Dynamics in Catalytic Asymmetric Diastereoconvergent (3 + 2) Cycloadditions with Isomerizable Nitrones and α-Keto Ester Enolates

Abstract

Reaction design in asymmetric catalysis has traditionally been predicated on a structurally robust scaffold in both substrates and catalysts, to reduce the number of possible diastereomeric transition states. Herein, we present the stereochemical dynamics in the Ni(II)-catalyzed diastereoconvergent (3 + 2) cycloadditions of isomerizable nitrile-conjugated nitrones with α-keto ester enolates. Even in the presence of multiple equilibrating species, the catalytic protocol displays a wide substrate scope to access a range of CN-containing building blocks bearing adjacent stereocenters with high enantio-and diastereoselectivities. Our computational investigations suggest that the enantioselectivity is governed in the deprotonation process to form (Z)-Ni-enolates, while the unique syn addition is mainly controlled by weak noncovalent bonding interactions between the nitrone and ligand.

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

“…This result indicates that the nitrile group in 5 plays a crucial role in selectively enhancing the syn-addition. 7) Further, the catalytic system works well even with simple substrates and a diamine ligand. For example, the reaction between 1a (R 1 = Me, R 2 = t Bu) and 5a (R 3 = Me) using the simple ligand (R,R)-3c (R = Me) under standard conditions [Ni(OAc) 2 •4H 2 O/(R,R)-3c (10 mol%), 5a (1.2 equivalent), 0 °C] afforded 6aa (R 1 = Me, R 2 = t Bu, and R 3 = Me) with comparably high diastereo- and enantioselectivities.…”

“…2) Our interest in this molecule and this reaction is to explore an asymmetric catalytic strategy that yields structurally unique isoxazolidines. Specifically, we have explored the inverseelectron-demand (3 + 2) cycloaddition (i.e., a type-III cycloaddition according to Sustmann's classification) 3,4) using α-keto ester enolates as formal 1,3-dipolarophiles [5][6][7] on the basis of the ambiphilic nature of α-keto esters 1, which inherently possess nucleophilic and electrophilic reactivity. 8,9) The reaction is initiated by the Mannich-like addition of an α-keto ester enolate to a nitrone, 10) which results in the formation of two adjacent stereocenters.…”

“…Stereochemically well-defined 5-hydroxyisoxazolidines have been used for several types of downstream transformations to yield a range of chiral building blocks, including cyclic and open-chained forms. 7,[11][12][13] During our studies, we encountered a unique diastereodivergence [14][15][16][17] in the (3 + 2) cycloaddition using a Ni(II) complex prepared from Ni(OAc) 2 •4H 2 O and (R,R)diamine 3 5,7) (Chart 1). Briefly, the reaction with cyclic (E)nitrones 2 afforded anti,anti-adducts 4.…”

“…5) In this reaction, the use of 3a having cyclohexyl groups in 3 is essential to attain high stereoselectivity. When we employed the reaction with typical π-conjugated (Z)-nitrones, 5,7) the corresponding cycloaddition adducts were not detected, probably because of the unfavorable steric repulsion between the (Z)-nitrone and diamine ligand. In marked contrast, the reaction with the E/Z-isomerizable C-CN nitrones 5 resulted in the formation of syn,anti-6 as the major adduct, although each geometrical isomer of 5 has a similar gap between the highest occupied molecular orbital (HOMO) and the lowest occupied molecular orbital (LUMO) to those of the other nitrones that we investigated.…”

“…For example, the reaction between 1a (R 1 = Me, R 2 = t Bu) and 5a (R 3 = Me) using the simple ligand (R,R)-3c (R = Me) under standard conditions [Ni(OAc) 2 •4H 2 O/(R,R)-3c (10 mol%), 5a (1.2 equivalent), 0 °C] afforded 6aa (R 1 = Me, R 2 = t Bu, and R 3 = Me) with comparably high diastereo- and enantioselectivities. 7) In addition to these experiments, we used density functional theory (DFT) calculations to identify the key catalytic parameter determining the rate- and stereo-determining step(s) (Fig. 1).…”