Asymmetric Mannich-type Reaction Research Articles

B(C6F5)3/Chiral Phosphoric Acid Promoted Asymmetric C-3 gem-Difluoroalkylation of Quinoxalin-2-ones with Difluoroenoxysilanes.

The asymmetric Mannich-type reaction of quinoxalin-2-ones with difluoroenoxysilanes has been developed for the synthesis of chiral gem-difluoroalkylated quinoxalin-2-ones. The reaction worked in the presence of chiral phosphoric acid CPA 1 and B(C6F5)3 in THF at room temperature. The reaction exhibited a good substrate scope furnishing the products in good yields (up to 97%) with up to 96% ee.

Ionic Liquid Supported Organocatalysts for the Asymmetric Mannich- Type Reaction of α-cyano α-sulfonyl Carbanions

Introduction: We synthesized proline functionalized ionic liquid and further character-ized it with analytical techniques. Method: After getting proper structural information on the above ionic liquid, we utilized them as a catalyst for the asymmetric Mannich-Type Reaction. Result: We synthesized 6 different types of β-amino α-cyano sulfones derivatives as Mannich ad-duct using various combinations of different imines and aryl sulphonyl as pre-nucleophiles. Conclusion: We obtained the corresponding chiral Mannich adduct followed by simple ether washing in excellent yield and stereoselectivity. We recycled the catalyst up to 6 runs without los-ing the catalytic activity.

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.

Synthesis of Non-canonical Amino Acids and Peptide Containing Them for Establishment of the Template for Drug Discovery.

Non-canonical amino acid derivatives are an attractive scaffold for novel drug candidates. Among the methods used to prepare this motif, the asymmetric Mannich-type reaction of α-imino carboxylic acid derivatives is a preeminent strategy because a wide variety of non-canonical amino acids can be accessed by changing only the nucleophile. Preparing the common substrate is difficult, however, which makes this method problematic. We developed a convenient method for synthesizing common substrates using MnO2-mediated oxidation of stable precursors. Peptides bearing non-canonical amino acids are another attractive synthetic target. We propose a new approach for synthesizing non-canonical amino acid-containing peptides by directly applying various organic reactions to peptidic substrates. Using hydrophobic anchor-supported peptides, we directly applied ring-closing metathesis and asymmetric Friedel-Crafts reactions to peptidic substrates. We also developed a novel recyclable organocatalyst according to the nature of the hydrophobic anchor tagged compound.

Stereoselective synthesis of 3,3′-pyrrolidinyl-spirooxindoles via the Zn(OAc)2-mediated asymmetric Mannich-type reaction

Zn(OAc)2-mediated Mannich-type reaction was studied for the synthesis of 3,3′-pyrrolidinyl-spirooxindole from l-2,3-dihydro-2-oxotryptophan methyl ester and aldehydes. The study indicates that the Mannich-type spirocyclization is significantly influenced by both the cation and anion of the metal salt, base, stoichiometry, stereoelectronics of aldehyde and temperature. With the enhancement by Zn(OAc)2, the substrate induced asymmetric reaction works on both aromatic and aliphatic aldehydes but at different temperatures. It could deliver the (2′S,3R,5‘S)-pyrrodinyl-spirooxindole with up to 96% of diastereomeric ratio in good yield under optimized conditions.

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.

Lewis Base Assisted Lithium Brønsted Base Catalysis: A New Entry for Catalytic Asymmetric Synthesis of β2,2-Amino Acids.

A new catalytic system comprising chiral Ag complex and Li aryloxide/bisphosphine oxide is developed for the synthesis of β2,2-amino acids via direct asymmetric Mannich-type reaction of 4-subsituted isoxazolidin-5-ones. The Mannich adduct is a direct precursor of β-peptidic compounds otherwise difficult to obtain.

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.

Stereoselective synthesis of spiro[pyrrolidin-3,3′-oxindoles] via organocatalyzed asymmetric Mannich-type reaction

The organocatalyzed asymmetric Mannich-type spirocyclization was employed to access the spiro[pyrrolidin-3,3′-oxindoles], a biologically privileged ring structure, from readily available 2-oxotryptaphan methyl ester and aromatic aldehydes. The stereoselectivity of this cyclization are closely correlated with the organocatalyst and solvent used for the reaction. The best diastereoselectivity (d.r. ≥99%) was achieved using only 5% loading of the bifunctional organocatalyst, Takemoto’s thiourea, and dioxane as solvent, resulting in the formation of the the spirocycle with the (2′R, 3R) configuration. The yield could be increased up to 97% when excess of benzaldehyde was used to overcome its trimerization.

A chiral Brønsted acid-catalyzed highly enantioselective Mannich-type reaction of α-diazo esters with in situ generated N-acyl ketimines.

A chiral phosphoric acid-catalyzed asymmetric Mannich-type reaction of α-diazo esters with in situ generated N-acyl ketimines, derived from 3-hydroxyisoindolinones has been demonstrated in this communication. A variety of isoindolinone-based α-amino diazo esters bearing a quaternary stereogenic center were afforded in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee). Furthermore, the synthetic utility of the products has been depicted by the hydrogenation of the diazo moiety of adducts.

Group-Assisted Purification Chemistry for Asymmetric Mannich-type Reaction of Chiral N-Phosphonyl Imines with Azlactones Leading to Syntheses of α-Quaternary α,β-Diamino Acid Derivatives †.

An asymmetric Mannich-type reaction between chiral N-phosphonyl imines and azlactones [oxazol-5(4H)-ones] has been established under convenient conditions at room temperature. The reaction was performed without using any bases, additives, or catalysts to achieve up to excellent chemical yields and diastereoselectivity for 32 examples. The α-quaternary syn-α,β-diamino acid products were purified simply by washing the crude mixtures with cosolvents, following the group-assisted purification chemistry/technology, without involving traditional chromatography or recrystallization methods. The auxiliary can be readily removed and recycled for reuse. The absolute configuration was unambiguously assigned by X-ray structural analysis.

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.

A new approach to the asymmetric Mannich reaction catalyzed by chiral N,N′-dioxide–metal complexes

A highly efficient asymmetric Mannich-type reaction between α-tetralone-derived β-keto esters/amides and 1,3,5-triaryl-1,3,5-triazinanes was realized in the presence of chiral N,N'-dioxide-Ni(ii) or Mg(ii) complex. A variety of optically active β-amino compounds with all-carbon quaternary stereocenters were obtained in good yields with excellent enantioselectivities. A possible transition state was proposed based on these experiments and previous reports.

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.

A highly efficient stereoselective synthesis of β-lactams

An efficient strategy for a one-pot, single step synthesis of β-lactams employing an imidazolidinone based chiral auxiliary with various aldimines via asymmetric Mannich-type reaction has been described.

Chiral ammonium betaine-catalyzed asymmetric Mannich-type reaction of oxindoles

A highly diastereo- and enantioselective Mannich-type reaction of 3-aryloxindoles with N-Boc aldimines was achieved under the catalysis of axially chiral ammonium betaines. This catalytic method provides a new tool for the construction of consecutive quaternary and tertiary stereogenic carbon centers on biologically intriguing molecular frameworks with high fidelity.

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

Advances on Asymmetric Organocatalyzed Mannich Reactions in Aqueous and Non-aqueous Media

Considerable number of nitrogen containing active pharmaceutical ingredients and natural products are frequently synthesized from optically pure β-amino ketones, aldehydes, esters, and alcohols. Synthesis of 1,3-amino ketones, aldehydes, alcohols and esters engages Mannich-type reactions, the most important basic reaction-types in organic chemistry. The current trend in the development of asymmetric Mannich-type reaction is to employ unmodified ketones and aldehydes as starting materials in the presence of simple and easily accessible metal-free organocatalysts under mild and convenient reaction conditions. Although L-Proline and its derivatives are commonly and extensively studied organocatalysts in Mannich reactions, many other organocatalysts based on bifunctional thiourea, chiral Bronsted acids and some other organocatalytic systems are also equally effective. The present review comprehensively describes an overview of asymmetric Mannich reactions under different organocatalytic systems in both organic and aqueous media. Keywords: Aminoalkylation, asymmetric synthesis, aqueous media, C-C bond formation, chiral bronsted acids, Mannich reaction, organic media, organocatalysis, L-proline, thioureas.

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.