Catalytic Enantioselective Aldol Reactions of Pyruvates as Nucleophiles with Chlorinated and Fluorinated Aldehydes and Ketones.

Reactions of pyruvates as nucleophiles under catalytic conditions are difficult to control without the use of enzymes as catalysts. Here, enantioselective aldol reactions of pyruvates with chlorinated and fluorinated aldehydes and ketones under organocatalytic conditions, in which pyruvates act as nucleophiles, are reported. Based on analyses of self-aldol reactions of pyruvates in the presence of model catalysts, catalysts of the desired cross aldol reactions were developed.

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 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.

1,3-Diamine-Derived Catalysts: Design, Synthesis, and the Use in Enantioselective Mannich Reactions of Ketones.

1,3-Diamine-derived catalysts were designed, synthesized, and used in asymmetric Mannich reactions of ketones. The reactions catalyzed by one of the 1,3-diamine derivatives in the presence of acids afforded the Mannich products with high enantioselectivities under mild conditions. In most cases, bond formation occurred at the less-substituted α-position of the ketone carbonyl group.

Limiting the Loading of Reactant 1,3-Cyclohexanedione Enables the Use of Less Catalyst.

We demonstrated that the loading amounts and concentrations of reactant 1,3-cyclohexanedione affect reaction rates and outcomes. In certain cases, reactions with higher concentrations of 1,3-cyclohexanedione were slower than those with lower concentrations. By minimizing the use of the cyclic 1,3-dione derivatives and by tuning the reaction concentration, the acid catalyst was reduced to 0.

Amines as Catalysts: Dynamic Features and Kinetic Control of Catalytic Asymmetric Chemical Transformations to Form C-C Bonds and Complex Molecules.

Carbonyl transformations involving enolates and/or enamines have been used for various types of bond-forming reactions. In this account, catalysts and catalyst systems that have amino acids or primary, secondary, and/or tertiary amines as key catalytic functional groups that we have developed to accelerate chemical transformations, including regio-, diastereo- and enantioselective reactions, are discussed. Our chemical transformation strategies and methods that use amine derivatives as catalysts are also discussed.

Organocatalytic Enantioselective γ-Position-Selective Mannich Reactions of β-Ketocarbonyl Derivatives.

Catalytic asymmetric Mannich reactions of β-ketocarbonyl derivatives (such as β-ketoesters and (2-oxopropyl)phosphonate), resulting in the formation of a C-C bond at the γ-position of the β-ketocarbonyl derivatives with high enantioselectivities, are reported. The bond formation at the α-position of the β-ketoester was reversible, and the γ-position-reacted product δ-amino β-ketoester derivative was kinetically formed and was stable. The dynamic kinetic process was key for the direct access to the γ-position-reacted products from β-ketocarbonyls under catalytic conditions.

Catalytic Enantioselective Construction of Decalin Derivatives by Dynamic Kinetic Desymmetrization of C2-Symmetric Derivatives through Aldol-Aldol Annulation.

We have developed and investigated a catalytic desymmetrization reaction strategy that affords functionalized decalin derivatives with high enantioselectivities from C2-symmetric derivatives through aldol-aldol annulation. We identified the structural moieties of the catalyst necessary for the formation of the decalin derivative with high enantioselectivity. We elucidated the mechanisms of the catalyzed reactions: the first aldol reaction step was reversible, and the second aldol step was rate-limiting and stereochemistry-determining and was enantioselective.

Control of Reactions of Pyruvates by Catalysts: Direct Enantioselective Mannich Reactions of Pyruvates Catalyzed by Amine-based Catalyst Systems.

Enantioselective Mannich reactions of pyruvates catalyzed by amine-based catalyst systems, in which pyruvates act as nucleophiles, are reported. The reactions of pyruvates and cyclic sulfonylimines afforded the desired Mannich products, including those bearing tetrasubstituted carbon centers, in high yields with high enantioselectivities in most cases. The selection of the acid used in the amine-based catalyst system was key for the formation of the Mannich products with high enantioselectivities.

Varying the Directionality of Protein Catalysts for Aldol and Retro-Aldol Reactions.

Natural aldolase enzymes and created retro-aldolase protein catalysts often catalyze both aldol and retro-aldol reactions depending on the concentrations of the reactants and the products. Here, we report that the directionality of protein catalysts can be altered by replacing one amino acid. The protein catalyst derived from a scaffold of a previously reported retro-aldolase catalyst, catalyzed aldol reactions more efficiently than the previously reported retro-aldolase catalyst.

Organocatalytic diastereo- and enantioselective oxa-hetero-Diels-Alder reactions of enones with aryl trifluoromethyl ketones for the synthesis of trifluoromethyl-substituted tetrahydropyrans.

Tetrahydropyran derivatives are found in bioactives, and introduction of the trifluoromethyl group into molecules often improves biofunctions. Here we report diastereo- and enantioselective oxa-hetero-Diels-Alder reactions catalyzed by amine-based catalyst systems that afford trifluoromethyl-substituted tetrahydropyranones. Catalyst systems and conditions suitable for the reactions to provide the desired diastereomer products with high enantioselectivities were identified, and various trifluoromethyl-substituted tetrahydropyranones were synthesized with high diastereo- and enantioselectivities.

Dynamic Kinetic Asymmetric Transformation of Racemic Diastereomers: Diastereo- and Enantioconvergent Michael-Henry Reactions to Afford Spirooxindoles Bearing Furan-Fused Rings.

Dynamic kinetic asymmetric transformation (DYKAT) reactions of racemic diastereomer mixtures that afford the products as essentially single diastereomers with high enantioselectivities are described. We demonstrated the DYKAT in the diastereo- and enantioselective synthesis of spirooxindoles bearing furan-fused rings. The starting materials of the DYKAT, dihydrobenzofuranone derivatives, were synthesized in racemic diastereomer mixtures, and these were transformed to the spirooxindole derivatives in high yields with high diastereo- and enantioselectivities through Michael-Henry cascade reactions with nitrostyrenes under organocatalytic conditions.

Intramolecular Formal [4 + 2] Cycloadditions: Synthesis of Spiro Isoindolinone Derivatives and Related Molecules.

Acid-catalyzed intramolecular reactions of isoindolinone-derived hydroxylactam derivatives bearing enones or enals that afford spiro isoindolinone derivatives and related molecules have been developed. From the hydroxylactam moieties, -acylenamides were generated in situ and reacted with the enone and the enal moieties via formal [4 + 2] cycloaddition reactions to construct cyclohexanone- and dihydropyran-fused ring systems and the spiro ring systems.

Enantioselective Direct -Selective Mannich-type Reactions Catalyzed by 3-Pyrrolidinecarboxylic Acid in the Presence of Potassium Carbonate: Addition of Potassium Carbonate Improves Enantioselectivities.

Mannich-type reactions of cyclohexanone and related six-membered-ring ketones with --methoxyphenyl-protected imines of arylaldehydes catalyzed by 3-pyrrolidinecarboxylic acid in the presence of KCO that afford -isomers of the Mannich products with high diastereo- and enantioselectivities are reported. Addition of KCO improved the enantioselectivities of the reactions catalyzed by 3-pyrrolidinecarboxylic acid while retaining the -selectivity of the reaction. Thus, the use of KCO expands the scope of these organocatalytic reactions for providing the products with high enantioselectivities.

Switching Electrophile Intermediates to Nucleophiles: Michael and Oxa-Diels-Alder Reactions to Afford Polyoxy-Functionalized Piperidine Derivatives with Tetrasubstituted Carbon.

Michael, Michael-annulation, and oxa-Diels-Alder reactions of carbohydrate derivatives that afford polyoxy-functionalized piperidine derivatives bearing tetrasubstituted carbon at the 3-position of the piperidine ring are reported. Iminium ions generated from carbohydrate derivatives with amines were converted to enamines in situ, which acted as nucleophiles. As a result, substituents were introduced at the 3-position or both 2- and 3-positions of the piperidines bearing polyoxy groups.

Direct Catalytic Asymmetric Synthesis of Oxindole-Derived δ-Hydroxy-β-ketoesters by Aldol Reactions.

Direct asymmetric synthesis of δ-hydroxy-β-ketoesters was accomplished via regio- and enantioselective aldol reactions of β-ketoesters with isatins catalyzed by cinchona alkaloid thiourea derivatives. The C-C bond formation of the reactions occurred only at the γ-position of the β-ketoesters. Reaction progress monitoring and product stability analyses under the conditions that included the catalyst indicated that the γ-position reaction products were formed kinetically.

Control of Chemical Reactions by Using Molecules that Buffer Non-aqueous Solutions.

Control of chemical reactions is necessary to obtain designer chemical transformation products and for preventing decomposition and isomerization reactions of compounds of interest. For the control of chemical events in aqueous solutions, the use of aqueous buffers is a common practice. However, no molecules that buffer non-aqueous solutions were commonly used.

Intramolecular Mannich and Michael Annulation Reactions of Lactam Derivatives Bearing Enals To Afford Bicyclic N-Heterocycles.

Acid-catalyzed intramolecular vinylogous Mannich reactions and intramolecular Michael reactions affording pyrrolizinone-fused N-heterocycles from hydroxylactam derivatives bearing enals have been developed. Depending on the substituent on the hydroxylactam, the enal moiety acted either as a nucleophile (i.e.

Mannich Reactions of Carbohydrate Derivatives with Ketones To Afford Polyoxy-Functionalized Piperidines.

Mannich reactions of carbohydrate derivatives with ketones that afford polyoxy-functionalized piperidines are reported. Ketone nucleophiles (enamines/enolates) were generated in the presence of the amines used for the formation of the iminium ions of sugar derivatives with or without an additive. Conditions to preferentially generate piperidine derivatives rather than tetrahydrofurans were identified.

Catalytic Enantioselective Formal (4+2) Cycloaddition by Aldol-Aldol Annulation of Pyruvate Derivatives with Cyclohexane-1,3-Diones to Afford Functionalized Decalins.

The decalin structure is found in bioactive molecules. We have developed catalytic enantioselective formal (4+2) cycloaddition reactions via aldol-aldol cascade reactions between pyruvate-derived diketoester derivatives and cyclohexane-1,3-dione derivatives that afford highly functionalized decalin derivatives. The reactions were performed using a quinidine-derived catalyst under mild conditions.

Correction: Synthesis of pyrrolidine-3-carboxylic acid derivatives via asymmetric Michael addition reactions of carboxylate-substituted enones.

Correction for 'Synthesis of pyrrolidine-3-carboxylic acid derivatives via asymmetric Michael addition reactions of carboxylate-substituted enones' by Feng Yin et al., Org. Biomol.

C-Glycosidation of Unprotected Di- and Trisaccharide Aldopyranoses with Ketones Using Pyrrolidine-Boric Acid Catalysis.

C-Glycoside derivatives are found in pharmaceuticals, glycoconjugates, probes, and other functional molecules. Thus, C-glycosidation of unprotected carbohydrates is of interest. Here the development of C-glycosidation reactions of unprotected di- and trisaccharide aldopyranoses with various ketones is reported.

Synthesis of pyrrolidine-3-carboxylic acid derivatives via asymmetric Michael addition reactions of carboxylate-substituted enones.

To concisely synthesize highly enantiomerically enriched 5-alkyl-substituted pyrrolidine-3-carboxylic acids, organocatalytic enantioselective Michael addition reactions of 4-alkyl-substituted 4-oxo-2-enoates with nitroalkanes have been developed. Using the developed reaction method, 5-methylpyrrolidine-3-carboxylic acid with 97% ee was obtained in two steps.

Determination of Relative Frequency of Carbanion Formation at α-Positions of Ketones under Aldol Reaction Catalysis Conditions.

To provide insight into aldol reaction catalysis, the relative frequencies of carbanion formation at each α-position of ketones under catalysis by DBU, proline, β-proline, and related catalysts were determined through the deuteration of the ketones in the presence of these catalysts. For selected cases, the deuteration rate was compared with the aldol reaction rate and whether the generated enolate/enamine resulted in return to the ketone or product formation was estimated.

Formal (4+1) Cycloaddition and Enantioselective Michael-Henry Cascade Reactions To Synthesize Spiro[4,5]decanes and Spirooxindole Polycycles.

Spiro[4,5]decanes and polycyclic compounds bearing spiro[4,5]decane systems are important biofunctional molecules. Described are diastereoselective formal (4+1) cycloaddition reactions to afford oxindole-functionalized spiro[4,5]decanes and organocatalytic enantioselective Michael-Henry cascade reactions of the (4+1) cycloaddition products to generate spirooxindole polycyclic derivatives bearing the spiro[4,5]decane system. Spiro[4,5]decanes bearing oxindoles containing three stereogenic centers and spirooxindole polycycles having seven stereogenic centers, including two all-carbon chiral quaternary centers and one tetrasubstituted chiral carbon center, were obtained with high diastereo- and enantioselectivities.

Discovery of SOAT2 inhibitors from synthetic small molecules.

Synthesis of new functionalized molecules and identification of biofunctional molecules can lead to the development of therapeutic leads and molecular tools for biomedical research. We have recently reported oxa-hetero-Diels-Alder reactions of enones with isatins to provide functionalized spirooxindole tetrahydropyran derivatives. Twenty-one compounds from the spirooxindole tetrahydropyran derivatives and related molecules were screened for inhibition of sterol O-acyltransferase (SOAT) isozymes SOAT1 and SOAT2.