Citation

Chen Chen, Zhou Jin, Jiang Jing, Li Yang, Mao Ting, Peng Cheng, Zhan Gu, Huang Wei. Remote stereocontrol in the (4 + 2) cycloadditions of 1,7-zwitterions: Asymmetric synthesis of multifunctionalized tetrahydroquinoline derivatives[J]. Chin. Chem. Lett., 2024, 35(1): 108295  

Chen Chen, Jin Zhou, Jing Jiang, Yang Li, Ting Mao, Cheng Peng, Gu Zhan^*, Wei Huang^*     

As one of the most important simple nitrogen heterocycles, tetrahydroquinoline widely exists in numerous natural products and bioactive compounds, including pharmaceuticals [1–5]. The bioactive tetrahydroquinoline derivatives usually possess one or more stereocenters in their structures. Therefore, the past decade has seen the rapid development of synthetic strategies for constructing chiral tetrahydroquinolines [6–9]. For example, great progress has been made through asymmetric hydrogenations [10–17], Povarov reactions [18–22], (4 + 2) cycloadditions of 1,4-π-allyl metal complex [23–29], and aza-Michael/Michael cascade reactions [30–35]. Despite these advances, developing new strategies for the synthesis of novel tetrahydroquinolines in a highly efficient and stereoselective manner is still highly desired.

Recent decades have witnessed the development of the field of asymmetric catalysis, which has been involved in several Nobel Prizes. Researchers can often use chiral ligands, catalysts, and enzymes to achieve the stereoselective synthesis of target molecules. Nevertheless, the scope of stereochemistry recognition usually occurs near the chiral scaffold of a ligand or catalyst. Remote stereocontrol, which can surpass the limits of stereorecognition of remote prochiral (or chiral) centers, has long been a challenging object of great interest in asymmetric catalysis [36–40]. So far, only limited studies on controlling the stereoselectivity of the reaction site more than six bonds away from the chiral catalyst [41–44].

The Morita-Baylis-Hillman (MBH) carbonates have emerged as powerful synthons in constructing diverse chiral cyclic compounds [45–49]. In the typical activation model, under the catalysis of chiral Lewis base, the allylic ylides generate and participate in the cycloaddition reactions to afford (3 + n) or (1 + n) products (Scheme 1a) [50–61]. The stereochemistry of reactions initiated at the C1- or C3-position can be induced by the adjacent chiral backbone of the Lewis base [62–70]. Recently, the Huang group developed a novel o-amino aryl MBH carbonates, which introduces a nucleophilic N atom at the remote site of the electrophilic site. This synthon could serve as useful 1,4-dipole or 1,6-dipole, and unconventional (6 + 2) and (4 + 2) cycloadditions with isocyanate have been achieved by Huang and Li [71–75], providing benzodiazocine and 3,4-dihydroquinazolinone products (Scheme 1b). When a Lewis base catalyst was utilized in the reaction of these MBH carbonates, deprotonation of the amino group would form a 1,7-zwitterion intermediate. Thus, the remote stereocontrol in the cycloaddition reaction of this 1,7-zwitterion can be expected to be a highly challenging task (Scheme 1c). So far, the construction of a remote stereocenter distant from the chiral catalyst has yet to be attained.

Scheme 1

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Scheme 1. Cycloaddition reactions of MBH carbonates and challenges in remote stereocontrol of 1,7-zwitterions.

In this work, we propose a new methodology for the asymmetric cycloaddition of the 1,7-zwitterion (Scheme 1d). Exploration of chiral bifunctional Lewis base catalysts demonstrates that the secondary interaction of H-bonding is effective in transmitting stereochemical information [76–81]. Furthermore, excellent diastereoselectivity and enantioselectivity were achieved in the (4 + 2) cycloadditions with electron-deficient alkenes, affording chiral multifunctionalized tetrahydroquinoline derivatives [82–87].

We initiated the study by investigating the model reaction of MBH carbonate 1a with α-phenylidene pyrazolone 2a. The feasibility of the (4 + 2) cycloaddition reaction was studied by using different racemic Lewis base catalysts, including triphenylphosphine, 4-dimethyl aminopyridine (DMAP), and 1,4-diazabicyclo[2.2.2]octane (DABCO). Tetrahydroquinoline product 3a could be obtained in good yield with >20:1 dr (Table 1, entries 1–3). Next, we evaluated a series of chiral Lewis bases for asymmetric transformation. Chiral tertiary phosphine C1 and C2 are not effective catalysts, probably due to the steric hindrance. Connon's chiral PPY catalyst C3-C5 exhibited high activity, while the products delivered were almost racemic. Using Chen's PPY catalyst C6 with an additional shielding group on the prolinol only provided 3a with 57:43 er. Moderate enantioselectivity was also observed in the reaction with tertiary amine C7. Despite these negative results for the remote stereocontrol, to our gratification, we observed a significant stereorecognition in the reaction using β-ICD C8 as the catalyst (entry 11). This bifunctional catalyst derived from cinchona alkaloid could provide 3a in 65% yield with 88:12 er, indicating that properly distributed H-bonds in the transition state may play an essential role in conveying stereochemical information.

Table 1

Table 1 Effects of catalyst and solvent on the reaction.a

Table 1 Effects of catalyst and solvent on the reaction.a

Further screening of solvents uncovered toluene as the optimum reaction medium for the generation of 3a (entry 13, 89% yield, with >20:1 dr, and 95:5 er). The use of ether (THF) or polar solvent (acetonitrile) proved detrimental, resulting in a significant decrease in enantioselectivity (entries 14 and 15). Excellent enantioselectivity could be obtained by adding MgSO₄ or 4Å MS to the reaction. These results suggest that a trace amount of water in the system may affect the H-bonding between C8 and the substrate. C8 showed high catalytic efficiency and still gave high yields with excellent enantioselectivities at 10% and 5% catalyst loading. When the loading was reduced to 1%, the conversion still could afford 3a in 73% yield with a slightly decreased er. Finally, we identified the optimal conditions as listed in entry 19 (5 mol% of C8, toluene as the solvent, and 4Å MS as the additive at room temperature).

After establishing the simple yet highly effective catalytic system for the remote stereocontrol in the asymmetric cycloaddition of the 1,7-zwitterion, we next explored the substrate scope for the assembly of diverse chiral multifunctionalized tetrahydroquinolines. First, we evaluated the influence of the substituents on the α-phenylidene pyrazolone 2. As demonstrated by results summarized in Scheme 2, a range of R¹ and R² groups are well tolerated, and the stereocontrol of the cycloaddition is not strongly affected by their electronic properties (3a-3m). Electron-rich and electron-deficient aryl substituents afford the corresponding spiropyrazolone tetrahydroquinolines in high yields with excellent enantioselectivities (up to 99:1 er). The steric properties of R¹ and R² showed limited influence on the efficiency and stereoselectivity of the reaction. Similar good results could be obtained with ortho-substituted (3b), 2,4-disubstituted phenyl (3g), and 2-naphthyl (3h) groups. Notably, most cases observed excellent diastereoselectivities, indicating effective stereocontrol at the remote site.

Scheme 2

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Scheme 2. Substrate scope for the synthesis of multifunctionalized tetrahydroquinolines. Reactions conditions: 1 (0.1 mmol), 2 (0.1 mmol), C8 (5 mol%) in 1.0 mL of toluene for 12 h; isolated yield.

Then, the scope of MBH carbonate 1 was investigated. Various 1 bearing different substituents (halogen atom, methyl, or methoxyl group) at different positions of the phenyl ring were compatible in the reaction, providing 3o-3s in 83%-90% yields with good stereoselectivities. In addition, MBH carbonate derived from the ethyl acrylate afforded product 3t in 95% yield with 96:4 er. The N-Boc or N-COOMe-protected substrates gave similar good results (3u and 3v).

To further explore the scope of this strategy, we switch to other electron-deficient olefins under identical reaction conditions. The reaction of 1a with 2-benzoyl-phenylacrylonitrile smoothly delivered multifunctionalized tetrahydroquinoline 3aa in 97% yield with exclusive diastereoselectivity and good enantioselectivity. The product structure and absolute configuration of 3aa were identified by X-ray analysis. A series of substituted 2-cyano-enones were tested in the process. The reaction efficiency and stereoselectivity were not affected in all these cases (3ab-3ae). Moreover, isopropyl substituted 2w and 2-benzylidene-1H-indene-1,3(2H)-dione 4 proved to be a suitable substrate. The spirocyclic tetrahydroquinoline products 3w and 5 were obtained with good results (Scheme 3a). This further highlights the effective remote stereorecognition and broad scope of our strategy.

Scheme 3

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Scheme 3. Other substrates, scale-up synthesis and product derivations.

To demonstrate the practicability of this method, the highly efficient (4 + 2) cycloaddition reaction was performed on a mmol scale (Scheme 3b). Product 3a was produced as a pale-yellow crystalline powder in 90% yield without affecting the stereoselectivities (>20:1 dr, 98.5:1.5 er, Scheme 3b). The structure and absolute configuration of 3a were confirmed by X-ray crystallography analysis of (CCDC: 2211981). Remarkably, multifunctionalized tetrahydroquinoline products 3 containing three consecutive stereocenters could be readily transformed into various derivatives. For example, the ester group of acrylate moiety could be selectively hydrolyzed to afford acid 6 with high dr, and er value remained (Scheme 3c). The 1,3-dipolar cycloaddition of 3a with in situ generated azomethine imine smoothly produced derivative 7 in high yield as a single diastereoisomer. The N-Boc group could be facilely removed by treating 3u with trifluoroacetic acid (Scheme 3d).

Next, we investigated the reaction mechanism by performing a series of control experiments to elucidate the stereocontrol model. First, caesium carbonate, which could activate o-amino aryl MBH carbonate 1a as a Brønsted base, was tested in the reaction with 2a (Scheme 4a) [71]. Interestingly, no reaction occurred, suggesting that the reaction may not undergo a simple Brønsted base activation pathway. The Pd(0)/L1 complex is not an effective catalyst in the process, with only a trace product generated. To further probe the reaction pathway, we conducted a control experiment of 2a with 9 or 10. Under the standard conditions, C8 could not promote the reaction to afford the (4 + 2) products, indicating that product 3 was not formed via a Brønsted base-catalyzed aza-Michael addition-initiated cyclization. Thus, Lewis base-initiated 1,7-zwitterion cyclization is a more plausible pathway. We then monitored the reaction between C8 and 1a by HRMS analysis. The result indicated that adduct 11 (m/z: 572.2755) was formed via S_N2′ reaction. Besides key intermediate 11 and product 3a, the generation of intermediate 12 (m/z: 833.3811) could be detected in the three-component reaction of 1a, C8, and 2a. These experiments excluded a possible Brønsted base-catalyzed aza-Michael-S_N2 process and supported the Lewis base-catalyzed 1,7-zwitterion cyclization pathway well. Based on these results, a possible mechanism was proposed (Fig. 1a). Initially, the S_N2′ reaction of highly nucleophilic catalyst C8 with 1a afford adduct 11. Deprotonation of the allylic site generates 1,7-zwitterion A. The aza-Michael between 1,7-zwitterion A and 2a delivers intermediate B and forms the remote stereocenter. Subsequent intramolecular S_N2′ reaction leads to the formation of the product and release of C8.

Scheme 4

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Scheme 4. Mechanistic studies.

Figure 1

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Fig. 1. Plausible mechanism and effect of H-bonding.

Guided by this mechanism, we analyzed the possible transition state for the aza-Michael step, which is crucial for the challenging stereorecognition of the remote prochiral center. To illustrate the possible effect of H-bonding, we tested the reaction using C9 with hydroxyl group methylated. In sharp contrast with the result using C8 (94% yield, >20:1 dr, 97.5:2.5 er), the enantioselectivity of 3a significantly decreased (62.5:37.5 er), indicating that the H-bonding between bifunctional C8 and the substrate is the key for long-range stereocontrol (Fig. 1b). In addition, the reaction of 1a with 2-benzylidene malononitrile gave product 3af with good yield with poor er value (57:43 er), which may result from the non-selective H-bond between each cyano group acceptor with -OH group of C8. Taking the reaction with 2a as an example, we proposed the possible transition state (Fig. 2). In the favored TS, the H-bond between the extended quinoline 6-OH group of C8 and carbonyl O-atom of 2a guides 1,7-zwitterion A to approach from the Si-face of 2a. The aza-Michael addition forms an (S)-stereocenter, finally providing 3a with high diastereoselectivity through the induction of adjacent chiral centers. In the disfavored TS, 1,7-zwitterion A attacked alkene 2a from the Re-face, while steric repulsion between the N-phenyl group of pyrazolone and the cinchona alkaloid scaffold will obviously raise the energy barrier of the aza-Michael step.

Figure 2

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Fig. 2. Possible transition states for remote stereocontrol of 1,7-zwitterion.

In summary, we first realized the challenging remote stereocontrol of 1,7-zwitterion intermediates formed from Huang's o-amino aryl MBH carbonates. With simple and easily accessible β-ICD as the bifunctional catalyst, multifunctionalized tetrahydroquinoline derivatives could be synthesized with excellent enantioselectivity and diastereoselectivity under very mild conditions. The strategy possesses broad substrate scope, and three types of electron-deficient enones are successfully applied under identical conditions. Mechanistic studies disclosed the Lewis base-catalyzed reaction pathway, and H-bonding between the catalyst and enones proves to be crucial for long-range stereocontrol. Moreover, the scale-up reaction and transformations of the multifunctionalized tetrahydroquinoline products demonstrated the potential of this strategy.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

We are grateful for financial support from the National Natural Science Foundation of China (Nos. 82073997 and 22001024), the Science & Technology Department of Sichuan Province (Nos. 2021YFS0044 and 2021YJ0402), Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (No. ZYYCXTD-D-202209), Xinglin Scholar Research Promotion Project of Chengdu University of TCM.