Enantioselective Formal [3 + 1 + 1] Cycloaddition Reaction by Ru(II)/Iminium Cocatalysis for Construction of Multisubstituted Pyrrolidines

Abstract

A Ru(II)/iminium cocatalyzed asymmetric formal [3 + 1 + 1] cycloaddition reaction of diazoacetophenones, anilines, and enals is disclosed to construct multisubstituted pyrrolidines in one step with excellent diastereoselectivity and enantioselectivity. The reaction mechanism was postulated as a successful trapping of Ru(II)-associated ammonium ylides via a selective 1,4-addition to chiral amine activated enals followed by a tandem aza-aldol process. The control experiments and theoretical density functional theory investigation revealed that the reversible NaOAc-facilitated aza-aldol process led to the diastereomeric conversion to provide a stable product.

Three-Component Ring-Opening Reactions of Cyclic Ethers, α-Diazo Esters, and Weak Nucleophiles under Metal-Free Conditions

“…For example, MCRs involving α-diazo esters have been widely used in the synthesis of a variety of esters . However, most of the reported α-diazo ester-based MCRs require a transition-metal catalyst (e.g., Rh, Ir, Ru, Pd, Cu, or Fe) to trap the carbene generated by release of nitrogen from the diazo group. The development of novel methods for metal-free α-diazo ester based MCRs is highly desirable.…”

Ruthenium-Catalyzed Cycloadditions to Form Five-, Six-, and Seven-Membered Rings

“…In 2017, Hu reported the enantioselective (3+1+1) cycloaddition reaction of enals, anilines, and α-diazoacetophenones to form trisubstituted pyrrolidines (Scheme ). The authors exploit a dual catalytic system in which the aniline, the α-diazoacetophenones, and ruthenium combine to form an ammonium ylide, which participates in an asymmetric conjugate addition to the iminium ion that arises upon condensation of the enal with the Hiyashi–Jørgensen secondary amine cocatalyst. Hydrolytic release of the organocatalyst followed by cyclization to form the N , O -acetal completes the catalytic cycle.…”

Recent Developments in Enantioselective Multicatalyzed Tandem Reactions

“…In 2017, the combination of ruthenium and iminium catalysis was applied by Hu and Liu to promote an enantioselective three‐component reaction of diazoacetophenones 112 , anilines 66 and α,β‐unsaturated aldehydes 2 . This formal [3+1+1] cycloaddition was performed at 35 °C in dichloromethane as the solvent in the presence of a combination of 5 mol% of [Ru( p ‐cymene)Cl 2 ] 2 with 20 mol% of proline‐derived chiral amine 40 and 20 mol% of NaOAc as an additive.…”