Catalytic Asymmetric Mannich-type Reaction Research Articles

Diastereoselective Direct Catalytic Asymmetric Mannich-Type Reactions of Alkylnitriles with a Ni(II)-Carbene Complex.

Despite recent advances in reactions using alkylnitriles as carbon nucleophiles, diastereoselective direct catalytic asymmetric reactions, in which two consecutive chiral centers could be controlled, remain largely unexplored. Herein, we report the addition of alkylnitriles (such as propionitrile) to imines in the presence of a catalytic amount of a chiral pincer-type Ni-carbene complex and potassium 2,6-di-tert-butyl-4-methylphenoxide (KBHT). BHT and molecular sieves were used as additives to improve the yields, diastereoselectivity, and enantiomeric ratio up to >99%, 90:10 anti/syn, and 97.5:2.5 er, respectively. The Mannich adducts can be readily converted to the corresponding β-amino acids.

Asymmetric Synthesis of Oxindole-Derived Vicinal Tetrasubstituted Acyclic Amino Acid Derivatives by the Mannich-Type Reaction.

The catalytic asymmetric Mannich-type reaction of 3-hydroxy/3-aminooxindoles with 2-aminoacrylates to afford oxindole-derived acyclic amino acid derivatives bearing vicinal tetrasubstituted stereocenters is reported. (DHQ)2PHAL (4g) and quinine-derived squaramide (4d) were identified as efficient catalysts. Transformations of the Mannich-type reaction products highlight the utility of this synthetic strategy.

Direct Catalytic Asymmetric Mannich-Type Reaction of an α-CF3 Amide to Isatin Imines

An α-CF3 amide underwent direct asymmetric Mannich-type reaction to isatin imines in the presence of a chiral catalyst comprising a soft Lewis acid Cu(I), a chiral bisphosphine ligand, and Barton’s base. The Mannich adduct was converted in one step into a unique tricycle bearing a trifluoromethylated chiral center and an α-tertiary amine moiety.

Catalytic Asymmetric Mannich Type Reaction with Tri-/Difluoro- or Trichloroacetaldimine Precursors.

A highly efficient catalytic asymmetric Mannich type reaction of CF3-, CF2H-, or CCl3-acetaldimine precursors by a chiral primary amine is presented. This protocol provides facile access to chiral CF3-, CF2H-, or trichloroethyl amines in excellent yields and high enantioselectivity (up to 99% yield, up to >99% ee).

α-Halo Amides as Competent Latent Enolates: Direct Catalytic Asymmetric Mannich-Type Reaction.

α-Halogenated carbonyl compounds are susceptible to dehalogenation and thus largely neglected as enolate precursors in catalytic enantioselective C-C bond-forming reactions. By merging the increased stability of the α-C-halogen bond of amides and the direct enolization methodology of the designed amide, we explored a direct catalytic asymmetric Mannich-type reaction of α-halo 7-azaindoline amides with N-carbamoyl imines. All α-halo substituents, α-F, -Cl, -Br, -I amides, were tolerated to provide the Mannich-adducts in a highly stereoselective manner without undesirable dehalogenation. The diastereoselectivity switched intriguingly depending on the substitution pattern of the aromatic imines, which is ascribed to stereochemical differentiation based on the open transition-state model. Functional group interconversion of the 7-azaindoline amide moiety of the Mannich-adducts and further elaboration into a diamide without dehalogenation highlight the synthetic utility of the present protocol for accessing enantioenriched halogenated chemical entities.

Catalytic asymmetric synthesis of 2,3,3,3-tetrafluoro-2-methyl-1-arylpropan-1-amines as useful building blocks for SAR-studies

The first protocol for the asymmetric synthesis of 2,3,3,3-tetrafluoro-2-methyl-1-arylpropan-1-amines which function as fluorinated surrogates for α-isopropylbenzylamines in SAR-studies is presented herein. Crucial for the successful synthesis was the application of a recently developed direct catalytic asymmetric Mannich-type reaction of fluorinated amide for the key bond-forming step. The utility of this versatile protocol was demonstrated by the synthesis of fluorinated analogues of a T-type selective Ca2+ channel blocker and a prolylcarboxypeptidase inhibitor. The predominant conformation of their fluorinated analogues was investigated by X-ray crystallography and NMR spectroscopy which revealed a strong influence of a fluorine mediated gauche effect.

ChemInform Abstract: Direct Catalytic Asymmetric Mannich‐Type Reaction of α‐N3 Amide.

ChemInformVolume 47, Issue 17 Natural Products ChemInform Abstract: Direct Catalytic Asymmetric Mannich-Type Reaction of α-N3 Amide. Zhongdong Sun, Zhongdong Sun Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorKarin Weidner, Karin Weidner Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorNaoya Kumagai, Naoya Kumagai Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorMasakatsu Shibasaki, Masakatsu Shibasaki Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this author Zhongdong Sun, Zhongdong Sun Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorKarin Weidner, Karin Weidner Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorNaoya Kumagai, Naoya Kumagai Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorMasakatsu Shibasaki, Masakatsu Shibasaki Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this author First published: 08 April 2016 https://doi.org/10.1002/chin.201617205Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume47, Issue17April, 2016 RelatedInformation

Direct Catalytic Asymmetric Mannich-Type Reaction of α- and β-Fluorinated Amides.

The last two decades have witnessed the emergence of direct enolization protocols providing atom-economical and operationally simple methods to use enolates for stereoselective C-C bond-forming reactions, eliminating the inherent drawback of the preformation of enolates using stoichiometric amounts of reagents. In its infancy, direct enolization relied heavily on the intrinsic acidity of the latent enolates, and the reaction scope was limited to readily enolizable ketones and aldehydes. Recent advances in this field enabled the exploitation of carboxylic acid derivatives for direct enolization, offering expeditious access to synthetically versatile chiral building blocks. Despite the growing demand for enantioenriched fluorine-containing small molecules, α- and β-fluorinated carbonyl compounds have been neglected in direct enolization chemistry because of the competing and dominating defluorination pathway. Herein we present a comprehensive study on direct and highly stereoselective Mannich-type reactions of α- and β-fluorine-functionalized 7-azaindoline amides that rely on a soft Lewis acid/hard Brønsted base cooperative catalytic system to guarantee an efficient enolization while suppressing undesired defluorination. This protocol contributes to provide a series of fluorinated analogs of enantioenriched β-amino acids for medicinal chemistry.

Direct Catalytic Asymmetric Mannich-Type Reaction of α-N3 Amide.

An α-N3 7-azaindoline amide serves as a latent enolate to directly engage in an asymmetric Mannich-type reaction with N-thiophosphinoyl imines by the action of a cooperative catalyst. The thus-obtained highly enantioenriched anti-adduct was transformed into β-amino-α-azido acid in high yield by simple acidic treatment.

ChemInform Abstract: Catalytic Asymmetric Mannich‐Type Reaction of N‐Alkylidene‐α‐aminoacetonitrile with Ketimines.

ChemInformVolume 46, Issue 34 Preparative Organic Chemistry ChemInform Abstract: Catalytic Asymmetric Mannich-Type Reaction of N-Alkylidene-α-aminoacetonitrile with Ketimines. Shaoquan Lin, Shaoquan Lin Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorYuji Kawato, Yuji Kawato Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorNaoya Kumagai, Naoya Kumagai Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorMasakatsu Shibasaki, Masakatsu Shibasaki Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this author Shaoquan Lin, Shaoquan Lin Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorYuji Kawato, Yuji Kawato Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorNaoya Kumagai, Naoya Kumagai Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorMasakatsu Shibasaki, Masakatsu Shibasaki Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this author First published: 06 August 2015 https://doi.org/10.1002/chin.201534060Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume46, Issue34August, 2015 RelatedInformation

A Carbon Nanotube Confinement Strategy to Implement Homogeneous Asymmetric Catalysis in the Solid Phase

A readily recyclable asymmetric catalyst has been developed based on the self-assembly of a homogeneous catalyst in a fibrous network of multiwalled carbon nanotubes (MWNTs). Dimerization of an amide-based chiral ligand with a suitable spacer allows for the efficient formation of a heterogeneous catalyst by self-assembly on addition of Er(OiPr)3. The self-assembly proceeds in the MWNT fibrous network and small clusters of assembled catalyst are confined in the MWNTs, producing an easily handled solid-phase catalyst. The resulting MWNT-confined catalyst exhibits a good catalytic performance in a catalytic asymmetric Mannich-type reaction, which can be conducted in a repeated batch system and in a continuous-flow platform.

Catalytic generation of α-CF3 enolate: direct catalytic asymmetric Mannich-type reaction of α-CF3 amide.

The introduction of the CF3 unit is a common strategy for modifying pharmacokinetic properties and slowing metabolic degradation in medicinal chemistry. A catalytic and enantioselective addition of α-CF3 enolates allows for expeditious access to functionalized chiral building blocks with CF3-containing stereogenicity. To date, α-CF3 enolates have been a less explored class of nucleophiles because of rapid defluorination. The present study reveals that a designed α-CF3 amide enables a direct asymmetric Mannich-type reaction in a cooperative catalytic system.

Catalytic Enantioselective Mannich-Type Reaction via a Chiral Silver Enolate

A catalytic asymmetric Mannich-type reaction of alkenyl trichloroacetates with aldimines was achieved using SEGPHOS·AgOTf as the chiral precatalyst and N,N-diisopropylethylamine as the base precatalyst in the presence of 2,2,2-trifluoroethanol. Optically active β-amino ketones with up to >99% ee were syn-selectively obtained in moderate to high yields via the in situ generated chiral silver enolates.

Direct Catalytic Asymmetric Mannich-Type Reaction of α-Sulfanyl Lactones

Catalytic asymmetric Mannich-type reactions of α-sulfanyl lactones to aldimines were promoted by a chiral Ag complex/DBU binary catalyst. The reaction proceeded in a syn-selective manner in high enantioselectivity. Alkylative activation of the sulfide of the Mannich adduct allowed for the formation of trisubstituted aziridines.

Chiral Calcium Iodide for Asymmetric Mannich‐type Reactions of Malonates with Imines Providing β‐Aminocarbonyl Compounds

Out of the pybox: We have developed a novel chiral calcium iodide catalyst from CaI2 and a pybox that is stable under moisture and oxygen. This catalyst was applied to catalytic asymmetric Mannich-type reactions of malonates with both N-Boc-protected aromatic and aliphatic imines, and resulted in moderate to high yields with high enantioselectivities. To the best of our knowledge, this is the first example of highly enantioselective metal-catalyzed asymmetric Mannich-type reactions of malonates with N-Boc-protected aliphatic imines. The Mannich adduct was successfully converted into the α-hydroxy β-amino acid derivative. We have also shown the unique structure of the chiral Ca complexes with malonates.

Catalytic asymmetric Mannich-type reactions of α-cyano α-sulfonyl carbanions

An efficient asymmetric Mannich-type reaction of α-cyano α-sulfonyl carbanions has been achieved by exploiting the structural modularity and anion-recognition ability of chiral 1,2,3-triazolium ions. This protocol has proven to be applicable to a variety of N-Boc imines and cyanosulfones, affording β-amino α-cyanosulfones in excellent yields with high stereoselectivities.

Stereodivergent Direct Catalytic Asymmetric Mannich‐Type Reactions of α‐Isothiocyanato Ester with Ketimines

Stereodivergent Direct Catalytic Asymmetric Mannich‐Type Reactions of α‐Isothiocyanato Ester with Ketimines

Catalytic asymmetric Mannich-type reactions of fluorinated ketoesters with N-Boc aldimines in the presence of chiral palladium complexes

The catalytic enantioselective Mannich reaction promoted by chiral palladium complexes is described. The treatment of α-fluoro-β-ketoesters with N-Boc-aldimines under mild reaction conditions afforded the corresponding β-aminated α-fluoro-β-ketoesters with excellent enantioselectivities (up to 99% ee).

Direct anti‐Selective Catalytic Asymmetric Mannich‐Type Reactions of α‐Ketoanilides for the Synthesis of γ‐Amino Amides and Azetidine‐2‐amides

AbstractMannich 'mal anders: Der Dinickelkomplex einer Biphenyldiamin‐Schiff‐Base katalysiert die anti‐selektive Mannich‐Reaktion von α‐Ketoaniliden (siehe Schema), die als nützliche Synthesebausteine für Azetidin‐2‐amide und α‐Hydroxy‐γ‐aminoamide fungieren. Dieser Ansatz ergänzt konventionelle Mannich‐Reaktionen, die β‐Aminocarbonylverbindungen ergeben. o‐Ns=o‐Nitrobenzolsulfonyl.magnified image

PdII‐Catalyzed Asymmetric Addition Reactions of 1,3‐Dicarbonyl Compounds: Mannich‐Type Reactions with N‐Boc Imines and Three‐Component Aminomethylation

This paper describes catalytic asymmetric Mannich-type reactions of beta-ketoesters and malonates using chiral palladium complexes. Although readily enolizable, carbonyl compounds are attractive substrates, the use of such compounds as nucleophiles in Mannich-type reactions has not been extensively investigated. In the presence of chiral Pd aqua complexes (2.5 mol %), beta-ketoesters reacted with various N-Boc imines (Boc=tert-butoxycarbonyl) to afford the desired beta-aminocarbonyl compounds in good yield with high to excellent stereoselectivity (up to 96:4 d.r., 95-99 % ee in most cases). In these reactions, construction of highly crowded vicinal quaternary and tertiary carbon centers was achieved in one step. A chiral Pd enolate is considered to be the key intermediate. To elucidate the stereoselectivity observed in the reaction, possible transition-state models are discussed, taking into account steric and stereoelectronic effects. Furthermore, this catalytic system was applied to the Mannich-type reaction of malonates with N-Boc imine as well as one-pot classical aminomethylation of beta-ketoesters using benzylamine salt and formalin. The reactions proceeded smoothly, and the corresponding Mannich products were obtained in high yield with moderate to good enantioselectivity.