Malonate-type bis(oxazoline) ligands with sp hybridized bridge carbon: synthesis and application in Friedel-Crafts alkylation and allylic alkylation

A series of simple and new C₂-symmetric diphenylmethylidene malonate-type bis(oxazoline) ligands were synthesized and applied to the Friedel-Crafts reaction and allylic alkylation. The Cu(II) complex of ligand 4b bearing the benzyl group afforded good to excellent enantioselectivity for the F-C adducts (up to >99% ee) between indole and alkylidene malonate, and the palladium complex of ligand 4c bearing the phenyl group afforded excellent enantioselectivity (up to 94% ee) for the allylic alkylation product.     

Rhodium/diene-catalyzed asymmetric arylation of N-Boc-protected α,β-unsaturated δ-lactam with arylboronic acids: enantioselective synthesis of 4-aryl-2-piperidinones

Utilizing toluene/isopropanol (20:1 to 40:1) as a solvent and KHF₂ as an additive, the rhodium/diene-catalyzed asymmetric arylation (RCAA) reaction of arylboronic acids to N-Boc-protected α,β-unsaturated δ-lactam proceeded smoothly to afford chiral 4-aryl-2-piperidinones with high to excellent yields (up to 94%) and enantioselectivities (up to >99% ee). Further conversion of adduct (R)-1-(tert-butyloxycarbonyl)-4-(4-chlorophenyl)-2-piperidone to (R)-Homobaclofen hydrochloride was also presented.     

Enantioselective anti-Mannich reaction catalyzed by modularly designed organocatalysts

A highly stereoselective method for achieving the anti-Mannich reaction of aldehydes and ketones with ethyl (4-methoxyphenylimino)acetate was realized using the modularly designed organocatalysts (MDOs) self-assembled from cinchona alkaloid derivatives and (R)-pyrrolidien-3-carboxylic acid in the reaction media. The desired anti-Mannich products were obtained in good to excellent yields (up to 93%), excellent diastereoselectivities (up to 99:1 dr), and good to high enantioselectivities (up to 99% ee).     

Pt(IV)-catalyzed generation and [4+2]-cycloaddition reactions of o-quinone methides

Novel intermolecular and intramolecular generations of ortho-quinone methides and their formal [4+2]-cycloaddition reactions with olefins catalyzed by PtCl₄ and AuCl₃ under mild conditions have been developed. Good to excellent yields (up to 99%) and diastereoselectivity (up to >99:1) of the chromans were obtained. PtCl₄ was found to be effective and compatible with various functional groups present in the substrates. A mechanism accounting for its catalytic cycle is proposed and discussed.     

l-Proline derived triamine as a highly stereoselective organocatalyst for asymmetric Michael addition of cyclohexanone to nitroolefins

l-Proline derived triamine 4 has been developed as a highly efficient and stereoselective organocatalyst for the asymmetric Michael addition of cyclohexanone to nitroolefins. In the presence of (CF₃SO₂)₂NH, 4 catalyzed the reaction of cyclohexanone to a variety of nitroolefins with high yields (up to 99%) and excellent diastereoselectivities (up to 99:1 dr) and enantioselectivities (up to 98% ee).     

Enhanced efficiency of recyclable C3-symmetric cinchonine-squaramides in the asymmetric Friedel–Crafts reaction of indoles with alkyl trifluoropyruvate

The highly enantioselective Friedel–Crafts reaction of indoles with trifluoropyruvate catalyzed by a C₃-symmetric cinchonine-squaramide is reported. A wide variety of trifluoromethylated indole derivatives were obtained in high yields and with excellent enantioselectivities (99% and up to >99% ee). Moreover the C₃ catalyst can be easily recovered and was used five times.     

Ruthenium-catalysed asymmetric transfer hydrogenation of N-(tert-butanesulfinyl)imines

The ruthenium complex prepared from [RuCl₂(p-cymene)]₂ and (1S,2R)-1-amino-2-indanol is a very efficient catalyst for the asymmetric transfer hydrogenation of (R)-N-(tert-butanesulfinyl)ketimines in isopropanol. By carefully removing all possible moisture from the reaction medium, chiral primary amines with very high optical purities (up to >99% ee) can be easily prepared in excellent yields by the diastereoselective reduction of the imines followed by removal of the sulfinyl group under mild acidic conditions. Reaction times of 1-4 h were needed to complete the reduction reactions when they were performed at 40 °C.     

Practical copper-catalyzed N-arylation of nitrogen heterocycles with aryl halides under ligand and additive free conditions

N-arylation of a wide variety of nitrogen heterocycles with aryl iodides catalyzed by copper iodide under mild ligand and additive free conditions (ⁿBu₄NBr, PhMe, NaOH, reflux, 22 h) was accomplished in good to excellent yields (up to 95%) and substrate conversions (up to 99%).     

Catalytic asymmetric brominative dearomatization reaction of benzofurans

A catalytic asymmetric brominative dearomatization reaction of benzofuran derivatives was achieved by using hydroquinidine 1,4-phthalazinediyl diether [(DHQ)₂PHAL] as the catalyst and N-bromoacetamide (NBAc) as the brominating reagent. A series of brominated spiro[benzofuran-2,5'-oxazoles] bearing two contiguous stereogenic centers were obtained in high yields (up to 99%) with excellent enantioselectivity (up to 97% ee).     

Highly enantioselective Michael addition of ketones to nitroolefins catalyzed by (S)-pyrrolidine arenesulfonamide

A new type of catalyst for the asymmetric Michael addition reaction has been designed and synthesized. This catalyst, (S)-pyrrolidine arenesulfonamide 1, resulted in high yields (up to 93%), excellent diastereoselectivities (syn/anti ratio up to 99/1), and excellent enantioselectivities (ee up to 99%) for various cyclic ketones and nitroolefins.     

Aromatic l-prolinamide-catalyzed asymmetric Michael addition of aldehydes to nitroalkenes

Two chiral aromatic l-prolinamides were synthesized in high overall yield (95%) from N-Boc-l-proline and served as organocatalysts in asymmetric Michael reactions of aldehydes to nitroalkenes. Under the optimized reaction conditions, (S)-N-tritylpyrrolidine-2-carboxamide 4 was found to be a highly efficient organocatalyst for the Michael addition, and the corresponding Michael adducts were obtained in good yields (up to 94%), with excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to 99:1 dr).     

Copper(II)-containing C2-symmetric bistetracarboline amides in enantioselective Henry reactions

A series of new C₂-symmetric chiral diamides were synthesized from l-tryptophan and used as chiral ligands chelated with Cu(II) in enantioselective Henry reactions. Ligand 4a with CuCl₂·2H₂O (5%) showed effective catalytic efficiency in Henry reaction. High yields (up to 99%) and excellent enantioselectivities (up to 98%) were achieved for both aromatic and aliphatic aldehyde substrates.     

Copper-catalyzed enantioselective addition of alcohols to isatin-derived ketimines

The first copper-catalyzed enantioselective addition of alcohols to imines was described. In the presence of 1?mol% Cu(OAc)₂ complexed with chiral cyclohexane-based N,P-ligand L4, chiral isatin-derived N,O-aminals were obtained in excellent yields (93–99%) and good-to-excellent enantioselectivities (up to 93% ee) under mild conditions.     

L-tert-Leucine derived urea-ammonium salts: Efficient bifunctional phase transfer catalysts for highly diastereo- and enantioselective aza-Henry reaction of isatin-derived N-Boc ketimines with α-aryl nitromethanes

An efficient way of aza-Henry reaction between isatin-derived N-Boc ketimines and α-aryl nitromethanes catalyzed by bifunctional phase transfer catalysts with a quaternary ammonium center derived from L-tert-Leucine has been developed. A series of 3-substituted 3-amino-oxindoles were constructed by this catalytic protocol in excellent yields (90–99%), with high enantioselectivities (83–95%) and diastereoselectivities (79:21–97:3). The asymmetric aza-Henry reaction of N-Boc amidosulfones and α-aryl nitromethanes were also investigated and gave the corresponding products in high to excellent yields (72–97%) with high enantioselectivities (up to 99%) and diastereoselectivities (up to >99:1).     

Calixarene-based chiral primary amine thiourea promoted highly enantioselective asymmetric Michael reactions of α,α-disubstituted aldehydes with maleimides

Calix[4]arene based chiral bifunctional thiourea-primary amines have been shown to act as effective catalysts for the Michael addition of aldehydes to maleimides for the first time. The corresponding adducts were generally obtained preferentially in (R)- or (S)-forms with high yields (up to 99%) and with high to excellent enantioselectivities (up to 98% ee).     

Highly diastereo- and enantioselective direct aldol reactions of cycloketones with aldehydes catalyzed by a trans-4-tert-butyldimethylsiloxy-l-proline amide

An organocatalyst derived from trans-4-hydroxy-l-proline and (1S,2S)-1,2-diphenyl-2-aminoethanol catalyzes the direct aldol reactions of cycloketones with a wide scope of aldehydes in high yields and with excellent diastereoselectivities of up to >99:1 and enantioselectivities of up to >99% ee.     

Highly diastereoselective synthesis of α-trifluoromethylated α-propargylamines by acetylide addition to chiral CF3-substituted N-tert-butanesulfinyl ketimines

A convenient and practical method for the preparation of enantiomerically pure α-trifluoromethylated α-propargylamines is described. A range of enantiopure α-trifluoromethylated α-propargyl sulfinamides were obtained by the addition of lithium acetylides generated in situ with n-BuLi and terminal alkynes to diverse chiral CF₃-substituted (S)-N-tert-butanesulfinyl ketimines in moderate to excellent yields (56–97%) and with uniformly excellent diastereoselectivities (>99:1) by using Ti(OⁱPr)₄ as the catalyst and THF as the polar solvent. Enantiomerically pure α-trifluoromethylated α,α-dibranched propargyl amines were then readily obtained in excellent yields (87–97%) by acidic cleavage of the tert-butanesulfinyl group.     

Catalytic and asymmetric Friedel-Crafts alkylation of indoles with nitroacrylates. Application to the synthesis of tryptophan analogues

An asymmetric Friedel-Crafts alkylation of indoles with nitroacrylates catalyzed by chiral (4R,5S)-DiPh-BOX (L1)-Cu(OTf)₂ complex (10 mol %) has been developed. The reactions provide tryptophan nitro-precursors in moderate diastereoselectivities (anti/syn up to 72:28) and good to excellent enantioselectivities (up to 99% ee). The alkylation products could be easily reduced to optically active tryptophan analogues with Zn/H⁺.     

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.     

Production of Enantiopure Chiral Epoxides with E. coli Expressing Styrene Monooxygenase

Styrene monooxygenases are a group of highly selective enzymes able to catalyse the epoxidation of alkenes to corresponding chiral epoxides in excellent enantiopurity. Chiral compounds containing oxirane ring or products of their hydrolysis represent key building blocks and precursors in organic synthesis in the pharmaceutical industry, and many of them are produced on an industrial scale. Two-component recombinant styrene monooxygenase (SMO) from Marinobacterium litorale was expressed as a fused protein (StyAL2StyB) in Escherichia coli BL21(DE3). By high cell density fermentation, 35 g_DCW/L of biomass with overexpressed SMO was produced. SMO exhibited excellent stability, broad substrate specificity, and enantioselectivity, as it remained active for months and converted a group of alkenes to corresponding chiral epoxides in high enantiomeric excess (˃95–99% ee). Optically pure (S)-4-chlorostyrene oxide, (S)-allylbenzene oxide, (2R,5R)-1,2:5,6-diepoxyhexane, 2-(3-bromopropyl)oxirane, and (S)-4-(oxiran-2-yl)butan-1-ol were prepared by whole-cell SMO.