Enantio‐ and Diastereoselective Hydrofluorination of Enals by N‐Heterocyclic Carbene Catalysis

Abstract

In contrast to well-established asymmetric hydrogenation reactions,e nantioselective protonation is an orthogonal approach for creating highly valuable methine chiral centers under redox-neutral conditions.R eported here is the highly enantio-and diastereoselective hydrofluorination of enals by an asymmetric b-protonation/a-fluorination cascade catalyzedb yN -heterocyclic carbenes (NHCs). The two nucleophilic sites of ah omoenolate intermediate,g enerated from enals and an NHC,a re sequentially protonated and fluorinated. The results show that controlling the relative rates of protonation, fluorination, and esterification is crucial for this transformation, and can be accomplished using ad ual shuttling strategy.S tructurally diverse carboxylic acid derivatives with two contiguous chiral centers are prepared in asingle step with excellent d.r.and ee values.There is much interest in the development of general synthetic strategies towards fluorine-containing compounds because of their broad applications of in pharmaceuticals and agrochemicals. [1] Direct, asymmetric hydrofluorination is particularly attractive given the abundance of common olefinic chemical feedstocks. [2] However,i ntroduction of two contiguous chiral centers,o ne of which bears af luorine,i n as ingle process is very challenging.A symmetric metal hydride addition to olefins followed by trapping of the corresponding organometallic species with af luorine source has been reported (Scheme 1A). [3] MacMillan et al. reported af ormal asymmetric addition of H À F + to electron-deficient olefins using iminium/enamine catalysis (Scheme 1B). [4] These approaches use reducing reagents for the hydride transfer and oxidative conditions for the fluorination, and proceeds in either as equential or stepwise manner. Herein, we report ac omplementary strategy of formal asymmetric addition of H + F + to enals by an enantioselective b-protonation/diastereoselective a-fluorination/esterification cascade (Scheme 1C). This redox neutral transformation demonstrates wide functional-group tolerance across various structural motifs.Recently,a symmetric protonation reactions catalyzed by N-heterocyclic carbenes (NHC) emerged as ageneral, redox-neutral strategy for the synthesis of b-chiral carboxy derivatives.I n2 015, Scheidt et al. reported asymmetric hydrogenation of b-ester enals,areaction which was later extended to b,b-aryl, alkyl enals by the same group. [5] In 2017, our group reported enantioselective hydrogenation of enals using bridgehead nitrogen amines as as elective proton-transfer agent. [6] Subsequently,w ed iscovered that the same transformation can be accomplished with ab roader substrate scope by using acombination of an achiral NHC and achiral phosphoric acid. [7] We recently applied this strategy to the synthesis of b-chiral amides,hydrazides,acid, esters,peresters, and heterocycles. [8] However,a ll asymmetric b-protonation reactions mentioned above are only applicable to products lacking an a-chiral center.W ee nvisioned that upon b-protonation of th...

Catalytic asymmetric nucleophilic fluorination using BF3·Et2O as fluorine source and activating reagent

“…In the wake of the emergence of the first electrophilic enantioselective fluorination of enolates using chiral N-fluoro camphorsultam reagent reported by the group of Lang 7 , significant progress for enantioselective fluorination studies have been presented 4,8,9 because of contributing to the development of catalytic asymmetric methodologies for electrophilic fluorine reagents (F + reagents), such as N-fluorobenzenesulfonimide (NFSI) [10][11][12] , N-fluoropyridinium salts 3 , and Selectfluor (Fig. 1a) [13][14][15][16][17][18] . These reagents exhibited efficient transfer of fluorine atom under the asymmetric fluorination, however, their industrial applications were significantly restricted by the poor atom economy in fluorination, expensive synthesis and other inherent characteristics of electrophilic reagent.…”