Organocatalytic and direct asymmetric vinylogous Michael addition of 3-cyano-4-methylcoumarins to α,β-unsaturated ketones

The first highly regio-, chemo-, and enantio-selective direct vinylogous Michael addition of 3-cyano-4-methylcoumarin derivatives to α,β-unsaturated ketones is described, employing readily available 9-amino-9-deoxy-epiquinine as the iminium organocatalyst.     

Organocatalytic asymmetric conjugate addition to allenic esters and ketones

The first example of an organocatalytic enantioselective conjugate addition of cyclic beta-ketoesters and glycine imine derivatives to electron-deficient allenes is described. We disclose that the corresponding chiral beta,gamma-unsaturated carbonyl compounds are formed exclusively under phase-transfer conditions using either cinchona-alkaloid-derived or biphenyl-based chiral quaternary ammonium salts as catalysts. The scope of the reaction for beta-ketoesters is outlined for allenes having a ketone or ester motif as electron-withdrawing group as well as different substituents in the 3-position, giving the optically active products in high yields and excellent diastereo- and enantioselectivities (90-96% ee). The conjugate addition also proceeds for a number of cyclic beta-ketoesters having different ring sizes, ring systems, and substituents in high yields and enantioselectivities. Glycine imine derivatives also undergo the asymmetric conjugate addition to electron-deficient allenes in high yields and with enantioselectivities in the range of 60-88% ee, thus providing a rapid entry to optically active alpha-vinyl-substituted alpha-amino acid derivatives. It is shown that the enantioselectivity is strongly dependent on the size of the ester moiety of the nucleophile in combination with the catalytic system used. The high synthetic value of the chiral products arising from these new catalytic processes is demonstrated by two straightforward transformations leading in one case to optically active hexahydrobenzopyranones and in the other to substituted pyroglutamates (gamma-lactames).     

Organocatalytic asymmetric direct Michael addition of aromatic ketones to alkylidenemalononitriles

The asymmetric direct Michael addition of aromatic ketones to highly active alkylidenemalononitriles was investigated by employing a chiral primary amine 9-amino-9-deoxyepicinchonine. In general modest to good enantioselectivities (71–84% ee) could be obtained in acceptable isolated yields (48–85%) for an array of substrates.     

Organocatalytic and direct asymmetric vinylogous Michael addition of alpha,alpha-dicyanoolefins to alpha,beta-unsaturated aldehydes

The first highly regio-, chemo-, diastereo- and enantioselective direct vinylogous Michael addition of alpha,alpha-dicyanoolefins to alpha,beta-unsaturated aldehydes is described, employing readily available chiral alpha,alpha-diarylprolinol salts as iminium organocatalysts.     

Organocatalytic enantioselective conjugate addition of ketones to isatylidine malononitriles

An enantioselective Michael addition of ketones to alkylidenemalononitriles catalyzed by chiral primary amine I with (R)-5c as a co-catalyst in good yields (>90%) and with good enantioselectivities (85-96% ee) has been developed. The strategy has also been extended to a three-component version through a domino Knoevenagel/Michael sequence with similar or better outcomes.     

Organocatalytic asymmetric alpha-bromination of aldehydes and ketones

The first organocatalytic enantioselective alpha-bromination of aldehydes and ketones is presented; a C2-symmetric diphenylpyrrolidine catalyst afforded the alpha-brominated aldehydes in good yields and up to 96% ee, while ketones were alpha-brominated by a C2-symmetric imidazolidine in up to 94% ee; furthermore, the organocatalytic enantioselective alpha-iodination of aldehydes is also demonstrated to proceed with up to 89% ee.     

Organocatalytic asymmetric aza-Michael addition of pyrazole to chalcone

An efficient enantioselective aza-Michael addition of pyrazole to chalcone was established. In the presence of the primary amine derived from cinchona alkaloid and acidic additive, the reactions afforded 1,4-adducts in high yields (up to 98%) with 68–88% ee.     

Organocatalytic asymmetric hydroxylation of beta-keto esters: metal-free synthesis of optically active anti-diols

The organocatalytic alpha-hydroxylation of beta-keto esters using cinchona-alkaloid derivatives as the catalyst and peroxides as the terminal oxidant has been investigated and is shown to proceed in high yields and with good enantioselectivity. The scope of the reaction is demonstrated for various substrates, and furthermore, the preparation of optically active anti-diols is presented.     

Organocatalytic asymmetric fulvene formation

The first catalytic asymmetric formation of a fulvene from a racemic α,α-disubstituted aldehyde has been developed. Dynamic kinetic resolution of rac-2-phenylpropanal by a simple, modularly designed supramolecular organocatalyst consisting of inexpensive components has been established, producing the desired fulvene in good yields and moderate enantioselectivities. Herein we propose a mechanistic interpretation of the observed solvent- and additive-induced stereoselectivity reversal.     

Organocatalytic asymmetric Mannich-type reaction of N-sulfonylimines with isocyanoacetate leading to optically active 2-imidazoline-4-carboxylates

The first asymmetric Mannich-type reaction of methyl isocyanoacetate with N-sulfonylimines catalyzed by cinchona alkaloid derivatives yielded 2-imidazolines with high diastereoselectivities and good enantioselectivities (up to >99:1 dr and 70% ee). This reaction provided a convenient route to access various substituted 2-imidazoline-4-carboxylates and related α,β-diamino acids in high enantiomeric purities.     

Organocatalytic asymmetric Michael addition of 2,4-pentandione to nitroolefins

[reaction: see text] A novel binaphthyl-derived amine thiourea organocatalyst has been developed and demonstrated to efficiently catalyze Michael addition reactions (using as low as 1 mol % loading) of diketones to nitroalkenes with remarkably high enantioselectivities.     

Organocatalytic asymmetric sulfa-Michael addition of thiols to 4,4,4-trifluorocrotonates

The first asymmetric sulfa-Michael addition of thiols to 4,4,4-trifluorocrotonates for the construction of a stereogenic center bearing a unique trifluoromethyl group and a sulfur atom has been achieved in high yields and excellent enantioselectivities with a 1 mol % bifunctional organocatalyst. Subsequent transformation led to the expedient preparation of enantioenriched thiochroman-4-one and the key intermediate of the potent inhibitor of MMP-3, (R)-γ-trifluoromethyl γ-sulfone hydroxamate.     

Organocatalytic asymmetric conjugate addition of thioacetic acid to β-nitrostyrenes

A method for organocatalytic, enantioselective Michael addition reactions of thioacetic acid with a range of trans-β-nitrostyrenes has been developed. The processes, promoted by the chiral amine thiourea organocatalyst, take place in high yields with up to 70% ee.     

Organocatalytic asymmetric michael addition of aldehydes to beta-nitroacroleine dimethyl acetal

[Structure: see text] The organocatalytic asymmetric Michael addition of aldehydes to beta-nitroacroleine dimethyl acetal has been studied in detail. The reaction took place with excellent yields and high stereoselectivities when a chiral beta-amino alcohol such as L-prolinol was employed as the catalyst, leaving a formation of highly functionalized enantioenriched compounds containing two differentiated formyl groups together with a nitro moiety.     

Organocatalytic direct asymmetric alpha-heteroatom functionalization of aldehydes and ketones

The direct enantioselective introduction of a stereogenic carbon-heteroatom bond adjacent to a carbonyl functionality leads to optically active compounds of significant importance for e.g. the life-science industry. Organocatalytic enantioselective amination, oxygenation, fluorination, chlorination, bromination and sulfenylation of aldehydes and ketones, using chiral amines as the catalysts, are reviewed in this feature article. Furthermore, a few other transformations are also outlined. The scope, potential and application of these organocatalytic asymmetric reactions are presented and the mechanistic aspects discussed.     

Direct catalytic asymmetric and anti-selective vinylogous addition of butenolides to chromones

An anti-selective catalytic asymmetric Michael-type vinylogous addition of β,γ-butenolides to chromones was developed. The catalyst system developed herein is characterized by tuning of the steric and electronic effects using a proper Biphep-type chiral ligand to invert the diastereoselection, and improvement of the catalyst turnover by a coordinative phenolic additive. The catalytic protocol renders potentially biologically active natural product analogs accessible in good yield with moderate diastereoselectivity and high enantiomeric purity, mostly greater than 99% ee.

An anti-selective catalytic asymmetric Michael-type vinylogous addition of β,γ-butenolides to chromones was developed.