Recent advances in chiral phosphoric acids for asymmetric organocatalysis: a catalyst design perspective

	Scheme 4 The CPA-4 catalyzed asymmetric 1,6-conjugated addition of thioacetic acid to p-quinone methides.

In the past decades, the nitroso-Diels–Alder (NDA) reaction has attracted enough attention from researchers and has been applied to synthesize a series of important compounds. For example, the NDA adduct-3,6-dihydro-1,2-oxazines can be used to synthesize natural products and bioactive molecules. However, there are some challenges when it comes to chiral versions of NDA reactions. First, there is the issue of controlling the O or N-regioselectivity. Second, the existence of fast background reaction(s), which, in theory, is not conducive to the control of stereoselectivity. Third, under acidic conditions, nitroso compounds are prone to dimerization.

	Scheme 6 CPA-5 catalyzed asymmetric synthesis of 2,2-disubstituted 2,3-dihydro-4-quinolones from isatins and 2′-aminoacetophenones.

Over the past two decades, axially chiral binaphthols (BINOLs) have achieved remarkable success in asymmetric catalysis. However, compared to these α-binaphthols, studies on axially chiral aryl-β-naphthols have remained largely unexplored. In 2024, the Zhu group reported an asymmetric catalytic method to efficiently construct β-naphthol skeletons with up to 99% yield and an enantiomeric ratio (er) of 95.5:4.5, using alkynyl esters 21 as precursors and cooperatively catalyzed by CPA-5 and a Lewis acid (Scheme 7).²⁷ The reaction's key steps involve oxygen atom transfer and de novo arene formation to establish the chiral axis precisely. This approach provides a versatile synthetic platform for the enantioselective preparation of structurally diverse β-naphthol analogs, which hold broad potential in bioactive molecule design and asymmetric catalysis.

	Scheme 7 CPA/Lewis acid-catalyzed enantioselective synthesis of aryl-β-naphthols.

Alkyne compounds, with their diverse functionalization and versatile reactivity, are pivotal intermediates in the synthesis of pharmaceuticals and organic materials. Among them, 2-alkynylnaphthols are extensively utilized to construct axially and centrally chiral compounds. However, traditional organocatalytic methods face challenges in achieving electrophilic addition reactions between 2-alkynylnaphthols and weak electrophiles such as aromatic aldehydes. In 2024, the Zhou group developed a novel catalytic system that integrates aromatic amines and CPA, enabling a cascade reaction between 2-alkynylnaphthols and aldehydes (Scheme 8).²⁸ This approach efficiently synthesizes flavanone analogues with outstanding stereoselectivity. The study demonstrated that the CPA-6, featuring a 9-anthryl group, achieves optimal performance in toluene at 50 °C over 4 days, delivering 94% ee and >20:1 dr.

	Scheme 8 CPA catalyzed cascade reaction of 2-alkynylnaphthols with aldehydes.

Substrate scope studies revealed that ortho-methyl substitution on the phenyl ring effectively suppresses racemization of intermediates. Aldehydes with electron-withdrawing groups (e.g., NO₂, CN) at the para or meta positions exhibit excellent compatibility (26a–26c), while ortho-substituted aldehydes display poor reactivity due to steric hindrance (26d). Mechanistic investigations confirmed that the reaction proceeds via a synergistic pathway: the CPA activates an imine intermediate, while the aromatic amine mediates enamine-imine tautomerization. Key steps include the formation of a vinylidene quinone methide (VQM), an enantioselectivity-determining intramolecular oxa-Michael addition, and subsequent hydrolysis. This work not only provides a novel strategy for activating weak electrophiles and establishes an efficient route to synthesize antitumor and anti-inflammatory agents but also elucidates the theoretical significance of hydrogen-bonding and imine-mediated cooperative catalysis.

Construction of axially chiral indole compounds has attracted significant interest from researchers. In this field, the catalytic asymmetric construction of axially chiral five-six-membered heterocyclic skeletons based on indoles is well developed. However, the catalytic asymmetric construction of N,N′ axially chiral indole skeletons has rarely been reported. In 2023, Shi and co-workers reported the first organocatalytic enantioselective synthesis of axially chiral N,N′-bisindoles via chiral phosphoric acid-catalyzed formal (3 + 2) cycloadditions of indole-based enaminones 27 as novel platform molecules with precursor of a 2,3-diketoester 28 (Scheme 9).²⁹ In this study, the CPA based on H₈-BINOL exhibited more excellent catalytic performance than the CPA based on BINOL. When the bulky 9-phenanthrenyl group occupied the C-3 position of the chiral phosphoric acid, the reaction achieved the highest yield and enantioselectivity. Using this strategy, various axially chiral N,N′-bisindoles were synthesized in good yields and with excellent enantioselectivities (up to 87% yield and 96% ee).

	Scheme 9 The enantioselective synthesis of N,N′-bisindoles.

After accomplishing the organocatalytic enantioselective synthesis of axially chiral N,N′-bisindoles, they applied this strategy to the enantioselective synthesis of axially chiral N,N′-pyrrolylindoles to demonstrate the generality of the strategy. They used pyrrole-based enaminones 30 as the platform molecules in the organocatalytic enantioselective formal (3 + 2) cycloadditions with 2,3-diketoester precursors 28 under previously optimized conditions (Scheme 10). A series of axially chiral N,N′-pyrrolylindoles 31 was successfully prepared in moderate to good yields (up to 84%) and high enantioselectivities (up to 98% ee). Similarly, in 2022, they also achieved a ring formation between N-aminoindoles and 1,4-diketones using a spirocyclic chiral phosphoric acid catalyst. They synthesized a series of N–N axially chiral indoles and pyrrole compounds with high yields and high enantioselectivity.³⁰

	Scheme 10 The enantioselective synthesis of N,N′-pyrrolylindoles 31.

Further, they performed a preliminary investigation on the cytotoxicity of some selected products 29 against PC-3 cancer cells (Scheme 11). Several axially chiral N,N′-bisindoles 29 exhibited some extent of cytotoxicity against PC-3 cancer cells, with IC50 values of 36.96–93.98 μg mL⁻¹. These preliminary results indicate the potential applications of axially chiral N,N′-bisindoles in medicinal chemistry.

	Scheme 11 Investigation on the cytotoxicity of selected products against PC-3 cancer cells.

Finally, they also explored their application of these axially chiral N,N′-bisindoles 29 and N,N′-pyrrolylindoles 31 in the design of new chiral ligands or organocatalysts (Scheme 12). This work not only provides a new strategy for the catalytic asymmetric synthesis of axially chiral N,N′-bisindole derivatives, but also explores the application prospects of such skeletons in asymmetric catalysis and medicinal chemistry for the first time.

	Scheme 12 Applications of axially chiral N,N′-bisindole and N,N′-pyrrolylindole as chiral ligand or organocatalysts.

As a further expansion of the research work on the catalytic asymmetric construction of axial chiral five-membered heteroaryl skeletons, in 2022, the Shi group reported the asymmetric (2 + 3) cyclization reaction of chiral phosphoric acid-catalyzed 3-arylindole platform molecules and propargyl alcohol.³¹ The cyclization reaction achieved the construction of this kind of skeleton efficiently and highly stereoselectively, and synthesized a series of aryl-pyrroloindole compounds with both axial chirality and central chirality (Scheme 13).

	Scheme 13 Synthesis of axially chiral aryl-pyrroloindoles and applications of the derived ligand in asymmetric catalysis.

Notably, this new type of axially chiral aryl-pyrroloindole skeleton has high configuration stability. The author has experimentally confirmed that the tertiary phosphine compounds derived from it can be used as efficient chiral ligands in palladium-catalyzed asymmetric reactions (Scheme 13b). Therefore, this type of axially chiral aryl-pyrroloindole skeleton is expected to be further developed into more universal chiral ligands or catalysts, which are more widely used in asymmetric catalysis.

Indolemethanol chemistry has become an emerging research field and has been used to catalyze the asymmetric construction of chiral indole backbones. However, the catalytic asymmetric cycloaddition reactions it participates in are all based on the reaction characteristics of monoindolemethanol. Indolemethanol, as a new type of indolemethanol, has little known about its reaction characteristics. The catalytic asymmetric cycloaddition reaction is a highly complex and challenging area of chemistry.

In order to solve this challenging problem, Shi group pioneered the concept of 2,3-indoledimethanol as a four-carbon (4C) platform molecule, designed and realized the first example of 2,3-indoledimethanol-involved catalytic asymmetric (4 + 2) and (4 + 3) cycloaddition reactions, constructed chiral indole-fused six-membered ring and seven-membered ring skeletons with high yields, high regioselectivities, and enantioselectivities, and identified some chiral indole-fused ring molecules with significant antitumor activity.³² This work not only represents the first example of catalytic asymmetric cycloaddition reaction involving indoledimethanol, but also provides an efficient strategy for the construction of chiral indole fused ring skeleton. More importantly, this work has carried out an in-depth exploration of the mechanism, intermediates, and activation modes of indoledimethanol participation in the reaction, and promoted the in-depth development of indolemethanol chemistry from single indolemethanol to indoledimethanol in a higher and broader direction (Scheme 14).

	Scheme 14 ent-CPA-5 catalyzed (4 + n) cycloadditions of 2,3 indolyldimethanols.

Following the above work, the concept of 2,3-indoledimethanol as a four-carbon (4C) platform molecule was creatively proposed, and the Shi group further expanded their application range. In 2024, this group reported the chiral phosphoric acid-catalyzed asymmetric (2 + 4) cyclization reaction of achiral furan-indoles 53 with 2,3-indoledimethanols 50, which achieved the highly regioselective, diastereoselective, and enantioselective synthesis of this kind of furan-indole compounds with multiple chiral elements.³³ This work provides a new strategy for the synthesis of furan compounds with multiple chiral elements and is expected to find more applications in asymmetric catalysis (Scheme 15).

	Scheme 15 Chiral phosphoric acid-catalyzed asymmetric (2 + 4) cyclization reaction of achiral furan-indoles with 2,3-indoledimethanols.

In the field of synthetic chemistry, catalytic asymmetric synthesis of five-membered cyclic alkene atropisomers has become a very challenging scientific problem, due to their structural characteristics such as remote ortho groups and unstable configurations. Faced with this challenging problem, Shi group achieved the efficient synthesis of cyclopentenyl[b]indoles atropisomers for the first time through a catalytic asymmetric rearrangement reaction involving 3-indolemethanol 55.³⁴ This work overcame the difficulty of controlling reaction activity and enantioselectivity during the rearrangement process, and synthesized a series of new cyclopentenyl[b]indoles atropisomers with both axial chirality and central chirality with high yields and high enantioselectivity, providing a new strategy for the synthesis of five-membered cyclic olefin atropisomers. More importantly, this new chiral skeleton has high stability and can be converted into new chiral ligands or organic small molecule catalysts for asymmetric catalysis (Scheme 16).

	Scheme 16 Design of cyclopentenyl[b]indole motifs with axial and point chirality.

In 2024, the Shi group reported the first case of chiral phosphoric acid-catalyzed asymmetric (3 + 3) cycloaddition of two different 2-indolemethanols 58 and 59.³⁵ Using this reaction, a variety of chiral indole-fused six-membered heterocycles 60 were synthesized with a yield of up to 96% and the highest 98% ee. In addition, theoretical calculations of reaction pathways and activation modes have facilitated the understanding of asymmetric cycloaddition reactions involving 2-indolemethanols (Scheme 17).

	Scheme 17 Catalytic asymmetric (3 + 3) cycloaddition between different 2-indolylmethanols.

In 2025, the Shi group designed an asymmetric (5 + 1) cycloaddition reaction of indole-based o-aminobenzamides 61 and 1-naphthalene aldehyde derivative 62 catalyzed by CPA-9, realizing the catalytic asymmetric construction of the N–N/C–C biaxial indole skeleton.³⁶ This work synthesized a series of N–N/C–C biaxial chiral indolylquinazolinone derivatives 63 with diverse structures, with a yield of up to 99% and an ee value of up to 98%, which provided an efficient strategy for catalytic asymmetric synthesis of biaxially chiral molecules (Scheme 18).

	Scheme 18 Catalytic atroposelective synthesis of indoles bearing N–N/C–C diaxes.

Spirocyclic frameworks have emerged as a privileged chiral scaffold in asymmetric catalysis and functional materials due to their unique structural rigidity. However, the construction of spirocyclic systems remains challenging, significantly limiting the structural diversity and applications of such compounds. In 2024, the Tan group reported a novel strategy for the efficient enantioselective construction of axially chiral spiro-bisindole skeletons via a chiral phosphoric acid-catalyzed intramolecular dehydration cyclization (Scheme 19).³⁷ Compared to traditional SPINOL frameworks, the substitution of phenolic hydroxyl groups with indole moieties 65 markedly enhances substrate nucleophilicity while eliminating tedious pre-activation steps. Leveraging the modifiable reactive sites of indole, the enantioenriched spiro-bisindoles can be rapidly derivatized into diverse functional architectures. Notably, this strategy enables convenient access to axially chiral fluorescent molecules exhibiting both exceptional asymmetric factors and quantum fluorescence efficiencies, opening new avenues for chiral luminescent materials development. Control experiments revealed that the unprotected N–H bond plays a critical role in reaction efficiency and stereochemical control. This work provides an effective way for the development and application of new chiral spiro skeletons and broadens the research field of spiro skeletons.

	Scheme 19 CPA-catalyzed enantioselective intramolecular dehydrative cyclization and application of axially chiral spiro-bisindoles.

Chiral spiro skeletons are the core skeletons of highly efficient chiral catalysts in many reactions.^38–40 However, the synthesis of these spiro structures is usually complicated and requires multiple steps of reaction, which limits their large-scale application. Therefore, developing a new method that can directly obtain the chiral spiro structure from simple and cheap raw materials and with minimum synthetic steps has important scientific significance and application value.

Recently, the Sun group has efficiently constructed a new type of chiral spiro-bisindole skeleton through a “one-pot self-assembly” synthesis strategy using inexpensive and readily available indoles and acetone as raw materials. The core of this strategy was to use the synergistic catalytic effect of CPA-4 and alcohol additive B1 to achieve efficient conversion from simple raw materials to complex chiral spiro structures (Scheme 20).⁴¹ In addition, through nuclear magnetic resonance (NMR) and density functional theory (DFT) studies, they confirmed that there is a favorable interaction between the CPA catalyst and the alcohol additive B1, which may be achieved through a hydrogen bond.

	Scheme 20 Synthesis of spindoles and representative transformation products.

Coincidentally, the Reid and List group recently reported excellent work that is closely related. Under the action of a highly hindered Brønsted acid catalystilDP-1, they also used acetone and indole as raw materials. They obtained the target product spindoles in extremely high yield (94% yield) and enantioselectivity (96% ee), which could be further developed into a series of chiral catalysts and ligands.⁴² This direct synthesis method can not only significantly simplify the synthesis steps, but also improve the atomic economy and environmental friendliness of the reaction while maintaining good enantioselectivity (Scheme 20).

	Scheme 21 Inherent polarity of imines and developed strategies for imine umpolung.

Recently, the Tan group has successfully achieved the polarity reversal of imines through a Brønsted acid-catalyzed arylation strategy.⁴³ The key to this reaction lies in the design of the N-electrophilic aromatic precursor, which utilizes electron-withdrawing imine-derived indoles and benzoquinones to accomplish the direct amination of (hetero)aryl groups by thermodynamically driven arylation with good reaction efficiency and enantioselectivity. In addition, highly efficient construction of chiral amino compounds, axially chiral aryl amides, and heteroaryl amides by aromatization-driven imine polarity reversal reaction in the presence of CPAs (Schemes 22–24).

	Scheme 22 CADA of 1-naphthols via umpolung of imines.

	Scheme 23 Catalytic asymmetric umpolung of iminoquinones to synthesize N-aryl atropisomers.

	Scheme 24 The synthesis of atropisomeric N-heteroaryls via catalytic asymmetric umpolung reaction of iminoquinones with C-2 substituted indoles.

	Scheme 27 Synthesis of SPINOL-derived CPAs and their application.

When the temperature was decreased to −60 °C, the enantioselectivity reached 96%, and the yield was not affected. Under the optimal conditions, a series of substrates was screened, resulting in a yield of up to 97% and an ee value of >99% (Scheme 28). Based on the previous study of this reaction, the authors proposed a possible reaction model (Scheme 28).⁵⁰ In this model, the catalyst activates both substrates via hydrogen bonding, and subsequently, the indole preferentially attacks the N-tosylimine from the Re-face to give the S-configuration product.

	Scheme 28 Enantioselective Friedel–Crafts reaction catalyzed by CPA-12f.

	Scheme 30 CPA catalyzed atroposelective C–H amination of arenes.

Although anthrones and their derivatives are important components of a variety of natural and synthetic compounds with pharmacological activities, access to chiral anthrone compounds is limited due to the sp²-rich nature of anthrones. Especially the construction of chiral elements directly on symmetrical anthrone cores is a thorny challenge. Based on the above research background, the Tan group reported the condensation of anthrone and hydroxylamine catalyzed by CPA-16 to introduce oxime ether functional groups to achieve the desymmetrization process of symmetrical anthrone, realizing the enantioselective synthesis of novel axially chiral anthrone oxime ether compounds.⁵³ This work has developed a new method for the synthesis of novel axially chiral anthrone compounds, providing new members for the axially chiral family. More importantly, the transformation of the axially chiral anthrone derivatives enables the efficient transfer of axial chirality to central chirality, and highly enantioselective synthesis of chiral dibenzoazepine compounds with great medicinal potential (Scheme 31).

	Scheme 31 Enantioselective synthesis of axially chiral anthrone-based oxime ethers and their applications.

	Scheme 34 The desymmetrization of meso-aziridine catalyzed by CPA-19.

In the study of the reaction mechanism, the authors found that the presence of trimethylsilyl groups was essential for the formation of ring-opened products. When the reaction was catalyzed by CPA-19 only, the reaction did not occur. Combining the obtained experimental results with relevant NMR experiments, the authors speculated that the reaction occurs by the mechanism shown in Scheme 35. First, CPA-19 interacts with TMSN₃ 102 to give chiral silane A, which subsequently activates aziridine to give intermediate B. Species B then undergoes attack by azide nucleophilic reagents, leading to C, and the catalyst CPA-19 is regenerated. Finally, compound C decomposes on silica gel to form product 103 (Scheme 35). This work opens a new avenue for chiral phosphoric acid-catalyzed asymmetric reactions and demonstrates the potential for versatile applications of VAPOL-based CPAs.

	Scheme 35 Proposed mechanism of the desymmetrization of meso-aziridines.

	Scheme 36 Enantioselective Mannich reaction catalyzed by CPA-20 derived from TADDOL.

Interestingly, the author found that the classical method of BINOL phosphoric acids synthesis could not be used for the synthesis of TADDOL phosphoric acids (CPA-20). Inspired by the work of Johnson,⁶⁹ the author used PCl₃, which is more reactive than POCl₃, to react with the TADDOL derivative, and subsequently, oxidation of dialkyl phosphite through I₂ successfully obtained the dialkyl phosphite (Scheme 36).

In order to further enhance the application of TADDOL phosphoric acids, various chiral phosphoric acids based on the TADDOL backbone were synthesized by Widhalm and co-workers in a new synthetic route (Scheme 37), and these CPAs were used to catalyze the Mannich reaction to verify their performance.⁷⁰ Among these newly synthesized chiral phosphoric acid catalysts, the sterically hindered CPA-25b obtained the highest yield and enantioselectivity (Table 2, entry 16, 96% yield and 96% ee).

	Scheme 37 Synthesis of TADDOLs and cyclic phosphoric acid: (a) R2CO (for CPA-21), R2C(OMe)2 (for CPA-22 and CPA-23), p-TsOH, MeCOCOMe/CH(OMe)3 (for CPA-24), cyclohexane reflux or NaH, BnBr, DMF (for CPA-22 and CPA-23). (b) Ar–MgBr, Ar–Li, (for CPA-26) THF. (c) i: PCl3, Et3N, ii: H2O. (d) I2, Py/H2O. (e) PCl3, Et3N. (f) 3-Hydroxypropionitrile. (g) H2O2. (h) DBU.

Next, they explored the scope of the substrate, and the results are shown in Table 3. Notably, the aryl aldimines with electron-donating substituents performed well (entries 1–3), with an ee value up to 96%, while those with electron-withdrawing groups gave relatively low enantioselectivities and yields (entries 4–7). Other substrates, such as 1-naphthyl and 2-naphthyl and pyridyl, have achieved good results (entries 8–10). Based on the result of the DFT experiments, the authors speculate that the high enantioselectivity of the reaction may be independent of the nucleophile and that it may arise from the dominance of a single dicoordinate substrate complex in order to drive the nucleophile to attack the imino group from the single enantiotopic face.

To compare the catalytic activities of NTPA-1 and NTPA-2 with common chiral phosphoric acids CPA-29, the asymmetric Diels–Alder reactions of ethyl vinyl ketone 131 were explored. It was found that when 5 mol% of CPA-29 was used with cyclopentadiene 132, no reaction took place (Scheme 42). However, NTPA-1 and NTPA-2 were able to produce the desired Diels–Alder product in high yields along with moderate enantiomeric excesses. The introduction of a NTf group into the phosphoric acid led to a significant enhancement in reactivity.

	Scheme 42 Comparison of common CPA and chiral phosphoramides catalytic activity.

Through the optimization of conditions, it was found that the bulky NTPA could further improve the reaction yield and enantioselectivity when toluene was used as the solvent at −78 °C. Subsequently, the substrate scope of the asymmetric Diels–Alder reactions between ethyl vinyl ketone and silyloxydienes was screened, and good results were obtained, with a yield up to 99% and an ee value up to 92% (Scheme 43).

	Scheme 43 Asymmetric Diels–Alder reaction of α, β-unsaturated ketone.

	Scheme 46 Enantioselective Friedel–Crafts Reaction of 2-alkynyphenols with aromatic Ethers catalyzed by chiral N-triflyl phosphoramide.

To demonstrate the application value of the reaction, the authors transformed the obtained adducts into useful synthetic intermediates with high enantioselectivity (Scheme 47). The olefins 143b could be easily converted into the corresponding triflate, and then the one-pot Pd(OAc)₂-catalyzed reaction between diphenyl phosphine oxide and the triflate at 120 °C furnished 144 in a 57% yield and 92% ee. In addition, NaH could also promote the reaction of 143g and Tf₂O in DCM, affording the corresponding triflate 145 in an 87% yield and with 93% ee. Then, nickel-catalyzed coupling reactions between the triflate 145 and MgBrCH₃ furnished 146 in an 84% yield and with 93% ee.

	Scheme 47 The transformations of 143b and 143g.

In 2019, the Tan group developed an asymmetric hydroarylation of N-aryl protected amino arylethynylenes 147 or hydroxynaphthylalkyne 150 with 2-naphthol 148 catalyzed by CPA, enabling the synthesis of a series of disubstituted 1,1′-(ethene-1,1-diyl)binaphthol (EBINOL) scaffolds in high yields and with excellent enantioselectivities (up to 99% yield and 99% ee) and complete E/Z-selectivity control (Scheme 48).⁸⁸ This Brønsted-acid-catalysed alkyne activation method showed excellent compatibility with different types of activating groups, and thus opens new avenues for organocatalytic functionalization of alkynes. Owing to its unique spatial configuration, this axially chiral skeleton serves as a valuable complement to BINOL and SPINOL skeletons in asymmetric catalysis.

	Scheme 48 Enantioselective hydroarylation of alkyne with 2-naphthol catalyzed by CPA.

Based on this principle, the Yamamoto group envisioned that the acidity of the chiral N-triflyl phosphoramide catalysts would be further enhanced by replacing the oxygen atoms with sulfur or selenium atoms in PO.⁹¹ According to the previous steps for the synthesis of chiral N-triflyl phosphoramides, they synthesized chiral N-triflyl thio- or selenophosphoramides. They applied them to the enantioselective protonation of prochiral enol derivatives 154 (Table 5).⁹² As predicted, chiral N-triflyl thio- or selenophosphoramides CPA-32 and CPA-33 exhibited excellent catalytic performance, while common chiral phosphoric acid CPA-5 and dithiophosphoric acid CPA-31. Hardly worked in this reaction even after long reaction times (entries 1 and 2). These results demonstrated that the introduction of an NTf group into the phosphoryl group could improve reactivity, and the substitution of the oxygen with sulfur or selenium in the phosphoramide could improve enantioselectivity as well as reactivity. Further optimization revealed that the more sterically hindered catalyst CPA-34 can obtain the target product with a higher yield and stereoselectivity (entry 6).

Entry	Time (h)	CPA	Yield (%)a	er.b
a Yield was measured by 1H NMR analysis, and the isolated yields are shown in parentheses.b Enantiomeric ratio (er) was determined by HPLC analysis. NR and ND mean no reaction and not determined, respectively.
1	96	CPA-5	NR	ND
2	96	CPA-31	Trace	ND
3	4.5	NTPA-2	>99(98)	77:23
4	3.5	CPA-32	>99(97)	89:11
5	8	CPA-33	>99(97)	86:14
6	3.5	CPA-34	>99(97)	91:9

Furthermore, when the catalyst loading of the reaction was reduced to 0.05 mol%, the reaction still obtained good enantioselectivity, which showed outstanding catalytic performance of the chiral N-Triflyl thio-phosphoramides catalyst, as shown in Table 6.

Entry	x mol%	CPA	Yield (%)a	er.
a Yield was measured by 1H NMR analysis except 5.b Isolated yields.
1	5	CPA-34	>99	96:4
2	1	CPA-34	>99	95:5
3	0.5	CPA-34	>99	94:6
4	0.1	CPA-34	>99	94:6
5b	0.05	CPA-34	80	93:7

In the past, BINOL phosphate has received sufficient attention and has been used in many types of reactions. However, in some reactions it did not behave so effectively or even did not work due to inadequate acidity. As we know, the sulfur atom can accommodate a negative charge better than the oxygen atom, resulting in a more stable dithiophosphate anion than its oxygen analogue, which makes dithiophosphates more acidic than their oxygen-containing analogues (Scheme 50).⁹⁰

	Scheme 50 Order of stability of the conjugated bases.

	Scheme 51 Enantioselective hydroamination reaction catalyzed by a dithiophosphoric acid.

Under the optimal reaction conditions, the author screened the scope of substrates and found that reaction substrates were well tolerated and different types of dienes can achieve this asymmetric transformation with moderate to excellent yields (up to 99%) and enantioselectivities, as shown in (Scheme 52a). It is worth noting that when allene 160 is used as the substrate, the reaction can also proceed smoothly, and the yield and enantioselectivity are the same as those observed from the corresponding 1,3-diene (159a and 159a′). Hydroxylamines were also proved to be useful substrates for the reaction, providing isoxazolidine products with very good enantioselectivities (Scheme 52c).

	Scheme 52 Performance of dienes in the enantioselective hydroamination reaction.

Moreover, the authors proposed a mechanism in which a chiral acid adds to a diene and then undergoes enantioselective S_N2 displacement, which is fundamentally distinct from those reactions that have been previously reported (Scheme 53a). Moreover, to further elucidate the mechanism of this transformation, some control experiments were carried out. As shown in Scheme 53(b), more than 95% of the cis products were obtained by adding deuterated non-chiral dithiophosphinic acid to acenaphthylene. Next, the author studied the reaction of the deuterated catalyst with cyclic substrates, which also showed syn-stereoselectivity (Scheme 53c). Based on the above experimental results, the author speculated the reaction path (Scheme 53d). In order to further prove the practicality of the reaction, the author studied the hydroarylation of indole compounds, the resulting tetrahydrocarbazole products with good to excellent ee value (Scheme 53e). Notably, the realization of this type of reaction by organic catalysis has never been reported before, demonstrating the excellent catalytic performance of BINOL-derived dithiophosphoric acid.

	Scheme 53 Experiments to elucidate the reaction mechanism and application to indolenucleophiles.

In response to these challenging problems, the Shi group designed the addition reaction of 2-indole methanol and 2-substituted indole catalyzed by chiral Brønsted acid. It achieved high yields and high enantioselectivities in the construction of the axial chiral 3,3′-bisindole skeleton (up to 98% yield, 96:4 er).⁹⁴ The reaction design was based on the theirs discovery that 2-indolemethanol has C3-polarity reversal properties,⁹⁵ and rationally designed 2-substituted indoles, that is, the group introduced at the C2 position (R) not only serves as a large hindered group, but also serves as an activating group and a post-functionalizing group, helping to control the enantioselectivity of the reaction. This work not only solves the challenging problem of catalytic asymmetric construction of axially chiral five-membered-five-membered heterodiaryl skeletons, but more importantly, these axially chiral indole compounds have potential application value in the design and development of new organic small molecule catalysts (Scheme 54).

	Scheme 54 Design of enantioselective synthesis of axially chiral 3,3′-bisindoles.