Catalytic enantioselective construction of two N-stereogenic centers of ethano- and propano-Tröger's bases

Abstract

Whereas enantioselective methods for constructing carbon stereocenters have been well established, those for creating heteroatomic stereocenters have received less attention. Nitrogen is the most abundant element in the Earth's atmosphere and plays an important role in the biochemical and physiological processes of organisms. However, owing to its rapid pyramidal inversion under general conditions, its stereochemistry has long been overlooked. Here, we report the catalytic enantioselective construction of two conformationally stable N-stereogenic centers of ethano- and propano-Tröger's bases. By using a Pd-catalyzed asymmetric annulative allylic alkylation reaction, various N-chiral ethano- and propano-TBs have been readily prepared in good yields with excellent enantioselectivities. Mechanistic investigations have shown that the two N-stereogenic centers are simultaneously established during intramolecular bridge formation. Furthermore, the synthesized TB products can serve as both an organo-catalyst for the aziridination reaction and a fluorescent/chiroptical probe for pH measurement.

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Introduction

The control of molecular chirality remains a focus of modern synthetic chemistry. Since the early 20th century, synthetic chemists have been dedicated to developing catalytic asymmetric strategies to achieve efficient and precise synthesis of chiral molecules. Compared with the extensive exploration of creating conformationally and configurationally locked tetrahedral carbon (C) stereocenters, the enantioselective construction of heteroatomic stereocenters has garnered less attention (Fig. 1A).^1–5 Although nitrogen (N) is the most abundant element in the Earth's atmosphere and plays an important role in the biochemical and physiological processes of organisms, its stereochemistry has long been overlooked due to rapid pyramidal inversion under general conditions (Fig. 1B).^6–8 Quaternization to form ammonium cations can prevent this inversion by locking the configuration of the nitrogen stereocenter, but only for some structurally special amine N-oxides⁹ and N-centered quaternary ammonium salts.^10,11 Alternatively, stable nitrogen stereocenters can be established in rigid cyclic tertiary amine structures, as ring tension can slow down or prevent the inversion of nitrogen's electron lone pair.^12–14

Fig. 1 Catalytic enantioselective synthesis of N-chiral ethano- and propano-TBs.

Tröger's base (TB) is a fascinating tertiary amine with a rigid bicyclic skeleton (Fig. 1C).^15–19 In terms of stereochemistry, TB is known as the first N-chiral compound to be resolved and has become a classic example of “chiral nitrogen” in many stereochemistry textbooks.^20,21 In addition, the two aromatic rings orient in a nearly perpendicular fashion, making TB a cleft-like V-shaped molecule with a hydrophobic cavity. Hence, TB has attracted widespread attention in the fields of molecular recognition, supramolecular chemistry, and materials science.^22–24 However, TB undergoes racemization through a ring-opened achiral methylene-iminium intermediate under acidic conditions,^25–27 which is an obstacle for its intended use as a chiral ligand or catalyst in asymmetric catalysis.^28–30 One opportunity to address this issue is bridge modification, which increases the number of atoms strapping the two bridgehead N-atoms, avoiding the conventional racemization pathway via reversible aminalization.^31,32 In this context, Lacour et al. reported a highly enantiospecific synthesis of ethano-TBs from enantiopure TBs via rhodium(II)-catalyzed [1,2]-Stevens rearrangement.^33,34 Nevertheless, a general strategy for the direct catalytic enantioselective synthesis of configurationally stable TB analogues continues to be an attractive yet challenging goal in terms of the simultaneous construction of two bridgehead stereogenic N-atoms.^35–38

The asymmetric allylic alkylation reaction is one of the most reliable methods for carbon–carbon and carbon–heteroatom bond formation.^39–44 A notable advancement is its annulative version, which consists of a metal-catalyzed asymmetric annulative allylic alkylation (AAAA) reaction between dual nucleophiles and allylic diol derivatives and has become a powerful tool for preparing distinct chiral cyclic compounds.⁴⁵ Although significant advancements have been made in recent years,^46–50 to our knowledge, the AAAA reaction has been employed only to synthesize heterocycles with C-stereogenic centers. Our group has a long-term interest in the synthesis of multi-nitrogen-containing heterocycles.^51–56 Recently, we have achieved the enantioselective synthesis of TBs via chiral phosphoric acid (CPA)-catalyzed aminalization.⁵⁷ Here, we present a Pd-catalyzed AAAA reaction to construct N-stereogenic centers (Fig. 1D). The reactions of tetrahydrodibenzodiazocines (THDBDAs) 1 with butene dicarbonates 2 or isobutylene dicarbonates 4 are believed to proceed via a Pd-catalyzed cascade of two N-allylic alkylation reactions, in which two N-stereogenic centers are simultaneously established during intramolecular bridge formation. By using this method, a wide range of N-chiral ethano- and propano-TBs have been obtained in good yields with excellent enantioselectivities. The diversified late-manipulation of these bridged bicyclic products demonstrates their utility in organic synthesis. Furthermore, the synthesized ethano-TB can be directly used as an organo-catalyst for the aziridination reaction, and the H⁺-induced fluorescence and electronic circular dichroism (ECD) responses of a propano-TB derivative suggest its potential application in pH fluorescent/chiroptical probes.

Results and discussion

We initiated the investigation with a model reaction between THDBDA 1a and (E)-butene dicarbonate 2a (Table 1). To our delight, by employing chiral phosphoramidite ligands, the projected AAAA reaction readily took place in CH₂Cl₂, affording the desired product ethano-TB 3a (entries 1–5). Among them, BINOL-derived ligands (L1, L2, and L3) furnished 3a in moderate yields and enantioselectivities (entries 1–3). When the backbone is changed to spiro-diol (L4 and L5), the ee value can be improved to a good level (entries 4–5). Phosphine ligands (L6, L7, and L8) were ineffective for this reaction (entries 6–8). The solvent effect was then studied, and chloroform provided 3a with 91% ee (entry 10). Several commonly used inorganic and organic bases were subsequently screened (entries 11–14). While they were all effective, Na₂CO₃ was identified as the best choice (entry 11). The reaction temperature had some impact on the yield (entries 15–17). At 60 °C, product 3a was obtained in 90% yield with 96% ee. Notably, only one diastereoisomer was observed during the investigation (all dr > 20 : 1).

Table 1 Reaction optimization^a

Entry	L	Solvent	Base	Temp./°C	Yield^b (%)	ee^c (%)
a Unless otherwise indicated, the reaction conditions were as follows: 1a (0.05 mmol, 1 equiv.), 2 (0.075 mmol, 1.5 equiv.), Pd2(dba)3·CHCl3 (5 mol%), L (15 mol%), and base (0.1 mmol, 2 equiv.) in the specified solvent at the given temperature for 24 h, all dr > 20 : 1.b Isolated yield.c Determined by chiral HPLC analysis. n.d. = not detected.
1	L1	CH2Cl2	Cs2CO3	35	65	25
2	L2	CH2Cl2	Cs2CO3	35	72	50
3	L3	CH2Cl2	Cs2CO3	35	56	37
4	L4	CH2Cl2	Cs2CO3	35	80	77
5	L5	CH2Cl2	Cs2CO3	35	85	89
6	L6	CH2Cl2	Cs2CO3	35	n.d.	—
7	L7	CH2Cl2	Cs2CO3	35	n.d.	—
8	L8	CH2Cl2	Cs2CO3	35	n.d.	—
9	L5	DCE	Cs2CO3	35	80	82
10	L5	CHCl3	Cs2CO3	35	52	91
11	L5	CHCl3	Na2CO3	35	86	95
12	L5	CHCl3	K2CO3	35	81	92
13	L5	CHCl3	KO^tBu	35	85	90
14	L5	CHCl3	DIPEA	35	83	92
15	L5	CHCl3	Na2CO3	20	81	95
16	L5	CHCl3	Na2CO3	40	86	96
17	L5	CHCl3	Na2CO3	60	90	96

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Under the best conditions, we examined the substrate generality of the Pd-catalyzed AAAA reaction (Fig. 2). The reaction conditions were compatible with various 2-butenylene dicarbonates (2a–d), which afforded 3a with consistently excellent enantioselectivity. We next investigated the effect of different substituents on the phenyl ring of THDBDAs 1. Alkyl groups at the 2(8)-position, such as ethyl (3b), n-propyl (3c), i-propyl (3d), n-butyl (3e), t-butyl (3f), n-amyl (3g), and benzyl (3h) groups, were well tolerated, providing the corresponding products in good yields (75–91%) with excellent enantioselectivities (93–97%). However, other types of substituents afforded delicate effects. When phenyl substituted THDBDA was employed, the corresponding product 3i was obtained in 80% yield with 90% ee. Unsubstituted THDBDA was suitable for this reaction, but the enantioselectivity was slightly reduced (3j). For the halogen substituents, the fluoro group (3k) provided a higher ee value than the chloro group (3l). Electron-donating groups such as SMe (3m), OMe (3n), and OBn (3o) were also compatible. Nevertheless, the reaction was applicable to THDBDAs bearing alkyl substituents, including methyl (3p), ethyl (3q), i-propyl (3r′), and t-butyl (3s′) groups, at the 3(9)-position. However, owing to unfavorable steric effects, the substituent at the 4(10)-position was not conducive to enantiocontrol, as exemplified in 3t. In a previous report on Tröger's bases, Lenev, Buss, and Kostyanovsky et al. demonstrated that the bis-ortho-substitution of the aromatic groups next to the nitrogen atoms dramatically increased the racemization barrier of the stereogenic nitrogen.⁵⁸ Di- and trisubstituted THDBDAs were employed as suitable substrates, leading to the formation of products 3u–x in ≥83% yields with up to 95% ee. When (hetero)ring-fused substrates (3y and 3z) were utilized, consistently good yields and excellent enantioselectivities were obtained. The use of unsymmetrical substrates resulted in the formation of 3a′ as a pair of diastereoisomers, which may be attributed to the regioselective allylic alkylation of the two amino groups on the two electronically differentiated aromatic rings. The absolute configuration of 3r′ was determined via X-ray crystallographic analysis.

Fig. 2 Substrate scope of ethano-TBs. Unless otherwise indicated, the reaction conditions were as follows: 1 (0.1 mmol, 1 equiv.), 2 (0.15 mmol, 1.5 equiv.), Pd₂(dba)₃·CHCl₃ (5 mol%), L5 (15 mol%), and Na₂CO₃ (0.2 mmol, 2 equiv.) in CHCl₃ (1 mL) under a N₂ atmosphere at 60 °C for 24 h, all dr > 20 : 1. [a] Followed by hydroboration–oxidation.

Encouraged by the successful synthesis of N-chiral ethano-TBs, we decided to apply this Pd-catalyzed AAAA reaction to prepare N-chiral propano-TBs. This structural variation is highly valuable as it could lead to a dramatic change in the shape of the TB scaffold.³¹ Despite its appeal, strapping two bridgehead nitrogens with three atoms is highly challenging.⁵⁹ Under standard conditions, the projected reaction of THDBDA 1a with isobutylene dicarbonate 4a readily occurred to yield propano-TB 5a with moderate enantioselectivity. By further optimizing the reaction conditions (see the SI for details), L1 was selected as the best ligand, and the reaction temperature was set to −10 °C, which afforded 5a in 78% yield with 90% ee. Subsequently, the substrate scope was examined, and the results are summarized in Fig. 3. The ester group of isobutylene dicarbonates 4 can be varied, from Me (4a), ⁿPr (4b), ^tBu (4c), to Bn (4d), with consistently high yields and excellent ee values. At the 2(8)-position of THDBDA, different types of substituents, including electron-neutral hydrogen, electron-donating alkyl and alkoxy groups, and electron-withdrawing halo groups, were well tolerated, providing propano-TBs 5b–5i in 65–91% yields with 92–97% ee. The alkyl substituents at the 3(9)-position appeared to be inconsequential to the reaction results, and excellent enantioselectivity was retained (5j and 5k). In particular, we examined the tolerance of the reaction to disubstituted substrates. While 5l and 5m were formed with 91% ee, racemic 5n was obtained presumably due to the unfavourable steric hindrance at the 5(10)-position. The reaction was also applicable to (hetero)ring-fused and unsymmetrical THDBDAs, delivering 5o–5r in 81–90% yields with 90–97% ee. The absolute configuration of 5a was determined via X-ray crystallographic analysis.

Fig. 3 Substrate scope of propano-TBs. Unless otherwise indicated, the reaction conditions were as follows: 1 (0.1 mmol, 1 equiv.), 4 (0.15 mmol, 1.5 equiv.), Pd₂(dba)₃·CHCl₃ (5 mol%), L1 (15 mol%), and Na₂CO₃ (0.2 mmol, 2 equiv.) in CHCl₃ (1 mL) under a N₂ atmosphere at −10 °C for 18 h.

To gain mechanistic insight, control experiments were performed (Fig. 4A). Both (E)- and (Z)-butene dicarbonates were subjected to the reaction under standard reaction conditions. The observed difference in the enantioselectivity of 3a indicated a mismatched relationship between the (Z)-double bond and chiral ligand. A nonlinear effect (NLE) study on the reaction of 1a with 2b was performed (Fig. 4B). A (+)-NLE effect was obtained, which indicated that in the reactive chiral Pd-complex, the palladium and ligand may be not present in a 1 : 1 ratio. However, given the relatively weak effect, other chiral perturbations, including reservoir effects, cannot be ruled out. Furthermore, to confirm the involvement of a tandem double alkylation process, we carried out stepwise experiments (Fig. 4C). Monoalkylated products 7 or 9 were pre-synthesized via the alkylation of 1a with allyl bromides 6 or 8. Under standard conditions, 7 and 9 were readily converted to ethano-TB 3a and propano-TB 5a in good yields with excellent enantioselectivities, respectively, proving that the monoalkylated product might be a viable intermediate in the tandem process. On the basis of the experimental results above and those of previous studies,^60–64 a plausible catalytic cycle for the synthesis of ethano-TB 3a is depicted in Fig. 4D (left). Treatment of the chiral Pd-complex generated in situ with (E)-butene dicarbonate 2a leads to a decarboxylative process, affording Pd(II)-π–allyl intermediate A. Subsequent allylation with 1a gives monoalkylated intermediate B, enabling a secondary decarboxylative process to form Pd(II)-π–allyl intermediate C. The subsequent intramolecular allylation completes the entire catalytic cycle, regenerating the chiral Pd(0) catalyst for the next catalytic cycle and forming product 3a. The reaction of 1a with isobutylene dicarbonate 4a involves a similar catalytic cycle (Fig. 4D, right) to afford propano-TB 5a.

Fig. 4 Mechanistic considerations.

Finally, further transformations and downstream applications were performed to demonstrate the synthetic utility of this protocol (Fig. 5). Under standard conditions, the large-scale syntheses of 3n and 5a proceeded smoothly and maintained excellent enantioselectivities (see the SI for details). Moreover, late-stage manipulations (Fig. 5A), such as hydrogenation (10) and deprotection (11), of ethano-TB 3n were readily conducted without erosion of enantiomeric purity. The terminal olefin underwent a standard hydroboration–oxidation reaction to yield alcohol 12 with excellent enantioselectivity (98% ee). The subsequent bromination and azidation reactions enabled the formation of bromide 13 and azide 14. The newly formed hydroxyl and azide groups are modifiable sites. For instance, esterification with 2-picolinic acid led to ethano-TB derivative 15 with a potential coordination site for ligand design, and a “click reaction” with acetylene resulted in ethano-TB-triazole 16. On the other hand, late-stage functionalization can also be carried out on the benzene ring or double bond of propano-TB (Fig. 5B). For example, 5g can undergo a Heck coupling reaction with 4-vinylpyridine to produce conjugated alkene 17, and hydroboration–oxidation of 5a delivers alcohol 18. In addition, ethano-TB 3a can promote the enantioselective aziridination of chalcones, which demonstrates the potential of these configurationally stable ethano-TBs for asymmetric catalysis (Fig. 5C).²⁸

Fig. 5 Further transformations and downstream applications.

By incorporating an electron-donating amine moiety and an electron-accepting pyridine group, propano-TB derivative 17 exhibited an intramolecular charge transfer effect (Fig. 6).⁶⁵ As shown in Fig. 6, the UV-vis absorption and fluorescence emission spectra of compound (−)-17 were measured under various acidic conditions. Along with H⁺ addition, the original absorption band at 330 nm decreased and a new band around 410 nm increased gradually (Fig. 6A). The fluorescence measurements were carried out with an excitation wavelength of 375 nm. Similarly, with the addition of an acid, the original emission band at 470 nm disappeared, and a new band emerged at approximately 550 nm (Fig. 6B). A notable fluorescence colour change from blue to yellow was observed with increasing acidity. Furthermore, the circular dichroism (CD) spectra of (−)-17 as a function of pH are displayed in Fig. 6C. Upon increasing the amount of H⁺, the original absorption band at 275 nm decreased, whereas the new absorption band near 310 nm gradually increased. Such fluorescence emission and circularly polarized light absorption properties enable TB derivative 17 to serve as a highly sensitive probe for pH measurement in acidic regions through fluorometric and chiroptical changes.

Fig. 6 Switchable photophysical and chiroptical properties. (A) UV/Vis absorption spectra, ε, molar extinction coefficient, (B) fluorescence spectra, and (C) circular dichroism (CD) spectra, Δε, molar circular dichroism. (−)-17 + TFA (× eq.) in MeOH at 25 °C, 2 × 10⁻⁵ M.

Conclusions

In conclusion, we constructed two N-stereogenic centers in ethano- and propano-Tröger's bases via a Pd-catalyzed asymmetric annulative allylic alkylation reaction. Control and stepwise experiments prove that the reaction cascade of tetrahydrodibenzodiazocines with butene dicarbonates or isobutylene dicarbonates proceeds via two tandem Pd-catalyzed N-allylic alkylation reactions and that the two N-stereogenic centers are simultaneously established during intramolecular bridge formation. A wide range of N-chiral ethano- and propano-TBs have been readily prepared in good yields with excellent enantioselectivities. The diversified late-manipulation of these bridged bicyclic products demonstrates their utility in organic synthesis. Furthermore, the synthesized ethano-TB can be used downstream as an organo-catalyst for the aziridination reaction, and the H⁺-induced fluorescence emission and circularly polarized light absorption responses of a propano-TB derivative enable it to work as a fluorescent/chiroptical probe for pH measurement in acidic regions. Along this line, further investigations on the construction of N-stereogenic centers are ongoing in our laboratory and will be reported in due course.

Author contributions

C.-Y. G., T. L., Y. L., C.-H. L., and X. X. performed and analyzed the experiments. G.-J. M. conceived and designed the project. G.-J. M. overall supervised the project. All authors prepared this manuscript.

Conflicts of interest

We have filed a patent application related to this work (application no. CN119350350A, filed on January 24, 2025). The patent is currently under review and has not yet been granted. The authors declare no other competing interests.

Data availability

CCDC 2390173 (3r′) and 2446125 (5a) contain the supplementary crystallographic data for this paper.^66a,b

The authors declare that the data relating to the characterization of products, experimental protocols and the computational studies are available within the article and its supplementary information (SI). Supplementary information: original NMR spectra of products 3–21. See DOI: https://doi.org/10.1039/d5sc05846e.

Acknowledgements

The authors acknowledge the financial support from the National Natural Science Foundation of China (22371265 and 22208302), Natural Science Foundation of Henan Province (232301420047), and the project of State Key Laboratory of Green Pesticide, Guizhou Medical University (GPLKF202507).

Notes and references

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