- Desymmetrization of Prochiral Cyclobutanones via Nitrogen Insertion: A Concise Route to Chiral γ-Lactams
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Asymmetric access to γ-lactams is achieved via a cyclobutanone ring expansion using widely available (1S,2R)-1-amino-2-indanol for chiral induction. Mechanistic analysis of the key N,O-ketal rearrangement reveals a Curtin–Hammett scenario, which enables a downstream stereoinduction (up to 88:12 dr) and is corroborated by spectroscopic, crystallographic, and computational studies. In combination with an easy deprotection protocol, this operationally simple sequence allows the synthesis of a range of optically pure γ-lactams, including those bearing all-carbon quaternary stereocenters. In addition, the formal synthesis of drug molecules baclofen, brivaracetam, and pregabalin further demonstrates the synthetic utility and highlights the general applicability of the presented method.
- Sietmann, Jan,Ong, Mike,Mück-Lichtenfeld, Christian,Daniliuc, Constantin G.,Wiest, Johannes M.
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p. 9719 - 9723
(2021/03/16)
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- Enantioselective Copper-Catalyzed Radical Ring-Opening Cyanation of Cyclopropanols and Cyclopropanone Acetals
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A novel approach for enantioselective cyanation of cyclopropanols and their derivatives through copper-catalyzed radical relay processes has been developed. Various cyclopropanols and cyclopropanone acetals are compatible to the catalytic conditions, providing β-carbonyl nitriles with excellent enantioselectivity. These products can be readily converted to chiral γ-amino acids derivatives and drugs such as (R)-baclofen. Preliminary mechanistic studies have supported a ring-opening process for cyclopropanoxy radicals followed by copper-catalyzed enantioselective cyanation of benzylic radicals to form the C?CN bonds in an enantioselective manner. (Figure presented.).
- Chen, Pinghong,Guo, Yin-Long,Liu, Guosheng,Wang, Lei,Wu, Lianqian
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p. 2189 - 2194
(2020/04/17)
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- Efficient synthesis of β-aryl-γ-lactams and their resolution with (S)-Naproxen: Preparation of (R)- and (S)-Baclofen
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An efficient synthesis of enantiomerically-pure β-aryl-γ-lactams is described. The principal feature of this synthesis is the practical resolution of β-aryl-γ-lactams with (S)-Naproxen. The procedure is based on the Michael addition of nitromethane to benzylidenemalonates, which was easily obtained, followed by the reduction of the γ-nitroester in the presence of Raney nickel and the subsequent saponification/decarboxylation reaction. The utility of this methodology was highlighted by the preparation of enantiomerically-pure (R)- and (S)-Baclofen hydrochloride.
- Montoya-Balbás, Iris J.,Valentín-Guevara, Berenice,López-Mendoza, Estefanía,Linzaga-Elizalde, Irma,Ordo?ez, Mario,Román-Bravo, Perla
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p. 22028 - 22043
(2016/01/25)
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- Multisite organic-inorganic hybrid catalysts for the direct sustainable synthesis of GABAergic drugs
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Multisite organic-inorganic hybrid catalysts have been prepared and applied in a new general, practical, and sustainable synthetic procedure toward industrially relevant GABA derivatives. The domino sequence is composed of seven chemical transformations which are performed in two one-pot reactions. The method produces both enantiomeric forms of the product in high enantiopurity as well as the racemate in good yields after a single column purification step. This protocol highlights major process intensification, catalyst recyclability, and low waste generation.
- Leyva-Perez, Antonio,Garcia-Garcia, Pilar,Corma, Avelino
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supporting information
p. 8687 - 8690
(2014/08/18)
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- Asymmetric synthesis of γ-nitroesters by an organocatalytic one-pot strategy
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An enantioselective synthesis of γ-nitroesters by a one-pot asymmetric Michael addition/oxidative esterification of α,β- unsaturated aldehydes is presented. The procedure is based on merging the enantioselective organocatalytic nitroalkane addition with an N-bromosuccinimide-based oxidation. The γ-nitroesters are obtained in good yields and enantioselectivities, and the method provides an attractive entry to optically active γ-aminoesters, 2-piperidones, and 2-pyrrolidones.
- Jensen, Kim L.,Poulsen, Pernille H.,Donslund, Bjarke S.,Morana, Fabio,Jorgensen, Karl Anker
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p. 1516 - 1519
(2012/06/05)
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- Organocatalytic Enantioselective Michael-Addition of Malonic Acid Half-Thioesters to β-Nitroolefins: From Mimicry of Polyketide Synthases to Scalable Synthesis of γ-Amino Acids
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Highly enantioselective biomimetic Michael addition reactions of malonic acid half thioesters (MAHTs) to a variety of nitroolefins, affording the optically active γ-amino acid precursors, were developed by employing the Cinchona-based squaramides (up to >
- Bae, Han Yong,Some, Surajit,Lee, Jae Heon,Kim, Ju-Young,Song, Myoung Jong,Lee, Sungyul,Zhang, Yong Jian,Song, Choong Eui
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supporting information; experimental part
p. 3196 - 3202
(2012/02/01)
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- A short, chemoenzymatic route to chiral β-aryl-γ-amino acids using reductases from anaerobic bacteria
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A short chemoenzymatic synthesis of β-aryl-γ-aminobutyric acids has been developed, based on a highly enantioselective biocatalytic reduction of β-aryl-β-cyano-α,β-unsaturated carboxylic acids.
- Fryszkowska, Anna,Fisher, Karl,Gardiner, John M.,Stephens, Gill M.
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supporting information; scheme or table
p. 533 - 535
(2010/05/11)
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- Asymmetrie synthesis of (R)-(-)-baclofen via asymmetric dihydroxylation
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A short and efficient asymmetric synthesis of (R)-(-)-baclofen, a selective GABAB agonist has been described with an overall yield of 14% and 85% ee. The Os-catalyzed Sharpless asymmetric dihydroxylation of a,β-unsaturated olefin constitutes the key step in introducing stereogenic centers into the molecule.
- Thakur,Paraskar,Sudalai
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p. 326 - 330
(2008/02/09)
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- Co-catalyzed reductive cyclization of azido and cyano substituted α,β-unsaturated esters with NaBH4: enantioselective synthesis of (R)-baclofen and (R)-rolipram
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Sodium borohydride in combination with a catalytic amount of CoCl2 has been found to be an excellent catalytic system in reductive cyclizations of suitably substituted azido and cyano groups of α,β-unsaturated esters to afford γ and δ-lactams in high yields. The process has been demonstrated for the enantioselective synthesis of (R)-baclofen, (R)-rolipram, and (R)-4-fluorophenylpiperidinone, a key intermediate for (-)-paroxetine.
- Paraskar, Abhimanyu S.,Sudalai, Arumugam
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p. 4907 - 4916
(2007/10/03)
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- Diastereoselective conjugate addition of cyanide to α,β- unsaturated oxazolidinones: Enantioselective synthesis of ent-pregabalin and baclofen
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Conjugate addition of cyanide to chiral α,β-unsaturated oxazolidinones catalyzed by samarium(III) isopropoxide proceeds with good diastereoselectivity. The addition products can be converted into the biologically active targets ent-pregabalin and baclofen
- Armstrong, Alan,Convine, Nicola J.,Popkin, Matthew E.
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p. 1589 - 1591
(2007/10/03)
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- A short and convenient chemoenzymatic synthesis of both enantiomers of 3-phenylGABA and 3-(4-chlorophenyl)GABA(Baclofen)
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Both enantiomers of the pharmacologically active GABA analogues 4-amino-3-phenyl and 4-amino-3-(4-chlorophenyl)butyric acid (Baclofen) with high enantiomeric excesses were synthesized by a chemoenzymatic method involving α-chymotrypsin mediated kinetic resolutions of the corresponding 3-phenyl- and 3-(4-chlorophenyl)-4-nitrobutyric acid methyl ester precursors.
- Felluga, Fulvia,Gombac, Valentina,Pitacco, Giuliana,Valentin, Ennio
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p. 1341 - 1345
(2007/10/03)
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- Asymmetric synthesis of β-substituted γ-lactams employing the samp-/ramp-hydrazone methodology. Application to the synthesis of (R-(-)-baclofen
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A short and efficient asymmetric synthesis of β-substituted γ-lactams is described. Key steps are the α-alkylation of aldehyde SAMP-hydrazones with alkyl bromoacetates, their MMPP mediated conversion to the corresponding nitriles and a reductive cyclization with Raney Ni or Ni boride to the title pyrrolidin-2-ones. The β-substituted γ-lactams are obtained in three steps, good overall yields (27-78%) and excellent enantiomeric excesses (ee=93-99%). The applicability of this procedure for the asymmetric synthesis of GABAs (γ-aminobutyric acids) is demonstrated for (R-(-)-baclofen hydrochloride, which is obtained in 4 steps 55% yield and 94% ee.
- Enders, Dieter,Niemier, Oliver
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p. 385 - 403
(2007/10/03)
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- Enantioselective synthesis of (R)-(-)-baclofen via Ru(II)-BINAP catalyzed asymmetric hydrogenation
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A short and efficient enantioselective synthesis of (R)-(-)-baclofen, a selective GABAB agonist has been described with an overall yield of 26% and 90% ee. Ru(II)-(S)-BINAP catalyzed asymmetric hydrogenations of C=C and C=O groups constitute the key steps in introducing stereogenic centers into the molecule.
- Thakur, Vinay V.,Nikalje, Milind D.,Sudalai
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p. 581 - 586
(2007/10/03)
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- Diastereoselective Michael reactions of (1R)-(+)-camphor methyl ketone enolates with nitro olefins
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The reaction of the sodium enolate of the methyl ketone 2 with a range of nitro olefins proceeds readily to give the corresponding Michael adducts in good yields and diastereoselectivities. Subsequent oxidative cleavage of the acyloin moiety provides γ-nitroalkanoic acids along with (1R)-(+)-camphor, the chiral auxiliary of the process, which can be recovered and reused.
- Palomo, Claudio,Aizpurua, Jesús M,Oiarbide,García, Jesús M,González, Alberto,Odriozola,Linden, Anthony
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p. 4829 - 4831
(2007/10/03)
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- Enantioselective Michael addition of nitromethane to α,β-enones catalyzed by chiral quaternary ammonium salts. A simple synthesis of (R)-baclofen
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(equation presented) R/S = 85/15, 97.5/2 after recryst. Enantioselective Michael addition of nitromethane to an α,β-enone is a key step in the synthesis of (R)-baclofen.
- Corey,Zhang, Fu-Yao
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p. 4257 - 4258
(2007/10/03)
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