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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 amine catalysis, List, Song, and co‐workers reported the enantioselective decarboxylative aldol reaction with aromatic aldehydes [27]. Cinchona alkaloid‐based 2f having a sulfonamide moiety was the optimum catalyst for the reaction, and the desired products were obtained with high enantioselectivities (Scheme 3.7).

Scheme 3.7. Enantioselective aldol reaction of malonic acid half thioesters 4 catalyzed by 2f. Source: Based on [27].

On the other hand, Wennemers and co‐workers introduced mono‐thiomalonates 5 as a thioester enolate equivalent [28]. As a remarkable application of these compounds as a pronucleophile, the enantioselective synthesis of oxindoles possessing adjacent tetrasubstituted stereogenic centers was accomplished [28c]. Cinchona alkaloid‐urea catalyst 2g or Takemoto’s catalyst 2a efficiently promoted the addition of mono‐thiomalonates 5 to isatin‐derived ketimines to provide the desired oxindoles in high yields with high diastereo‐ and enantioselectivities (Scheme 3.8).

Scheme 3.8. Synthesis of oxindoles possessing adjacent tetrasubstituted stereogenic centers. Source: Based on [28c].

The same group further investigated the enantioselective reactions of fluorinated variants of malonic acid half thioesters 6 and mono‐thiomalonates, and successfully developed the decarboxylative aldol reaction and the direct Mannich‐type reaction, respectively, by using chiral bifunctional catalysts (Scheme 3.9) [29].

Scheme 3.9. Enantioselective aldol reaction of fluorinated malonic acid half thioesters 6 catalyzed by 2h.

Source: [29].

Figure 3.7. N‐Heterocyclic compounds used as a pronucleophile.

Azlactones 7 are recognized as a useful pronucleophile and widely used in asymmetric synthesis because the hydrolysis of the adducts affords enantio‐enriched α,α‐disubstituted amino acid derivatives (Figure 3.7) [30]. Palomo and co‐workers investigated the enantioselective reactions of the related N‐heterocyclic compounds that were less explored as a pronucleophile, such as thiazolones 8 and imidazolones 9 and 10 [31]. For instance, the group developed the enantioselective addition of thiazolones 8 to nitroalkenes by using chiral bifunctional catalyst 2i having a ureidopeptide moiety as a hydrogen bond donor unit (Scheme 3.10) [31a]. The products of the reaction were readily converted to functionalized tertiary thiols otherwise difficult to synthesize.

Scheme 3.10. Enantioselective addition of thiazolones 8 to nitroalkenes catalyzed by 2i.

Source: Based on [31a].

Protected hydroxy malononitriles 11, known as masked acyl cyanide (MAC) reagents, are among the versatile umpolung synthons [32]. Rawal and co‐workers successfully applied MAC reagents 11 as a pronucleophile in enantioselective addition to enones [33]. The reaction was efficiently catalyzed by amine‐squaramide catalyst 2j (Scheme 3.11). The method was utilized for the total synthesis of (+)‐fornicin C.

Scheme 3.11. Enantioselective addition of MAC reagents 11 to enones catalyzed by 2j. Source: Based on [33].

Takemoto and co‐workers used glyoxylate cyanohydrins 12, which have a similar structure to MAC reagents, as a pronucleophile for the first time in enantioselective reactions [34]. Specifically, the group developed the direct Mannich‐type reaction of 12 mediated by chiral bifunctional catalysts 2k and 2l, both possessing a benzothiadiazine moiety as a strong hydrogen bond donor unit (Scheme 3.12). Interestingly, the tuning of the substituents on the catalysts, namely the choice of 2k and 2l, resulted in the diastereodivergent synthesis. The enantio‐enriched adducts were readily converted into a series of chiral motifs.

Scheme 3.12. Enantioselective addition of glyoxylate cyanohydrins to imines catalyzed by 2k and 2l. Source: Based on [34].

Palomo and co‐workers established a new strategy for enantioselective α‐functionalization of 2‐alkyl azaarenes [35]. The addition of 2‐cyanomethylpyridine N‐oxides 13 to enones proceeded under the influence of amine‐squaramide catalyst 2m to provide the adducts having an all‐carbon quaternary stereogenic center in a highly enantioselective manner (Scheme 3.13). In the reaction system, the N‐oxide moiety played strategic roles as a removable activating group, which enhances the acidity of α‐proton, and a stereodirecting group.

Scheme 3.13. α‐Functionalization of 2‐alkyl azaarene N‐oxides 13. Source: Based on [35].

The same group designed 2‐alkylthio‐4,6‐dioxopyrimidines 14 as barbituric acid equivalents, and developed the enantioselective Michael addition to enones catalyzed by amine‐squaramide 2n (Scheme 3.14) [36]. This is the first example of highly enantioselective synthesis of chiral barbituric acid derivatives with an in‐ring tetrasubstituted stereogenic center.

Scheme 3.14. Enantioselective Michael addition of barbituric acid derivatives 14 to enones catalyzed by 2n.

Source: Based on [36].