Chiral Brønsted acids have found widespread applications as organocatalysts. Weakly acidic species such as diols and (thio)ureas, typically classified as hydrogen bonding catalysts, as well as stronger phosphoric acids, have proven to be highly effective in catalyzing a wide range of asymmetric transformations. In contrast, the use of chiral carboxylic acids as Brønsted acid catalysts is much less developed but has recently garnered increased attention. Given that their pK's generally lie between those of typical hydrogen bond donors and chiral phosphoric acids, chiral carboxylic acids provide the opportunity to activate a different set of substrates requiring intermediate catalyst acidity. In addition, by taking advantage of judicious catalyst design, the acidity of carboxylic acids can be modulated, for instance by stabilizing the corresponding carboxylate counterion. This review provides an overview of this field, with the aim of highlighting both catalyst design and synthetic applications.

Triggered largely by the seminal studies of Akiyama et al. [1] and Uraguchi and Terada [2] nearly a decade ago, the field of asymmetric Brønsted acid catalysis has experienced rapid growth. [3] Chiral phosphoric acids in particular have enabled an ever increasing number of asymmetric transformations. [3] In a continuing trend, catalysts that surpass the acidity of phosphoric acids are being prepared for the purpose of activating moderately basic substrates through asymmetric ion-pairing catalysis. [3,4] Cooperative approaches in which a Brønsted acid acts in concert with either another Brønsted acid [5] or with a (thio)urea catalyst [6] have emerged and hold exceptional promise. [7] Intriguing applications of asymmetric cooperative Brønsted acid catalysis have been reported by Jacobsen and co-workers who have demonstrated that a combination of achiral Brønsted acids and chiral (thio)urea catalysts can enable a range of enantioselective transformations. [8] The main role of the (thio)urea catalyst is to act as a chiral anion receptor for the Brønsted acids conjugate base. [4,9,10] Herein we introduce a complementary concept for asymmetric Brønsted acid catalysis which merges certain features of previous approaches while perhaps offering some unique advantages.As illustrated in Figure 1, we envisioned a new type of chiral Brønsted acid in which the acidic site of the catalyst is connected by an appropriate linker to an anion receptor moiety such as a thiourea. [11][12][13] Upon substrate protonation, the conjugate base associates with the anion recognition site, [14] thus resulting in the formation of a substrate/catalyst ion pair of type I. Alternatively, the catalyst could facilitate the condensation of two different substrates to result in an ion pair of type II. While the anion may still interact with the substrate through hydrogen bonding in the type I ion pair, [15] hydrogen bonding between the ions should be reduced markedly in the type II ion pair, thus resulting in strict ion pairing. [4j] Importantly, both types of ion pairs feature a rigid anion which should facilitate an efficient transfer of chirality.While a range of acidic groups, XH, may be linked to an anion recognition site, we were particularly intrigued by the idea of using simple carboxylic acids. Although there are notable exceptions, in particular the prominent work of the Maruoka group, chiral carboxylic acids have not yet found widespread applications as asymmetric Brønsted acid catalysts. [16] This is likely because carboxylic acids are ultimately limited by their relatively weak acidities, thus restricting the number of substrates which can be activated. The propensity of carboxylate to engage in hydrogen bonding with a protonated substrate also reduces the potential level of substrate activation, as this interaction lowers the electrophilicity of the protonated species. Internal stabilization of the conjugate base (e.g., carboxylate) should circumvent both of these problems. Firstly, anion binding to the conjugate base is expected to lo...

A novel and recyclable catalyst, a C 3 -symmetrical cinchonine-squaramide, has been developed for the asymmetric Michael addition of 1,3-dicarbonyl compounds to nitroalkenes. When using only 1 mol% of catalyst 1a for the reaction, high reaction yields with excellent enantioselectivities and diastereoselectivities (up to 96% yield, > 99% ee, > 99:1 dr) were achieved, in which the results for cyclic keto esters are the best ever achieved. Moreover, 1a can be easily recovered by simple precipitation and was used for six cycles without losing any selectivity and activity.

A readily available chiral Brønsted acid was identified as an efficient catalyst for intramolecular Povarov reactions. Polycyclic amines containing three contiguous stereogenic centers were obtained with excellent stereocontrol in a single step from secondary anilines and aldehydes possessing a pendent dienophile. These transformations constitute the first examples of catalytic enantioselective intramolecular aza-Diels-Alder reactions.

Iminium ions generated in situ via copper(I) bromide catalyzed oxidation of N-aryl amines readily undergo [4 + 2] cycloadditions with a range of dienophiles. This method involves the functionalization of both a C(sp3)–H and a C(sp2)–H bond and enables the rapid construction of polycyclic amines under relatively mild conditions.