Tandem asymmetric conjugate addition--silylation of enantiomerically enriched zinc enolates. Synthetic importance and mechanistic implications

[formula: see text] The zinc enolates, resulting from the copper-catalyzed enantioselective conjugate addition of dialkyl zinc reagents to cyclic and acyclic enones, could be trapped, quantitatively, as silyl enol ethers with TMSOTf in apolar solvents or with TMSCI and NEt3. These enantiomerically enriched silyl enol ethers were submitted to four synthetic transformations to show their synthetic utility. The zinc enolates obtained from acyclic enones were found to be configurationally stable, as shown by the stereochemistry of the silyl enol ethers.     

One-pot asymmetric conjugate addition-trapping of zinc enolates by activated electrophiles

The copper-catalyzed asymmetric conjugate addition of dialkyl zinc leads to homochiral zinc enolates. These intermediates were trapped in situ with activated allylic electrophiles, without the need of additional palladium catalysis. High trans selectivity (85/15 to 100/0) and excellent enantioselectivities (up to 99%) could be attained. The functionalized nature of the electrophiles makes the new synthons potential candidates for further elaboration.     

Solvent-free asymmetric conjugate addition of malonates to enones using a diaminomethylenemalononitrile organocatalyst

Diaminomethylenemalononitrile organocatalyst 1 efficiently promotes the asymmetric conjugate addition of malonates to α,β-unsaturated ketones to afford the corresponding addition products in high to excellent yields with up to 98% ee.     

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.     

A development of a reusable copper supported imidazolium functionalized ionic liquid catalyzed asymmetric Michael addition reaction

An eco-friendly copper supported Imidazolium functionalized ionic liquid [[Gmim]Cl–Cu (II)] used as green catalyst in solvent free asymmetric Michael addition at 25^OC. This technique covers simplified product isolation, high conversion and catalyst recycling.     

Catalytic asymmetric approaches towards enantiomerically enriched diarylmethanols and diarylmethylamines

Enantiopure diarylmethanols and diarylmethylamines are important intermediates for the synthesis of pharmaceutically relevant products with antihistaminic, antiarrhythmic, diuretic, antidepressive, laxative, local-anesthetic and anticholinergic properties. Furthermore, they have been used as precursors for 1,1-diarylalkyl moieties, which occur in other antidepressants as well as in antimuscarinics and endothelin antagonists. In this critical review catalytic strategies towards enantioenriched diarylmethanols and diarylmethylamines are discussed, including methods for asymmetric carbon-carbon bond formations by aryl transfer reactions to aldehydes and arylimines, respectively, and enantioselective reductions of diarylketones.     

Copper catalyzed tandem asymmetric conjugate addition-cyclization reaction in the presence of chiral phosphoramidite ligands

Copper-catalyzed intramolecular conjugate addition-cyclization in the presence of chiral phosphoramidite ligands was described. Cyclic products with multiple chiral centers were obtained with up to 93:7 diastereomeric ratio and 94% ee.     

A practical asymmetric conjugate addition to cyclic enones with chiral bifunctional Ru amido catalysts

A practical asymmetric C-C bond formation to synthetically useful β-chiral cyclic ketones (>99% ee) using bifunctional chiral amido Ru catalysts under an S/C = 1000, the highest ratio achieved so far in the literature for this class of reactions, is described. The catalytic reactivity decreases in the order of Ru(Msdpen)(hmb) > Ru(Pfbsdpen)(hmb) > Ru(Tsdpen)(hmb) > Ru(PMsdpen)(hmb), where Ru(Pfbsdpen)(hmb) is a newly developed chiral bifunctional catalyst. Complex Ru(Msdpen)(hmb) was identified as the best in terms of reactivity and enantioface selectivity, whereas Ru(PMsdpen)(hmb) gave unsatisfactory results. An importance of the NH proton in the bifunctional catalyst for determining the enantioselectivity has been experimentally demonstrated. Valuable information for the reaction mechanism was accumulated.     

Benzoazabicyclo[4.3.1] derivatives by intramolecular Michael addition of piperidinone enolates to enoates

Piperidinones with a 2-bromobenzyl substituent in the 5-position were subjected to a Heck coupling reaction with ethyl acrylate resulting in the highly functionalized cinnamates 9a-d. A subsequent deprotonation of the piperidinones using NaN(SiM₃)₂ in THF induced an intramolecular Michael addition of the enolate to the cinnamate part. In this way, a range of novel 2,6-methano-4H-4-benzazonines 10-13 were obtained. In each case, a separable mixture of endo/exo-diastereomers was obtained.     

Chiral enolates for highly stereoselective aldol reactions—Scope and limitations

Enantioselective approaches to the formation of α,β-disubstituted ketones through aldol reactions are compared. A one-pot ACA/aldol domino process is lower yielding than alternative procedures involving enantiomerically pure β-substituted silyl enol ethers. The use of chiral acetals derived from hydrobenzoin provides access to syn and anti diols in moderate to good yields and high diastereoselectivities. A novel synthesis of functionalized β,γ-unsaturated acetals is also described.     

A new kind of organophosphorus compounds as an efficient catalyst for asymmetric C-C bond formation reactions

A new class of chiral pyrrolidine-phosphite organocatalysts, available from commercially starting materials, has been synthesized and shown to be good catalytic activity for asymmetric Michael and Aldol reactions. The reactions proceeded to give the products in good yield and in a highly selective manner. Ionic liquid [Bmim][BF₄] as an efficient green solvent has been employed in the Michael addition.     

Conjugate additions of cyclic oxygen-bound nickel enolates to alpha,beta-unsaturated ketones

The reaction of nickel enolates displaying a metallacyclic structure with the alpha,beta-unsaturated ketones methyl vinyl ketone (MVK) or methyl propenyl ketone (MPK) takes place in two stages, affording initially bicyclic adducts, which subsequently isomerize to the corresponding open-chain products. The former are generated with high stereoselectivity and can be considered as the products of the [2+4] cycloaddition of the enolate to the enone. The ring opening process involves a prototropic rearrangement that can be catalyzed by water. In the case of the reaction of the parent nickel enolate complex 1 (which displays an unsubstituted Ni-O=C(R)CH2 arrangement) with MVK, a double-addition process has been observed, consisting of two successive cycloaddition/isomerization reactions. The carbonylation of the different cyclic and noncyclic products affords the corresponding lactones that retain the stereochemistry of the organometallic precursors. This methodology allowed trapping the primary product of the reaction of 1 with MPK as the corresponding organic lactone, demonstrating that the cycloaddition process takes place with exo selectivity. DFT modeling of the latter reaction provides further support for a quasi-concerted cycloaddition mechanism, displaying a nonsymmetric transition state in which the C-C and the C-O bond are formed in an asynchronous manner.     

Novel bifunctional sulfonamides catalyze an enantioselective conjugate addition

A new bifunctional organocatalyst with a novel structural and functional motif has been developed. This bifunctional sulfonamide organocatalyst was used in the conjugate addition of 1,3-dicarbonyl compounds (13) to β-nitrostyrenes (12). Yields up to 91% and enantiomeric excesses up to 79% were obtained in this reaction. This catalyst activates both 13 via its basic moiety and 12 through hydrogen bonding.     

Stereoselective conjugate addition of lactams to nitroalkenes and formal total synthesis of indolizidine 167B

Optically active 5-substituted pyrrolidin-2-ones underwent conjugate addition to nitroalkenes to give the corresponding adducts in a diastereoselective manner. The presence of 18-crown-6 was crucial to achieve good stereoselective addition. Addition of 6-substituted piperidin-2-ones also gave the corresponding adduct in a stereoselective manner. The adduct was readily converted into a bicyclic lactam through intramolecular nitroaldol reaction, and the formal synthesis of indolizidine 167B was achieved.     

Copper catalyzed asymmetric conjugate addition-bromination of α,β-unsaturated ketones: a highly efficient one-pot reaction for the synthesis of chiral α-bromo-β-alkylketones

An efficient one-pot reaction for the synthesis of chiral α-bromo-β-alkyl ketones was developed. The final products were obtained with excellent enantiomeric excess and good isolated yields. The synthetic potential was illustrated by the radical cyclization of the α-brominated ketone.