Highly Regio‐ and Stereodivergent Access to 1,2‐Amino Alcohols or 1,4‐Fluoro Alcohols by NHC‐Catalyzed Ring Opening of Epoxy enals

Abstract

Described is an unprecedented NHC-catalyzed (NHC=N-heterocyclic carbene), stereoselective ring opening of epoxy and cyclopropyl enals to deliver valuable compounds bearing multiple stereocenters. A straightforward three-step procedure involving two catalytic enantioselective transformations has been developed and leads to a regio- and stereodivergent synthesis of either 1,2-amino alcohols/diamines or 1,4-fluoro alcohols with excellent diastereo- and enantiopurity.

Unravelling the Mechanism and Selectivity of the NHC‐catalyzed Three‐Membered Ring‐Opening/Fluorination of Epoxy Enals: A DFT Study

“…As an important note, the dienolate intermediate had two active sites ( i. e ., α‐carbon and γ‐carbon) and both of them were capable of reacting with fluorine reagent to give the fluorinated products. Whereas, only the R ‐configured α‐fluorinated product was obtained . Suggesting that α‐addition mode is prior to γ‐addition mode and understanding origin of stereoselectivity needs further studies.…”

“…Furthermore, in α‐addition, the formation of R ‐configurational intermediate M5R α occurs prior to the formation of S ‐configurational intermediate M5S α . The computational results align well with the experimental observations . In the following steps, we only discuss the R ‐configured pathway as reference.…”

“…The calculated results indicate that the Re addition mode leading to the R ‐configured product is the energetically favorable, which aligns well with the experimental observations. The prediction value of enantiomeric excess is 99.8 % according to the Boltzmann distribution analysis, which agrees well with the experimentally observed ee value of 99 % . Then, we perform the non‐covalent interaction (NCI) analysis to predict the origin of the stereoselectivity between the stereoselective transition states, which has been extensively utilized for recognizing weak interactions.…”

“…Later on, this protocol was further used in ring expansion reactions (Scheme C) . Recently, Zhao and coworkers described an NHC‐catalyzed stereoselective ring‐opening/fluorination cascade reaction (Scheme D) …”

Dual N-heterocyclic carbene/photocatalysis: a new strategy for radical processes

“…The authors proposed that the dienolate intermediate could be generated from γ-cyclopropane enal through NHC-catalyzed C-C bond cleavage, which was in agreement with Zhao's pathway. 9 The following similar steps to those in Scheme 2B afforded the product 9 and closed the catalytic cycle.…”