Catalytic stereodivergent and simultaneous construction of axial and point chirality

Abstract

Atropisomers possessing additional stereogenic centres have found wide applications in various fields; however, the development of catalytic asymmetric reactions for their preparation through a single transformation has been much less studied. In particular, no example of catalytic diastereodivergent and enantioselective simultaneous construction of axial and point chirality has been disclosed, which stands for an unmet synthetic challenge. Herein, we report the realization of such a goal for the first time. An unprecedented silver-catalyzed desymmetric [3 + 2] cycloaddition reaction of N-quinazolinone maleimides with isocyanoacetates was developed, producing a series of bicyclic N-heterocycles bearing a remote chiral N–N axis and three contiguous stereogenic carbon centres with high efficiencies and high-to-excellent stereoselectivities. Most strikingly, an interesting diastereodivergent synthesis was also achieved allowing facile access to both endo- and exo-cycloadducts. DFT calculations revealed that the stereoselectivity is mainly controlled by the coordination type of the ligand, ligand–substrate non-bonding interaction, and distortion of the annulation transition state.

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Introduction

Owing to the profound applications of atropisomers,^1–3 developing effective approaches for their preparation concerning structural complexity and diversity has attracted great attention from the chemical science community over the past few decades.⁴ Along these lines, incorporating a second chiral element into atropisomers would certainly enrich their topological chemical space and thus open up opportunities to discover new chemical entities with distinct application potential.⁵ In particular, atropisomers featuring additional stereogenic centres have found widespread applications as bioactive molecules in drug discovery or as chiral organocatalysts/ligands in asymmetric catalysis (Scheme 1a).⁶ Therefore, the implementation of efficient strategies to access such scaffolds is in high demand and has become an emerging research topic.

Scheme 1 Background and project synopsis.

However, compared to the extensive studies on the synthesis of conventional atropisomers bearing a sole stereogenic axis (scenario I, Scheme 1b), the development of catalytic asymmetric reactions towards the synchronous control of axial and point chirality in one step has been much less studied and stands for a daunting task (scenario II).^7,8 In this context, both issues of diastereo- and enantioselectivity need to be addressed properly to prevent the generation of a complex mixture of stereoisomers. Furthermore, it would be ideal and extremely desirable to establish catalyst-controlled diastereodivergent processes^9,10 that allow access to different diastereomers from identical starting materials (scenario III), since individual diastereomers may exhibit significantly distinct biological activities against the same target.¹¹ For example, (S)-atropisomer A was found to be 200-fold more potent than its corresponding (R)-epimer A′ as APJ receptor agonists.^6b Nevertheless, achieving such a goal is much more difficult. Generally, generating one of the possible diastereomers is inherently preferred through substrate control, while the selective formation of other diastereomers requires overriding the natural diastereoselective bias.¹² In this regard, to the best of our knowledge, no example of the catalytic diastereodivergent and enantioselective simultaneous creation of both axial and point chirality in a single step has been disclosed so far and remains an unmet synthetic challenge.

In alignment with our continuous interest in isocyanide chemistry,^8d,g,13,14 especially inspired by our previous work on the simultaneous construction of C–N axial and point chirality (Scheme 1c),^8d we report herein the development of an unprecedented silver-catalyzed desymmetrization reaction¹⁵ of newly designed prochiral N-quinazolinone maleimides¹⁶ with isocyanoacetates. This reaction delivers a wide range of highly functionalized 5,5-fused bicyclic N-heterocycles possessing a remote chiral N–N axis and three contiguous stereogenic carbon centres in high yields with high-to-excellent stereoselectivities (Scheme 1d). Most importantly, intriguing ligand-induced diastereodivergence was also achieved: while the phosphine-squaramide bifunctional ligand L3 resulted in the formation of endo-selective [3 + 2] cycloadducts, employing Trost ligand L9 led to a complete reversal to the exo-cycloadducts, realizing the first example of the diastereodivergent synthesis of atropisomers bearing both axial and point chirality via a single transformation. In addition, the use of either ent-L3 or ent-L9 allowed facile access to the corresponding opposite enantiomers, respectively. Moreover, DFT calculations were performed to elucidate the origin of such stereoselectivity.

Results and discussion

To initiate our study, the easily accessible prochiral N-quinazolinone maleimide 1a was prepared and applied in the reaction with isocyanoacetate 2a for the optimization of reaction conditions (Table 1). The structure of 1a was unambiguously determined by X-ray diffraction analysis. A panel of chiral phosphine ligands was tested in combination with 5 mol% Ag₂CO₃ as the catalyst for this model reaction. In general, 1,2-diamine-derived bifunctional ligands bearing a hydrogen-bond donor moiety¹⁷ such as urea (L1 and L5), thiourea (L2), and squaramide (L3 and L4) all generated the endo-selective [3 + 2] cycloadduct 3aa as the major product (entries 1–5). Among them, L3 proved superior to all others leading to a highly efficient synthesis of 3aa (entry 3, >20 : 1 dr, 91% yield, and 98% ee). In comparison, the use of both Dixon-type ligands (L6 and L7)¹⁸ and Trost ligands (L8 and L9) led to a reversal in the diastereoselectivity, affording the exo-selective [3 + 2] cycloadduct 4aa as the major product (entries 6–9). In particular, L9 resulted in the formation of 4aa with >20 : 1 dr, 80% yield, and 95% ee (entry 9). This observation adds a new entry to the intriguing ligand-induced diastereodivergent reactions.⁹ Notably, this is the first time to report that Trost ligands could be successfully employed in catalytic asymmetric reactions of isocyanoacetates,^13c thus expanding the choice of chiral ligands in this field. With the optimal ligands being identified, further evaluation of other parameters such as metal salts and solvents was carried out; however, it did not lead to better results (see the ESI† for details). The use of Ag₂CO₃ alone led to an obvious decrease in both efficiency and diastereoselectivity (entry 10, 2 : 1 dr, 22% yield), while no reaction took place without Ag₂CO₃ (entries 11 and 12). These results indicated that: (1) Ag₂CO₃ is indispensable for the reaction; (2) L3/L9 is crucial for tuning diastereoselectivity as well as enhancing reactivity. It is noteworthy that all reactions were conducted under an ambient atmosphere without the requirement to exclude air or moisture.

Table 1 Identification of the ligand-induced diastereodivergent reaction profile^a

Entry	Ligand	dr^b (3aa : 4aa)	Yield^c (%)	ee of 3aa^e (%)	ee of 4aa^e (%)
a Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), Ag2CO3 (5 mol%), and ligand (10 mol%) in 1.0 mL DCE at 25 °C for 12 h. b Determined by crude ^1H NMR. c Isolated yield in pure form. d Combined yield. e Determined by chiral HPLC. f Without Ag2CO3.
1	L1	9 : 1	43	94	—
2	L2	6 : 1	38^d	82	—
3	L3	>20 : 1	91	98	—
4	L4	4 : 1	82^d	92	—
5	L5	>20 : 1	75	84	—
6	L6	1 : 13	52	—	36
7	L7	1 : 17	49	—	39
8	L8	1 : >20	50	—	80
9	L9	1 : >20	80	—	95
10	—	2 : 1	22^d	—	—
11^f	L3	—	<5	—	—
12^f	L9	—	<5	—	—

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After establishing the optimal conditions, we first explored the scope of the Ag/L3-catalyzed endo-selective [3 + 2] cycloaddition reaction (Scheme 2). Of note, high-to-excellent diastereoselectivities (10 : 1 to >20 : 1) and uniformly excellent enantioselectivities (≥94%) were obtained. The generality of N-quinazolinone maleimides was evaluated with 2a as the model isocyanoacetate substrate. ortho-tert-Butyl-substituted N-quinazolinone maleimides possessing an electron-donating (Me and OMe) or withdrawing group (F, Cl, Br, I, and CF₃) at different positions of the quinazolinone skeleton proved to be well tolerated, affording the desired products 3ba–3ma with uniformly excellent stereoselectivities (16 : 1–>20 : 1 dr and 97%–>99% ee). In addition, the tert-butyl substituent at the ortho position could be replaced by other alkyl groups, such as isopropyl, cyclohexyl, and benzyl, giving the corresponding 3na–3pa in good-to-high yields with excellent diastereo- and enantioselectivities. Moreover, N-quinazolinone maleimides bearing an ortho-aryl (3qa–3va) or a heteroaryl (3wa) substituent turned out to be compatible substrates as well, undergoing smooth reactions with 2a under the standard conditions, further expanding the substrate scope as well as highlighting the versatility of this catalytic system.

Scheme 2 Endo-selective [3 + 2] cycloaddition of N-quinazolinone maleimides with isocyanoacetates. Reaction conditions: 1 (0.1 mmol), 2 (0.1 mmol), Ag₂CO₃ (5 mol%), and L3 (10 mol%) in 1.0 mL DCE at 25 °C for 12 h.

The scope of isocyanoacetates was also examined under the standard conditions with 1a as the model maleimide substrate. To our delight, the introduction of different substituents (OMe, Cl, and Me) into the phenyl ring did not affect the stereoselectivity too much (3ab–3aevs.3aa). Besides, naphthyl-substituted isocyanoacetate was also applicable, delivering the desired product 3af with >20 : 1 dr, 84% yield, and 99% ee. The relative and absolute configurations of 3pa were unambiguously determined by X-ray diffraction analysis, and those of other products were assigned by analogy.

To further expand the scope of the Ag/L3 catalytic system, the reaction of N-indole maleimide 5a with 2a was tested under the same set of conditions (Scheme 3). Gratifyingly, the desired endo-cycloadduct 6a was obtained with >20 : 1 dr, 93% yield, and 99% ee. Access to the opposite enantiomer ent-6a was also achieved by simply replacing L3 with ent-L3. Encouraged by these exciting results, we moved forward to examine the scope of N-indole maleimides. As shown, the incorporation of various substituents at different positions on the indole ring did not affect the result obviously, affording 6b–6e with uniformly excellent stereoselectivities (>20 : 1 dr and >99% ee for all cases). Replacing the ortho ester group with amide was tolerated as well to generate 6f with >20 : 1 dr, 72% yield, and 90% ee. In addition, enantiopure N-indole maleimides derived from complex bioactive molecules (L-Menthol, 5g; L-Borneol, 5h) underwent reactions smoothly with 2a under the standard conditions, delivering 6g and 6i in 91% and 95% yields, respectively, with uniformly excellent diastereoselectivities (>20 : 1 dr for both cases). On the other hand, the reaction of 5g and 5h with 2a conducted with ent-L3 instead of L3 resulted in the synthesis of opposite diastereomers 6h and 6j with comparable yields and diastereoselectivities. These experimental results suggested a mechanism involving catalyst control rather than substrate control when using enantiomerically pure substrates. The relative and absolute configurations of 6a were unambiguously determined by X-ray diffraction analysis, and those of other products were assigned by analogy.

Scheme 3 Endo-selective [3 + 2] cycloaddition of N-indole maleimides with 2a. Reaction conditions: 5 (0.1 mmol), 2a (0.1 mmol), Ag₂CO₃ (5 mol%), and L3 (10 mol%) in 1.0 mL DCE at 25 °C for 12 h. ^a With ent-L3.

Next, the scope of the Ag/L9-catalyzed exo-selective [3 + 2] cycloaddition reaction was evaluated. As shown in Scheme 4, a wide range of ortho-tert-butyl-substituted N-quinazolinone maleimides with diverse substitution patterns underwent the reactions smoothly with 2a to give the corresponding exo-cycloadducts 4ba–4na in good yields (56%–78%) with uniformly excellent diastereo- and enantioselectivities (>20 : 1 dr for all cases, 90%–98% ee). However, different from the Ag/L3 catalytic system, an undesired ortho-substituent effect was discovered. Changing the tert-butyl group to less steric substituents, such as isopropyl or phenyl, all led to complex mixtures. In comparison, the scope of isocyanoacetates proved to be broad. The presence of substituents with different electronic properties (OMe, Cl, and Me) at diverse positions (para, meta, and ortho) on the isocyanoacetate structure had little influence on the stereocontrol, delivering 4ab–4ae with >20 : 1 dr and 90%–95% ee. Other than benzyl-substituted isocyanoacetates, the use of 2g bearing a methyl substitute afforded the desired product 4af with >20 : 1 dr and 51% yield, albeit with a moderate 71% ee.

Scheme 4 Exo-selective [3 + 2] cycloaddition of N-quinazolinone maleimides with isocyanoacetates. Reaction conditions: 1 (0.1 mmol), 2 (0.1 mmol), Ag₂CO₃ (5 mol%), and L9 (10 mol%) in 1.0 mL DCE at 25 °C for 12 h.

Considering that our products represent a new member of N–N atropisomers,¹⁹ the stereochemical stability regarding the chiral N–N axis was evaluated by performing thermal epimerization experiments. Specifically, structurally different compounds 3aa, 3pa, 3qa, 4aa, and 6a were selected as representative compounds and were heated in DMSO-d₆ at 100 or 80 °C for 12 h, respectively, and epimerization was monitored by ¹H NMR (see the ESI† for details). Gratifyingly, all these compounds belong/near to class 3 atropisomers according to the LaPlante classification system,^1b which is beneficial for further synthetic transformations and applications. As shown, no corresponding epimer generated by the rotation of the N–N bond was detected for 3aa, 3pa, and 4aa (Fig. 1). In comparison, relatively lower stability was observed for 3qa and 6a, with rotation barriers determined to be 30.7 and 28.7 kcal mol⁻¹, respectively.²⁰

Fig. 1 Evaluating the stability of N–N axial chirality.

To illustrate the stereodivergence of this study, we performed the reaction between 1a and 2a in the presence of catalytic Ag₂CO₃ with four different chiral ligands: L3, ent-L3, L9, and ent-L9 (Scheme 5a). In this way, we were able to obtain four stereoisomers 3aa, ent-3aa, 4aa, and ent-4aa, respectively, in uniformly high yields with excellent stereoselectivities. In addition, gram-scale syntheses of 3aa, 4aa, and 6g were achieved with comparable efficiencies and stereoselectivities without any variation of the standard conditions (Scheme 5b), demonstrating the practicality and robustness of our method. Moreover, the existence of an imine functionality in our products laid the roots for further synthetic transformations. For example, upon treatment with NaBH₃CN, 4aa could be facilely reduced to the corresponding pyrrolidine 7 in 84% yield (Scheme 5c). The relative and absolute configurations of 7 were unambiguously determined by X-ray diffraction analysis, and those of other products were assigned by analogy. Alternatively, the nucleophilic addition of indole to 4aa took place smoothly with the use of AgBF₄, generating 8 in an almost quantitative yield with exclusive diastereoselectivity. The absolute configuration of the newly generated stereogenic centre in 8 was determined by NOE analysis (see the ESI† for details).

Scheme 5 Synthetic applications.

To elucidate the mechanism and stereoselectivity of the silver-catalyzed [3 + 2] cycloaddition reaction, DFT calculations were performed. Fig. 2a illustrates the proposed mechanism for the asymmetric [3 + 2] cycloaddition between N-quinazolinone maleimide 1a and isocyanoacetate 2a catalyzed by silver complexes with ligands L3 and L9. Deprotonation of 2a coordinated to a ligand-Ag₂CO₃ complex forms the metal-substrate complex L3/L9-Int1, which is set as a relative zero point in our calculated free energy profiles. A concerted [3 + 2] cycloaddition then occurs between metal-bound 2a and 1a through the transition state L3/L9-TS2, giving intermediate L3-Int3-A and L9-Int3-B exothermically by 13.1/10.1 kcal mol⁻¹. Finally, the protonation of L3/L9-Int3 yields products 3aa/4aa. This cycloaddition step is critical as it determines axial and point chirality as well as diastereoselectivity.

Fig. 2 Mechanistic study based on DFT calculations. (a) Proposed divergent reaction pathways for the cycloaddition of 1a with 2a. (b) Geometrical structures of cycloaddition transition states. (c) Dihedral information of L3-int1, L3-TS2-A, and L3-TS2-B. (d) Front molecular orbital analysis and bond angle information of L9-TS2-A and L9-TS2-B.

Thus, we further analysed the cycloaddition transition states L3/L9-TS2 (Fig. 2b). When squaramide L3 is employed as the chiral ligand, 1a can approach 2a by either the upper (L3-TS2-A) or lower (L3-TS2-B) side in the cycloaddition step. In the favoured transition state L3-TS2-A, both N–H bonds in the squaramide moiety can form intermolecular hydrogen bonds with carbonyls in 1a. However, in the disfavoured transition state L3-TS2-B, only one intermolecular hydrogen bond can be formed. In addition, a larger distortion is detected in L3-TS2-B: the dihedral angle of N–C–C–N in the diaminocyclohexane moiety is 51.0°, considerably deviating from the value in L3-Int1 (61.2°), indicating a large twist of the squaramide ligand (Fig. 2c). In contrast, the dihedral angle value in the favoured transition state L3-TS2-A is 58.5°, close to the value in L3-Int1, indicating a definitely smaller twist. The extra hydrogen bond and smaller twist in L3-TS2-A provide a relative free energy of 4.2 kcal mol⁻¹ lower than L3-TS2-B, leading to the major product 3aa. On the other hand, the Trost ligand L9 has two phosphine atoms, and therefore it is capable of serving as a bidentate ligand and binds silver and 1a in a T-shaped configuration. We found that stereoselectivity is mainly attributed to the distortion: the bond angle of N–C–Ag in L9-TS2-A is 143.0°, considerably deviating from the linear structure, indicating a large distortion (Fig. 2d). In addition, the molecular orbital analysis showed an insufficient orbital overlap between 1a and the Ag centre in HOMO−3. In contrast, the bond angle of N–C–Ag in L9-TS2-B is 165.7°, indicating a smaller distortion; meanwhile, the molecular orbital analysis showed a better overlap in HOMO−3. As a result, the calculated relative free energy of L9-TS2-B is 2.2 kcal mol⁻¹ lower than L9-TS2-A, favouring the formation of 4aa.

Conclusions

In conclusion, we have developed an unprecedented desymmetric [3 + 2] cycloaddition reaction of prochiral N-quinazolinone maleimides with isocyanoacetates. Under silver catalysis, a broad range of structurally novel and complex N–N atropisomers containing additional three contiguous stereogenic carbon centres were obtained in good yields with high-to-excellent diastereo- and enantioselectivities. Of particular note, by simply switching the chiral ligand (L3/L9), both endo- and exo-cycloadducts were generated. DFT calculations revealed that L3 and L9 act in different ways. Squaramide L3 acts as a monodentate ligand, and the stronger ligand–substrate non-bonding interaction and smaller distortion of the ligand in the annulation step lead to the generation of endo-selective cycloadducts. Trost ligand L9 acts as a bidentate ligand, and the smaller distortion of isocyanoacetate–Ag coordination together with better Ag–C σ-orbital overlap contributes to the generation of exo-selective [3 + 2] cycloadducts. The success of this study not only represents the first example of the catalytic stereodivergent and simultaneous construction of axial and point chirality but also inspires the design of other useful stereodivergent processes.

Author contributions

L. Q. and J.-Y. L. designed the project. W.-T. W., S. Z., Z.-H. L., D. H., and F. H. carried out the experiments and analysed the data. W. L., R. B., and Y. L. performed the computational study. W.-T. W., S. Z., and W. L. contributed equally to this work. J.-Y. L. directed the project and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Data availability

Experimental details and characterization data for all new compounds in this article are available in the ESI.† Crystallographic data for compounds 1a, 3pa, 6a, and 7 have been deposited in the Cambridge Crystallographic Data Centre (CCDC) under accession numbers CCDC 2261237, 2261239, 2261241, and 2261240, respectively.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We acknowledge financial support from the National Natural Science Foundation of China (82273887 and 22271034), the Joint Funds of the Zhejiang Provincial Natural Science Foundation of China (LTZ22B020001), and Zhejiang University. We also thank Mr Jiyong Liu (Chemistry Instrumentation Center, Zhejiang University) for X-ray crystallographic analysis and Mr Jiadong Xue (Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University) for performing NMR spectroscopy for structure elucidation.

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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures, characterization of all new compounds, and crystallographic data of 1a, 3pa, 6a, and 7. CCDC 2261237 and 2261239–2261241. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo00294f

‡ These authors contributed equally.

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