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In the field of asymmetric Brønsted base catalysis, one of the most important pioneering works would be a series of studies on enantioselective Michael additions conducted by Wynberg and co‐workers, in which cinchona alkaloids were employed as readily available chiral tertiary amine organobase catalysts [9]. For instance, they reported that the addition of aryl thiols to cyclic enones proceeded with moderate enantioselectivities by using cinchonidine (1a) as a catalyst (Scheme 3.1) [10]. In the report, the importance of the C9 hydroxy group as a hydrogen bond donor site, namely the bifunctional catalysis, was also suggested [11].

Scheme 3.1. Enantioselective addition of aryl thiols to cyclic enones catalyzed by 1a.

Source: Based on [10].

Cinchona alkaloids are complex small molecules containing five stereogenic centers, a basic quinuclidine nitrogen, a chiral secondary alcohol moiety, and a quinoline unit (Figure 3.3). A highlighted advantage of the use of cinchona alkaloid‐based chiral organobase catalyst is the attainability of either enantiomer of desired products owing to the availability of pseudo‐enantiomeric pairs, such as cinchonidine (1a)/cinchonine (1b) and quinine (1c)/quinidine (1d). Thus, cinchona alkaloids are nowadays not only used directly as a chiral organobase catalyst but also utilized as a versatile chiral scaffold for the development of various chiral organobase catalysts [4].

On the other hand, the prevailing design of chiral tertiary amine catalysts is the “chiral acid–base bifunctional catalyst,” in which an additional acidic hydrogen bond donor unit is introduced into a catalyst molecule along with a basic tertiary amine moiety. This catalyst design is based on the idea of dual activation of a pronucleophile and an electrophile; a chiral tertiary amine activates a pronucleophile and a hydrogen bond donor simultaneously activates an electrophile (Figure 3.4a).

There are three common structural motifs utilized widely in the development of chiral acid–base bifunctional catalysts. The first motif is the catalyst consisting of a tertiary amine and a double hydrogen donor unit, such as a thiourea, connected by a chiral two‐carbon linker (Figure 3.4b). In 2003, Takemoto and co‐workers developed the seminal amine‐thiourea bifunctional catalyst 2a [12]. They reported that catalyst 2a efficiently promoted the Michael addition of malonates to nitroalkenes in a highly enantioselective manner (Scheme 3.2).

Figure 3.3. Cinchona alkaloids and derivatives.

Figure 3.4. Chiral acid–base bifunctional catalysts.

Scheme 3.2. Enantioselective addition of malonates to nitroalkenes catalyzed by 2a. Source: Based on [12].

It should be noted that the authors originally proposed the reaction mechanism involving the cooperative activation of the pronucleophile and the electrophile by the tertiary amine and the thiourea moieties of the catalysts to account for the significant enhancement in the rate and stereoselectivity of the reaction (ternary complex A in Figure 3.5) [13]. On the other hand, Pápai and co‐workers proposed a different mode of activation based on their computational study [14]. In their proposal, the pronucleophile was sequentially activated by the thiourea and the tertiary amine while the electrophile was activated by the resulting ammonium proton (ternary complex B). The study also implied that the proposed mode of activation is not restricted to the Takemoto’s catalyst but it is applicable to other bifunctional catalysts having a double hydrogen bond donor unit and a tertiary amine. Later, Takemoto and co‐workers conducted the detailed mechanistic study, and the result of the study supported the Pápai’s activation model [15].

Based on the design of Takemoto’s catalyst, a variety of related catalysts possessing different substituents on the tertiary amine moiety, on the chiral linker, and on the nitrogen of thiourea moiety was developed and utilized in a vast number of enantioselective reactions [16]. In addition, highly efficient catalysts having a urea, squaramide, and thiosquaramide as a double hydrogen bond donor unit were also developed, indicating that the replacement of a double hydrogen bond donor unit is the other important option for optimizing the catalyst structure [17].

Figure 3.5. Proposed mechanism of the bifunctional amine‐thiourea catalyzed reaction.

The second motif is the cinchona alkaloid‐derived catalyst having a hydrogen bond donor unit at the C9 position (Figure 3.4c). In 2005, four groups reported enantioselective Michael addition reactions catalyzed by cinchona alkaloids having a thiourea moiety at the C9 position (Scheme 3.3) [18].

Scheme 3.3. Enantioselective addition of nitromethane to chalcone derivatives catalyzed by 2b. Source: Based on [18b].

Since the emergence of these catalysts, a variety of catalysts having a different functional group at the C9 position was developed. As an important achievement, in 2008, Rawal and co‐workers developed catalyst 2c, which is the first chiral bifunctional tertiary amine catalyst utilizing a squaramide as a double hydrogen bond donor (Scheme 3.4) [19a]. Since then, squaramides have been widely utilized as an effective alternative to thioureas in the field of chiral tertiary amine catalysis [20].

Scheme 3.4. Enantioselective addition of β‐ketoesters to nitroalkenes catalyzed by 2c.

Source: Based on [19].

The third motif is the cinchona alkaloid‐derived catalyst having a hydrogen bond donor moiety at the C6’ position of a quinoline ring (Figure 3.4d). Cupreine (1e) and cupreidine (1f), which are the demethylated derivatives of quinine and quinidine, possess a phenoxy group at the C6’ position. In 2004, Deng and co‐workers reported that 1e, 1f, and their C9‐ether derivatives could serve as chiral bifunctional catalysts in enantioselective addition of malonates and β‐ketoesters to nitroalkenes [21]. On the other hand, Jørgensen and co‐workers reported the highly enantioselective amination of β‐dicarbonyl and related compounds with azodicarboxylates by using β‐isocupreidine (β‐ICD, 1g) as a chiral bifunctional catalyst [22]. Deng and co‐workers then proposed the transition‐state model in their report on the enantio‐ and diastereoselective addition of β‐ketoesters and the related compounds to nitroalkenes, which rationalized the stereochemical outcome (Scheme 3.5 and Figure 3.6) [23]. In the proposed model, the catalyst adopts an anti‐open conformation to activate and orient the pronucleophile and electrophile simultaneously by using a network of hydrogen bond interaction.

Scheme 3.5. Enantioselective addition of β‐ketoesters to nitroalkenes catalyzed by 1f.

Source: Based on [23].

Following from these works, several catalysts having a different C9‐ether moiety and a hydrogen bond donor unit, such as 2d, have been developed [24], although the application of this motif is somewhat limited compared to those of the other two common motifs [25].