Asymmetric Michael reactions of α,α-disubstituted aldehydes with maleimides using a primary amine thiourea organocatalyst

Primary amine thiourea organocatalyst 8 was used to promote Michael additions of bulky α,α-disubstituted aldehydes, such as isobutyraldehyde with maleimides to afford the corresponding adducts in high to excellent yields and with up to 91% ee.     

Calixarene-based highly efficient primary amine–thiourea organocatalysts for asymmetric Michael addition of aldehydes to nitrostyrenes

The synthesis of calix[4]arene-based chiral bifunctional primary amine–thiourea catalysts has been described from p-tert-butylcalix[4]arene for the first time. The calix[4]arene-based catalysts were successfully applied to promote Michael addition of aldehydes with nitroalkenes affording preferentially the (R)- or (S)-adducts in high yields (up to 95%) and excellent enantioselectivities (up to 99% ees).     

Enantioselective Michael addition of α,α-disubstituted aldehydes to maleimides organocatalyzed by chiral primary amine-guanidines

New primary amine-guanidines derived from the monoguanylation of (1S,2S)- and (1R,2R)-cyclohexane-1,2-diamine have been prepared and used as chiral organocatalysts for the enantioselective conjugate addition of α,α-disubstituted aldehydes to maleimides. The corresponding Michael adducts bearing a new stereocenter were generally obtained in high or quantitative yields and with good enantioselectivities (up to 93% ee).     

Highly enantioselective Michael addition of α,α-disubstituted aldehydes to maleimides catalyzed by new primary amine-squaramide bifunctional organocatalysts

New bifunctional primary amine-squaramides catalyzed asymmetric Michael addition reaction of α,α-disubstituted aldehydes to maleimides has been developed. This organocatalytic asymmetric reaction provides easy access to functionalized succinimides with a broad substrate scope. Both enantiomers of desired succinimide derivatives were obtained in good to excellent yields (up to 98%) with excellent enantioselectivities (up to >99%?ee).     

Asymmetric Michael addition of α-substituted isocyanoacetates with maleimides catalyzed by chiral tertiary amine thiourea

A highly diastereoselective and enantioselective Michael addition of α-substituted isocyanoacetates with maleimides catalyzed by bifunctional tertiary amine thioureas has been developed. Various chiral succinimide derivatives bearing adjacent quaternary and tertiary stereocenters were prepared in excellent yields (up to 98%), diastereoselectivities (up to 99:1), and enantioselectivities (up to 98% ee). The synthetic utility of chiral succinimide derivatives is also demonstrated in the preparation of h5-HT(1d) receptor agonist motifs.     

Highly asymmetric Michael additions of α,α-disubstituted aldehydes to β-nitroalkenes promoted by chiral pyrrolidine-thiourea bifunctional catalysts

A series of secondary amine-thiourea catalysts derived from l-proline and chiral diamine were prepared and first applied to the Michael addition of α,α-disubstituted aldehydes to trans-β-nitroalkenes. Moderate yields (47-75%) and excellent enantioselectivities (up to 96% ee) were obtained for a variety of aryl and heteroaryl nitroalkenes.     

Highly effective and enantioselective Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones promoted by simple chiral primary amine thiourea bifunctional catalysts

Highly asymmetric Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones promoted by chiral primary amine thiourea bifunctional catalysts was developed and a series of Michael adducts were obtained in excellent yields (up to 97%) and enantioselectivities (up to 95% ee). Optically pure S-warfarin was easily obtained in 99% ee after single recrystallization.     

Primary amine catalyzed electrophilic amination of α,α-disubstituted aldehydes

Organocatalytic α-amination of α,α-disubstituted aldehydes promoted by 9-amino-(9-deoxy)-epi-quinine is described. α-Hydrazino aldehydes bearing a quaternary stereogenic center are obtained in good to excellent yields and enantioselectivities.     

Cinchona-based primary amine-catalyzed enantioselective aza-Michael reactions of pyrroles with α,β-unsaturated aldehydes

The cinchona-based primary amine-catalyzed enantioselective aza-Michael reaction of α,β-unsaturated aldehydes with 4,5-dihalo-1H-pyrrole-2-carbonitriles as the N-centered heteroaromatic nucleophile, followed by chemoselective reduction provided the corresponding chiral aza-Michael products in good yields and with excellent enantioselectivities (90–97% ee).     

Highly efficient asymmetric organocatalytic Michael addition of α,α-disubstituted aldehydes to nitroolefins under solvent-free conditions

A chiral pyrrolide-based diamine in combination with benzoic acid has been found to be an effective organocatalyst for Michael addition of α,α-disubstituted aldehydes with nitroolefins. The reaction provided the desired Michael products possessing all-carbon quaternary center with high yields (76–98%) and high levels of enantioselectivities (up to 97% ee) under solvent-free reaction conditions. The procedure presented is simple and makes this method suitable for practical use.     

Solvent-dependent enantioswitching in the Michael addition of α,α-disubstituted aldehydes to maleimides organocatalyzed by mono-N-Boc-protected cyclohexa-1,2-diamines

Enantiomerically pure mono-N-Boc-protected trans-cyclohexa-1,2-diamines are used as organocatalysts for the enantioselective conjugate addition of α,α-disubstituted aldehydes to maleimides. Using a single enantiomer of the organocatalyst, both enantiomeric forms of the resulting Michael adducts bearing a new quaternary stereocenter are obtained in high yields, by only changing the reaction solvent from chloroform (up to 86% ee) to aqueous DMF (up to 84% ee).     

Direct regiospecific and highly enantioselective intermolecular α-allylic alkylation of aldehydes by a combination of transition-metal and chiral amine catalysts

The first direct intermolecular regiospecific and highly enantioselective α-allylic alkylation of linear aldehydes by a combination of achiral bench-stable Pd(0) complexes and simple chiral amines as co-catalysts is disclosed. The co-catalytic asymmetric chemoselective and regiospecific α-allylic alkylation reaction is linked in tandem with in situ reduction to give the corresponding 2-alkyl alcohols with high enantiomeric ratios (up to 98:2 e.r.; e.r.=enantiomeric ratio). It is also an expeditious entry to valuable 2-alkyl substituted hemiacetals, 2-alkyl-butane-1,4-diols, and amines. The concise co-catalytic asymmetric total syntheses of biologically active natural products (e.g., Arundic acid) are disclosed.     

Enantioselective α-amination of branched aldehydes promoted by simple chiral primary amino acids

A series of simple chiral primary amino acids were first successfully applied to promote the enantioselective α-amination of branched aldehydes with azadicarboxylates and the desired adducts bearing quaternary stereogenic centers were obtained in excellent yields (up to 99%) and enantioselectivities (up to 97% ee).     

Enantioselective aldol reactions of α,β-unsaturated ketones with trifluoroacetophenone catalyzed by a chiral primary amine

Chiral primary amine catalyzed direct asymmetric aldol reactions of ketones with trifluoroacetophenone, afforded trifluoromethylated β-hydroxycarbonyl aldol products bearing a quaternary carbon stereogenic center in high yields (up to 93% yield) and with high to excellent enantioselectivities of up to 99% ee.     

Highly effective and enantioselective α-amination of aldehydes promoted by chiral proline amide-thiourea bifunctional catalysts

A series of secondary amine-thiourea catalysts derived from l-proline and chiral diamine were prepared and successfully applied to the highly effective and enantioselective α-amination of unmodified aldehydes with various azodicarboxylates in excellent yields (up to 99%) and enantioselectivities (up to 99% ee) within a few minutes.     

Enantioselective Michael addition of α,α-disubstituted aldehydes to nitroolefins catalyzed by a pyrrolidine-pyrazole

An efficient protocol for the asymmetric catalytic Michael additions of α,α-disubstituted aldehydes to nitroolefins with a pyrrolidine-pyrazole is described. The desired products γ-nitrocarbonyl compounds possessing an all-carbon quaternary center, were obtained in good yields and with high levels of enantioselectivities under solvent-free reaction conditions, employing benzoic acid as an additive.     

One-pot highly enantioselective catalytic Mannich-type reactions between aldehydes and stable α-amido sulfones: asymmetric synthesis of β-amino aldehydes and β-amino acids

A highly enantioselective catalytic route to carbamate- and benzoate-protected β-amino aldehydes and β-amino acids is presented. The amino acid-catalyzed one-pot asymmetric reaction between unmodified aldehydes and α-amido sulfones gives the corresponding β-amino compounds with up to 95:5 dr and 97->99% ee.     

Atropoisomeric (P,N) ligands for the highly enantioselective Pd-catalyzed intramolecular asymmetric α-arylation of α-branched aldehydes

Three-in-one: a short synthetic route readily gives access to a new class of chiral (P,N) ligands characterized by three distinct elements of chirality. These ligands are highly enantioselective in the challenging Pd-catalyzed intramolecular asymmetric α-arylation of α-branched aldehydes.     

Catalytic, asymmetric synthesis of α,α-disubstituted amino acids

Copper(salen) complex 1 has been found to catalyse the asymmetric alkylation of enolates derived from a variety of amino acids. There is a clear relationship between the size of the side chain in the substrate and the enantioselectivity of the process, so that the enantioselectivity decreases in the order alanine>aminobutyric acid>allylglycine>leucine>phenylalanine>valine. A transition state model which accounts for the influence of the size of the side chain on the enantioselectivity of the reactions is presented.     

Enantioselective α-benzoyloxylation of ketones promoted by primary amine catalyst

A mixture of 9-amino-(9-deoxy)epi-dihydroquinidine and salicylic acid was able to promote the direct reaction of various cyclohexanones with dibenzoyl peroxide, thus affording the corresponding protected α-hydroxy carbonyl compounds in high yield and enantioselectivity. Interestingly the same catalytic salt was found to be active when 1-indanones derivatives were directly employed in the reaction with dibenzoyl peroxide furnishing chiral 1-oxo-2,3-dihydro-1H-inden-2-yl benzoates in high yields and enantioselectivity. Furthermore their treatment with NaBH(4) gives easy access to the corresponding enantioenriched 1,2-diols in high yields and without any loss of stereoselectivity.