Highly diastereo- and enantioselective direct aldol reactions promoted by water-compatible organocatalysts bearing a pyrrolidinyl-camphor structural scaffold

Efficient synthetic routes have been developed for the synthesis of a series of pyrrolidinyl-camphor containing organocatalysts (1-10). Structural modifications were made by varying the stereo- and electronic properties of the camphor scaffold and the aromatic substituents. These readily tunable and amphiphilic organocatalysts were evaluated for the direct asymmetric aldol reaction of various aromatic aldehydes and cyclohexanone either in organic solvents or in the presence of water. The aldol reaction proceeded smoothly with excellent chemical yields (up to 99%), enantioselectivities (up to 99% ee), and anti-diastereoselectivities (up to 99:1) with a catalytical amount of the bifunctional organocatalysts (20 mol %) under optimal reaction conditions. Mechanistic transition models are proposed and the stereochemical bias of the asymmetric aldol reaction is presented.     

Catalytic enantioselective electrophilic α-hydrazination of β-ketoesters using bifunctional organocatalysts

The catalytic enantioselective electrophilic α-hydrazination promoted by chiral bifunctional organocatalysts is described. Treatment of β-ketoesters with azodicarboxylates as electrophilic amination reagents under mild reaction conditions afforded the corresponding α-amino β-ketoesters with excellent enantiomeric excesses (93-99% ee).     

Doubly stereocontrolled asymmetric conjugate addition of acetylacetone to nitroolefins catalyzed by bifunctional tertiary amine-thiourea catalysts derived from both acyclic α-amino acids and carbohydrates

A novel class of easily preparative, cheap, and fine-tunable bifunctional chiral tertiary amine-thiourea organocatalysts have been developed by combining both acyclic diamines derived from acyclic α-amino acids and carbohydrates. These organocatalysts promoted the enantioselective conjugate addition of acetylacetone to various nitroolefins in good yields (up to 93%) with good enantioselectivities (up to 91% ee). The present research demonstrates the advantages of incorporating two stereocontrolling structures into a single catalyst. Notably, it offers a simple and convenient doubly stereocontrolled approach for the catalytic asymmetric synthesis of a chiral organic molecule.     

Structure-reactivity relationships of l-proline derived spirolactams and α-methyl prolinamide organocatalysts in the asymmetric Michael addition reaction of aldehydes to nitroolefins

l-Proline derived spirolactams and α-methyl prolinamides act as organocatalysts for the asymmetric conjugate addition of aldehydes to nitroolefins in excellent yields, with good diastereoselectivity and enantioselectivity. Furthermore, low catalyst loadings (5 mol %) and a low aldehyde molar excess (1.5 M equiv) were achieved.     

Organocatalytic synthesis of quaternary stereocenter bearing a fluorine atom: enantioselective conjugate addition of α-fluoro-β-ketoesters to nitroalkenes

The catalytic enantioselective conjugate addition reaction of α-fluoro-β-ketoesters to nitroalkenes promoted by chiral bifunctional organocatalysts is described. The treatment of α-fluoro-β-ketoesters with nitroalkenes under mild reaction conditions afforded the corresponding Michael adducts containing a fluorinated quaternary stereogenic center with excellent enantioselectivity (up to >99% ee).     

Enantio- and diastereoselective Michael addition reactions of α-cyanoketones to nitroalkenes catalyzed by binaphthyl-derived organocatalyst

The catalytic enantioselective and diastereoselective Michael addition reactions promoted by chiral bifunctional organocatalysts are described. The treatment of α-cyanoketones with nitroalkenes under mild reaction conditions afforded the corresponding γ-niro α-cyanoketones with excellent diastereoselectivities (up to syn/anti >99/1) and excellent enantioselectivities (up to 99% ee).     

Self-association free bifunctional thiourea organocatalysts: synthesis of chiral α-amino acids via dynamic kinetic resolution of racemic azlactones

Concentration-independent high enantioselectivity in the dynamic kinetic resolution (DKR) of racemic azlactones affording chiral α-aminoesters has been achieved using self-association free thiourea-based dimeric cinchona alkaloid organocatalysts. Detailed experimental studies and single crystal X-ray analysis confirmed that these bifunctional organocatalysts I do not form H-bonded self-aggregates in either solution or solid state.     

Enantioselective Michael addition of α,α-disubstituted aldehydes to maleimides organocatalyzed by chiral primary amine-guanidines

New primary amine-guanidines derived from the monoguanylation of (1S,2S)- and (1R,2R)-cyclohexane-1,2-diamine have been prepared and used as chiral organocatalysts for the enantioselective conjugate addition of α,α-disubstituted aldehydes to maleimides. The corresponding Michael adducts bearing a new stereocenter were generally obtained in high or quantitative yields and with good enantioselectivities (up to 93% ee).     

Enantioselective organocatalytic conjugate addition of α-nitroacetate to α,β-unsaturated ketones in water

The catalytic enantioselective conjugate addition reaction of α-nitroacetate to α,β-unsaturated ketones promoted by chiral bifunctional organocatalysts is described. The treatment of α-nitroacetate to α,β-unsaturated ketones under aqueous-phase reaction conditions afforded the corresponding Michael adducts with high enantioselectivity. The conjugate addition adducts are easily converted to chiral δ-keto nitroalkanes and δ-keto esters.     

Custom synthesis of substituted butenolides, dihydropyranones, and α-E-alkylidenelactones via alkenylalumination

Alkenylalumination of aldehydes with [α-(ethoxycarbonyl)-β-(t-butyldimethylsilyloxyalkyl)alkenyl]diisobutylaluminum provides the corresponding α-Z-alkylidene-β′-hydroxy esters, which upon protection and treatment with trifluoroacetic acid lactonizes to furnish α-acetoxyalkyl butenolides (n = 1) and dihydropyranones (n = 2) in 40% overall yield. Conjugate addition to these lactenones and concurrent acetate elimination constitute a general and stereospecific synthesis of the corresponding α-E-alkylidene lactones.     

Enantioselective catalytic epoxidation of α,β-enones promoted by fluorous α,α-diaryl-l-prolinols

Enantioselective (up to 87% ee) epoxidation of a variety of α,β-enones to form α,β-epoxy ketones is described using a series of fluorous α,α-diaryl-l-prolinols as bifuncational organocatalysts and tert-butyl hydrogenperoxide (TBHP) as an oxidant.     

Enantioselective organocatalytic oxyamination of unprotected 3-substituted oxindoles

An enantioselective α-oxyamination of unprotected 3-substituted oxindoles with nitrosobenzene catalyzed by tertiary amine-thiourea bifunctional organocatalysts has been developed and affords the corresponding 3-amino-2-oxindole derivatives in good yields and with moderate to excellent enantioselectivities (up to > 99.9?:?0.1 er when the product is isolated by direct filtration from the reaction mixture). The absolute configuration of the major enantiomers of the products has been established both by chemical correlation and by comparison between the theoretically calculated and the experimental ECD.     

Highly enantioselective Michael addition of isobutyraldehyde to nitroalkenes

The asymmetric catalytic Michael reaction between isobutyraldehyde and nitroalkanes with chiral primary amine thiourea organocatalysts was described. In the presence of 10 mol % of 1-((1R,2R)-2-amino-1,2-diphenylethyl)-3-benzylthiourea, the desired products were achieved in excellent enantioselectivity (up to>99% ee) with up to 98% yield.     

Enantioselective conjugate addition of fluorobis(phenylsulfonyl)methane to α,β-unsaturated ketones catalyzed by chiral bifunctional organocatalysts

The catalytic enantioselective conjugate addition reaction of fluorobis(phenylsulfonyl)methane to α,β-unsaturated ketones promoted by chiral bifunctional organocatalysts is described. The treatment of fluorobis(phenylsulfonyl)methane to α,β-unsaturated ketones under mild reaction conditions afforded the corresponding Michael adducts with high enantioselectivity. The conjugate addition adducts are useful for the synthesis of chiral monofluoromethylated compounds.     

N-Heterocyclic carbene containing element organic frameworks as heterogeneous organocatalysts

A bifunctional imidazolium linker was used for the production of highly crosslinked element organic frameworks by Suzuki-coupling with tetrafunctional boronic acids. The resulting porous materials are good heterogeneous organocatalysts in the N-heterocyclic carbene-catalyzed conjugated umpolung of α,β-unsaturated cinnamaldehyde.     

Enantioselective conjugate addition of both aromatic ketones and acetone to nitroolefins catalyzed by chiral primary amines bearing multiple hydrogen-bonding donors

A new class of chiral primary amine catalysts bearing multiple hydrogen-bonding donors have been designed and synthesized. The newly developed bifunctional organocatalysts efficiently catalyzed not only enantioselective conjugate addition of aromatic ketones to nitroolefins in good yields (up to 87%) with excellent enantioselectivities (97→99% ee) but also enantioselective conjugate addition of acetone to nitroolefins in excellent yields (90-96%) with high enantioselectivities (up to 97% ee).     

α,α-Diarylprolinol-derived chiral ionic liquids: recoverable organocatalysts for the domino reaction between α,β-enals and N-protected hydroxylamines

Chiral ionic liquids bearing α,α-diarylprolinol units were synthesized and applied for the first time as organocatalysts for the domino reaction between α,β-enals and N-protected hydroxylamines involving aza-Michael and intramolecular acetalization steps. Corresponding 5-hydroxy-3-arylisoxazolidines with either an (S)- or (R)-configuration at C-3 were obtained in excellent yields (up to 94%) and with moderate to high enantioselectivities (64 to >99% ee). The ionic liquid supported catalyst can be easily recycled and reused for at least four times without a significant loss of chemical yield or enantioselectivity.     

Acceleration of the DABCO-promoted Baylis-Hillman reaction using a recoverable H-bonding organocatalyst

It has been shown that catalytic amounts (20-40 mol %) of bis-aryl (thio)ureas greatly accelerate the DABCO-promoted Baylis-Hillman reaction between a range of aromatic aldehydes and methyl acrylate in the absence of solvent. These robust organocatalysts are superior mole per mole promoters of the reaction than either methanol or water and are recoverable in high yield after the reaction by column chromatography.     

l-Prolinamide derivatives as efficient organocatalysts for aldol reactions on water

A series of l-prolinamide derivatives have been evaluated as potential organocatalysts for aldol reactions. To synthesize these catalysts, a novel and simple route has been developed using proline N-carboxyanhydride (proline-NCA). A new catalyst with a trifluoromethyl-sulfonamide group has been found exhibiting excellent diastereoselectivity (anti/syn: 97/3) and enantioselectivity (99% ee) with 10 mol % loading and being easily recyclable in water.     

Study of aggregation,denaturation and reduction of interferon alpha-2 products by size-exclusion high-performance liquid chromatography with fluorescence detection and biological assays

Interferon alpha-2 (IFN α-2) products have been widely used as antivirals for the treatment of serious diseases such as hepatitis B and C. However, reports of adverse reactions following treatment have prompted investigations into the cause of these undesirable events. In this study size-exclusion HPLC (SE-HPLC) methods coupled with intrinsic fluorescence detection were developed for evaluating the stability and degradation profiles of IFN α-2 drug substances and drug products. The method allowed baseline resolution of the active ingredient from the excipients present in the finished products that included large amounts of albumin. Limits of detection (S/N ≥ 3) for IFN α-2a and IFN α-2b were 32 ng/mL and 28 ng/mL, respectively and good repeatability of chromatographic profiles (%RSD < 2.1) was obtained. High molecular weight (HMW) aggregates with apparent molecular weight of ∼650 kDa as well as dimers, denatured and reduced variants were successfully identified and separated from native IFN α-2 proteins. This chromatographic method, which quantitatively measures physical and chemical changes taking place in solution formulations, was found to be capable of monitoring IFN α-2a and IFN α-2b stability. Potency assay results revealed up to 87% decrease in biological activity of the physically and chemically altered variants compared to the original IFNs.