Theoretical study on mechanism of cinchona alkaloids catalyzed asymmetric conjugate addition of dimethyl malonate to β‐nitrostyrene

The mechanism and enantioselectivity of the asymmetric conjugate addition of dimethyl malonate to β‐nitrostyrene catalyzed by cinchona alkaloid QD‐4 as organic catalyst are investigated using density function theory and ab initio methods. Six different reaction pathways, corresponding to the different approach modes of β‐nitrostyrene to dimethyl malonate are considered. Calculations indicate that the reaction process through a dual‐activation mechanism, in which the tertiary amine of cinchona alkaloid QD‐4 first works as a Brønsted base to promote the activation of the dimethyl malonate by deprotonation, and then, the hydroxyl group of QD‐4 acts as Brønsted acid to activate the β‐nitrostyrene. The rate‐determining step is the proton transfer process from the tertiary amine of QD‐4 to α‐carbon of β‐nitrostyrene. The comparison of the mechanisms and energies of the six reaction channels enable us to learn the fact that QD‐4 has good catalytic activities for the system, and implies C9? OH in QD‐4 may not be involved in the activation. These calculation results account well for the observations in experiments. © 2014 Wiley Periodicals, Inc.     

Highly efficient and enantioselective Michael addition of acetylacetone to nitroolefins catalyzed by chiral bifunctional organocatalyst bearing multiple hydrogen-bonding donors

A new efficient catalyst system for the asymmetric addition of acetylacetone to nitroolefins using a chiral bifunctional organocatalyst bearing multiple hydrogen-bonding donors was developed. When using the organocatalyst 2c derived from natural cinchona alkaloid in optimal conditions, up to 98% chemical yield and 98% ee were observed with a variety of aromatic nitroolefins.     

Magnetic nanoparticles supported cinchona alkaloids for asymmetric Michael addition reaction of 1,3-dicarbonyls and maleimides

New magnetically recoverable cinchona alkaloid organocatalysts have been successfully developed for the asymmetric Michael addition reaction of 1,3-dicarbonyls and maleimides.     

The Mannich reaction of malonates with simple imines catalyzed by bifunctional cinchona alkaloids: enantioselective synthesis of beta-amino acids

We describe the first efficient, direct asymmetric Mannich reactions with malonates and N-Boc aryl and alkyl imines by cooperative hydrogen-bonding catalysis with a cinchona alkaloid bearing a thiourea functionality. We have also extended the scope of this reaction to beta-ketoesters. The synthetic value of this new reaction is demonstrated in the establishment of a convergent enantioselective route toward the biologically important beta-amino acids under mild and air- and moisture-tolerant conditions.     

Asymmetric Mannich reaction of dicarbonyl compounds with alpha-amido sulfones catalyzed by cinchona alkaloids and synthesis of chiral dihydropyrimidones

The highly enantioselective cinchona alkaloid-catalyzed Mannich reaction of dicarbonyl compounds with alpha-amido sulfones as acyl imine precursors is described. The reaction requires 10 mol % of the cinchona alkaloid catalyst, which serves as a general base to generate acyl imines in situ, and aqueous Na2CO3 to maintain the concentration of free alkaloid catalyst. The reaction products are obtained in good yields and high enantioselectivities, and in diastereoselectivities that range from 1:1 to >95:5. The cinchonine-catalyzed reactions provide practical access to highly functionalized building blocks which have been employed in the synthesis of chiral dihydropyrimidones, a class of compounds rich in diverse biological activity. Dihydropyrimidone modifications include a highly diastereoselective hydrogenation of the enamide moiety, using an H-Cube flow hydrogenator and a Rh(II)-mediated 1,3-dipolar cycloaddition to afford highly functionalized complex heterocycles.     

Highly enantioselective aza-henry reaction of ketimines catalyzed by a chiral bifunctional thiourea-tertiary amine derived from quinine

We have developed a highly enantioselective aza-Henry reaction of aryl α-ketoester-derived N-Ts ketimines with a wide range of substrate scope by a simpler bifunctional thiourea-tertiary amine catalyst derived from quinine. A variety of ketimines were investigated and corresponding products were obtained in excellent yields (up to 99% yield) with excellent enatioselectivities (up to 99% ee).     

Enantioselective C-S bond formation by iron/Pybox catalyzed Michael addition of thiols to (E)-3-crotonoyloxazolidin-2-one

The enantioselective Michael addition of thiols to (E)-3-crotonoyloxazolidin-2-one was effectively catalyzed by the Fe(BF₄)₂·6H₂O/(S,S)-ip-Pybox catalyst, and the addition product was obtained with up to a 95% ee.     

Enantioselective synthesis of 2-amino-3-nitrile-chromenes catalyzed by cinchona alkaloids:A remarkable additive effect

2-Amino-3-nitrile-chromenes with potential antitumor activity were constructed by a novel catalytic system. In combination with α-naphthol, quinine could effectively promote the Michael-cyclization process of malononitrile with functionalized chalcones in high yields and moderate to good enantioselectivity(up to 84% ee). It is notable that the enantioselectivity could be greatly improved when α-naphthol was employed as additive.     

Enantioselective addition of diethylzinc to aromatic aldehydes catalyzed by C2-symmetric chiral diols

Optically pure C₂-symmetric diols have been synthesized with moderate yields in a straightforward manner, and are used as catalysts in the enantioselective alkylation of aromatic aldehydes with diethylzinc. The addition of diethylzinc to benzaldehyde and sterically hindered 1-naphthaldehyde was achieved with excellent enantioselectivities (97–99% ee) under catalysis with (1R,2R)-1,2-bis(3,5-dibromophenyl)-ethane-1,2-diol and (1R,2R)-1,2-bis(3,5-diphenylphenyl)-ethane-1,2-diol.     

A facile synthesis of benzo[b][1,4]thiazepine derivatives by palladium acetate catalyzed reaction

The preparation of steroid/nonsteroid fused benzo[b][1,4]thiazepines and 2-arylsubstituted benzo[b][1,4]thiazepines is described from Pd(OAc)₂ catalyzed reaction of steroidal/nonsteroidal β-halovinyl aldehydes and 2-aminothiophenols in DMF under heating condition.     

Enantioselective addition of diethylzinc to aldehydes catalyzed by 5-cis-substituted proline derivatives

5-Cis-substituted prolinols, prolinamines, and prolinamine sulfonamides proved to be efficient ligands for the enantioselective addition of diethylzinc to aldehydes, providing up to 99% ee. The sense of asymmetric induction can be controlled by the nature of the exocyclic functional group (CPh₂OH vs. CH₂NHR vs. CH₂NHSO₃R). The additional 5-cis substituent exerts a strong beneficial effect on the chirality transfer since it rigidifies the catalyst structure. The stereochemical outcome of the reactions is discussed in detail on the respective transition states.     

Copper-catalyzed enantioselective intramolecular conjugate addition/trapping reactions: synthesis of cyclic compounds with multichiral centers

The Cu-catalyzed enantioselective conjugate addition of dialkylzinc to bis-alpha,beta-unsaturated carbonyl compounds followed by the intramolecular trapping of the zinc enolate in the presence of chiral phosphoramidite ligands was investigated. Cyclic and heterocyclic compounds with multichiral centers were formed as a mixture of two diastereomers with excellent diastereoselectivities (up to 99:1) and enantioselectivities (up to 94 % ee, ee=enantiomeric excess). The stereochemistry was determined to be trans,trans for the major products and trans,cis for the minor products. The absolute configuration of the cyclic compounds was assigned by comparison with the analogous adduct derived from trans-3-nonen-2-one and Et(2)Zn or the adduct obtained through conjugate addition of Me(2)Zn to trans-1-phenyl-non-2-en-1-one. Further transformation of these cyclic products into more complex compounds is under investigation in our laboratory.