Theoretical Insights into the Substrate-Dependent Diastereodivergence in (3 + 2) Cycloaddition of α-Keto Ester Enolates with Nitrones

Abstract

Controlling catalytic asymmetric space has received increasing attention for the on-demand synthesis of chiral molecules of interest. However, the identification of the key parameters controlling the stereodetermining step in transition metal catalysis is challenging and involves the thorough characterization of the rate-and stereo-determining transition state(s). In this paper, we describe the computational analysis of the (3 2) cycloaddition of Ni(II)-enolate with cyclic (E)-nitrone to provide a comprehensive analysis of how the bond-forming processes are regulated in the two-electron manifold in the triplet state. Our molecular orbital analysis, in particular, reveals the occurrence of the singly occupied molecular orbital-highest occupied molecular orbital (SOMO-HOMO) level inversion in the Ni(II)-enolate. Further, distortion and interaction analysis are also used to explain the substrate-dependent diastereodivergence in this reaction by alternating the structure of the nitrone. Using a range of computational analyses, we show that the rate-and stereo-determining step in the (3 2) cycloaddition of (E)-nitrone is regulated integrally by (1) isomerism of the octahedral Ni(II) complex, (2) E/Z isomerism of the Ni(II)-enolate, and (3) steric repulsion between the reactants and ligand.

Experimental and Computational Investigation of Facial Selectivity Switching in Nickel–Diamine–Acetate-Catalyzed Michael Reactions

“…However, the computational model could not account for the observed enantioselectivity in the Michael reaction of β-nitrostyrene with dimethyl malonate when they performed the computational analysis with a chiral diimine ligand. On the basis of our previously reported Ni(II)–enolate chemistry, − we planned to examine the reaction pathways with a different set of substrates.…”

“…Chiral Ni­(II)–enolates have been widely utilized to explore catalytic asymmetric α-functionalization of carbonyl compounds. − Our group has proven the synthetic utility of Ni­(II)–enolates through the development of catalytic asymmetric halogenations, , Michael reactions, and (3+2) cyloadditions. − The key to the success of these catalytic transformations is soft enolization; Ni­(II) is believed to act as a Lewis acid to activate the carbonyl substrate, thereby enhancing the deprotonation process even with the use of a relatively weak Brønsted base . However, despite substantial progress in asymmetric Ni catalysis, − structural and mechanistic studies of Ni­(II)–enolates remain conspicuously scarce. − ,− The difficulty arises from several inherent factors in Ni­(II)–enolates. First, considering the coordination isomerism that occurs in Ni­(II)–enolates, several distinct diastereomeric transition states (TSs) are possible. , Second, the open-shell property of these complexes often impairs NMR kinetic analysis, thereby making it difficult to characterize the stereodetermining TSs even when using DFT calculations.…”

“…However, despite substantial progress in asymmetric Ni catalysis, − structural and mechanistic studies of Ni­(II)–enolates remain conspicuously scarce. − ,− The difficulty arises from several inherent factors in Ni­(II)–enolates. First, considering the coordination isomerism that occurs in Ni­(II)–enolates, several distinct diastereomeric transition states (TSs) are possible. , Second, the open-shell property of these complexes often impairs NMR kinetic analysis, thereby making it difficult to characterize the stereodetermining TSs even when using DFT calculations. In addition, if we consider the Ni/ligand bifunctional activation mechanism, − we also have to carefully evaluate the dispersive interactions in the TSs. − Thus, mechanistic studies of Ni catalysis are not only attractive for the replacement of noble metals but also challenging in rationalizing the reactivity and selectivity in Ni­(II) catalysis. − …”

“…Such substrate-dependent selectivity switching in metal–enolate chemistry − has been sporadically reported; however, the mechanistic origin has not often been computationally rationalized. Guided by our recent mechanistic studies of Ni­(II)-catalyzed (3+2) cycloadditions, − we postulated that facial selectivity switching in the nitroalkene could be explained by the difference in (1) the coordination structure of the octahedral Ni­(II) complex and (2) the combined activation mode of the nitroalkene. The asymmetric Michael reaction has been frequently used as a benchmark test to evaluate the catalytic performance of a transition metal with a chiral ,,,− or achiral ligand. − The critical importance of the metal-bound N–H functionality has been recognized − since the metal–ligand bifunctional mechanism in the asymmetric hydrogen transfer reaction was initially characterized in 2000 on the basis of early computational studies .…”

“…Guided by our recent mechanistic studies of Ni­(II)-catalyzed (3+2) cycloadditions, − we postulated that facial selectivity switching in the nitroalkene could be explained by the difference in (1) the coordination structure of the octahedral Ni­(II) complex and (2) the combined activation mode of the nitroalkene. The asymmetric Michael reaction has been frequently used as a benchmark test to evaluate the catalytic performance of a transition metal with a chiral ,,,− or achiral ligand. − The critical importance of the metal-bound N–H functionality has been recognized − since the metal–ligand bifunctional mechanism in the asymmetric hydrogen transfer reaction was initially characterized in 2000 on the basis of early computational studies . Meanwhile, the cooperative effect between the coordination geometry in the metal–enolate complex (inner-sphere activation mode) ,,− and ligand-enabled H-bonding interaction (outer-sphere activation mode) − has not been systematically analyzed.…”