Organocatalytic Asymmetric Mannich Reaction Research Articles

Organocatalytic enantioselective Mannich and retro-Mannich reactions and combinations of these reactions to afford tetrasubstituted α-amino acid derivatives.

Organocatalytic asymmetric Mannich reactions and kinetic resolutions of the products via retro-Mannich reactions that afford enantiomerically enriched tetrasubstituted α-amino acid derivatives (α,α-disubstituted-α-amino acid derivatives) were developed. Furthermore, the combination of the Mannich reaction and the retro-Mannich reaction allowed access to products with almost perfect enantiopurities.

A Data-Driven Workflow for Assigning and Predicting Generality in Asymmetric Catalysis.

The development of chiral catalysts that can provide high enantioselectivities across a wide assortment of substrates or reaction range is a priority for many catalyst design efforts. While several approaches are available to aid in the identification of general catalyst systems, there is currently no simple procedure for directly measuring how general a given catalyst could be. Herein, we present a catalyst-agnostic workflow centered on unsupervised machine learning that enables the rapid assessment and quantification of catalyst generality. The workflow uses curated literature data sets and reaction descriptors to visualize and cluster chemical space coverage. This reaction network can then be applied to derive a catalyst generality metric through designer equations and interfaced with other regression techniques for general catalyst prediction. As validating case studies, we have successfully applied this method to identify-through-quantification the most general catalyst chemotype for an organocatalytic asymmetric Mannich reaction and predicted the most general chiral phosphoric acid catalyst for the addition of nucleophiles to imines. The mechanistic basis for catalyst generality can then be gleaned from the calculated values by deconstructing the contributions of chemical space and enantiomeric excess to the overall result. Finally, our generality techniques permitted the development of mechanistically informative catalyst screening sets that allow experimentalists to rationally select catalysts that have the highest probability of achieving a good result in the first round of reaction development. Overall, our findings represent a framework for interrogating catalyst generality, and this strategy should be relevant to other catalytic systems widely applied in asymmetric synthesis.

Organocatalytic enantioselective Mannich reaction of isoxazol-5(4H)-ones to isatin-derived ketimines.

An efficient organocatalytic asymmetric Mannich reaction between isoxazol-5(4<i>H</i>)-ones and isatin-derived ketimines has been developed. A bifunctional squaramide/Brønsted base organocatalyst catalyzed the enantioselective Mannich addition to afford chiral 3-aminooxindoles bearing a tetrasubstituted stereocenter at C3 decorated with an isoxazole moiety in good yields and with excellent enantioselectivities. Additionally, several synthetic transformations were described showing the versatility of the prepared compounds.

Advances in the Organocatalytic Asymmetric Mannich Reaction of Six‐Membered Unsaturated Heterocycles: Methodology and Application

AbstractThe organocatalytic asymmetric Mannich reaction has always been an area of active interest in the community of chemistry. The Mannich products, optically active β‐amino−carbonyl compounds, can be used as important intermediates for biologically active molecules. Compared with the well‐researched acyclic imines, the organocatalytic asymmetric Mannich reactions of cyclic unsaturated substrates have been on the rise in recent years, which provide an exciting platform for the construction of various enantioenriched nitrogen‐containing polyheterocycles. In this minireview, we will summarize the advances in the field of organocatalytic asymmetric Mannich and related reactions, including decarboxylative Mannich reactions and Mannich involved cascade processes of six‐membered unsaturated heterocycles, and their applications in the synthesis of natural products and pharmaceuticals.

Organocatalytic Asymmetric Mannich Reaction of Dihydro‐3‐carboalkoxy‐2‐quinolones with Preformed N‐Boc Imines

An organocatalytic enantioselective Mannich reaction involving dihydro‐3‐carboalkoxy‐2‐quinolone and preformed N‐Boc imines has been developed leading to the formation of biologically important 3,3‐disubstituted‐dihydro‐2‐quinolones. Cinchona alkaloid derived thiourea catalysts were found to be effective for this reaction. The desired products were obtained in good yields with good to high enantioselectivities and moderate diastereoselectivities.

Aldehyde Catalysis: New Options for Asymmetric Organocatalytic Reactions

Recently in Science, Zhao and co-workers reported a novel organocatalytic asymmetric Mannich reaction by introducing chiral aldehydes as the catalysts. The key to success was the design of the N-quaternized pyridoxal-type catalysts, which allowed the umpolung of the classical electrophilic reactivity in the α-position of amines.

Organocatalytic Asymmetric Decarboxylative Mannich Reaction of β-Keto Acids with Cyclic α-Ketiminophosphonates: Access to Quaternary α-Aminophosphonates.

An organocatalytic asymmetric decarboxylative Mannich reaction of β-keto acids with cyclic α-ketiminophosphonates has been developed. By using saccharide-derived bifunctional amine-thiourea catalysts bearing an axial chiral binaphthyl scaffold, a wide range of quaternary α-amino-γ-oxophosphonates were obtained in up to 93% yield and >99% ee. Furthermore, two interesting α-aminophosphonate derivatives were synthesized from the corresponding decarboxylative Mannich product via simple transformations.

An organocatalytic asymmetric Mannich reaction for the synthesis of 3,3-disubstituted-3,4-dihydro-2-quinolones.

The first organocatalytic asymmetric Mannich reaction employing 3,4-dihydro-2-quinolones has been developed for the synthesis of biologically important 3,3-disubstituted-dihydro-2-quinolones. N-Boc imine precursor amidosulfones as well as pre-formed N-Boc imine were used for this purpose. Cyclohexyldiamine derived bifunctional amino-thiourea catalysts were employed to provide the products in high enantio- and good diastereoselectivities.

An organocatalytic asymmetric Mannich reaction of pyrazoleamides with cyclic trifluoromethyl ketimines: enantioselective access to dihydroquinazolinone skeletons.

An organocatalyzed asymmetric Mannich reaction of pyrazoleamides and cyclic trifluoromethyl ketimines with a chiral bifunctional amine-squaramide as the catalyst was developed. A wide range of trifluoromethyl dihydroquinazolinone derivatives bearing adjacent quaternary and tertiary stereogenic centers were readily obtained in good to excellent yields (up to 99%) with high diastereo- and enantioselectivities (up to 99% ee and >20 : 1 dr). The large scale experiment and transformation of the product have also been demonstrated.

ChemInform Abstract: Organocatalytic Asymmetric Mannich Reaction of 3‐Hydroxyoxindoles/3‐Aminooxindoles with in situ Generated N‐Boc‐Protected Aldimines for the Synthesis of Vicinal Oxindole—Diamines/Amino Alcohols.

A highly efficient asymmetric Mannich reaction of 3-monosubstituted 3-aminooxindoles/3-hydroxyoxindoles with in situ generated N-Boc-protected aldimines catalyzed by the chiral bifunctional thiourea–tertiary amine catalyst has been developed. Under mild reaction conditions, a series of structurally diverse vicinal oxindole–diamines/amino alcohols were smoothly obtained in moderate to high yields (up to 99%) with good to excellent diastereoselectivities and enantioselectivities (up to 95:5 dr and 96% ee). The synthetic application of this protocol was also demonstrated by the versatile transformation of chiral vicinal oxindole–diamine/amino alcohol into spirocyclic oxindoles.

First example of an organocatalytic asymmetric Mannich reaction between aldimines of glycinates and sulphonyl imines

The catalytic enantioselective Mannich-type reaction between glycinate Schiff base and imines has been one of the most efficient routes for accessing α,β-diamino acids. However, the glycinate Schiff bases used in the references were almost ketimines. Only several examples of aldimines were used in the presence of metal catalyst. We developed the first example of an asymmetric direct Mannich reaction using aldimines of glycinates instead of ketimines of glycinates. The reaction was well catalyzed by chiral guanidine with high yield (up to 92%) and moderate stereoselectivity (up to 65%).

Organocatalytic Asymmetric Mannich Reaction of 3-Hydroxyoxindoles/3-Aminooxindoles with in Situ Generated N-Boc-Protected Aldimines for the Synthesis of Vicinal Oxindole-Diamines/Amino Alcohols.

A highly efficient asymmetric Mannich reaction of 3-monosubstituted 3-aminooxindoles/3-hydroxyoxindoles with in situ generated N-Boc-protected aldimines catalyzed by the chiral bifunctional thiourea-tertiary amine catalyst has been developed. Under mild reaction conditions, a series of structurally diverse vicinal oxindole-diamines/amino alcohols were smoothly obtained in moderate to high yields (up to 99%) with good to excellent diastereoselectivities and enantioselectivities (up to 95:5 dr and 96% ee). The synthetic application of this protocol was also demonstrated by the versatile transformation of chiral vicinal oxindole-diamine/amino alcohol into spirocyclic oxindoles.

Organocatalytic Asymmetric Mannich Reaction through Hydrogen Bonding

Organocatalytic Asymmetric Mannich Reaction through Hydrogen Bonding

ChemInform Abstract: Highly Regio‐, Diastereo‐, and Enantioselective Mannich Reaction of Allylic Ketones and Cyclic Ketimines: Access to Chiral Benzosultam.

An organocatalytic asymmetric Mannich reaction of allylic ketones with cyclic N-sulfonyl α-iminoester has been developed. By using a saccharide-derived chiral tertiary amino-thiourea catalyst, a range of allylic ketones and N-sulfonyl ketimines reacted smoothly to afford tetrasubstituted α-amino esters in high yields with good to excellent regio-, diastero-, and enantioselectivities.

Highly Regio-, Diastereo-, and Enantioselective Mannich Reaction of Allylic Ketones and Cyclic Ketimines: Access to Chiral Benzosultam.

An organocatalytic asymmetric Mannich reaction of allylic ketones with cyclic N-sulfonyl α-iminoester has been developed. By using a saccharide-derived chiral tertiary amino-thiourea catalyst, a range of allylic ketones and N-sulfonyl ketimines reacted smoothly to afford tetrasubstituted α-amino esters in high yields with good to excellent regio-, diastero-, and enantioselectivities.

Remote chirality control based on the organocatalytic asymmetric Mannich reaction of α-thio acetaldehydes

Remote chirality control leading to 1,4-difunctionalized compounds such as 1,4-amino alcohols and 1,4-diamines was achieved by both syn- and anti-selective asymmetric Mannich reactions of α-thio acetaldehydes, the subsequent olefination and the stereospecific 2,3-sigmatropic rearrangement.

ChemInform Abstract: Asymmetric Mannich Reaction of α‐Keto Imines Catalyzed by Diarylprolinol Silyl Ether.

AbstractThe reaction proceeds via base‐promoted desulfonative generation of an intermediary electrophilic imine followed by organocatalytic asymmetric Mannich reaction yielding an β‐aminoaldehyde.

ChemInform Abstract: Organocatalytic Asymmetric Mannich Reactions of 5H‐Oxazol‐4‐ones: Highly Enantio‐ and Diastereoselective Synthesis of Chiral α‐Alkylisoserine Derivatives.

The first organocatalytic Mannich reaction of 5H-oxazol-4-ones with various readily prepared aryl- and alkylsulfonimides has been developed. Two commercially available pseudoenantiomeric Cinchona alkaloids-derived tertiary amine/ureas have been demonstrated as the most efficient catalysts to access the opposite enantiomers of the Mannich products with equally excellent enantio- and diastereoselectivities. From the Mannich adducts, important α-methyl-α-hydroxy-β-amino acid derivatives, such as the α-methylated C-13 side chain of taxol and taxotere, can be conveniently prepared.

Organocatalytic Asymmetric Mannich Reactions of 5H‐Oxazol‐4‐ones: Highly Enantio‐ and Diastereoselective Synthesis of Chiral α‐Alkylisoserine Derivatives

AbstractThe first organocatalytic Mannich reaction of 5H‐oxazol‐4‐ones with various readily prepared aryl‐ and alkylsulfonimides has been developed. Two commercially available pseudoenantiomeric Cinchona alkaloids‐derived tertiary amine/ureas have been demonstrated as the most efficient catalysts to access the opposite enantiomers of the Mannich products with equally excellent enantio‐ and diastereoselectivities. From the Mannich adducts, important α‐methyl‐α‐hydroxy‐β‐amino acid derivatives, such as the α‐methylated C‐13 side chain of taxol and taxotere, can be conveniently prepared.

Stereocontrolled Synthesis of Vicinal Diamines by Organocatalytic Asymmetric Mannich Reaction of N-Protected Aminoacetaldehydes: Formal Synthesis of (−)-Agelastatin A

The 1,2-diamine (vicinal diamine) motif is present in a number of natural products with interesting biological activity and in many chiral molecular catalysts. The efficient and stereocontrolled synthesis of enantioenriched vicinal diamines is still a challenge to modern chemical methodology. We report here both syn- and anti-selective asymmetric direct Mannich reactions of N-protected aminoacetaldehydes with N-Boc-protected imines catalyzed by proline and the axially chiral amino sulfonamide (S)-3. This organocatalytic process represents the first example of a Mannich reaction using Z- or Boc-protected aminoacetaldehyde as a new entry of α-nitrogen functionalized aldehyde nucleophile in enamine catalysis. The obtained optically active vicinal diamines are useful chiral synthons as exemplified by the formal synthesis of (-)-agelastatin A.