Catalytic Asymmetric Synthesis. Группа авторов

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].

      3.2.1. Application of Designed Pronucleophiles

      Following are the remarkable applications of chiral tertiary amine catalysts selected from our point of view.

      The expansion of the scope of pronucleophiles is one of the most important tasks in the field of asymmetric Brønsted base catalysis because it broadens the range of accessible chiral building blocks. To this end, a variety of rationally designed pronucleophiles has been applied to the catalysis, and highly enantioselective reactions have been developed to date.

Barbas and co‐workers designed pyrazoleamides 3 as a pronucleophile and developed the enantioselective addition to nitroalkenes by using cinchona alkaloid‐urea catalyst 2e (Scheme 3.6). This is a rare example of the use of amide derivatives as pronucleophiles in chiral tertiary amine catalysis [26]. The pyrazoleamide moiety potentially functions as a good leaving group for further transformations.

Figure 3.6. Transition‐state model of Michael addition catalyzed by 1f.

      Source: Based on [23].

Scheme 3.6. Enantioselective addition of pyrazoleamides 3 to nitroalkenes catalyzed by 2e. Source: Based on [26].

Malonic acid half thioesters 4 are popular as an (thio)ester enolate equivalent. As a useful application of these compounds in chiral tertiary