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The reaction mechanism and enantioselectivity of asymmetric Michael addition reaction between alkynone (R1) with α-angelica lactone (R2) catalyzed by chiral N, N'-dioxide-Sc(III) complex were investigated at the M06/6-31G(d,p) (acetonitrile, SMD) level. The α-angelica lactone substrate could isomerize to the active enolized form in the presence of Sc(OTf)3 reagent, assisted by the counter trifluoromethanesulfonate anion OTf-. The alkynone substrate and enolized angelica lactone (or its anion) coordinated to Sc(III) center of N,N'-dioxide-Sc(III) complex catalyst simultaneously, forming a high active hexacoordinate-Sc(III) complex. The catalytic reaction occurred via a two-step mechanism, in which C2 Cγ bond formation was predicted to be the chirality-controlling step as well as the rate-determining step (RDS), affording predominant S-enantiomer. The counterion OTf- facilitated C H construction as a proton-shuttle, producing mainly E-configuration product observed in experiment. The steric repulsion from the ortho-substituent of amide moiety as well as the chiral backbone of N, N'-dioxide-Sc(III) catalyst played the key role for chiral induction in the asymmetric reaction. The less destabilizing Pauli repulsion and more stabilizing attractive interaction, especially the orbital interaction, along the si-face attack pathway enhanced the enantiodifference of the two competing pathways for high enantioselectivity. The energy barriers for E/Z isomerization of S or R-enantiomer assisted by HOTf was as high as 34.6–35.0 kcal mol−1, indicating that the product with Z-conformation was difficult to be obtained. These results were in good agreement with experimental observations.

The mechanism and enantio- as well as diastereo-selectivity of asymmetric direct aldol reaction of isatin with α-angelica lactone catalyzed by chiral N, N'-dioxide-Sc(OTf)3 were studied at the B3LYP(SMD, THF)/6-31G(d,p) level. The calculations indicated that the reaction occurred along stepwise mechanism, that is, C C bond formation followed by H-transfer from α-angelica lactone to carbonyl group of isatin. The H-transfer step was predicted to be the rate-determining step(RDS), with the energy barrier of 23.3 ∼ 26.2 kcal mol−1 for four stereoisomeric products. The ortho-isopropyl groups of amide in ligand blocked the reacting site from re-face of isatin and induced the re-face of α-angelica lactone to approach to the si-face of isatin, leading to the predominant product with 3S, 2′S-configuration. In this asymmetric catalysis, the interaction energy term (ΔEint), especially stabilizing orbital energy (ΔEoi) and electrostatic energy (ΔVelstat), were the main contributors to the enantioselectivity of the reaction, while the activation strain energy (ΔEstrain) of α-angelica substrate enhanced the diastereodifferentiation of the two competing pathways, contributing to high diastereomeric ratio (d.r.). The turnover frequency (TOF) along the favorable si-face pathway was predicted to be 2.76 × 10−21 s−1, with the rate constant of k(T) = 7.5 × 10−2 exp(-108390/RT) dm3 mol−1 s−1 over 258.15 K ∼ 358.15 K temperature range. These results provided explanation for the good reactivity as well as excellent asymmetric induction of chiral N, N'-dioxide-Sc(OTf)3 in direct aldol reaction of isatin.

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.