysts are able to promote the reduction of N-alkyl ketimines, often in quantitative yield and up to 87% enantioselectivity; it: is worth mentioning that for such transformations only one other organocatalytic system has been reported so far.
- Guizzett, Stefania,Benaglia, Maurizio,Celentano, Giuseppe
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experimental part
p. 3683 - 3687
(2009/12/03)
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- Stereoselective 5-exo-trig radical cyclization in the enantioselective synthesis of Pregabalin
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A practical stereoselective 5-exo-trig radical cyclization procedure was developed in order to prepare enantiomerically pure GABA derivative precursors (4-alkyl-pyrrolidin-2-ones). This procedure allows much more rapid access to optically pure GABA derivatives, such as the powerful antiepileptic agent (S)-(+)-3-aminomethyl-5-methylhexanoic acid (Pregabaline).
- Rodríguez, Verónica,Quintero, Leticia,Sartillo-Piscil, Fernando
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p. 4305 - 4308
(2008/02/12)
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- Synthesis of enantiomerically pure (+)- and (-)-protected 5-aminomethyl-1,3-oxazolidin-2-one derivatives from allylamine and carbon dioxide
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The stereoselective synthesis of enantiomerically pure (5R)- and (5S)-aminomethyl-oxazolidinones with different protecting groups have been carried out from an allyl amine as the source of the carbon backbone. The key reaction is the high yield iodiocyclization of enantiomerically pure allylphenethyl amine in the presence of carbon dioxide.
- Fernandez, Isabelle,Munoz, Luis
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p. 2548 - 2557
(2007/10/03)
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- The 5-exo-trig radical cyclization reaction under reductive and oxidative conditions in the synthesis of optically pure GABA derivatives
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Free radical precursors 4a and 4b were synthesized and treated under reductive or oxidative conditions to obtain the corresponding optically pure pyrrolidinones 5-8, which were subsequently transformed into corresponding optically pure GABA derivatives 9-11. When reductive radical conditions (4a→7 and 8) were used, a Ph1-5 migration product 14 was obtained; presumably depending upon the specific conformation of the rotamer precursor and also 14 was found to be a kinetic product.
- Rodríguez, Verónica,Sánchez, Mario,Quintero, Leticia,Sartillo-Piscil, Fernando
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p. 10809 - 10815
(2007/10/03)
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- Pilot Plant Preparation of an αvβ3 Integrin Antagonist. Part 1. Process Research and Development of a (S)-β-Amino Acid Ester Intermediate: Synthesis via a Scalable, Diastereoselective Imino-Reformatsky Reaction
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Described are four process research investigations directed toward discerning a scalable, enantioselective method for preparing (S)-β-amino acid ester 3, a key intermediate to the αvβ3 integrin antagonist 1. Reported are an asymmetric Michael reaction approach, attempts to enantioselectively hydrogenate an enamine, resolution of (±)-3 via diastereomeric salt formation, and a synthetic route employing a novel, diastereoselective imino-Reformatsky reaction. This last research initiative proved successful and was employed as the enabling route to initial API supply. Process development of this enabling chemistry is reported. The technical issues researched and optimized were (1) the necessity of employing MEM-protection for high yield and diastereoselectivity in the imino-Reformatsky reaction, (2) the reaction kinetics of MEM chloride hydrolysis and the application of these data to an on-scale quench procedure, (3) the efficient formation of the (S)-phenylglycinol imine 15 in NMP and a dehydration of this product solution on-scale, employing molecular sieves, (4) a calorimetric study of the Reformatsky reaction and the application of these data, (5) the replacement of Pb(OAc)4 with NaIO4 and the use of methylamine to sequester competing oxazolidine formation, and (6) further development of the isolation and purification protocol for the ethyl ester, p-TsOH salt of (S)-3. The results and challenges associated with two campaigns in which the potential commercial process was practiced are discussed.
- Clark, Jerry D.,Weisenburger, Gerald A.,Keith Anderson,Colson, Pierre-Jean,Edney, Albert D.,Gallagher, Donald J.,Peter Kleine,Knable, Carl M.,Lantz, Melissa K.,Moore, Christine M. V.,Murphy, James B.,Rogers, Thomas E.,Ruminski, Peter G.,Shah, Ajit S.,Storer, Neil,Wise, Bruce E.
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supporting information
p. 51 - 61
(2013/09/04)
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- A three-step synthesis of optically active 5-halomethyl-2-oxazolidinones; asymmetric desymmetrization of prochiral 1,3-dihalo-2-propyl carbamates
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Optically active 5-bromomethyl-2-oxazolidinones (2a and 3a) and 5-chloromethyl-2-oxazolidinones (2b and 3b) were readily prepared from prochiral 1,3-dibromo-2-propanol (7a) and 1,3-dichloro-2-propanol (7b) by a three-step sequence involving formation of carbamates (6a-c) followed by asymmetric desymmetrization (up to 50% de) and debenzylation by anisole-methanesulfonic acid system.
- Sugiyama, Shigeo,Morishita, Kenji,Ishii, Keitaro
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p. 353 - 364
(2007/10/03)
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- Diastereocontrolled synthesis of pyrrolidines by nickel promoted tandem cyclization-quenching of aminobromodienes
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The nickel promoted tandem cyclization-quenching of tethered aminobromodienes has been extended to the synthesis of 2,3,4-trisubstituted pyrrolidines. By a judicious choice of substituents on the starting aminohalodiene, the diastereoselectivity of the process can be efficiently controlled. When a chiral auxiliary on the nitrogen atom is used, enantiomerically enriched pyrrolidines can be obtained after removal of the auxiliary.
- Cancho, Yolanda,Martin, Joan M.,Martinez, Maria,Llebaria, Amadeu,Moreto, Josep M.,Delgado, Antonio
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p. 1221 - 1232
(2007/10/03)
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- Amination of(η3-allyl)dicarbonylnitrosyliron complexes: A route to γ- amino-α,β-unsaturated carboxylic acid derivatives
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Amines reacted regioselectively with (ν3-allyl)dicarbonylnitrosyliron complexes having ester group on the allyl ligand to give γ-amino-α,β- unsaturated esters in high yields. A remarkable effect of the substituents attached to the allyl ligand was observed on the reaction rate and regioselectivity of the amination. The methoxycarbonyl group significantly accelerates the reaction rate and enhances the regioselectivity of the reaction. The phenyl group retards the reaction, but enhances the regioselectivity, while alkyl groups retard the reaction and diminish the regioselectivity.
- Nakanishi, Saburo,Okamoto, Kenji,Yamaguchi, Hiroshi,Takata, Toshikazu
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p. 1735 - 1741
(2007/10/03)
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- Cyclisation of (R)- and (S)-N-allyl-N-(1-phenylethyl)methoxycarbonylacetamide mediated by Mn(III): Preparation and structural assignment of 3-aza-2-oxobicyclo[3.1.0]hexanes
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(R)- and (S)-N-allyl-N-(1-phenylethyl)methoxycarbonylacetamide, 5 and 6, underwent oxidative cyclisation mediated by Mn(III), to give easily separable diastereomeric mixtures of 3-aza-2-oxobicyclo[3.1.0]hexanes 8a,b and 9a,b, respectively, whose structure
- Galeazzi, Roberta,Geremia, Silvano,Mobbili, Giovanna,Orena, Mario
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p. 3573 - 3584
(2007/10/03)
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- Selective deprotection of allyl amines using palladium
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Mono and diallylamines can be cleaved using Pdf(0) catalyst and 2-mercaptobenzoic acid as nucleophile. This methodology has been successfully used for the sequential deprotection of diallylamines. The yields of desallylation are good to quantitative.
- Lemaire-Audoire,Lemaire-Audoire, Sandrine,Savignac,Savignac, Monique,Genet,Genet, Jean Pierre,Bernard,Bernard, Jean-Marie
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p. 1267 - 1270
(2007/10/02)
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- ?-Allyl palladium methodology for selective deprotection of allylamines. Practical synthesis of secondary amines
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The palladium-promoted deallylation of allylamines derived from primary and secondary amines is achieved with high to quantitative yield in the presence of 2-mercaptobenzoic acid as an allyl scavenger.This method was used for the sequential cleavage of diallylamines.A synthetic application of this procedure is presented in the preparation of secondary amines from diallylamines. - Keywords: allylamine; deallylation; sequential deprotection; ?-allyl palladium complexes; 2-mercaptobenzoic acid; substitution of amines
- Lemarie-Audoire, Sandrine,Savignac, Monique,Dupuis, Christophe,Genet, Jean Pierre
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p. 1157 - 1166
(2007/10/03)
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- Lithium (α-Methylbenzyl)allylamide: A Differentially Protected Chiral Ammonia Equivalent for the Asymmetric Synthesis of β-Amino Acids and β-Lactams
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The addition products from the highly stereoselective conjugate additions of lithium (αS)-(α-methylbenzyl)allylamide to α,β-unsaturated tert-butyl esters are efficiently deallylated with tris(triphenylphosphine)rhodium(I) chloride and converted, after tra
- Davies, Stephen G.,Fenwick, David R.
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p. 1109 - 1110
(2007/10/02)
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- Diastereoselective Preparation of Chiral Lithiated Allyl Amines: Application in EPC-Synthesis
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Lithiation of chiral allylamine (R)-1 with BunLi and ButLi leads to the formation of intermediate (R)-2, which by reaction with D2O, Me2CO or (CH2)5CO affords the expected chiral compounds (R)-3, (R)-4 and (R)-5, respectively.With Bu
- Yus, Miguel,Foubelo, Francisco,Falvello, Larry R.
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p. 2081 - 2092
(2007/10/03)
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- Photochemical rearrangement of 2-(N-allyl-N-alkylamino)cyclohex-2-enones
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Irradiation at 366 nm of 2-(N-allyl-N-alkylamino)cyclohex-2-enones led, surprisingly, to very unstable 1-azaspirooctan-4-ones rather than to the expected intramolecular photocycloaddition.The corresponding alcohols could be isolated in good y
- Meyer, Catherine,Pete, Jean-Pierre,Piva, Olivier
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p. 492 - 497
(2007/10/03)
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- SYNTHESIS AND STRUCTURAL ASSIGNMENT OF DIASTEREOMERICALLY PURE N-SUBSTITUTED 4-ALKYLPYRROLIDIN-2-ONES, INTERMEDIATES FOR THE PREPARATION OF 3-ALKYLPYRROLIDINES IN BOTH ENANTIOMERICALLY PURE FORMS
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By radical cyclization of N--N-allyliodoacetamides (6a-d), 4-substituted pyrrolidin-2-ones (7a-d) and (8a-d) were prepared as diastereomeric equimolar mixtures which were seperated by column chromatography.The preferred conformation of
- Cardillo, Barbara,Galeazzi, Roberta,Mobbili, Giovanna,Orena, Mario,Rossetti, Monica
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p. 2663 - 2676
(2007/10/02)
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- Diastereoselection in the intramolecular diels-Alder reaction of o-quinodimethanes
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An efficient diastereoselective synthesis of 2 is presented. A key feature is the intramolecular Diels-Alder reaction of o-quinodimethanes intermediates 3 derived from benzocyclobutenes 4 in which the exotransition state is favored by incorporation of an amide functionality.
- Basha,McClellan,DeBernardis
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p. 5469 - 5472
(2007/10/02)
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- A new approach to the synthesis of enantiomerically pure 2,3-diaminoacids through chiral imidazolidin-2-ones
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The synthesis of enantiomerically pure 5-iodomethylimidazolidin-2-ones (3a-c) and (4a-c) is reported, by means of iodocyclisation of allylic tosylureas (2a-c). Starting from pure (3a) and (4a), a synthesis of both (R)- and (S)-2,3-diaminopropanoic acid is
- Cardillo, Giuliana,Orena, Mario,Penna, Maurizio,Sandri, Sergio,Tomasini, Claudia
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p. 2263 - 2272
(2007/10/02)
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