•The π-π stacking effect stabilized exo-transition state for diastereofacial selectivity.•Coupling of two pseudoradical centers from reactivity sites controlled regio-selectivity.•Catalyst exerted asymmetric induction by bulky ortho-iPr group and chiral backbone.The mechanism and selectivity of the asymmetric cycloaddition reactions of 3-vinylindole towards methyleneindolinone (Diels–Alder reaction) or ketimine (aza-Diels–Alder reaction) were investigated theoretically by DFT and ONIOM methods. The non-catalytic DA reaction occurred in a two-stage one-step mechanism with the energy barriers of 17.0–29.6 kcal mol−1. Reactivity index analysis indicated that the cycloaddition tended to occur by the most nucleophilic terminal C4 center in 3-vinylindole and the most electrophilic Cβ center in methyleneindolinone with lower activation energies, which accounted for the regioseletivity observed in experiment. For non-catalytic reactions, the slightly exo-preference stemmed from the stabilizing π-π stacking of two indole rings in substrates. In the presence of chiral N,N'-dioxide-Ni(II) complex, the bulky ortho-iPr group in aniline of ligand provided sufficient steric shielding around dienophile from the si-face attack in Diels–Alder reaction or re-face attack in aza-Diels–Alder reaction by diene, resulting in predominant products with excellent enantioselectivity (the favorable re-face attack in Diels–Alder reaction or si-face attack in aza-Diels–Alder reaction). A “pocket-like” chiral cavity constructed by chiral catalyst enhanced exo-diastereofacial selectivity significantly by maximizing the overlap of the two indole rings of substrates to avoid unfavorable steric repulsion between indole ring of 3-vinylindole and chiral ligand. Compared with catalytic aza-Diels–Alder reaction of 3-vinylindole and ketimine, the improved catalytic activity of chiral N,N'-dioxide-Ni(II) catalyst in Diels–Alder reaction of 3-vinylindole with methyleneindolinone contributed to the high turnover frequency (TOF = 1.05 × 106 s−1). These results were in good agreement with experimental observations.Download high-res image (115KB)Download full-size image

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.

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.

The mechanism and origin of the stereoselectivity of the asymmetric carbonyl-ene reaction between N-methyl-protected isatin and 2-methyloxypropene catalyzed by the N,N′-dioxide–Mg(OTf)2 complex were investigated by DFT and ONIOM methods. The background reaction occurred via a two-stage, one-step mechanism with a high activation barrier of 30.4 kcal mol–1 at the B3LYP-D3(BJ)/6-311G**(SMD, CH2Cl2)//B3LYP/6-31G*(SMD, CH2Cl2) level at 303 K. Good linear correlations between the global nucleophilicity index (N) and the activation energy barrier (ΔG⧧) were found. The chiral N,N′-Mg(II) complex catalyst could enhance the electrophilicity of the isatin substrate by forming hexacoordinate Mg(II) reactive species. The substituent at the ortho positions of aniline combined with the aliphatic ring of the backbone in the chiral N,N′-dioxide ligand played an important role in the construction of a favorable “pocket-like” chiral environment (chiral pocket) around the Mg(II) center, directing the preferential orientation of the incoming substrate. An unfavorable steric arrangement in the re-face attack pathway translated into a more destabilizing activation strain of the ene substrate, enhancing enantiodifferentiation of two competing pathways for the desired R product. This work also suggested a new phosphine ligand (N-L1) for the formation of the Mg(II) complex catalyst for the asymmetric carbonyl-ene reaction. The chiral environment and Lewis acidity of the Mg(II) complex could be fine-tuned by introduction of P-donor units into the ligand for highly efficient asymmetric catalysis.

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.

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.