Noyori’s Ts-DPEN ligand: an efficient bifunctional primary amine-based organocatalyst in enantio- and diastereoselective Michael addition of 1,3-dicarbonyl indane compounds to nitroolefins

Noyori’s Ts-DPEN ligand bearing an amino sulfonamide moiety and with a primary amino group on a chiral scaffold was found to be a simple and efficient bifunctional organocatalyst for the asymmetric Michael addition of 1,3-dicarbonyl compounds to nitroolefins, which gave highly functional Michael adduct with quaternary stereocenters in good enantioselectivities (up to 84%ee) and dr (up to 5.7:1 dr).     

Enantioselective Michael reaction of malonates to nitroolefins catalyzed by bifunctional organocatalysts

Michael reaction of malonates to nitroolefins with chiral bifunctional organocatalysts, bearing both a thiourea and tertiary amino group, afforded Michael adducts with high yields and enantioselectivities (up to 95%, up to 93% ee).     

Enantioselective synthesis of enol lactones from tandem Michael addition/lactonization catalyzed by a chiral squaramide catalyst

The enantioselective tandem Michael addition reaction of dimedone and related 1,3-dicarbonyl compounds with α,β-unsaturated N-acylated succinimides catalyzed by a chiral squaramide catalyst has been investigated. This reaction provides a new approach for the synthesis of chiral enol lactones in good yields with moderate to high enantioselectivities (up to 88% ee) through the enantioselective Michael addition followed by lactonization and removal of the succinimide auxiliary.     

New class of bifunctional thioureas from l-proline: highly enantioselective Michael addition of 1,3-dicarbonyls to nitroolefins

A new class of bifunctional tertiary amine thiourea was synthesized from l-proline. The reported thiourea is amenable to steric and electronic modifications at the stereogenic center bearing a thiourea moiety. Excellent enantioselectivity was obtained in the Michael addition of 2,4-pentanedione to various nitro olefins using the new organocatalyst. The construction of contiguous stereocenters via the Michael reaction of substituted 1,3-dicarbonyls to nitro olefins was also carried out with very good yield, enantioselectivity, and diastereoselectivity.     

Direct generation of nucleophilic chiral palladium enolate from 1,3-dicarbonyl compounds: catalytic enantioselective Michael reaction with enones

Generation of chiral palladium enolates from 1,3-dicarbonyl compounds with the palladium aqua complex and its application to the highly efficient catalytic enantioselective Michael reaction with enones are described. The palladium aqua complexes are likely to supply Br?nsted base and Br?nsted acid successively during the reaction. The former activates the carbonyl compounds to give chiral palladium enolates, and the latter cooperatively activates enones. Using a catalytic amount (2-10 mol %) of the palladium complexes, the various 1,3-dicarbonyl compounds including diketones and beta-ketoesters were converted to the desired Michael adducts in good yields (69-92%) with excellent enantiomeric excesses (89-99% ee).     

Direct asymmetric Michael reactions of cyclic 1,3-dicarbonyl compounds and enamines catalyzed by chiral bisoxazoline-copper(II) complexes

The catalytic direct Michael addition of cyclic 1,3-dicarbonyl compounds and enamines to unsaturated 2-ketoesters is presented. A series of different 4-hydroxycoumarins, 4-hydroxy-6-methyl-2-pyrone, 3-hydroxy-1H-phenalene-1-one, 2-hydroxy-1,4-naphthoquinone, 5,5-dimethyl-1,3-cyclohexanedione, and various enamines of cyclic 1,3-diketones all add to unsaturated 4-substituted 2-ketoesters in an enantioselective manner. The reaction is catalyzed by chiral bisoxazoline-copper(II) complexes and proceeds in the absence of base to afford Michael adducts in good to high yields and with up to 98% ee. The products formed are substructures found in skeletons of important biological and pharmaceutical molecules. The scope and potential of the new reaction are discussed as well as the mechanism for the catalytic enantioselective reaction.     

Enantioselective synthesis of 2-substituted-1,4-diketones from (S)-mandelic acid enolate and α,β-enones

An approach for the synthesis of chiral non-racemic 2-substituted-1,4-diketones from (S)-mandelic acid and α,β-enones has been developed. The reaction of lithium enolate of the 1,3-dioxolan-4-one derived from optically active (S)-mandelic acid and pivalaldehyde with α,β-unsaturated carbonyl compounds proceeds readily to give the corresponding Michael adducts in good yields and with high diastereoselectivities. The addition of HMPA (3 equiv) reverses and strongly enhances the diastereoselectivity of the reaction. A change in the reaction mechanism from a lithium catalyzed to the one where catalysis has been suppressed by coordination of HMPA to lithium is proposed to explain these results. Subsequent basic hydrolysis of the 1,3-dioxolan-4-one moiety yields the corresponding α-hydroxy acids (in hemiacetal form), which after decarboxylation with oxygen in the presence of pivalaldehyde and the Co(III)Me₂opba complex as catalyst give chiral 2-substituted 1,4-dicarbonyl compounds with very high enantiomeric excesses. In this approach, (S)-mandelic acid acts as an umpoled chiral equivalent of the benzoyl anion.     

Highly enantioselective direct Michael addition of 1,3-dicarbonyl compounds to β-fluoroalkyl-α-nitroalkenes

Cinchona alkaloid catalysts were used in the Michael addition reaction of 1,3-dicarbonyl compounds to β-fluoroalkyl-α-nitroalkenes for the first time. The catalytic system performed well over a broad scope of substrates including β-keto esters and 1,3-diketones with high diastereoselectivities and excellent enantioselectivities (up to 99% ee) under mild conditions. A wide range of useful fluorinated chiral building blocks was synthesized.     

Organocatalytic asymmetric one-pot sequential reaction: synthesis of highly substituted spirocyclohexanepyrazolones with six contiguous stereogenic carbons

An atom-economical synthesis of chiral polyfunctionalized spiropyrazolone derivatives based on the development of a new organocatalytic enantioselective one-pot sequential Michael/Michael/Aldol reaction of 1,3-dicarbonyl compounds with unsaturated pyrazolones and α,β-unsaturated aldehydes has been developed. The notable features of this one-pot sequential process include the generation of up to six consecutive stereogenic carbon centers including one quaternary stereocenter and five tertiary stereocenters with high enantioselectivities (up to 95% ee) and excellent diastereoselectivities (>99:1 d.r.).     

Enantioselective synthesis of spiro[4H-pyran-3,3′-oxindole] derivatives catalyzed by cinchona alkaloid thioureas: Significant water effects on the enantioselectivity

An efficient stereoselective three-component reaction for the synthesis of functionalized spiro[4H-pyran-3,3′-oxindole] derivatives was realized through an organocatalyzed domino Knoevenagel/Michael/cyclization reaction using a cinchonidine-derived thiourea as the catalyst. Using water as the additive was found to improve the product ee values significantly. Under the optimized conditions, the reactions between isatins, malononitrile, and 1,3-dicarbonyl compounds yield the desired spirooxindole products in good yields (71–92%) and moderate to high ee values (up to 87% ee).     

Ni(II)-Bis[(R,R)-N,N'-dibenzylcyclohexane-1,2-diamine]Br2 catalyzed enantioselective Michael additions of 1,3-dicarbonyl compounds to conjugated nitroalkenes

A highly enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes has been developed that employs a newly developed Ni(II)-(bis)diamine based catalyst. The reaction scope includes substituted and unsubstituted malonates, beta-ketoesters, and nitroalkenes bearing aromatic and aliphatic residues. Ease of synthesis of this complex is noteworthy.     

Enantioselective organocatalytic direct Michael addition of nitroalkanes to nitroalkenes promoted by a unique bifunctional DMAP-thiourea

A new catalyst is designed, synthesized, and evaluated for the asymmetric Michael addition of nitroalkanes to nitroalkenes. The obdurate nature of this reaction has made this a formidable challenge to subdue by asymmetric catalysis. The catalyst design includes a thiourea function to activate the nitroalkene by a double H-bond and a 4-dimethylaminopyridine unit to deprotonate the nitroalkane and to bind the resulting nitronate anion also by a double H-bond. The chiral scaffold for the catalyst is 2,2'-diamino-1,1'-binaphthalene (BINAM), and a bis-conjugate is prepared by the attachment of the thiourea unit and the dimethylaminopyridine moiety (DMAP) via the two amino groups. The resulting catalyst will effect the reaction of nitroalkanes to a variety of nitrostyrenes and gives excellent asymmetric inductions (91-95% ee) over a range of 10 substrates. Remarkably, the asymmetric induction increases with decreasing catalyst loading with the optimal compromise between rate and induction at a loading of 2 mol %.     

邻甲基苯磺酸铜催化"一锅法"合成3,4-二氢嘧啶-2(1H)-酮

二氢嘧啶酮(DHPMs)及其衍生物具有广泛的生物活性,如抗病毒、抗肿瘤、抗癌、抗高血压及消炎等作用[1].此外,DHPMs及其衍生物作为钙通道阻滞剂、α1a-对抗剂和神经肽Y的对抗剂,显示出良好的药理活性[2].更重要的是,最近几种含二氢嘧啶酮-5-羧酸盐的海洋生物碱被成功分离出来,并表现出重要的生物学性质[3],某些可以阻止HIVgp-120-CD4键的形成,是一种潜在的HIV抑制剂[4].因此,对DHPMs及其衍生物的研究成为生物活性有机杂环化合物的研究热点之一.     

N,N′-Dioxide-nickel(II) complex catalyzed asymmetric Michael addition of cyclic 1,3-dicarbonyl compounds to β,γ-unsaturated α-ketoesters

A direct asymmetric Michael addition of cyclic 1,3-dicarbonyl compounds to β,γ-unsaturated α-ketoesters could be efficiently catalyzed by an N,N′-dioxide-nickel(II) complex. A series of chiral warfarin derivatives were obtained in excellent yields (up to 99%) with high enantioselectivities (up to 90% ee) under mild conditions within shorter reaction time.     

Asymmetric Michael addition reactions catalyzed by a novel upper-rim functionalized calix[4]squaramide organocatalyst

A novel upper-rim functionalized calix[4]squaramide organocatalyst bearing bis-squaramide and cyclohexanediamine scaffolds was designed and prepared to catalyse a serial of asymmetric Michael addition of 1,3-dicarbonyl compounds to α,β-unsaturated carbonyl compounds in high yields (up to 99 %) and good to excellent enantiomeric excesses (up to 99% ee). The comparative experiments indicated that the cooperative effect between calixarenes cavitives and chiral catalytic centers on this calix[4]squaramide catalyst could promote these reactions. Moreover, this strategy also provides valuable and easy access to chiral chromene, naphthoquinone and acetylacetone derivatives, which are important skeletons in biological and pharmaceutical compounds.     

Synthesis and properties of chiral thioureas bearing an additional function at a remote position tethered by a 1,5-disubstituted triazole

The synthesis and properties of multifunctional thioureas bearing a variety of functional groups at a position remote from the thiourea moiety are described. A 1,5-disubstituted triazole tether connected with a thiourea and another functional group was synthesized via ruthenium catalyzed Huisgen cycloaddition. We demonstrate the utility of the synthetic thioureas as asymmetric catalysts and probes for the mechanistic elucidation of the course of the Michael reaction of an α,?-unsaturated imide.     

Organocatalytic enantioselective Michael addition of 2,4-pentandione to nitroalkenes promoted by bifunctional thioureas with central and axial chiral elements

Two novel bifunctional amine-thiourea organocatalysts 1 and 2, which both bear central and axial chiral elements, have been developed to promote enantioselective Michael reaction between 1,3-dicarbonyl compounds and nitro olefins. The catalyst 2 afforded the desired products with good levels of enantioselectivity (up to 96% ee), showing clearly that two chiral elements of 2 are matched, and enhance the stereochemical control.     

Asymmetric Michael addition reactions catalyzed by a novel upper-rim functionalized calix[4]squaramide organocatalyst

A novel upper-rim functionalized calix[4]squaramide organocatalyst bearing bis-squaramide and cyclohexanediamine scaffolds was designed and prepared to catalyse a serial of asymmetric Michael addition of 1,3-dicarbonyl compounds to α,β-unsaturated carbonyl compounds in high yields (up to 99 %) and good to excellent enantiomeric excesses (up to 99% ee). The comparative experiments indicated that the cooperative effect between calixarenes cavitives and chiral catalytic centers on this calix[4]squaramide catalyst could promote these reactions. Moreover, this strategy also provides valuable and easy access to chiral chromene, naphthoquinone and acetylacetone derivatives, which are important skeletons in biological and pharmaceutical compounds.     

Axially chiral guanidine as enantioselective base catalyst for 1,4-addition reaction of 1,3-dicarbonyl compounds with conjugated nitroalkenes

A new strategy for designing chiral guanidine molecules is presented, which features the introduction of an axially chiral binaphthyl backbone. The axially chiral guanidine catalysts thus developed facilitated the highly enantioselective 1,4-addition reaction of 1,3-dicarbonyl compounds with a broad range of conjugated nitroalkenes and showed extremely high catalytic activity.     

Bifunctional transition metal-based molecular catalysts for asymmetric syntheses

The discovery and development of conceptually new chiral bifunctional transition metal-based catalysts for asymmetric reactions is described. The chiral bifunctional Ru catalyst was originally developed for asymmetric transfer hydrogenation of ketones and imines and is now successfully applicable to enantioselective C-C bond formation reaction with a wide scope and high practicability. The deprotonation of 1,3-dicarbonyl compounds with the chiral amido Ru complexes leading to the amine Ru complexes bearing C- or O-bonded enolates, followed by further reactions with electrophlies gives C-C bond formation products. The present bifunctional Ru catalyst offers a great opportunity to open up new fundamentals for stereoselective molecular transformation including enantioselective C-H and C-C as well as C-O, C-N bond formation.