ScIII‐Doped Zeolites as New Heterogeneous Catalysts: Mukaiyama Aldol Reaction

Sc^III‐doped solids based on zeolite materials have been investigated for the first time as catalysts in organic synthesis. Sc^III–USY zeolite proved to be a novel and very efficient heterogeneous catalyst for the Mukaiyama aldol reaction. This easy‐to‐prepare catalyst exhibited wide scope and compatibility with functional groups and is very simple to use, easy to remove (by simple filtration), and is recyclable (up to three times without loss of activity).     

Carbene‐Catalyzed Enantioselective Aldol Reaction: Post‐Aldol Stereochemistry Control and Formation of Quaternary Stereogenic Centers

The dominated approaches for asymmetric aldol reactions have primarily focused on the aldol carbon–carbon bond‐forming events. Here we postulate and develop a new catalytic strategy that seeks to modulate the reaction thermodynamics and control the product enantioselectivities via post‐aldol processes. Specifically, an NHC catalyst is used to activate a masked enolate substrate (vinyl carbonate) to promote the aldol reaction in a non‐enantioselective manner. This reversible aldol event is subsequently followed by an enantioselective acylative kinetic resolution that is mediated by the same (chiral) NHC catalyst without introducing any additional substance. This post‐aldol process takes care of the enantioselectivity issues and drives the otherwise reversible aldol reaction toward a complete conversion. The acylated aldol products bearing quaternary/tetrasubstituted carbon stereogenic centers are formed in good yields and high optical purities.     

C1‐Symmetric Aminosulfoximines in Copper‐Catalyzed Asymmetric Vinylogous Mukaiyama Aldol Reactions

Vinylogous Mukaiyama‐type aldol reactions have been catalyzed by a combination of Cu(OTf)₂ and readily available C₁‐symmetric aminosulfoximines. After a fine‐tuning of the reaction conditions and an optimization of the modularly assembled ligand structure, high stereoselectivities and excellent yields have been achieved in catalyzed reactions involving various electrophile/nucleophile combinations. The relative and absolute configurations of two products were assigned by X‐ray single crystal structure analysis and a comparison of calculated and experimental CD spectra.     

Direct Catalytic Enantio‐ and Diastereoselective Ketone Aldol Reactions of Isocyanoacetates

A catalytic asymmetric aldol addition/cyclization reaction of unactivated ketones with isocyanoacetate pronucleophiles has been developed. A quinine‐derived aminophosphine precatalyst and silver oxide were found to be an effective binary catalyst system and promoted the reaction to afford chiral oxazolines possessing a fully substituted stereocenter with good diastereoselectivities and excellent enantioselectivities.     

Site‐Selective 1,2‐Dicarbofunctionalization of Vinyl Boronates through Dual Catalysis

A modular, site‐selective 1,2‐dicarbofunctionalization of vinyl boronates with organic halides through dual catalysis is described. This reaction proceeds under mild conditions and is characterized by excellent chemo‐ and regioselectivity. It thus represents a complementary new technique for preparing densely functionalized alkyl boron architectures from simple and accessible precursors.     

Construction of Chiral 2,3‐Allenols through a Copper(I)‐Catalyzed Asymmetric Direct Alkynylogous Aldol Reaction

Chiral 2,3‐allenols were constructed through copper(I)‐catalyzed asymmetric direct alkynylogous aldol reaction. With aromatic and heteroaromatic aldehydes, the alkynylogous aldol reaction with (R)‐DTBM‐SEGPHOS as the ligand proceeded smoothly to furnish the products in excellent regioselectivity with good to high diastereoselectivity and excellent enantioselectivity. In the cases of aliphatic aldehydes, esters of but‐2‐yn‐1‐ol as the substrates and (R,R)‐Ph‐BPE as the ligand were found to be crucial to get good to high regio‐ and diastereoselectivity. The produced chiral 2,3‐allenols are easily transformed into synthetically useful 2‐furanones through cyclization. Finally, the developed method was successfully applied in the rapid synthesis of two chiral intermediates toward the synthesis of two pharmaceutically active compounds that have been proposed for the treatment of neurological disorders.     

Direct Catalytic Asymmetric Aldol Reaction of an α‐Azido Amide

A direct aldol reaction of an α‐azido 7‐azaindolinylamide, promoted by a Cu‐based cooperative catalyst, is documented. Aromatic aldehydes bearing an ortho substituent exhibited diastereodivergency depending on the nature of the chiral ligands used. Smooth reactions with ynals highlighted the broad substrate scope. A vicinal azido alcohol unit in the product allowed direct access to the corresponding aziridine and facile hydrolysis of the 7‐azaindolinylamide moiety furnished enantioenriched β‐hydroxy‐α‐azido carboxylic acid derivatives.     

Chirally Functionalized Hollow Nanospheres Containing L‐Prolinamide: Synthesis and Asymmetric Catalysis

Chirally functionalized hollow nanospheres with different surface properties were successfully synthesized by co‐condensation of (2S,1′R,2′R)‐N‐tert‐butyloxycarbonylpyrrolidine‐2‐carboxylic acid [2′‐(4‐trimethoxysilylbenzylamide)cyclohexyl] amide with 1,2‐bis(trimethoxysilyl)ethane or tetramethoxysilane using F127 (EO₁₀₆PO₇₀EO₁₀₆) as surfactant in water. The TEM and N₂ sorption characterizations show that the particle size of the hollow nanosphere is 15–21 nm with a core diameter of 10–16 nm. These L ‐prolinamide‐functionalized hollow nanospheres are highly efficient solid catalysts for the direct asymmetric aldol reaction between cyclohexanone and aromatic aldehydes. It was found that the addition of water in the reaction system not only enhanced the catalytic activity but also increased the enantioselectivity, which is probably due to the enhanced hydrogen bond between the amide oxygen atom and the hydroxyl group of water. Moreover, the catalytic activity increases sharply as the surface hydrophobicity of the hollow nanospheres increases. These hollow nanospheres are quite stable and can be reused with almost the same enantioselectivity and only a slight decrease in catalytic activity.     

Development of a syn‐Selective Mannich Reaction of Aldehydes with Propargylic Imines by Dual Catalysis: Asymmetric Synthesis of Functionalized Propargylic Amines

Direct coupling of enolizable aldehydes with C‐alkynyl imines is realized affording the corresponding propargylic Mannich adducts of syn configuration, thus complementing previous methods that gave access to the anti‐isomers. The combination of proline and a urea Brønsted base cocatalyst is key for the reactions to proceed under very mild conditions (3–10 mol % catalyst loading, dichloromethane as solvent, ?20 °C, 1.2 molar equivalents of aldehyde) and with virtually total stereocontrol (syn/anti ratio up to 99:1; ee up to 99 %). Some possibilities of further chemical elaboration of adducts are also briefly illustrated.     

Catalyzed Vinylogous Mukaiyama Aldol Reactions with Controlled Enantio‐ and Diastereoselectivities

In control : A new catalytic vinylogous Mukaiyama aldol reaction provides products with high diastereo‐ and enantioselectivities (up to 99 % de and ee; see scheme). The relative and absolute stereochemistry of a representative product was rigorously assigned by NMR and CD spectroscopies (measured and calculated), X‐ray diffraction, and quantum‐chemical calculations.

     

Engineering the Donor Selectivity of D‐Fructose‐6‐Phosphate Aldolase for Biocatalytic Asymmetric Cross‐Aldol Additions of Glycolaldehyde

D ‐Fructose‐6‐phosphate aldolase (FSA) is a unique catalyst for asymmetric cross‐aldol additions of glycolaldehyde. A combination of a structure‐guided approach of saturation mutagenesis, site‐directed mutagenesis, and computational modeling was applied to construct a set of FSA variants that improved the catalytic efficiency towards glycolaldehyde dimerization up to 1800‐fold. A combination of mutations in positions L107, A129, and A165 provided a toolbox of FSA variants that expand the synthetic possibilities towards the preparation of aldose‐like carbohydrate compounds. The new FSA variants were applied as highly efficient catalysts for cross‐aldol additions of glycolaldehyde to N‐carbobenzyloxyaminoaldehydes to furnish between 80–98 % aldol adduct under optimized reaction conditions. Donor competition experiments showed high selectivity for glycolaldehyde relative to dihydroxyacetone or hydroxyacetone. These results demonstrate the exceptional malleability of the active site in FSA, which can be remodeled to accept a wide spectrum of donor and acceptor substrates with high efficiency and selectivity.     

Zinc(II)‐Catalyzed Intermolecular Hydrative Aldol Reactions of 2‐En‐1‐ynamides with Aldehydes and Water to form Branched Aldol Products Regio‐ and Stereoselectively

This work describes zinc(II)‐catalyzed hydrative aldol reactions of 2‐en‐1‐ynamides with aldehydes and water to afford branched aldol products regio‐ and stereoselectively. The anti and syn selectivity can be modulated by the sizes of sulfonamides to yield E‐ and Z‐configured zinc(II) dienolates selectively. This new reaction leads to enantiopure aldol products by using a cheap chiral sulfonamide. The mechanistic analysis reveals that the sulfonamide amides of the substrates can trap a released proton to generate dual acidic sites to activate a carbonyl allylation reaction.     

CuI/Pd0 Cooperative Dual Catalysis: Tunable Stereoselective Construction of Tetra‐Substituted Alkenes

This paper describes a tunable and stereoselective dual catalytic system that uses copper and palladium reagents. This cooperative silylcupration and palladium‐catalyzed allylation readily affords trisubstituted alkenylsilanes. Fine‐tuning the reaction conditions allows selective access to one stereoisomer over the other. This new methodology tolerates different substituents on both coupling partners with high levels of stereoselectivity. The one‐pot reaction involving a Cu^I/Pd⁰ cooperative dual catalyst directly addresses the need to develop more time‐efficient and less‐wasteful synthetic pathways.