Proline‐Catalyzed Asymmetric Aldol Reaction in Guanidine‐ Derived Ionic Liquids

A remarkable improvement of both the chemical yield (from 6% to 82%) and the enantiomeric excess (up to >99%), of (S)‐proline catalyzed direct aldol reactions of a wide range of aldehydes with acetone was found when hexasubstituted or pentasubstituted guanidinium salts were added as ionic liquids. Effects of temperature, amount of proline and the type of guandidinium salts on the outcome of the reaction were investigated.     

The Addition Reaction of Samarium Enolates and 2‐Haloenolates Derived from Esters,and Amides to Imines. Totally Stereoselective Synthesis of Enantiopure 3,4‐Diamino Esters or Amides

The addition reaction of samarium enolates and 2‐haloenolates derived from esters and amides to imines takes place in an efficient manner. A novel protocol to perform the addition reaction of samarium enolates derived from esters or amides to chiral 2‐aminoimines, with total stereoselectivity and without racemization, is also reported. The use of samarium enolates in place of other classic metallic enolates (lithium, magnesium, etc.) could be a valuable alternative to obtain enantiopure 3,4‐diamino esters or amides, when enolates of low basicity are necessary.     

Pyrrole‐Assisted and Easy Oxidation of Cyclic α‐Amino Acid‐ Derived Diketopiperazines under Mild Conditions

A new procedure for the aerobic oxidation of α‐amino acids acylated by pyrrole‐carboxylic acid with triplet dioxygen is introduced. The reaction is general for a variety of pyrrole‐amino acid derivatives and represents a very practical and controllable method for the selective preparation of α‐hydroperoxy‐ or α‐hydroxy‐α‐amino acid diketopiperazines with molecular dioxygen. Furthermore, the non‐catalyzed direct oxidation of amino acid derivatives at the α‐position with molecular dioxygen represents a fundamental question.     

Asymmetric Mukaiyama‐Aldol Reaction in Aqueous Media Promoted by Zinc‐Based Chiral Lewis Acids

Asymmetric aldol reactions in aqueous media have been realized by using zinc‐based chiral Lewis acids. The aldol products have been obtained with high yield, diastereocontrol and a good level of enantioselectivity. The reactivity of both acetophenone and propiophenone enol ether surrogates was tested with a range of aldehydes.     

Solid Acids as Heterogeneous Support for Primary Amino Acid‐Derived Diamines in Direct Asymmetric Aldol Reactions

We have achieved the non‐covalent immobilization of chiral primary amino acid‐derived diamines on organic and inorganic sulfonated solid acids through acid‐base interaction. With the commercial sulfonated fluoropolymer nafion® NR50 as support an optimal balance was found between activity and stereoselectivity of the supported catalyst in direct asymmetric aldol reactions of linear ketones and aromatic aldehydes. Under optimized conditions aldol products were obtained in high yields and with excellent enantioselectivities for the syn‐product (up to 98% ee). Furthermore, catalysis with the supported diamine was demonstrated to occur truly heterogeneously and the loaded nafion® NR50 beads could be reused several times. Ultimately, the immobilized catalyst/nafion® NR50 system was successfully implemented in a fixed‐bed reactor set‐up under continuous flow conditions.     

An Enantioselective Recyclable Polystyrene‐Supported Threonine‐Derived Organocatalyst for Aldol Reactions

A series of primary amino acids covalently supported onto polystyrene through alkyne–azide cycloaddition reactions has been synthesized and evaluated as catalysts in asymmetric aldol reactions. A polymer‐supported threonine behaves as an easily recyclable, highly reactive and stereoselective (up to 99% ee) catalyst in the aldol reaction of both cyclic and acyclic ketone donors with aromatic aldehydes in aqueous environments. While cyclic ketones react with anti diastereoselectivity, syn adducts are predominantly obtained with acyclic substrates. The heterogenized threonine catalyst has been used for the sequential synthesis of a small library of enantiopure aldol products.

     

Highly Enantioselective Biginelli Reaction Promoted by Chiral Bifunctional Primary Amine‐Thiourea Catalysts: Asymmetric Synthesis of Dihydropyrimidines

The diastereospecific formation of dihydropyrimidines (DHPMs) has been achieved in moderate to high yields with up to 99% ee by a Biginelli reaction. The reaction was performed by using a combined catalyst consisting of a chiral bifunctional primary amine‐thiourea 9f and a Brønsted acid with tert‐butylammonium trifluoroacetate (t‐BuNH₂⋅TFA) as additive in dichloromethane at room temperature. The possible mechanism for the reaction has been proposed to explain the origin of the activation and the asymmetric induction.     

Asymmetric Aldol Reaction of 3‐Acetyl‐2H‐chromen‐2‐ones and Isatins Catalyzed by a Bifunctional Quinidine Urea Catalyst

The asymmetric aldol reaction of 3‐acetyl‐2H‐chromen‐2‐ones and isatins has been realized by using a bifunctional quinidine‐derived urea as the catalyst. The corresponding 3‐hydroxyoxindole derivatives containing a 2H‐chromen‐2‐one moiety were obtained in good yields and high enantioselectivities. When (Z)‐ethyl 2‐benzylideneacetoacetate was used as the substrate, a mixture of two diastereomers (both Z and E) was obtained due to isomerization of the double bond under the reaction conditions.

     

Asymmetric Synthesis of α‐Amino Acids under Operationally Convenient Conditions

A new multipurpose glycine equivalent for the general asymmetric synthesis of α‐amino acids is introduced. The chiral reagent can be transformed to various amino acids by alkylations with alkyl halides as well as aldol and Michael addition reactions under operationally convenient reaction conditions at room temperature with virtually complete stereochemical control.

     

Chiral Phosphoric Acid‐Catalyzed Asymmetric Aza‐Friedel–Crafts Reaction of Indoles with Cyclic N‐Acylketimines: Enantioselective Synthesis of Trifluoromethyldihydroquinazolines

An enantioselective aza‐Friedel–Crafts (F‐C) reaction of indoles with cyclic N‐acylketimines has been developed. By using chiral phosphoric acid catalysts, a wide range of enantioenriched trifluoromethyldihydroquinazolines was obtained in excellent yields (up to 98%) with good to high enantioselectivities (up to 99% ee).

     

Organocatalytic Enantioselective Strecker Synthesis of α‐Quaternary α‐Trifluoromethyl Amino Acids

The first organocatalytic enantioselective Strecker synthesis of α‐quaternary α‐trifluoromethylated amino acids has been developed. Employing Takemoto’s thiourea catalyst the nucleophilic addition of trimethylsilyl cyanide to trifluoromethyl ketimines affords α‐amino nitriles in good to excellent yields (50–99%) and very good enantioselectivities (ee=83–95%). The enantiopure amino nitriles can be obtained by recrystallization. Deprotection and hydrolysis leads to the title amino acids.     

Tandem Gold‐Catalyzed Hydrosilyloxylation–Aldol and –Mannich Reaction with Alkynylaryloxysilanols in 6‐exo Mode

The tandem gold‐catalyzed hydrosilyloxylation–aldol and hydrosilyloxylation–Mannich reactions were developed through the formation of an enol silyl ether catalytically generated in situ from alkynylaryloxysilanols in the 6‐exo mode in one reaction vessel.     

In Situ Formed Bifunctional Primary Amine‐Imine Catalyst: Application to the Construction of Chiral Tertiary Alcohols through Asymmetric Aldol‐Type Reaction

An in situ formation method to obtain chiral bifunctional primary amine‐imine catalysts from the C₂‐symmetric chiral diimines has been developed. The efficiency of this method in the construction of chiral tertiary alcohols which are valuable pharmaceutical intermediates is proved by its application to the asymmetric aldol‐type reaction of cyclic ketones with other activated ketone compounds as the enamine acceptors, i.e., β,γ‐unsaturated α‐keto esters and isatins. In general, good to excellent diastereoselectivities and enantioselectivities (up to 96/4 dr, 96% ee for β,γ‐unsaturated α‐keto esters and up to 91/9 dr, 94% ee for isatins) were obtained. The active primary amine‐imine catalylst and enamine intermediate in the reaction process could be demonstrated by ESI‐MS analysis.     

A 100 Gram‐Scale Production of a Key Building Block of Antibacterial Vancomycin: The Use of an Air‐Stable Chiral Zirconium Catalyst and Complete Recovery of a Silicon Source in Catalytic Asymmetric Mukaiyama Aldol Reaction

We have achieved a 100 gram‐scale production of anti‐(2S,3S)‐β‐(p‐benzyloxy‐m‐chloro)phenyl‐N‐trifluoroacetyl‐L ‐serine methyl ester ( 1 ) in high yield with high diastereo‐ and enantioselectivities based on a catalytic asymmetric Mukaiyama aldol reaction. The use of an air‐stable zirconium‐molecular sieves combined catalyst [(R)‐I₄‐ZrMS] facilitates easy manufacturing operation and reproducibility. Moreover, this is the first example of the complete recovery of the silicon source in a Mukaiyama aldol reaction.     

Alkali Metal tert‐Butoxides,Hydrides and Bis(trimethylsilyl)amides as Efficient Homogeneous Catalysts for Claisen–Tishchenko Reaction

Shelf‐available alkali metal tert‐butoxides, hydrides and bis(trimethylsilyl)amides were shown to be highly efficient homogeneous precatalysts for the disproportionation of aldehydes to the corresponding carboxylic esters. Potassium compounds in combination with 18‐crown‐6 ether could drastically increase the rate of reaction in a few cases. Alternatively, efficient aldol condensations were found for aldehydes possessing an enolizable methylene group at the α‐position to the aldehyde functionality. The active species involved in this esterification using any of these alkali metal catalysts is expected to be the metal alkoxide. Potassium compounds were found to be much more efficient when compared to analogous sodium compounds and kinetic studies revealed the rate‐determining step to be a second order concerted hydride transfer from a potassium hemiacetal species to another molecule of aldehyde.     

Simple Chiral Diaminobinaphthyl Dilithium Salts for Intramolecular Catalytic Asymmetric Hydroamination of Amino‐1,3‐dienes

Simple and easily accessible chiral lithium amide salts are reported as efficient (pre)catalysts for the diastereo‐ [up to (E:Z)=92:8] and enantioselective [up to 72% ee (E)] hydroamination/cyclisation of conjugated primary aminodienes. These chiral lithium salts are straightforwardly prepared by in situ combination of an N‐substituted (R)‐(+)‐1,1′‐binaphthyl‐2,2′‐diamine ligand and a commercial methyllithium solution. Information on the solid‐state structure of these salts was obtained by X‐ray analysis of a single crystal.     

L‐Prolinethioamides – Efficient Organocatalysts for the Direct Asymmetric Aldol Reaction

A series of novel L ‐proline derived thioamides has been synthesised. They have been evaluated as organocatalysts in the direct asymmetric aldol reaction for the first time. Thioamides exhibit catalytic ability higher than proline itself and the model aldol reaction of 4‐cyanobenzaldehyde with acetone proceeds well in the presence of 5 mol % of catalyst (ee up to 100%). Other aromatic aldehydes gave aldol products with high ees and moderate yields. Small changes in the catalyst's structure [e.g., N‐Bn versus N‐CH(CH₃)Ph] as well as the addition of an acid have a profound effect on their activity. The unexpected formation of the catalyst‐derived cyclic adducts was observed and their reactivity was established giving valuable insight into the course of the reaction.