N‐Heterocyclic Carbene‐Catalyzed Asymmetric C−O Bond Construction Between Benzoic Acid and o‐Phthalaldehyde: Mechanism and Origin of Stereoselectivity

Abstract

A computational study was contributed to explore the origin of stereoselectivity of NHC‐mediated cyclization reaction between benzoic acid and o‐phthalaldehyde for asymmetric construction of phthalidyl ester. The most energetically favorable pathway mainly includes the following steps: (1) nucleophilic attack on carbonyl carbon of o‐phthalaldehyde by catalyst NHC, (2) formation of Breslow intermediate, (3) oxidation by DQ, (4) asymmetric formation of dual C−O bonds, and (5) dissociation of catalyst with the product. The C−O bond formation was testified as the stereoselectivity‐determining step, the R‐configurational pathway is more energetically favorable than the S‐configurational one. The non‐covalent interaction (NCI) and atom‐in‐molecule (AIM) analyses were performed to reveal that the O−H ⋅⋅⋅ O and C−H ⋅⋅⋅ O hydrogen‐bond interactions are the key factors for controlling the stereoselectivity. The detailed mechanism and origin of stereoselectivity give useful insights for understanding organocatalytic reactions for asymmetric construction of C−O bond.

NHC-Catalyzed Reaction of Aldehydes for C(sp2)–O Bond Formation

“…Several examples of oxidative cyclization were reported [81][82][83][84][85]. The NHC-catalyzed aerobic oxidation of ynamide-tethered benzaldehyde 28 was studied (Scheme 7) [84].…”

Oxidative N‐Heterocyclic Carbene Catalysis

“…On the subject, a recent computational study by Qiao and Wei on the reaction between o-phthalaldehyde and benzoic acid has helped clarify both the detailed mechanism and the origin of stereoselectivity for the NHC-catalyzed asymmetric acetalization reaction (Scheme 19). [37] Preferential Si-face attack of NHC on the aldehyde group of phthalaldehyde (transition state 9) is followed by i) HCO 3 Àassisted 1,2-proton transfer (transition state 10) [38] and ii) oxidation of the Breslow intermediate thus formed (transition state 11). Next, dual CÀ O/CÀ O bond assemblage comes in a concerted fashion, the route moving towards the R-configured isomer being energetically more favorable than that for the Sconfigurational one.…”

“…On the subject, a recent computational study by Qiao and Wei on the reaction between o ‐phthalaldehyde and benzoic acid has helped clarify both the detailed mechanism and the origin of stereoselectivity for the NHC‐catalyzed asymmetric acetalization reaction (Scheme 19 ). [37] …”

A DFT study of NHC-catalyzed reactions of [3+3] annulations of 2-bromoenals and thioamides: mechanisms and regio- and stereoselectivities

“…[18][19][20][21][22] The essence of NHC-catalyzed umpolung reactions lies in that the employed NHCs are able to convert the electrophiles (such as aldehydes and enals) to nucleophilic intermediates via nucleophilic attack of the NHCs on the carbonyl group, and then the reactive intermediates couple with other electrophiles, offering great potential for a variety of transformations, such as C-C [23][24][25] /C-X (X = O, N etc.) [26][27][28] bond construction and C-X (X = H, F, Cl, OR, etc.) bond activation.…”