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BINOL‐derived CPA 6a is available in bulk amounts and is employed as a resolving reagent for amines [34]. In 2004, Akiyama reported a Mannich‐type reaction between aldimines bearing the 2‐hydroxyphenyl moiety on nitrogen and ketene silyl acetals catalyzed by CPA 6c, derived from (R)‐BINOL bearing 4‐nitrophenyl groups at 3,3′‐positions, which gave β‐amino‐α‐alkyl or α‐siloxy amino esters in preference of the syn isomer with 81–96% ee (Scheme 2.1a) [8]. The use of aldimines derived from 2‐hydroxyaniline is critical for the excellent enantioselectivity. Based on the theoretical study by Yamanaka, the Mannich‐type reaction is proposed to proceed through the protonation of imine with CPA followed by the nucleophilic attack via zwitterionic and nine‐membered cyclic transition state (TS‐1) [35]. Concurrently, Terada reported a direct Mannich reaction between N‐Boc aldimines and pentan‐2,4‐dione catalyzed by CPA 6j to give the adducts with 90–98% ee (Scheme 2.1b) [9].

Scheme 2.1. Mannich reaction by Akiyama (a)

(Source: Based on [8])

, and by Terada (b)

(Source: Based on [9]).

Yamamoto reinvestigated the Mannich‐type reaction[8] and found that CPA 6k, bearing 2,4,6‐Me₃‐3,5‐(NO₂)₂C₆ moiety, was more effective for the Mannich‐type reaction, furnishing β‐amino esters with higher enantioselectivity in comparison with CPA 6b (Scheme 2.2a) [36]. The higher enantioselectivity (up to >99% ee) was ascribed to both steric and electronic effects from the three methyl groups. Furthermore, when phosphoramide 2a bearing 3,5‐(NO₂)‐4‐CH₃C₆H₂ groups was used, N‐phenyl aldimines were also found to be suitable substrates and use of N‐2‐hydroxyphenyl‐substituted aldimine was obviated without compromising the enantioselectivity (Scheme 2.2b).

Scheme 2.2. Mannich reaction with N‐(2‐hydroxyphenyl)‐imine (a) and with N‐phenyl imine (b).

Lambert developed a novel chiral Brønsted acid 15, which is readily prepared from (–)‐menthol and 1,2,3,4,5‐pentacarbomethoxycyclopentadiene, and reported Mannich‐type reaction using as low as 0.01 mol% of 15 (Scheme 2.2a). A chiral anion pathway is proposed. It is noted that 15 can be synthesized inexpensively for about US$4/g because (–)‐menthol is a naturally occurring compound [37].

Ishihara developed the chiral bisammonium salt of (R)‐BINSA (1,1′‐binaphthyl‐2,2′‐disulfonic acid) 8b as a chiral Brønsted acid for the direct Mannich reaction [38]. Although CPA requires bulky 3,3′‐substituents for attaining high enantioselectivity, the BINSA ammonium salt achieved excellent enantioselectivity without 3,3′‐substituents using as low as 1 mol% of the catalyst loading (Scheme 2.3).

Scheme 2.3. Mannich reaction of 2,4‐pentandione and N‐Cbz‐imine.

List recently reported an enantioselective synthesis of unprotected β‐amino acids by the reaction between bis‐silyl ketene acetal and silylated aminomethyl ether, followed by hydrolytic workup using a confined IDPi 11a (Scheme 2.4) [39].

Scheme 2.4. Mannich reaction between bisi‐silyl ketene acetal and silylated aminomethyl ether.

Source: Based on [39].

In 2006, List reported a Pictet‐Spengler reaction between substituted tryptamines and aldehyde catalyzed by CPA (S)‐6e, bearing 2,4,6‐(i‐Pr)₃C₆H₂ moieties at 3,3′‐positions, to furnish the corresponding tetrahydro‐β‐carbolines with 72–99% ee (Scheme 2.5a) [40]. The presence of bisethoxycarbonyl moieties is critical for the reaction. It is noted that CPA 6e is called TRIP, and is the most frequently used chiral phosphoric acid. You reported a Pictet‐Spengler reaction of indolyl dihydropyridines to afford tetrahydro‐β‐carbolines with 72–99% ee employing SPINOL‐derived CPA (R)‐13b (Scheme 2.5b) [41].

Scheme 2.5. Pictet‐Spengler reaction between tryptamine and aldehyde (a) (

Source: Based on [40]

), and of indolyl dihydropyridines (b) (

Source: Based on [41]).

The development of novel synthetic reactions and catalyst designs is normally accomplished by empirical optimization. Denmark demonstrated the utility of machine learning for predicting optimized catalyst CPA 6l (TCYP) using the addition reaction between thiol and imino ketones. The predicted enantioselectivity correlated strongly with the experimental values. It is noted that this is the first example of the machine‐learning‐driven catalyst design in the field of asymmetric acid catalysts. The results constitute a potential transformation of empirical selection and optimization of a chiral catalyst by synthetic chemists into a mathematical‐guided process (Scheme 2.6) [42].

Scheme 2.6. Addition of thiol.

Source: Based on [42].

Zhu reported a nucleophilic addition of N‐monosubstituted hydrazones to N‐Boc imines catalyzed by (S)‐6l, which gave β‐amino N,N′‐dialkyldiazenes in excellent yields, and the obtained β‐amino N,N′‐dialkyldiazenes were transformed into vicinal diamines (Scheme 2.7) [43]. N‐Alkyl hydrazones served as the α‐azo carbanion equivalents.

Scheme 2.7. Addition of hydrazone.

Source: Based on [43].

Zhao reported a polyene cyclization reaction using BINOL‐derived chiral phosphoramide (R)‐14b to furnish fused tricyclic compounds (Scheme 2.8). The cyclization reaction was applied to the total synthesis of (–)‐ferruginol [44].

The Friedel‐Crafts alkylation reaction between electron‐rich heterocycles and imine is an important method for the preparation of chiral indole derivatives. You reported a Friedel‐Crafts alkylation reaction between indole and aldimines using BINOL‐derived CPA 6f [45]. Lin synthesized novel CPA from (S)‐1,1′‐spirobiindane‐7,7′‐diol ((S)‐SPINOL), and found that 13c, bearing the 1‐naphthyl moiety at 6,6′‐positions, exerted similar reactivity and enantioselectivity to BINOL‐derived phosphoric acid (Scheme 2.9) [19, 46]. Numerous kinds of Friedel‐Crafts alkylation reactions of indoles with aldimines and other electrophiles have been reported to proceed efficiently using organocatalysts [47].

The construction of a quaternary carbon center is a challenging task. Ishihara developed chiral monopotassium binaphthyl disulfonate 8c as a strong Brønsted acid catalyst and realized Friedel‐Crafts alkylation reaction between indole and ketimine to generate quaternary stereogenic centers (Scheme 2.10a) [48]. Ishihara also developed C₁‐symmetric BINOL‐derived bisphosphoric acid 16 and achieved a Friedel‐Crafts alkylation reaction between 2‐methoxyfuran and α‐imino esters (Scheme 2.10b) [49]. The bisphosphoric acid 16 exhibited stronger acidity in comparison with monophosphoric acid due to the intramolecular hydrogen bond network. This is an example of the Brønsted acid‐assisted Brønsted acid catalysis [50].

Scheme 2.8. Polyene cyclization.

Scheme 2.9. Friedel‐Crafts alkylation reaction between indoles and imines.

Source: [19, 46].

In general, N‐aryl ketimines are stable, whereas N‐H imines are labile. In contrast, trifluoromethylated N‐H ketimines are relatively stable. Akiyama reported Friedel‐Crafts alkylation reaction between CF₃‐substituted N‐H ketimines and pyrroles using CPA 6e to furnish 2‐pyrrole derivatives with 83–97% ee (Scheme 2.11a) [51, 52]. 4,7‐Dihydroindoles also participated in the Friedel‐Crafts alkylation reaction with CF₃‐subsituted ketimine, and subsequent dehydrogenation with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone (DDQ) furnished 2‐substituted indoles with 76–95% ee (Scheme 2.11b) [53].

Ohshima developed C₁‐symmetric 3‐monosubstituted BINOL phosphoric acid 17 and achieved a highly enantioselective Friedel‐Crafts alkylation reaction between N‐unprotected α‐iminoesters and indoles (Scheme 2.12) [54]. Interestingly, use of C₂‐symmetric 3,3′‐disubstituted BINOL phosphoric acid gave lower enantioselectivity: 93% ee with CPA 17 and 61% ee with CPA 6h.

Akiyama reported an enantioselective synthesis of tetrahydroquinoline derivatives by the internal redox reaction catalyzed by biphenol‐derived CPA 18 [55]. This reaction was proposed to proceed by a [1,5]‐H shift to generate a zwitterionic intermediate, followed by a 6‐endo cyclization to yield tetrahydroquinoline derivatives (Scheme 2.13). An enantioselective C–H activation was proposed.

Radical reactions are an underexplored area in the field of chiral Brønsted acid catalysis. Kim reported a radical addition reaction that used iodoalkane as the radical precursor in the presence of chiral phosphoramide 14c, which furnished addition products in good yields and with moderate to good enantioselectivity (73–84% ee) (Scheme 2.14). (Me₃Si)₃SiH (TTMSSH) and Et₃B were employed as initiators [56].

Scheme 2.10. Friedel‐Crafts alkylation reaction with ketimines and indoles (a) (

Source: Based on [48]

) and furans (b) (

Source: Based on [49]).

Scheme 2.11. Friedel‐Crafts alkylation reaction between N‐H trifluoromethylated ketimines and pyrroles (a) (

Source: [51, 52]

) and 4,7‐dihydroindole (b) (

Source: Based on [53]).

Scheme 2.12. Friedel‐Crafts alkylation reaction between indole and N‐H trifluoromethylated iminoesters.

Source: Based on [54].

Scheme 2.13. Internal redox reaction.

Scheme 2.14. Radical addition to imines.