Zhishan Su

Asymmetric Direct Aldol Reaction of Functionalized Ketones Catalyzed by Amine Organocatalysts Based on Bispidine

Organocatalysts containing primary-secondary amine based on bispidine and amino acid have been designed to catalyze the asymmetric direct aldol reaction of functionalized ketones including alpha-keto phosphonates, alpha-keto esters, as well as alpha,alpha-dialkoxy ketones as aldol reaction acceptors. The corresponding products with chiral tertiary alcohols were obtained in moderate to high yields (up to 97%) and high enantioselectivities (up to 98% ee). A theoretical study of transition structures demonstrated that protonated piperidine was important for the reactivity and enantioselectivity of this reaction.

Enantioselective Liquid–Liquid Extractions of Underivatized General Amino Acids with a Chiral Ketone Extractant

The chiral ketone (S)-3 shows high kinetic enantioselectivities toward the L form for general underivatized amino acids with hydrophobic side chains and a high thermodynamic enantioselectivity toward the D form for cysteine with its -SH polar side chain when used as an extractant in enantioselective liquid-liquid extractions in the presence of Aliquat 336. Consecutive extractions by imine formation and hydrolysis increase the enantiopurity of the amino acid, as both of these reactions are L-form-selective.

Unique Steric Effect of Geminal Bis(silane) To Control the High Exo-selectivity in Intermolecular Diels–Alder Reaction

The unique steric effect of geminal bis(silane) [(R3Si)2CH] allows an exo-selective intermolecular Diels-Alder reaction of geminal bis(silyl) dienes with α,β-unsaturated carbonyl compounds. The approach shows good generality to form ortho-trans cyclohexenes in good yields with high exo-selectivity and high enantioselectivity in some asymmetric cases. The excellent exo-stereocontrol aptitude of (R3Si)2CH group is highlighted by comparing with R3SiCH2 and R3Si groups, which leads to endo-selectivity predominantly. The conformational analysis of dienes suggests that (R3Si)2CH group effectively shields both sides of the diene moiety, ensuring the desired exo-selectivity. Moreover, the geminal bis(silane) can be further functionalized to transform the resulting ortho-trans cycloadducts into useful synthons, which makes the approach hold great potential for organic synthesis.

Highly Enantioselective Extraction of Underivatized Amino Acids by the Uryl-Pendant Hydroxyphenyl-Binol Ketone

The hydroxyphenyl chiral ketone, (S)-3, reacts with D-amino acids bearing hydrophobic side chains exclusively over the L-amino acids in a two-phase liquid-liquid extraction, and thus acts as a highly stereoselective extractant. Calculations for the energy-minimized structures for the imine diastereomers and the comparison of the selectivities with other phenyl ketones, (S)-4 and (S)-5, demonstrate that the hydrogen bond between the carboxylate group and the phenolic hydroxyl group contributes to the remarkable enantioselectivities. The multiple hydrogen bonds present in the imine of (S)-3 reinforce the rigidity, and results in the difference between the stabilities of the imine diastereomers. The imine could be hydrolyzed in methanolic HCl solution, and the extraction of the evaporated residues revived the organic layer of (S)-3, which could enter into a new extractive cycle and leaves the D-amino acid with enantiomeric excess (ee) values of over 97 % in the aqueous layer.

Mechanism of Ketone Allylation with Allylboronates as Catalyzed by Zinc Compounds: A DFT Study

The mechanism of the allylation reaction between 4-chloroacetophenone and pinacol allylboronates catalyzed by ZnEt(2) with alcohols was investigated using density functional theory (DFT) at the M05-2X/6-311++G(d,p) level. The calculations reveal that the reaction prefers to proceed through a double γ-addition stepwise reaction mechanism rather than a Lewis acid-catalyzed concerted one. The intermediate with a four-coordinated boron center, which is formed through proton transfer from EtOH to the ethyl group of ZnEt(2) mediated by the boron center, is the active species and an entrance for the catalytic cycle. The latter is composed of three elementary steps: 1) boron to zinc transmetalation leading to the formation of allylzincate species, 2) electrophilic addition of ketone to allylzincate species, and 3) generation of the final product with recovery of the catalyst. The boron to zinc transmetalation step has the largest energy barrier of 61.0 kJ mol(-1) and is predicted to be the rate-determining step. The calculations indicate that the additive EtOH plays important roles both in lowering the activation free energy for the formation of the four-coordinated boron active intermediate and in transforming the low catalytic activity ZnEt(2) into high activity zinc alkoxide species. The alcohols with a less sterically encumbering R group might be the effective additives. The substituted groups on the allylboronates might primarily affect the boron to zinc transmetalation, and the allylboronates with substituents on the C(γ)  atom is poor in reactivity. The comparison of the catalytic effect between the zinc compounds investigated suggest that Zn(OEt)(2), Zn(OH)(2), and ZnF(2) exhibit higher catalytic efficiency for the boron to zinc transmetalation due to the activation of the B-C(α) bond through orbital interactions between the p orbitals of the EtO, OH, F groups and the empty p orbital of the boron center.

Theoretical Investigations on the Mechanism of Hetero‐Diels–Alder Reactions of Brassard’s Diene and 1, 3‐Butadiene Catalyzed by a Tridentate Schiff Base Titanium(IV) Complex

The mechanism of the hetero-Diels-Alder reactions of Brassards diene and 1,3-butadiene catalyzed by a titanium(IV) complex of a tridentate Schiff base was investigated by DFT and ONIOM methods. The calculations indicate that the mechanism of the reaction is closely related to the nucleophilicity-electrophilicity between diene and carbonyl substrates. A stepwise pathway is adopted for Brassards diene, and the step corresponding to the formation of the C--C bond is predicted to be the rate-determining step with a free-energy barrier of 8.4 kcal mol(-1). For 1,3-butadiene, the reaction takes place along a one-step, two-stage pathway with a free-energy barrier of 14.9 kcal mol(-1). For Brassards diene as substrate, the OCH(3) and OSi(CH(3))(3) substituents may play a key role in the formation of the transition state and zwitterionic intermediate by participating in charge transfer from Brassards diene to formaldehyde. The combination of the phenyl groups at the amino alcohol moiety and the ortho-tert-butyl group of the salicylaldehyde moiety in the chiral tridentate Schiff base ligand plays an important role in the control of the stereoselectivity, which is in agreement with experimental observations.

Theoretical investigation on copper hydrides catalyzed hydrosilylation reaction of 3-methylcyclohex-2-enone: mechanism and ligands' effect

The mechanism of the hydrosilylation reactions of 3-methylcyclohex-2-enone with tetramethyldisiloxane (TMDS) catalyzed by (Ph3P)CuH and (IPr)CuH has been investigated by DFT. The catalytic cycle is composed of two steps: the addition of the copper hydrides to the CC bond in the substrate, and the regeneration of the copper hydrides assisted by TMDS. The calculations indicate that the catalyst recovery step is the rate-determining step. The assistances of IPr and Ph3P ligands to the CuH catalysts make the transition state structures compact and stable. The steric bulk of the ligands could help to stabilize the central Cu atom and promote the coordination of the central Cu atom with the substrate. The higher nucleophilicity of the catalysts and the stronger interaction of the ligands with the central Cu atom make the catalysts interact more easily with the substrate. The hydrosilylation reaction proceeds more favorably when catalyzed by (IPr)CuH as compared to (Ph3P)CuH.

Computational investigation on stereochemistry in titanium-salicylaldehydes-catalyzed cyanation of benzaldehyde.

Theoretical simulation on the enantioselective cyanation of benzaldehyde over titanium-salicylaldehyde catalysts is performed with B3LYP//ONIOM methods. The calculations predict that the attack of cyanide to adsorbed benzaldehyde is the rate-determining step for the entire reaction. The stereochemistry of the titled reaction might be controlled not only by the attack directions of cyanide to benzaldehyde but also by different coordination modes of benzaldehyde to the chiral catalysts. In addition, to evaluate the accuracy of the employed method, the stereoselectivities of the reactions with five different chiral ligands are theoretically predicted. The theoretical predictions are qualitatively in agreement with experiments, and a linear relationship between calculated Delta DeltaG(double dagger) and experimental ones is obtained, especially for the reactions using the ligands with a single chiral center.

Regioselective 1,4- over 1,2-addition of 3,3-bis(silyl) allyloxy lithium to enals, enones and enoates. The remarkable α-effect of silicon.

A remarkable α-effect of silicon has been discovered that results in soft nucleophilicity at the Cγ of 3,3-bis(silyl) allyloxy lithium 1. The addition of 1 to α,β-unsaturated carbonyl compounds, including enals, proceeds in a 1,4- over 1,2-manner with medium to good regioselectivity, whereas the parent allyloxy lithium 4 undergoes complete 1,2-addition. The results from DFT calculations of HMPAcomplexed 1 and 4 provide the rationale to explain this different regioselectivity.

Theoretical and experimental studies on the structure–property relationship of chiral N,N′-dioxide–metal catalysts probed by the carbonyl–ene reaction of isatin

The structure and electronic properties of metallic complexes formed by coordinating chiral N,N′-dioxide ligands with different amino acid skeletons or straight-chain alkyl spacers (linkage) to Mg2+ and Ca2+ are studied at the B3LYP-D3(BJ)/6-311G**(SMD, CH2Cl2)//ONIOM (B3LYP/6-31G*: UFF) (SMD, CH2Cl2) level. The N-oxide unit in the ligand exhibits a stronger O-donor ability than the carbonyl of the amide in the formation of the chiral N,N′-dioxide–Mg(II) catalyst. Coordination of the chiral N,N′-dioxide ligand to the metal center forms a pocket-like chiral environment (“chiral pocket”), which can be characterized by four structural descriptors, which are the bite angle αO1–M–O2, the average M–O distance, the torsion angle θ2 (C1–O1⋯O2–C2) and the dihedral angle (DC1–N3–C7–C8 or DC2–N4–C9–C10). The Lewis acidity of the metal ion decreases when the number of –CH2 spacers between two N-oxide units increases from 1 to 5, which is attributed to increasing Pauli repulsion as well as deformation of fragments. The stereoselectivity of asymmetric carbonyl–ene reaction is dependent on the blocking effect of ortho-iPr of aniline on the reaction site of isatin, which could be adjusted by changing the linkage and chiral backbone as well as metal ion. An unfavorable steric arrangement in the re-face attack pathway translated into a more destabilizing activation strain of the ene substrate, enhancing the enantiodifferentiation of two competing pathways for the desired (R)-product. The counterion might change the catalytic species as well as the associated chiral pocket by taking part in coordination towards the metal center, consequently affecting the reaction mechanism and stereoselectivity.