Theoretical Study on Cooperation Catalysis of Chiral Guanidine/ Copper(I) in Asymmetric Azide-Alkyne Cycloaddition/[2 + 2] Cascade Reaction.

Density functional theory (DFT) calculations with BP86-D3(BJ) functionals were employed to reveal the mechanism and stereoselectivity of chiral guanidine/copper(I) salt-catalyzed stereoselective three-component reaction among N-sulfonyl azide, terminal alkyne, and isatin-imine for spiroazetidinimines that was first reported by Feng and Liu (Angew. Chem. Int. Ed. 2018, 57, 16852-16856). For the noncatalytic cascade reaction, the denitrogenation to generate ketenimine species was the rate-determining step, with an activation barrier of 25.8-34.8 kcal mol-1. Chiral guanidine-amide promoted the deprotonation of phenylacetylene, generating guanidine-Cu(I) acetylide complexes as active species. In azide-alkyne cycloaddition, copper acetylene coordinated to the O atom of the amide moiety in guanidium, and TsN3 was activated by hydrogen bonding, affording the Cu(I)-ketenimine species with an energy barrier of 3.5∼9.4 kcal mol-1. The optically active spiroazetidinimine oxindole was constructed via a stepwise four-membered ring formation, followed by deprotonation of guanidium moieties for C-H bonding in a stereoselective way. The steric effect of the bulky CHPh2 group and chiral backbone in the guanidine, combined with the coordination between the Boc group in isatin-imine with a copper center, played important roles in controlling the stereoselectivity of the reaction. The major spiroazetidinimine oxindole product with an SS configuration was formed in a kinetically more favored way, which was consistent with the experimental observation.

Mechanistic Study of Asymmetric Alkynylation of Isatin-Derived Ketimine Mediated by a Copper/Guanidine Catalyst.

In this work, we performed a mechanistic study of asymmetric alkynylation of isatin-derived N-Boc ketimine that was first reported by Feng, Liu, and co-workers (Chem. Commun. 2018, 54, 678-681). Guanidine-amide promoted the formation of highly nucleophilic copper acetylene species by abstracting the terminal proton of phenylacetylene with an imine moiety. The guanidinium salt-Cu(I) complex was the most active species in the addition of the C═N bond, in which copper acetylene coordinated to the O atom of the amide moiety, and the isatin-derived ketimine substrate was activated by hydrogen bonding as well as tert-butoxycarbonyl···Cu(I) coordination. Due to weak interaction between Cu(I) and the Ph group in the amide of guanidine, as well as the repulsion between the tert-butyl group in ketimine and the cyclohexyl group in guanidine, the copper acetylene preferred to attack isatin-derived ketimine from the re-face, leading to the S-configuration product with excellent stereoselectivity. The affinity of the counterion for the Cu(I) center in the copper salt affected the deprotonation of phenylacetylene and the formation of guanidinium salt active species. In contrast to CuBr and CuCl, the combination of CuI with aniline-derived guanidine-amide exhibited high catalytic activity and a chiral induction effect, contributing to a high turnover frequency (9.70 × 10-4 s-1) in catalysis and ee%.

Catalytic asymmetric synthesis of spirocyclobutyl oxindoles and beyond via [2+2] cycloaddition and sequential transformations.

Efficient asymmetric synthesis of a collection of small molecules with structural diversity is highly important to drug discovery. Herein, three distinct types of chiral cyclic compounds were accessible by enantioselective catalysis and sequential transformations. Highly regio- and enantioselective [2+2] cycloaddition of (E)-alkenyloxindoles with the internal C[double bond, length as m-dash]C bond of N-allenamides was achieved with N,N'-dioxide/Ni(OTf)2 as the catalyst. Various optically active spirocyclobutyl oxindole derivatives were obtained under mild conditions. Moreover, formal [4+2] cycloaddition products occurring at the terminal C[double bond, length as m-dash]C bond of N-allenamides, dihydropyran-fused indoles, were afforded by a stereospecific sequential transformation with the assistance of a catalytic amount of Cu(OTf)2. In contrast, performing the conversion under air led to the formation of γ-lactones via the water-involved deprotection and rearrangement process. Experimental studies and DFT calculations were performed to probe the reaction mechanism.

Mechanism and Selectivity of Cyclopropanation of 3-Alkenyl-oxindoles with Sulfoxonium Ylides Catalyzed by a Chiral N,N'-Dioxide-Mg(II) Complex.

The mechanism and stereoselectivity of an asymmetric cyclopropanation reaction between 3-alkenyl-oxindole and sulfoxonium ylide catalyzed by a chiral N,N'-dioxide-Mg(II) complex were explored using the B3LYP-D3(BJ) functional and the def2-TZVP basis set. The noncatalytic reaction occurred via a stepwise mechanism, with activation barriers of 21.6-23.5 kcal mol-1. The C2-Cα bond formed followed by the carbanion SN2 substitution, constructing a three-membered ring in spiro-cyclopropyl oxindoles, accompanied by the release of dimethylsulfoxide. The electron-withdrawing N-protecting t-butyloxy carbonyl (Boc) and acetyl (Ac) groups in isatin enhanced the local electrophilicity of the C2 atom and the repulsion between the two COPh groups in the reactants, contributing to high reactivity as well as good diastereoselectivity results. The N-Boc-3-phenacylideneoxindole coordinated to the chiral ligand (L-PiPr2) in a bidentate fashion, forming a hexacoordinate-Mg(II) complex as the reactive species. The origin of enantioselectivity was from the shielding effect of 2,6-diisopropylphenyl groups in the ligand toward the si-face of oxindole. The repulsion between the SO(CH3)2 and COPh groups in 3-alkenyl-oxindole and the neighboring ortho-iPr group in the ligand directed the re-face of ylide to attack the re-face of oxindole preferably, contributing to the high diastereoselectivity of the product. A metal-ion-ligand matching relationship was important for a good asymmetric induction effect of the chiral N,N'-dioxide-metal catalyst. A large chiral cavity in the Zn(II) catalyst weakened the shielding effect of 2,6-diisopropylphenyl groups in the ligand toward the prochiral face of oxindole, leading to inferior enantioselectivity observed in the experiment.