β-Carbon activation of saturated carboxylic esters through N-heterocyclic carbene organocatalysis

Abstract

The activation of the α-carbons of carboxylic esters and related carbonyl compounds to generate enolate equivalents as nucleophiles is one of the most powerful strategies in organic synthesis. We reasoned that the horizons of chemical synthesis could be greatly expanded if the typically inert β-carbons of saturated esters could be used as nucleophiles. However, despite the rather significant fundamental and practical values, direct use of the β-carbons of saturated carbonyl compounds as nucleophiles remains elusive. Here we report the catalytic activation of simple saturated ester β-carbons as nucleophiles (β-carbon activation) using N-heterocyclic carbene organocatalysts. The catalytically generated nucleophilic β-carbons undergo enantioselective reactions with electrophiles such as enones and imines. Given the proven rich chemistry of ester α-carbons, we expect this catalytic activation mode for saturated ester β-carbons to open a valuable new arena for new and useful reactions and synthetic strategies.

Asymmetric catalysis with N-heterocyclic carbenes as non-covalent chiral templates

“…Although transesterification of unactivated esters has been reported through the use of achiral NHC catalysts [35][36][37][38] , only highly reactive vinyl esters were successful in the asymmetric versions 39 . Alternative nucleophile catalysis by NHC may occur for these reactions, as supported by recent work by Chi and co-workers 25,40,41 . Presumably, an acyl imidazolium cation intermediate is formed by the substitution of the vinyl alcohol with NHC, which in turn undergoes alcoholysis.…”

“…1a, for example, Benzoin condensation 21 and the Stetter reaction 22,23 ). NHCs can also react with acyl halides/anhydrides/esters 24,25 , electron-deficient olefins 26,27 and ketenes 28,29 , forming either highly reactive acylating agents or Baylis-Hillman-type intermediates through a nucleophilic addition reaction (Fig. 1b,c) 30 .…”

Achieving elusive transformations with organocatalysis: direct $\beta $-carbon activation of saturated carbonyl compounds

“…The potential of NHC catalysts have further been Although the method suffered with some shortcomings such as ester hydrolysis, lower yields with β -alkylated esters, and, specifically, the deactivation of the nucleophilic catalyst, it offered a practical solution for the enantioselective formation of cyclic compounds in a domino-type transformation by NHC-catalyzed reaction of esters with electrophiles such as enones to produce cyclopentenes, trifluoroketones to produce γ -lactones, and hydrazones to deliver γ -lactams (Scheme 11). 55 Good to excellent yields and high enantioselectivity of structurally complex and intriguing molecular structures are obtained from this very efficient direct activation of β -carbon through NHC catalysis.…”

Mechanistic Studies on Stereoselective Organocatalytic Direct β-C–H Activation in an Aliphatic Chain by Chiral N-Heterocyclic Carbenes

“…This energy separation corresponds to 92% ee, which is in excellent agreement with the experimentally reported value of 94%. 9 Similarly, the diastereoselectivity computed on the basis of the difference in Gibbs free energy between TS(6-7) si,re and TS(6-7) si,si is 53% de, which is concert with the experimental value (71%). 9 The energy differences between the stereocontrolling transition states obtained using different functionals such as the B3LYP-D3 (L3), M06-2X (L4), and B3LYP (L5) all convey the same trends (Figure 4).…”

“…The reactivity of nucleophilic β-carbon has been demonstrated with a range of electrophiles such as enones, trifluoroketones, and hydrazones with high stereoselectivity. 9 One of the most recent illustrations of a β-C−H functionalization by using a chiral NHC is provided in Scheme 2. This method provides an elegant access to highly functionalized γ-lactams.…”