Asymmetric organocatalytic cascade Michael/acyl transfer reaction of 2-hydroxychalcones with α-nitroketones

A highly enantioselective (84–97% ee) cascade Michael/acyl transfer reaction of α-nitroketones to a wide range of 2-hydroxychalcones was established in the presence of a bifunctional squaramide. Although aliphatic α-nitroketones were revealed to be a class of challenging substrates with unsatisfactory reactivity or enantioselectivity by previous reports, good isolated yields and excellent enantiopurities have been achieved via our catalytic protocol. γ-Nitroketones created by this new methodology were versatile building blocks possessing profound further synthetic utility.     

Organocatalytic asymmetric conjugate addition of α-substituted cyanoacetates to maleimides

The asymmetric conjugate addition of α-substituted cyanoacetates to N-substituted maleimides has been developed. A number of cinchona alkaloids and amine thioureas were evaluated as catalysts. Takemoto’s catalyst was found to be the most efficient for the transformation. Chiral succinimides with two adjacent quaternary and tertiary stereogenic carbon centers were obtained in good yields, enantioselectivities, and diastereoselectivities. The products were converted to chiral γ-lactams conveniently without a loss in the enantioselectivity.     

Thiourea-catalyzed asymmetric conjugate addition of α-substituted cyanoacetates to maleimides

Chiral isosteviol-derived tertiary amine-thiourea was proven to be effective in catalyzing the asymmetric conjugate addition between α-substituted cyanoacetate and maleimides. Diverse succinimides bearing vicinal quaternary-tertiary stereocenters were obtained in excellent yields, excellent diastereoselectivities, and with good to high enantioselectivities. This catalytic system can be used efficiently in large-scale reactions with the yields and stereoselectivities being maintained at the same level.     

Organocatalytic conjugate addition of 1-bromonitroalkanes to α,β-unsaturated aldehydes: synthesis of nitrocyclopropanes

A variety of secondary amines were studied as the catalyst in the conjugate addition of 1-bromonitromethane to α,β-unsaturated aldehydes. Proline was identified as the best catalyst for this reaction. MeOH/AcONa system was found to provide much better yields than CHCl₃/Et₃N system reported before. Good yields of nitrocyclopropane products were obtained with a variety of β-aryl acroleins. Several substituted 1-bromonitromethanes were also examined in the reaction. Both 1-bromonitroethane and 1-phenyl-1-bromonitromethane gave the corresponding nitrocyclopropanes in good yields. The diastereoselectivity of the reaction was strongly affected by the steric hindrance of 1-bromonitroalkanes.     

Organocatalytic asymmetric Michael-type reaction between β,γ-unsaturated α-keto ester and α-nitro ketone

A Michael-type reaction of β,γ-unsaturated α-keto ester and α-nitro ketone was established. With a thiourea catalyst derived from cinchona alkaloid, the reactions afford products in 47-94% yields with 68-96% ee.     

Organocatalytic asymmetric direct vinylogous Michael addition of α,β-unsaturated γ-butyrolactam to nitroolefins

The first organocatalytic enantioselective direct vinylogous Michael reaction of α,β-unsaturated γ-butyrolactam to nitroolefins is developed using cinchona alkaloids as the catalysts. Both product enantiomers are accessible with moderate to good enantioselectivity.     

Enantioselective formal hydration of α,β-unsaturated acceptors: asymmetric conjugate addition of silicon and boron nucleophiles

The direct enantioselective 1,4-addition of water to α,β-unsaturated acceptors is an open challenge in asymmetric catalysis. Enantioselective conjugate addition of either silicon or boron nucleophiles and subsequent enantiospecific oxidative degradation of the carbon-element bond represents, however, an attractive detour. A single extra step thereby enables an indirect enantiocontrolled construction of (in a broader sense) aldols from α,β-unsaturated carbonyl and carboxyl compounds. While that strategy had been obvious for a long time, it was recent stunning progress in transition metal-catalysed activation of interelement linkages that brought about the solution to that long-standing problem. A concise introduction of existing protocols for stereoselective 1,4-addition of oxygen nucleophiles is followed by a comprehensive summary of the recent rapid advances in transition metal-catalysed (and metal-free) asymmetric conjugate transfer of nucleophilic silicon and boron onto α,β-unsaturated acceptors.     

Organocatalytic asymmetric nitrocyclopropanation of α,β-unsaturated aldehydes

A novel organocatalytic highly enantioselective nitrocyclopropanation reaction of α,β-unsaturated aldehydes is presented. The 1-nitro-2-formylcyclopropane derivatives synthesized from this catalytic transformation were converted to the corresponding β-nitromethyl-acid esters, which are excellent precursors of GABA analogues such as Baclofen, by subsequent organocatalytic chemoselective ring-opening.     

Synthesis of α-alkoxyalkyltributyllead compounds via the reaction of tributylplumbyllithium with α-chloroethers,and the conjugate addition of tributylplumbyllithium to enones

α-Alkoxyalkyltributylleads 1 were prepared from the reaction of tributylplumbyllithium with α-chloroethers 2. This procedure is more convenient than the conventional method which involves transmetallation from the corresponding α-alkoxyalkyltrialkyltin. Tributylplumbyllithium was also used for the synthesis of β-oxo-organolead 4.     

The synthesis and stereoselective conjugate addition reactions of α-alkoxyorganocuprate reagents

α-Alkoxyorganocuprate reagents have been prepared from α-alkoxyorganostannanes. The cuprates undergo diastereoselective conjugate addition reactions with cyclohexenone with up to 8:92 selectivity. The effects of trimethylsilyl chloride on the chemical yields and the diastereoselectivity of the reaction are described.     

Organocatalytic asymmetric Michael-type/Wittig reaction of phosphorus ylides: synthesis of chiral α-methylene-δ-ketoesters

An asymmetric Michael-type reaction of phosphorus ylides and α,β-unsaturated ketones under the catalysis of a chiral ion pair catalyst has been described. The ion pair catalyst containing a chiral counteranion was prepared by simply mixing 9-amino-(9-deoxy)-epi-quinine with l-N-Boc-proline. The optically active α-methylene-δ-ketoesters could be obtained with good to excellent enantioselectivities (up to 95% ee) under mild reaction conditions.     

Organocatalytic synthesis of α-hydroxy and α-aminophosphonates

A new and highly flexible procedure is described for the synthesis of α-amino- and α-hydroxy phosphonates. In the presence of a catalytic amount of oxalic acid (10 mol %), trimethyl phosphite reacts with aldehydes or imines (generated in situ from an aldehyde and an amine) to yield the corresponding coupled products in good yield.     

Organocatalytic direct asymmetric vinylogous Michael reaction of an α,β-unsaturated γ-butyrolactam with enones

An organocatalytic asymmetric direct vinylogous Michael addition of α,β-unsaturated γ-butyrolactam to enones has been achieved with a simple bifunctional thiourea-tertiary amine catalyst, affording the γ-substituted butyrolactam products with high diastereo- and enantioselectivity (up to >40:1 dr and 94-99% ee).     

Backbone modification of β-hairpin-forming tetrapeptides in asymmetric acyl transfer reactions

Synthetic oligopeptides as mimics of enzymes have been increasingly exploited as catalysts for asymmetric reactions, but highly effective oligopeptide catalysts with relatively low molecular weight are still in great demand. In this paper, we showed the conformational engineering of the β-hairpin-forming tetrapeptide 4 which was first reported by Miller's group as the catalyst for the asymmetric acyl transfer reaction of trans-2-(N-acetylamino)cyclohexan-1-ol (k(rel)=28). Through our backbone modification strategy, thioamide and sulfonamide as the isosteres of amide were introduced in the β-hairpin secondary structure. The thioxo peptides also adopt β-hairpin conformations as the oxopeptide supported by the combined use of NMR, IR, and X-ray techniques. Thioxo tetrapeptide 14 formed a more constrained β-hairpin conformation and therefore delivered much higher enantioselectivity (k(rel)=109) in the same reaction. Moreover, the examination of the conformational changes of tetrapeptide 8 upon the protonation of the N(π)-methylhistidine moiety provided evidence to explain the variation of its catalytic efficiency in the asymmetric acyl-transfer reaction.     

Intermediate as catalyst: catalytic asymmetric conjugate addition of nitroalkanes to α,β-unsaturated thioamides

Catalytic asymmetric conjugate addition of nitroalkanes to α,β-unsaturated thioamides is promoted by a mesitylcopper/(R)-DTBM-Segphos precatalyst, affording γ-nitrothioamides in moderate to high syn-selectivity and excellent enantioselectivity. The intermediate Cu-thioamide enolate functions as a soft Lewis acid/hard Br?nsted base cooperative catalyst to drive the catalytic cycle efficiently under proton transfer conditions.     

NHC-copper-catalyzed asymmetric conjugate silylation of access chiral α-aminosilanes

Chiral α-aminosilane and its derivatives have found potential applications in pharmaceuticals. Yet there are rare examples have been reported for the synthesis of these molecules. Herein we report a catalytic asymmetric conjugate silylation reactions of β-amido-acrylonitriles and β-amido-acrylates for the first time in the presence of catalytic amount of chiral N-heterocyclic carbene (NHC)/Copper(I) complex. A variety of functionalized chiral α-aminosilanes were obtained at room temperature in good yields with high enantioselectivities in the presence of NHC (10 mol%), CuCl (10 mol%), NaOtBu or NaOMe (20 mol%), and MeOH (2 equivalents).     

Theoretical insight into phosphoric acid-catalyzed asymmetric conjugate addition of indolizines to α,β-unsaturated ketones

A theoretical investigation of the mechanism and origin of enantioselectivity for phosphoric acid-catalyzed asymmetric conjugate addition of indolizines to α,β-unsaturated ketones.