Enantioselective Vinylogous Mannich Reaction Research Articles

Chiral Spirophosphoric-Acid-Catalyzed Divergent Vinylogous Mannich and aza-Friedel-Crafts Reactions of 2-Methoxyfuran.

The first enantioselective vinylogous Mannich reaction is developed using 2-methoxyfuran under chiral spirophosphoric acid catalysis. The strategy involves 4-isoxazoline derivatives as cyclic ketimine surrogates and provides γ-butenolide scaffolds (up to 97% ee and >20:1 dr). The mechanistic investigations suggest that an in situ generated water molecule plays a crucial role in delivering γ-butenolide, while the use of molecular sieves delivers aza-Friedel-Crafts products. The synthetic utility of γ-butenolide is shown toward obtaining piperidone skeleton via a lactone-lactam rearrangement.

Synthesis of the DEF-Ring Spirocyclic Core of Cyclopamine.

A stereoselective synthesis of the DEF-ring spirocyclic core of cyclopamine was accomplished using commercially available materials. The key steps in the synthesis were (i) the enantioselective vinylogous Mannich reaction, followed by lactamization to generate the piperidine F ring, and (ii) intramolecular oxidative dearomative spiroetherification to construct the DEF-ring spirocyclic core of cyclopamine. We found that the stereochemistry of the spirocyclization was controlled by the configuration of the methyl group (C-20) in the substrate.

Cu-Catalyzed Direct Enantioselective Vinylogous Mannich Reaction between β,γ-Unsaturated Pyrazoleamides and Ketimines.

A catalytic asymmetric vinylogous Mannich-type reaction between β,γ-unsaturated amides and ketimines has been developed in excellent regio-, diastereo-, and enantioselectivities. The methodology provides an efficient approach to construct chiral homoallylic amines with a 3-amino-2-oxindole scaffold. Moreover, the transformations of the chiral products, including the removal of the pyrazole group or Boc group, the reduction of the C-C double bond, and Suzuki coupling, have been investigated.

A quinine-squaramide catalyzed enantioselective vinylogous Mannich reaction between benzothiazolimines and γ-butenolides for efficient preparation of chiral N-benzothiazole butyrolactones.

A highly effective and enantioselective vinylogous Mannich reaction between benzothiazolimines and γ-butenolides catalyzed by a quinine based squaramide has been disclosed. A series of chiral benzothiazole amines containing a γ,γ-disubstituted butanolide scaffold bearing an adjacent chiral stereocenter have been successfully obtained in good to excellent yields (up to 91%) with excellent enantioselectivities (up to >99% ee) and diastereoselectivities (>20 : 1 dr) with broad substrate generality under mild conditions. The new scaffold integrated with both chiral benzothiazolimine and γ-butenolide moieties may provide a possibility for the development of new pharmaceutical entities.

Catalytic Diastereo- and Enantioselective Vinylogous Mannich Reaction of Alkylidenepyrazolones to Isatin-Derived Ketimines.

A valuable organocatalytic vinylogous Mannich reaction between alkylidenepyrazolones and isatin-derived ketimines has been successfully established. Squaramide organocatalyst, prepared from quinine, catalyzed the diastereo- and enantioselective vinylogous Mannich addition, affording a range of aminooxindole-pyrazolone adducts (24 examples) with excellent outcomes: up to 98% yield with complete diastereoselectivity and excellent enantioselectivity (up to 99% ee). Additionally, different synthetic transformations were performed with the chiral pyrazolone-oxindole adducts.

Enantioselective Vinylogous Mannich Reaction of Acyclic Vinylketene Silyl Acetals with Acyclic Ketimines

AbstractThe first enantioselective vinylogous Mannich reaction of acyclic vinylketene silyl acetals with acyclic ketimines derived from alkynyl ketoesters was developed. Excellent yields and enantioselectivities were obtained from the reaction using bis(imidazoline)‐Zn(II) catalyst. Based on experiments and MO calculation, a plausible transition state was proposed to explain the stereoselectivity of the reaction. The obtained products were converted into various amines and a lactam. This process provides an efficient route for the synthesis of acyclic δ‐amino‐α,β‐unsaturated carbonyl compounds and their derivatives.magnified image

Enantioselective Vinylogous Mannich Reaction of Acyclic Vinylketene Silyl Acetals with Ketimines Using Chiral Bis(imidazoline)-Cu(II) Catalysts.

The enantioselective vinylogous Mannich reaction of ketimines derived from isatins with acyclic vinylketene silyl acetals has been developed using a chiral bis(imidazoline)-Cu(II) catalyst. A series of chiral 3-aminooxindole derivatives bearing tetra-substituted stereogenic centers with an α,β-unsaturated ester moiety were obtained in excellent yields (up to 99%) with high enantioselectivities (up to 98% ee). Enantioselective bisvinylogous Mannich reaction to ketimines derived from isatins also afforded product with high enantioselectivity. Based on the experimental investigations, a possible transition state has been proposed to explain the origin of the asymmetric induction.

The asymmetric vinylogous Mannich reaction of noncyclic dicyanoolefins catalyzed by a bifunctional thiourea–ammonium salt phase transfer catalyst

An efficient enantioselective vinylogous Mannich reaction of N-Boc aminosulfones with noncyclic α,α-dicyanoolefins has been realized using an extraordinary bifunctional thiourea–ammonium salt phase transfer catalyst derived from quinine.

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).

ChemInform Abstract: An Organocatalytic Enantioselective Vinylogous Mannich Reaction of α,α‐Dicyanoolefins with Isatin N‐Boc Ketimines.

The first catalytic enantioselective vinylogous Mannich reaction of α,α-dicyanoolefins with ketimines derived from isatins has been developed. High yields and enantioselectivities were observed for the reaction of various ketimines and α,α-dicyanoolefins using a tertiary butyl substituted cinchona alkaloid type squaramide catalyst.

An organocatalytic enantioselective vinylogous Mannich reaction of α,α-dicyanoolefins with isatin N-Boc ketimines

The first catalytic enantioselective vinylogous Mannich reaction of α,α-dicyanoolefins with ketimines derived from isatins has been developed. High yields and enantioselectivities were observed for the reaction of various ketimines and α,α-dicyanoolefins using a tertiary butyl substituted cinchona alkaloid type squaramide catalyst.

ChemInform Abstract: Direct Enantioselective Vinylogous Mannich Reaction of Ketimines with γ‐Butenolide by Using Cinchona Alkaloid Amide/Zinc(II) Catalysts.

AbstractVarious arylalkyl, hetarylalkyl, and dialkyl ketimines including cyclic ones are efficiently transformed according to the title reaction to form the products in high yields and with high diastereomeric and enantiomeric excess.

ChemInform Abstract: N‐Substituted Tertiary and O‐Substituted Quaternary Carbon Stereogenic Centers by Site‐, Diastereo‐ and Enantioselective Vinylogous Mannich Reactions.

AbstractThe triphenylphosphine derived amino‐acid containing catalyst (PCA) is applied in the Ag‐catalyzed condensation of imines (I) and (VII) with siloxypyrroles to afford lactams (III) and (IX) in good stereoselectivity.

Inside Cover: Direct Enantioselective Vinylogous Mannich Reaction of Ketimines with γ-Butenolide by Using Cinchona Alkaloid Amide/Zinc(II) Catalysts (Chem. Eur. J. 27/2015)

Inside Cover: Direct Enantioselective Vinylogous Mannich Reaction of Ketimines with γ-Butenolide by Using Cinchona Alkaloid Amide/Zinc(II) Catalysts (Chem. Eur. J. 27/2015)

Direct Enantioselective Vinylogous Mannich Reaction of Ketimines with γ-Butenolide by Using Cinchona Alkaloid Amide/Zinc(II) Catalysts.

A direct enantioselective vinylogous Mannich reaction of ketimines with γ-butenolide has been developed. Good yields and enantioselectivities were observed for the reaction of various ketimines by using a cinchona alkaloid amide/Zn(OTf)2 catalyst and Et3N. Both enantiomers of the products could be obtained by using pseudoenantiomeric chiral catalysts.

N-Substituted tertiary and O-substituted quaternary carbon stereogenic centers by site-, diastereo- and enantioselective vinylogous Mannich reactions

A readily accessible small-molecule phosphine, derived from commercially available starting materials such as an enantiomerically pure amino acid, serves as the precursor to a Ag-based chiral complex that can be prepared and used in situ to promote a variety of enantioselective vinylogous Mannich (EVM) reactions that involve siloxypyrroles as reaction partners. Transformations with unsubstituted nucleophilic components proceed efficiently and with exceptional site- (γ vs α-addition), diastereo- and enantioselectivity [up to 98% yield, generally >98:2 γ/α and diastereomeric ratio (dr) and up to 99:1 enantiomeric ratio (er)]. The first examples of efficient, diastereo- and enantioselective vinylogous Mannich additions with 5-methyl-substituted siloxyfuran, resulting in the formation of O-substituted quaternary carbon stereogenic centers are presented as well. Appreciable efficiency and diastereo- and enantioselectivity (up to >98:2dr and >99:1er) is accompanied by formation of α-addition products that can be oxidatively removed.

ChemInform Abstract: Cinchona Alkaloid Amide/Copper(II) Catalyzed Diastereo‐ and Enantioselective Vinylogous Mannich Reaction of Ketimines with Siloxyfurans.

AbstractThe asymmetric vinylogous Mannich reaction of unactivated ketimines with siloxyfurans using cinchona alkaloids and Cu(OAc)2 as catalysts is reported.

Cinchona Alkaloid Amide/Copper(II) Catalyzed Diastereo‐ and Enantioselective Vinylogous Mannich Reaction of Ketimines with Siloxyfurans

The asymmetric vinylogous Mannich reaction of unactivated ketimines with siloxyfurans using cinchona alkaloids and Cu(OAc)2 as catalysts is reported.

Cinchona Alkaloid Amide/Copper(II) Catalyzed Diastereo‐ and Enantioselective Vinylogous Mannich Reaction of Ketimines with Siloxyfurans

Cinchona Alkaloid Amide/Copper(II) Catalyzed Diastereo‐ and Enantioselective Vinylogous Mannich Reaction of Ketimines with Siloxyfurans

ChemInform Abstract: Highly Diastereo‐ and Enantioselective Vinylogous Mannich Reactions of Fluorinated Aldimines with Siloxyfurans.

A highly regio- and enantioselective asymmetric vinylogous Mannich reaction of readily available fluorinated aldimines bearing a chiral auxiliary [(S)-1-phenylethyl group] with siloxyfurans to afford chiral fluorine-containing γ-butenolide or γ-lactone derivatives has been developed in the presence of silver acetate (10 mol%) and axially chiral phosphine-oxazoline ligand L1 (11 mol%). In most cases, the corresponding fluorinated adducts were obtained in high yields, good to excellent enantiomeric excesses and up to > 20:1 dr.