Asymmetric anti‐Selective Michael Reaction of Imidazole‐Modified Ketones with trans‐β‐Nitroalkenes

The successful application of imidazole‐modified ketones in asymmetric anti‐selective Michael reactions with trans‐β‐nitroalkenes is presented by employing a newly developed 3‐bromothiophene‐modified chiral diamine ligand. The corresponding conjugate adduct was submitted to further transformations with Grignard reagents to solve the problem of α‐site selectivity of simple linear ketones. Additionally, the syn‐selective product was obtained by treating the anti‐selective adduct with a simple base. In this way, the site‐specific products for both diastereomers in the asymmetric conjugate addition of simple ketones to nitroalkenes can be obtained.     

A novel synthesis of γ-nitro ketones via detrifluoroacetylative Michael addition of 1-trifluoromethyl-1,3-diketones to conjugated nitroalkenes

A novel synthesis of γ-nitro ketones via detrifluoroacetylative Michael addition of 1-trifluoromethyl-1,3-diketones to conjugated nitroalkenes in the presence of sodium acetate in ethanol at room temperature is developed. A series of trifluoromethylated 1,3-diones and nitroalkenes are surveyed to determine the scope of this high-yielding reaction.     

Gel Entrapped Base Catalysed (GEBC) Henry Reaction: Synthesis of Conjugated Nitroalkenes

A new, simple and practical procedure for direct transformation of aldehydes or ketones and nitromethane into conjugated nitroalkenes by using novel gel entrapped base catalyst (GEBC) has been described.     

Asymmetric conjugate addition of carbonyl compounds to nitroalkenes catalyzed by chiral bifunctional thioureas

Readily available chiral thioureas derived from cyclohexane-1,2-diamine were prepared and found to be highly effective organocatalysts for the conjugate addition of aldehydes and ketones to nitroalkenes. Excellent enantioselectivities and yields were obtained for a variety of aryl and heteroaryl nitroalkenes. The base additives are essential for good yields and excellent enantioselectivities in this transformation. Based on new experimental evidence, a modified catalytic mechanism was proposed to rationalize the important role of the base additives.     

Organocatalysts wrapped around by poly(ethylene glycol)s (PEGs): a unique host-guest system for asymmetric Michael addition reactions

Asymmetric Michael addition reactions of unmodified ketones to nitroalkenes were performed in PEGs catalyzed by novel pyrrolidinyl-thioimidazolium salts to give products in up to 97% yield and 99% enantioselectivity; ESI mass spectrometric detection for the first time gave evidence of the presence of the PEG-organocatalyst host-guest complex.     

Asymmetric synthesis of α-alkyl α-selenocarbonyl compounds catalyzed by bifunctional organocatalysts

A new organocatalytic approach for the synthesis of a variety of α-alkyl, α-phenylselenyl ketones as well as their corresponding esters and amides, by the addition of α-selenocarbonyl derivatives to nitroalkenes catalyzed by thiourea or squaramide cinchona catalysts, is presented. This catalytic system allows the preparation in high yields of enantiomerically enriched selenocarbonyl derivatives bearing two chiral centers with excellent ee's and dr's by using catalytic loadings of 3 mol%.     

Asymmetric Synthesis of a Quaternary Carbon Stereogenic Center by Organocatalysis Using a Primary Amino Acid and Its Salt

In this personal account, our recent developments on the asymmetric synthesis of a quaternary carbon stereogenic center by organocatalysis using a primary amino acid and its salt as a catalyst are described in three chapters: (1) conjugate addition to nitroalkenes and vinyl ketones, (2) nucleophilic addition to π-allyl palladium complexes, and (3) nucleophilic substitution reactions with allyl and propargyl halides. By these methods, asymmetric α-allylation of α-branched aldehydes and ketones smoothly proceeded to give γ-nitroaldehydes, ketoaldehydes, α-allylated aldehydes, and α-allylated β-ketoesters possessing a quaternary carbon stereogenic center in good yields with high enantioselectivities.     

Asymmetric synthesis of beta-nitro ketones via Michael addition of lithiated alpha-amino nitriles to nitroalkenes

Alpha-amino nitriles, easily prepared from aldehydes, KCN, and an enantiopure secondary amine auxiliary, are metalated and used as nucleophiles in asymmetric Michael additions to nitroalkenes to afford the Michael adducts in good yields and good to excellent diastereoselectivities. After chromatographic purification, the diastereomerically pure 1,4-adducts are cleaved under acidic conditions to give the beta-nitro ketones in good yields and with two exceptions in good to excellent enantiomeric excesses (ee = 86-99%). The absolute configuration was determined by X-ray structure analysis.     

Proline-based reduced dipeptides as recyclable and highly enantioselective organocatalysts for asymmetric Michael addition

A series of novel proline-based reduced dipeptides was developed and evaluated for a direct Michael addition of ketones and aldehydes to nitroalkenes. Excellent yields (up to 95%), diastereoselectivities (up to 98% dr) and enantioselectivities (up to 98% ee) were achieved in the presence of 5 mol% catalyst without any additional additives at room temperature.     

From C2- to D2-symmetry: atropos phosphoramidites with a D2-symmetric backbone as highly efficient ligands in Cu-catalyzed conjugate additions

Atropos phosphoramidites with the D₂-symmetric biphenyl backbone were diastereoselectively prepared with ease from achiral tetrahydroxy biphenyls. This type of ligands is proved to be highly efficient in the Cu-catalyzed conjugate additions of diethylzinc to α,β-unsaturated ketones and nitroalkenes. The unique D₂-symmetric backbone endows the ligands with an excellent chiral environment.     

Nef Reaction with Molecular Oxygen in the Absence of Metal Additives,and Mechanistic Insights

A Nef reaction has been developed that is conducted under mildly basic conditions with molecular oxygen as an oxidant, without the need for metal additives. Whereas nitroalkanes are converted into ketones in good yield, nitroalkenes are transformed into α,β‐unsaturated ketones in one‐pot by double‐bond isomerization followed by the oxygen‐mediated Nef reaction. The reaction protocol is both mild and general, and tolerates acid‐ and base‐labile functionality or protecting groups. When oxygen‐saturated solvents are employed, the reaction completes within 20 min. Mechanistically, the addition of nitronate ion and molecular oxygen is proposed to proceed initially through a single‐electron transfer event, as indicated by radical clock experiments. This ultimately generates a putative 1,1‐dioxirane, which reacts further with another nitronate ion to generate the ketone. Involvement of a 1,1‐dioxirane is supported by intramolecular trapping experiments with sulfide at the γ‐position of the nitro‐moiety.     

Combining proline and ‘click chemistry’: a class of versatile organocatalysts for the highly diastereo- and enantioselective Michael addition in water

Based on ‘click chemistry’ conditions, a class of novel, facile, versatile pyrrolidine-based triazole derivatives were prepared, and proved to be efficient catalysts for the highly diastereoselective and enantioselective Michael addition of ketones to nitroalkenes. The Cu(I)-catalyzed 1,3-dipolar ‘click’ azide–alkyne cycloaddition provides modular and tunable features for the pyrrolidine-based triazole organocatalysts, and the resulting triazole moiety can serve as a phase tag to complete the reaction in water with an excellent yield and high enantiomeric excess.     

Palladium-catalyzed conjugate addition of organosiloxanes to alpha,beta-unsaturated carbonyl compounds and nitroalkenes

The addition of aryltrialkoxysilanes to alpha,beta-unsaturated carbonyl compounds (ketones, aldehydes) and nitroalkenes in the presence of SbCl(3), TBAF, AcOH, and a catalytic amount of Pd(OAc)(2), in CH(3)CN at 60 degrees C, provides the corresponding conjugate addition products in moderate to good yields. The addition of equimolar amounts of SbCl(3) and TBAF is necessary for this reaction to proceed smoothly. The arylpalladium complex, which is generated by the transmetalation from a putative hypercoordinate silicon compound, is considered to be the catalytically active species.     

Highly diastereo- and enantioselective direct aldol reaction under solvent-free conditions

An efficient, solvent-free protocol for the asymmetric aldol reaction between aldehydes and ketones using prolinamides 1–4 as organocatalysts is reported. Catalysts 2–4, in the presence of TFA (the ratio of catalyst and TFA = 1/1.5), proved to be excellent catalysts, giving the aldol products between aromatic aldehydes and ketones with nearly perfect diastereo- and enantioselectivities (up to >99:1 dr and >99% ee). This catalytic system can also be applied in the cross-aldol reaction of isatin with ketones and the Michael reaction between cyclohexane and nitroalkenes. A mechanism is proposed to account for the formation of the major enantiomer in this reaction.     

Reductive biotransformation of nitroalkenes via nitroso-intermediates to oxazetes catalyzed by xenobiotic reductase A (XenA)

A novel reductive biotransformation pathway for β,β-disubstituted nitroalkenes catalyzed by flavoproteins from the Old Yellow Enzyme (OYE) family was elucidated. It was shown to proceed via enzymatic reduction of the nitro-moiety to furnish the corresponding nitroso-alkene, which underwent spontaneous (non-enzymatic) electrocyclization to form highly strained 1,2-oxazete derivatives. At elevated temperatures the latter lost HCN via a retro-[2 + 2]-cycloaddition to form the corresponding ketones. This pathway was particularly dominant using xenobiotic reductase A, while pentaerythritol tetranitrate-reductase predominantly catalyzed the biodegradation via the Nef-pathway.     

Asymmetric domino aza-Michael–Michael reaction of o-N-protected aminophenyl α,β-unsaturated ketones: construction of chiral functionalized tetrahydroquinolines

The diastereo- and enantioselective synthesis of 2,3,4-trisubstituted tetrahydroquinolines has been developed through organocatalytic domino aza-Michael–Michael reaction of o-N-tosylaminophenyl α,β-unsaturated ketones with nitroalkenes. This useful and simple domino process afforded diverse highly functionalized tetrahydroquinolines, some of which are not easily accessible using other methodologies, in good yields and with excellent diastereo- and enantioselectivities (up to >30:1 dr, >99% ee).     

Investigation of lipase-catalyzed Michael-type carbon–carbon bond formations

Conjugate additions of carbon nucleophiles to appropriate acceptor molecules were investigated with respect to the synthetic potential and stereochemistry of the products. Reactions of short-chain α,β-unsaturated ketones and mono-substituted nitroalkenes with CH-acidic carboxylic ester derivatives were catalyzed by various immobilized lipases. Using methyl nitroacetate complete conversion with methyl vinyl ketone and trans-β-nitrostyrene was obtained. The reactions proceeded without enantioselectivity. Evidence for enzyme catalysis is provided by the observation that after denaturation of Candida antarctica lipase B or inhibition no reaction took place. Docking studies with the chiral addition product methyl 2-methyl-2-nitro-5-oxohexanoate did not reveal any specific binding mode for this reaction product, which would have been the requirement for stereoselective additions. These results support the experimental findings that the conjugate addition takes place without enantiopreference.     

Straightforward Synthesis of 1,2‐Dicyanoalkanes from Nitroalkenes and Silyl Cyanide Mediated by Tetrabutylammonium Fluoride

A straightforward synthesis of 1,2‐dicyanoalkanes by reacting nitroalkenes with trimethylsilyl cyanide in the presence of tetrabutylammonium fluoride is described. The reaction proceeds through a tandem double Michael addition under mild conditions. Employing the hypervalent silicate generated from trimethylsilyl cyanide and tetrabutylammonium fluoride is essential for achieving this transformation. Mechanistic studies suggest that a small amount of water included in the reaction media plays a key role. This protocol is applicable to various types of substrates including electron‐rich and electron‐deficient aromatic nitroalkenes, and aliphatic nitroalkenes. Moreover, vinyl sulfones were found to be good alternatives, particularly for electron‐deficient nitroalkenes. The broad substrate scope and functional group tolerance of the reaction makes this approach a practical method for the synthesis of valuable 1,2‐dicyanoalkanes.     

Pyrrolidinyl–Camphor Derivatives as a New Class of Organocatalyst for Direct Asymmetric Michael Addition of Aldehydes and Ketones to β‐Nitroalkenes

Practical and convenient synthetic routes have been developed for the synthesis of a new class of pyrrolidinyl–camphor derivatives ( 7 a–h ). These novel compounds were screened as catalysts for the direct Michael addition of symmetrical α,α‐disubstituted aldehydes to β‐nitroalkenes. When this asymmetric transformation was catalyzed by organocatalyst 7 f , the desired Michael adducts were obtained in high chemical yields, with high to excellent stereoselectivities (up to 98:2 diastereomeric ratio (d.r.) and 99 % enantiomeric excess (ee)). The scope of the catalytic system was expanded to encompass various aldehydes and ketones as the donor sources. The synthetic application was demonstrated by the synthesis of a tetrasubstituted‐cyclohexane derivative from (S)‐citronellal, with high stereoselectivity.     

Synthesis and anticancer activity studies of alpha-aminoalkylated conjugated nitroalkenes

Novel alpha-aminoalkylated conjugated nitroalkenes which inhibit human cervical cancer (HeLa) cell proliferation by binding to tubulin were synthesized by imidazole/LiCl-mediated reaction of conjugated nitroalkenes with N-tosylimines.