Asymmetric Vinylogous Mannich Research Articles

Copper-Catalyzed Direct Asymmetric Vinylogous Mannich Reaction between β,γ-Alkynyl-α-ketimino Esters and β,γ-Unsaturated N-Acylpyrazoles.

We report a Cu(I)-Ph-BPE-catalyzed asymmetric vinylogous Mannich reaction of β,γ-alkynyl-α-ketimino esters with β,γ-unsaturated N-acylpyrazoles. In this process, the Cu(I)-Ph-BPE catalyst activates the β,γ-alkynyl-α-ketimino ester through N,O-coordination, enabling the subsequent nucleophilic addition of a dienolate generated from the β,γ-unsaturated N-acylpyrazole via α-position deprotonation with a catalytic amount of tertiary amine. The reactions gave useful products with very high enantioselectivities. A broad range of substrates with various substituents are tolerated in this reaction. The versatility of this method was demonstrated by a gram-scale reaction, and subsequent elaboration of the Mannich adducts was also provided.

Direct Asymmetric Vinylogous Mannich Reactions of Acyclic α,β-Unsaturated Ketones Catalyzed by Chiral Boranes

Direct Asymmetric Vinylogous Mannich Reactions of Acyclic <i>α</i>,<i>β</i>-Unsaturated Ketones Catalyzed by Chiral Boranes

Direct Asymmetric Vinylogous Mannich Addition of 3,5-Disubstituted-4-nitroisoxazoles to Isatin-Derived Imines Catalyzed by a Bifunctional Phase-Transfer-Catalyst.

Asymmetric Mannich-type addition of 3,5-disubstituted-4-nitroisoxazoles to isatin-derived Boc-protected imines has been realized by using 0.01 equiv of amide phosphonium salt as a phase transfer catalyst. Our current methodology allows for the formation of 3-isoxazolylmethyl-substituted 3-aminooxindoles in excellent yields with good to excellent enantioselectivities. The practical value of this methodology was exemplified by a gram-scale synthesis of 5an, a key intermediate for the formal synthesis (+)-AG-041R.

Chiral VAPOL Imidodiphosphoric Acid-Catalyzed Asymmetric Vinylogous Mannich Reaction for the Synthesis of Butenolides

Chiral butenolides were synthesized by the enantioselective vinylogous Mannich reaction. Chiral (VAPOL)-type imidodiphosphoric acids are efficient catalysts for the asymmetric vinylogous Mannich (AVM) reaction of aldimines and trimethylsiloxyfuran in toluene. Under the optimized conditions, a series of butenolides were obtained with high yields (up to 98%) and enantioselectivities (up to 97% ee) as well as excellent diastereoselectivities (up to 99:1 dr).

Progress in Heterocycles-Based Asymmetric Vinylogous Mannich Reactions and Applications to the Synthesis of Alkaloids

Progress in Heterocycles-Based Asymmetric Vinylogous Mannich Reactions and Applications to the Synthesis of Alkaloids

ChemInform Abstract: A Decade of Advance in the Asymmetric Vinylogous Mannich Reaction

AbstractReview: [70 refs.

A Decade of Advance in the Asymmetric Vinylogous Mannich Reaction

When the principle of vinylogy is applied to imines as electrophiles, the so-called vinylogous Mannich reaction (VMR), γ-aminocarbonyl (such as butenolides) and β-aminocarbonyl compounds are generated in a very efficient manner. The asymmetric version of this vinylogous Mannich reaction gives access to highly functionalized chiral synthons, which are suitable for further transformations. The versatility of this methodology is exemplified with the synthesis of several alkaloids and natural products. 1 Introduction 2 Asymmetric Vinylogous Mannich Reactions (VMR) with 2-Silyl­oxyfurans and 2-Silyloxypyrroles 3 Asymmetric VMR with Acyclic Silyl Dienolates and Silyl Dienol Ketene Acetals 4 Asymmetric VMR with γ-Butenolides and γ-Butyrolactams 5 Asymmetric VMR with α,α-Dicyanoolefins 6 Miscellaneous Donors in Asymmetric VMR 7 Application of the VMR to Natural Product Synthesis 8 Conclusions

Studies on the Second-Generation Approach to Loline Alkaloids: Synthesis of N-Bus-norloline through N-tert-Butanesulfinyl Imine Based Asymmetric Vinylogous Mannich Reaction

A strategy is outlined for the synthesis of loline alkaloids. This second-generation approach features direct access to the requisite vicinal diamino motif by a Cu(OTf)₂-mediated highly <i>trans</i>-diastereoselective vinylogous Mannich reaction (VMR) of Ellman <i>N</i>-<i>tert</i>-butanesulfinyl imine derived from isopropylidene-protected (<i>S</i>)-glyceraldehyde, with <i>N</i>-Boc-2-<i>tert</i>-(butyldimethylsilyloxy)pyrrole (TBSOP). Fleming’s method was employed for the introduction of a hydroxyl group at C4 of the adduct, which gave the undesired diastereomer in 40% yield. The intramolecular S_N reaction of the pyrrolizidine derivative to build the etheral bridge proved to be difficult, and produced <i>N</i>-Bus-norloline in only 20% yield. In light of the valuable information gained during this investigation, an improved version of the second-generation approach is being investigated, which is expected to provide a concise and efficient access to the challenging loline alkaloids.

ChemInform Abstract: Organocatalytic Direct Asymmetric Vinylogous Mannich Reaction of γ‐Butenolides with Isatin‐Derived Ketimines.

AbstractThe title reaction proceeds in the presence of quinidine‐derived catalyst to form 3‐aminooxindole derivatives with moderate diastereoselectivities and high enantioselectivities.

Regio- and Diastereoselective Vinylogous Mannich Addition of 3-Alkenyl-2-oxindoles to α-Fluoroalkyl Aldimines

An efficient asymmetric vinylogous Mannich (AVM) addition reaction of 3-alkenyl-2-oxindoles to α-fluoroalkyl aldimines has been developed. This reaction provided various optical active α-alkylidene-δ-amino-δ-fluoroalkyl oxindoles in excellent yields, complete γ-site ­regioselectivity, and excellent diastereoselectivities.

ChemInform Abstract: New Silver(I)—Monophosphine Complex Derived from Chiral Ar‐BINMOL: Synthesis and Catalytic Activity in Asymmetric Vinylogous Mannich Reaction.

Abstract A new family of C2-axially chiral monophosphines (Ar-NNPs) from Ar-BINMOLs was developed for silver-catalyzed asymmetric vinylogous Mannich reaction of (furan-2-yloxy)trimethylsilane with aromatic aldimines. It was found that the enantioselective vinylogous Mannich-type reactions of trimethylsiloxyfuran with aldimines are catalyzed efficiently by silver(I) complexes of the Ar-BINMOL-derived chiral monophosphine. This procedure displays wide aldimine versatility, excellent yields (up to 99% isolated yields), moderate to good enantioselectivity (up to 78%ee) and exceptional diastereoselectivity (>99:1 dr) in most cases examined. The molecular structure of silver–monophosphine complex was confirmed by X-ray analysis and revealed that the benzyl group on chiral monophosphine provided dual function with weak silver–π/π–π stacking and steric repulsion to favour the diastereoselective Re-nucleophilic addition of siloxyfuran to imine.

2-Chlorotetrafluoroethanesulfinamide induced asymmetric vinylogous Mannich reaction

The generality of (S)-2-chlorotetrafluoroethanesulfinamide (CTFSA) induced asymmetric vinylogous Mannich (AVM) addition reaction has been investigated. The reaction of aldimines derived from (S)-CTFSA with 2-(tert-butyldimethylsilyloxy) furan (TBSOF) took place regioselectively at the γ-site at room temperature in DMSO under air atmosphere to give the desired addition products in syn-configuration with high diastereoselectivities (up to 98:2 dr). However, anti-configuration product as major isomer was obtained in the presence of tetra-butyl ammonium fluoride (TBAF) at −78 °C. Facile removal of the auxiliary group without epimerization demonstrated their synthetic potential for piperidone derivatives.

ChemInform Abstract: Recent Advances in Metal‐Catalyzed Asymmetric Mannich Reactions

AbstractReview: 122 refs.

Recent Advances in Metal-Catalyzed Asymmetric Mannich Reactions

In this review, recent works on metal-catalyzed asymmetric Mannich, aza-Henry and vinylogous Mannich reactions are described. The asymmetric Mannich reaction is one of the most powerful methodologies among the carbon–carbon bond-forming reactions, and provides direct access to a wide range of optically active natural products with useful biological properties. 1 Introduction 2 Catalytic Asymmetric Mannich Reactions 2.1 BINOL Ligands 2.2 BINAP Ligands 2.3 Bisoxazoline Ligands 2.4 Pyridine Bisoxazoline Ligands 2.5 Diamine Ligands 2.6 P,N-Ligands 2.7 P,S-Ligands 2.8 P,P-Ligands 2.9 N,N-Ligands 2.10 Miscellaneous 3 Asymmetric Aza-Henry Reactions 3.1 BINOL Ligands 3.2 Bisoxazoline Ligands 3.3 N,N-Ligands 3.4 Miscellaneous 4 Asymmetric Vinylogous Mannich Reactions 5 Conclusion

ChemInform Abstract: Direct Asymmetric Vinylogous Mannich Reaction of 3,4‐Dihalofuran‐2(5H)‐one with Aldimine Catalyzed by Quinine.

AbstractFuranones of type (III) are useful synthons which can be converted into optically active butyrolactones such as (IV) and amino diols like (V).

Direct Asymmetric Vinylogous Mannich Reaction of 3,4-Dihalofuran-2(5H)-one with Aldimine Catalyzed by Quinine

The direct asymmetric vinylogous Mannich reaction of 3,4-dihalofuran-2(5H)-one with aldimine catalyzed by quinine was first reported, and γ-butenolides have been obtained in excellent yield (up to 98%) and enantioselectivities (up to 95% ee). The synthetic applications of this protocol are demonstrated in the preparations of γ-substituted amino butyrolactones and vicinal amino alcohols.

Asymmetric Vinylogous Mannich Reactions: A Versatile Approach to Functionalized Heterocycles

Asymmetric vinylogous Mannich reaction (VMR) of 2-(tert-butyldimethylsilyloxy)furan (TBSOF, 1) with (R(S))- or (S(S))-t-BS-imines (3) furnished 5-aminoalkylbutenolides 7a-k in 75-87% yields with anti/syn ratios ranging from 75:25 to 97:3. Butenolides 7a-f,k were readily converted into substituted lactones 8 and 5 and 6-substituted 5-hydroxypiperidin-2-ones 11a-g, which are, in turn, key intermediates for the synthesis of many bioactive compounds.

ChemInform Abstract: Highly Efficient Asymmetric Vinylogous Mannich Reaction Induced by O‐Pivaloylated D‐Galactosylamine as the Chiral Auxiliary.

AbstractA new and efficient asymmetric access to a number of γ‐butenolide derivatives is presented.

The application of chiral phosphine-Schiff base type ligands in silver(I)-catalyzed asymmetric vinylogous Mannich reaction of aldimines with trimethylsiloxyfuran

Catalytic asymmetric vinylogous Mannich (AVM) reactions of readily available aldimines with trimethylsiloxyfuran in the presence of catalytic amount of AgOAc and chiral phosphine-Schiff base type ligands are described, affording the corresponding products in up to 91% yield, anti/ syn >99:1 and 81% ee.

Ag-Catalyzed Diastereo- and Enantioselective Vinylogous Mannich Reactions of α-Ketoimine Esters. Development of a Method and Investigation of its Mechanism

An efficient diastereo- and enantioselective Ag-catalyzed method for additions of a commercially available siloxyfuran to alpha-ketoimine esters is disclosed. Catalytic transformations require an inexpensive metal salt (AgOAc) and an air stable chiral ligand that is prepared in three steps from commercially available materials in 42% overall yield. Aryl- as well as heterocyclic substituted ketoimines can be used effectively in the Ag-catalyzed process. Additionally, two examples regarding reactions of alkyl-substituted ketoimines are presented. An electronically modified N-aryl group is introduced that is responsible for high reaction efficiency (>98% conversion, 72-95% yields after purification) as well as diastereo- (up to >98:2 dr) and enantioselectivity (up to 97:3 er or 94% ee). The new N-aryl unit is crucial for conversion of the asymmetric vinylogous Mannich (AVM) products to the unprotected amines in high yields. Spectroscopic and X-ray data are among the physical evidence provided that shed light on the identity of the Ag-based chiral catalysts and some of the mechanistic subtleties of this class of enantioselective C-C bond forming processes.