Asymmetric Dual-Catalytic Cascade by Chiral N-Heterocyclic Carbene and Quinuclidine: Mechanism and Origin of Enantioselectivity in Benzofuranone Formation

Abstract

Contemporary literature offers a number of interesting examples for asymmetric multicatalytic reactions using chiral N-heterocyclic carbenes (NHCs) in conjunction with other catalysts. One of the very recent examples demonstrated a convenient strategy toward realizing chiral benzofuranones from salicylaldehyde and dimethyl acetylenedicarboxylate (DMAD). In this article, we report the mechanism and insights on the origin of asymmetric induction as obtained through a comprehensive density functional theory (M06-2X and mPW1K) investigation. Different likely catalyst−substrate combinations as well as the timing/sequence of activation of different substrates are carefully examined so as to identify the most preferred pathway. In the lowest energy path, the activation of DMAD by quinuclidine occurs first; the resulting zwitterionic intermediate then undergoes a Michael addition with a salicylate ion to yield a salicylate−DMAD adduct, which, in turn, is intercepted by the chiral NHC. In the next crucial step, an enantioselective C−C bond formation via an intramolecular Stetter reaction furnishes the benzofuranone framework bearing a chiral carbon atom. Two transition state models, with and without an explicitly bound catechol (an additive employed in the reaction that resulted in enhanced enantioselectivity), are considered. A distinct energetic advantage, of the order of 3.4 kcal/mol, for the addition of the re face of the Breslow intermediate (derived from the chiral NHC and the salicylate−DMAD adduct) to the re face of the dimethyl maleate moiety is noticed in the stereocontrolling C−C bond formation step. The Gibbs free energy difference between the diastereomeric transition states for (re,re) and (re,si) modes of addition is traced to the differential nonbonding interactions (O−H•••π, lone pair (lp)•••π, and C−H••• O). The predicted enantioselectivity is in good agreement with the experimental observations.

Hollow Mesoporous Organic Polymeric Nanospheres (HMOPNs)‐Supported Carbene Rovis Catalyst: Mesopore and Morphology‐Dependent Catalytic Performances in Asymmetric Organocascade

“…From Table , although the yields of the reactions were limited to approximately 80 % due to the formation of side pro‐duct chromene derived from intramolecular aldol of intermediate enolates, it was found that both electron‐rich and electron‐deficient salicylaldehydes with electron‐withdrawing and electron‐donating groups participated in homogeneous asymmetric Michael/Stetter sequence to afford the corresponding products in moderate to good yields (62–84 %) and good to excellent enantioselectivities (83–96 %ee). Similar to the ever‐reported homogeneous catalytic results, the lowest yields were observed for ortho ‐substituted salicylaldehydes, which resulted from the steric hindrance of ortho ‐substituents to nucleophilic addition.…”

“…Of particular note was that both mesopore‐abundant HMOPNs‐supported Rovis catalyst and mesopore‐deficient PS‐7 promoted the Stetter reaction of salicylaldehyde (R=H) with the sharply decreased enantioselectivities with 7–8 %ee decrements, compared with homogeneous Rovis catalyst (93 %ee) (Table ). It was ever‐reported that the enantioselectivities of products appeared to be independent of steric or electronic factors of substituted salicylaldehydes, and its enantiocontrol was exerted by a network of noncovalent interactions between Rovis catalyst and substrates . Therefore, it was conjectured that the anchorage of Rovis catalyst into solid affected the noncovalent interactions such as π…π stacking interaction between the N‐aryl(C 6 F 5 ) group and salicylaldehyde moiety, and resulted in the increased cis ‐( re , si )‐ transition state of Breslow intermediate leading to a S configuration.…”

“… Optimized geometries of the diastereomeric transition states of two Breslow intermediates with low Gibbs free energies at the M06‐2X/6‐31+G** level of theory for enantioselective C−C bond formation …”

“…It was well-known that the asymmetric Michael/Stetter cascade of salicylaldehyde with DMAD contained two catalytic cycles to furnish optically pure benzofuranone product in one-pot fashion. [13] The first cycle involved three key mechanistic steps including the formation of (Z), (E)-aldehyde intermediate via Michael addition of DABCO to DMAD, succedent Michael addition to salicylaldehyde and final expelling of DABCO. The second cycle was the formation of benzofuranone product via nucleophilic addition of Rovis catalyst, proton transfer, intramolecular Michael addition and release of Rovis catalyst.…”

“…It was ever-reported that the enantioselectivities of products appeared to be independent of steric or electronic factors of substituted salicylaldehydes, [12] and its enantiocontrol was exerted by a network of noncovalent interactions between Rovis catalyst and substrates. [13] Therefore, it was conjectured that the anchorage of Rovis catalyst into solid affected the noncovalent interactions such as p…p stacking interaction between the N-aryl(C 6 F 5 ) group and salicylaldehyde moiety, and resulted in the increased cis-(re,si)-transition state of Breslow intermediate leading to a S configuration.…”