Mechanisms and regio- and stereoselectivities in NHC-catalyzed [3+3] annulations for the synthesis of axially and centrally chiral dihydropyridinones

Abstract

Organocatalytic annulation strategies serve as an ideal approach for constructing molecules integrating both axial and central chirality, yet theoretical studies on the origin of stereoselectivity remain insufficient. In this study, the NHC-catalyzed [3+3] annulation between cinnamaldehyde and 2-aminomaleate was systematically investigated through density functional theory (DFT) calculations. The catalytic cycle involves eight key steps: nucleophilic addition, 1,2-proton transfer, oxidation, Michael addition, protonation, deprotonation, ring closure, and catalyst dissociation. Deprotonation is identified as the rate-determining step, with an overall energy barrier of 19.7 kcal mol⁻¹. The Michael addition step is the stereoselectivity-controlling step that preferentially generates the R-configuration product, consistent with the experimental results. The calculated enantiomeric excess value of 89.3% aligns well with experimental observations (90% ee). Noncovalent interaction (NCI) analysis revealed that the stability of the key stereoselective transition state can be traced to LP⋯π, C–H⋯O and C–H⋯N interactions. The mechanistic insights should be helpful for understanding the origins of stereoselectivity in NHC-catalyzed atroposelective annulations.

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1. Introduction

Chirality is a fundamental property of nature¹ and includes various forms such as central chirality, axial chirality, and face chirality. One of the most cutting-edge fields in organic synthesis is the enantioselective synthesis of chiral compounds by asymmetric catalysis.² Especially in the last decade, a class of axially chiral molecules have been synthesized using asymmetric catalytic strategies that can serve as important structural units for drugs, chiral materials and bioactive molecules.^3–8 Among them, atropisomers combining both axial and central chirality can serve as fundamental scaffolds for organocatalysts and chiral ligands in asymmetric synthetic reactions, thus attracting increasing attention.^9–14 Previous studies showed that organocatalysts or ligands integrating central and axial chirality can significantly enhance chiral transfer in diverse enantioselective transformations.^15–18 Therefore, the synthesis of atropisomers bearing central and axial chiral elements is of great importance.

As a highly efficient and environmentally benign organocatalyst, N-heterocyclic carbene (NHC) exhibits unique activation modes and provides diverse asymmetric synthetic pathways for constructing chiral molecules.^19–23NHC-catalyzed annulation/addition reactions, kinetic resolution (KR) and desymmetrization are practical methods for constructing atropisomers.^24–29 It is worth noting that the lower stability of the C–N axis renders the construction of atropisomers around this bond particularly challenging.^30–34 Most reported NHC-catalyzed strategies predominantly construct axial chirality alone, with only a few examples achieving construction of C–N axial chirality with central chirality simultaneously. In this context, theoretical investigations to elucidate detailed reaction mechanisms become critically important for developing novel, efficient, and sustainable methods to synthesize atropisomers concurrently bearing both axial and point chirality. Recently, Qi's group³⁵ reported the NHC-catalyzed [3+3] annulation reaction between cinnamaldehyde and 2-aminomaleate, which afforded dihydropyridinones bearing both axial and central chirality with high yield (74%) and stereoselectivity (90%). Scheme 1 shows the details of the experiment.

Scheme 1 Reaction model of cinnamaldehyde and 2-aminomaleate.

In recent years, numerous computational studies have been reported to investigate NHC-catalyzed asymmetric synthesis reactions for understanding their detailed mechanism.^36–42 However, the reaction developed by Qi's group has not yet been theoretically investigated, and several critical questions remain unresolved: (1) what is the catalytic mechanism of this reaction? (2) What are the key factors controlling stereoselectivity? (3) Four potential mechanisms for oxidation were proposed: hybrid transfer to the oxygen/carbon (HTO/HTC),^43–46 single electron transfer followed by hydrogen atom transfer (SET-HAT)^47–50 and hydrogen atom transfer followed by single electron transfer (HAT-SET).^51–54 Which one is more preferred? (4) What factors are responsible for maintaining axial chirality? In this work, we used density functional theory (DFT) computations to examine the catalytic reaction in order to answer these fundamental problems.

2. Computational details

All calculations in this study are based on density functional theory (DFT) and have been performed using the Gaussian16 program (Revision A03).⁵⁵ Density functional theory has shown excellent performance in reactions such as transition metal catalysis^56–62 and organocatalysis.^63–69 Geometry optimization of reactants, transition states, intermediates and products was carried out using the M06-2X functional⁷⁰ with the 6-31G(d,p) basis set. The M06-2X functional has been employed in many previous theoretical studies of NHC-catalyzed reactions^71–74 owing to its good performance in describing thermodynamics, kinetics and noncovalent interactions. The mixed solvents (CH₃CN : THF = 3 : 1) were simulated using the IEF-PCM^75,76 implicit solvation model. In this model, the mixed solvent is treated as a continuous medium, characterized by the dielectric constant (ε = 28.622 and ε_∞ = 1.847), which embeds a molecular-shape cavity containing the solute. Frequency analyses were subsequently conducted at the same level to confirm the nature of stationary points: minima (reactants, intermediates, and products) showed no imaginary frequencies, while transition states exhibited one imaginary frequency. Afterward, intrinsic reaction coordinate (IRC)^77,78 calculations were performed to verify the connectivity between each transition state and its associated reactants/products. For more accurate energy evaluations, single point energy calculations were carried out using the M06-2X-D3 functional with the 6-311++G(2df,2dp) basis set and the IEF-PCM implicit solvation model. To validate the computational level, alternative DFT methods (ωB97X-D⁷⁹ and B3LYP-D3⁸⁰), basis sets (6-311++G(d,p) and 6-31G(d,p)), and solvation models (IEF-PCM and SMD⁸¹) were tested for the stereoselectivity-controlling step, with detailed discussions provided in Tables S1 and S2, SI. Analysis of the noncovalent interaction (NCI)⁸² was conducted using Multiwfn software^83,84 to elucidate the origins of stereoselectivity. Optimized geometries were visualized using CYLView.⁸⁵ SambVca⁸⁶ was employed to calculate the buried volume and generate topographic steric maps of the products.

3. Results and discussion

3.1. Reaction mechanism

Based on the experimental results of Qi's group³⁵ and our DFT computations, we proposed a mechanism for the NHC-catalyzed oxidative [3+3] annulation reaction involving cinnamaldehyde and 2-aminomaleate. The key steps of the catalytic cycle are described in Scheme 2. The precatalyst Pre-NHC undergoes deprotonation using base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to generate the actual catalyst NHC and DBU·H⁺ (see Fig. S1, SI). Additionally, Pre-R2 undergoes deprotonation to yield R2 (see Fig. S2, SI). The catalytic cycle consists of the following eight steps: (1) nucleophilic attack of NHC to R1 to generate intermediate M1, (2) the 1,2-proton transfer process to form the Breslow intermediate M2, (3) the oxidation process to produce intermediate M3, (4) addition of M3 to R2 to produce intermediate M4, (5) protonation of M4 to produce intermediate M5, (6) deprotonation to produce intermediate M6, (7) ring-closure to form intermediate M7, and (8) dissociation of NHC from the final product P. In the subsequent section, we will present the mechanism in terms of eight steps.

Scheme 2 The possible catalytic cycle for [3+3] cyclization.

3.1.1. First step: nucleophilic addition. In this step, the attack of the C1 atom of NHC on the re/si-face of the C2 atom of R1 results in the formation of the intermediate re/si-M1 (Scheme 2). The calculated energy barrier of 12.3/12.8 kcal mol⁻¹ for re/si-TS1 indicates that the nucleophilic addition is feasible under the experimental conditions (Fig. 1). By comparison, we found that the energy barrier difference between re-TS1 and si-TS1 is within the error margin of the computational method used, and re-M1 (6.2 kcal mol⁻¹) and si-M1 (6.3 kcal mol⁻¹) exhibit similar stability. Therefore, we considered both transformation pathways. The C1–C2 bond is reduced from 2.03/2.04 Å in re/si-TS1 to 1.54/1.54 Å in re/si-M1, as shown in Fig. 2 and Fig. S3, indicating the complete complexation between the catalyst and the reactant.

Fig. 1 Free energy profiles (kcal mol⁻¹) of the catalytic cycle.

Fig. 2 Optimized geometries of intermediates and transition states (distance in Å).

3.1.2. Second step: 1,2-proton transfer. The 1,2-proton transfer of M1 leads to the formation of the Breslow intermediate M2, wherein proton H3 migrates from the C2 atom to the O4 atom. As illustrated in Scheme 3, three possible mechanisms were examined to identify the most plausible pathway. Computational results revealed that the direct proton transfer process exhibits a high energy barrier of 40.0/42.2 kcal mol⁻¹ (re/si-TS2D, Fig. S4, SI), rendering this pathway unlikely. This result aligns with previous studies that direct proton transfer involves a high barrier.^36,41,42 Further investigation focused on the proton transfer assisted by DBU. The presence of a DBU molecule significantly reduced the energy barrier to 17.7/17.7 kcal mol⁻¹ (re/si-TS2B, Fig. S4, SI). Additionally, the energy barriers were further reduced with the introduction of DBU·H⁺ as a mediator, reaching 13.0 and 18.4 kcal mol⁻¹viare-TS2 and si-TS2, respectively (Fig. 1).

Scheme 3 Possible mechanism for M1 → M2 conversion (energies in kcal mol⁻¹).

In summary, under the assistance of DBU·H⁺, the pathway of generating intermediate re-M2 through 1, 2-proton transfer has a significantly lower energy barrier and is the most feasible reaction pathway. This result is consistent with previous studies that protic mediators play crucial roles in proton transfer.^38–42 Alternative [1,2]-proton transfer mechanisms can thus be excluded.

3.1.3. Third step: oxidation. In the third step of the catalytic cycle, the Breslow intermediate re-M2 undergoes a hydride transfer to oxygen (HTO) process. As illustrated in Fig. 1, the transfer of hydride H5 from M2 to 3,3′,5,5′-tetra-tert-butyldiphenoquinone (DQ) generates intermediate M3via the transition state TS3. This step requires overcoming a remarkably low energy barrier of 1.7 kcal mol⁻¹via the transition state TS3, yielding intermediate M3 with a relative energy of −20.1 kcal mol⁻¹. Fig. 2 demonstrates the formation of the O1′–H5 bond, as evidenced by the shortening of its bond length from 1.25 Å in the transition state TS3 to 0.96 Å in intermediate M3. Additionally, three other possible mechanisms including the hydride transfer to carbon pathway (HTC), the single electron transfer-hydrogen atom transfer pathway (SET-HAT), and the hydrogen atom transfer-single electron transfer pathway (HAT-SET) were evaluated. As shown in Schemes S1 and S2, SI, all these pathways required overcoming relatively higher energy barriers compared to the HTO pathway and were thus excluded from further consideration. These results are consistent with previous studies showing that the HTO pathway is the most feasible pathway for oxidation.^87,88

3.1.4. Fourth step: addition of M3 to R2. In the Michael addition step, the re/si face of reactant R2 can react with the re/si face of intermediate M3, leading to the formation of four stereoisomeric transition states (Fig. 3). As shown in Fig. 1, after passing through the transition states TS4(RR) (5.4 kcal mol⁻¹), TS4(RS) (11.6 kcal mol⁻¹), TS4(SR) (5.1 kcal mol⁻¹), and TS4(SS) (3.7 kcal mol⁻¹), the intermediates M4(RR), M4(RS), M4(SR), and M4(SS) were formed with relative energies of −29.1, −26.2, −30.4, and −30.9 kcal mol⁻¹, respectively. Notably, conformational analysis of TS4 (Fig. S5 and Table S3, SI) confirms that the selected conformers (TS4(RR/RS/SR/SS)) in Fig. 1 exhibit the lowest energy. By comparison, the reaction pathway viaTS4(SS) is energetically more favorable compared to the other three pathways. Therefore, only the SS-configuration pathway will be discussed in the main text, and the pathways of the RR/RS/SR-configuration can be found in Fig. S6, SI. As shown in Fig. 2, the C6–C7 bond decreases from 2.39 Å in TS4(SS) to 1.60 Å in M4(SS). This change confirms the formation of the C6–C7 bond.

Fig. 3 Possible stereochemistry of Michael addition.

3.1.5. Fifth step: protonation. In the fifth step, the proton H10 of DBU·H⁺ is transferred to the C8 atom of intermediate M4(SS)via transition state TS5(SS), yielding intermediate M5(SS) (Scheme 4). As illustrated in Fig. 1, the proton transfer requires overcoming an energy barrier of 12.5 kcal mol⁻¹. As shown in Fig. 2, from TS5(SS) to M5(SS), the length of the N15–H10 bond is prolonged from 1.40 to 2.06 Å, whereas the C8–H10 bond is reduced from 1.33 to 1.11 Å. These changes in the bond length confirm the dissociation of the N15–H10 bond and the formation of the C8–H10 bond.

Scheme 4 Possible mechanism for M4 → M6 conversion (energies in kcal mol⁻¹).

3.1.6. Sixth step: deprotonation. In the sixth step, the proton H9 is transferred from the C7 atom of intermediate M5(SS) to DBUvia transition state TS6(SS), generating intermediate M6(R). This process requires overcoming an energy barrier of 10.9 kcal mol⁻¹ (Fig. 1). The deprotonation (M4(SS) → TS6(SS)) is also found to be the rate-determining step, with an overall energy barrier of 19.7 kcal mol⁻¹. It is noteworthy that after deprotonation, the C7 atom becomes achiral, and the C6 atom experiences chirality inversion. For the sake of clarity, the R/S in the name of the stationary points (M6 → P) indicates the chirality of the C6 atom. As demonstrated in Fig. 2, the C7–H9 bond length increases from 1.09 Å in intermediate M5(SS) to 1.41 Å in transition state TS6(SS), indicating the cleavage of the C7–H9 bond.

For the transformation of M4(SS) to M6(R), the direct and DBU-assisted pathways were also examined (Scheme 4). However, these pathways can be excluded due to the related high energy barriers. For details, see Fig. S7, SI.

3.1.7. Seventh step: ring-closure process. In the seventh step, the N11 atom in intermediate M6(R) attacks the C2 atom viaTS7(R), forming the six-membered ring intermediate M7(R). This process requires overcoming an energy barrier of 10.8 kcal mol⁻¹ (Fig. 1). As shown in Fig. 2, the C2–N11 bond decreases from 1.99 Å in TS7(R) to 1.58 Å in M8(R), indicating the formation of the C2–N11 bond.

3.1.8. Eighth step: elimination of NHC. In the last step, intermediate M7(R) undergoes C1–C2 bond cleavage through transition state TS8(R), yielding product P(R) and regenerating the NHC catalyst. Energy calculations (Fig. 1) indicate that this step proceeds via a low energy barrier of 1.3 kcal mol⁻¹. As shown in Fig. 2, the length of the C1–C2 bond increases from 1.60 Å in M7(R) to 1.93 Å in TS8(R), indicating bond dissociation.

3.2. Other regioselective reaction pathways

In addition to the Michael addition of R2 and M3 discussed above, computational investigations were extended to the C2–C7 and C2–N11 bond-forming pathways. In the C2–C7 bond formation pathway, the re/si face of reactant R2 reacts with the re/si face of intermediate M3 generating intermediates NM4(RR), NM4(RS), NM4(SR), and NM4(SS) (Fig. S8). The related energy barriers are 12.0, 11.8, 8.7 and 9.0 kcal mol⁻¹ for NTS4(RR/RS/SR/SS), which are much higher than the 3.7 kcal mol⁻¹ for TS4SS (Michael addition), ruling out these pathways.

In the C2–N11 bond formation pathway, the reactant R2 attacks the re/si face of the C2 atom in intermediate M3. Fig. S9 shows that after passing through transition states re-TS4 (17.0 kcal mol⁻¹) and si-TS4 (14.2 kcal mol⁻¹), the intermediates re-M4 and si-M4 are formed with relative energies of −11.2 and −8.1 kcal mol⁻¹, respectively. Compared with the Michael addition pathway (ΔG^‡ = 3.7 kcal mol⁻¹, TS4(SS)), these two pathways require higher energy barriers, and the stabilities of re/si-M4 are significantly lower than that of intermediate M4(SS). Therefore, these two pathways are excluded.

3.3. Origin of stereoselectivity

Two chiral centers (C6 and C7) were generated in the Michael addition of M3 to R2, indicating that this step is the stereoselectivity-controlling step. Based on the preceding discussion, the si-face of R2 reacts with the re-face of the acyl intermediate M3viaTS4SS yielding the R-configuration product, which is energetically most favorable. As shown in Fig. 1, the energy barrier difference between transition states TS4(RR) and TS4(SS) is 1.7 kcal mol⁻¹, corresponding to an enantiomeric excess (ee) of 89.3%, in excellent agreement with the experimentally observed value of 90% ee.³⁵

To elucidate the origin of stereoselectivity, noncovalent interaction (NCI) analysis was performed to investigate the nature of interactions between R2 and M3. Fig. 4 shows that transition states TS4(RR), TS4(SR) and TS4(SS) exhibit three C–H⋯O, one C–H⋯N, three C–H⋯π and one π⋯π interactions. Although the lone pair LP⋯π interaction exists in these three transition states, the LP⋯π interaction in TS4(SS) is stronger than that in TS4(RR)/TS4(SR) (3.065 and 3.312 versus 3.022/3.090). Additionally, the interactions (two C–H⋯O, two C–H⋯π, and two LP⋯π interactions) in TS4(RS) are weaker than those in TS4(SS). Overall, the noncovalent interactions in TS4(SS) are stronger than those in TS4(RR/RS/SR), which leads to the pathway associated with TS4(SS) having a lower energy barrier.

Fig. 4 NCI plots for TS4(RR/RS/SR/SS) (isosurface = 0.008). Distances are given in Å. The blue, green, and red regions represent strong, weak, and repulsive interactions, respectively.

3.4. Substituent effects

Experimental studies³⁵ showed that the substituents on cinnamaldehyde could affect the stereoselectivity in the annulation reaction of 2-aminomaleate with cinnamaldehyde. To understand this result, we calculated the energy barrier differences of key transition states in the stereoselectivity-controlling step, as summarized in Table 1. The energy barrier differences of entries 1–5 are in good agreement with the enantiomeric excess values reported in experiments, demonstrating that our results are reliable.

Table 1 The computed energy barrier differences for the stereoselectivity-controlling step

Entry	R	ΔΔG^‡ (kcal mol^−1)	ee (%) in the experiment
1	3-MeC6H4	2.1	93
2	2-OMeC6H4	2.5	96
3	β-Heteroaryl	1.3	85
4	Me	1.9	90
5	β-Alkynyl	3.1	97

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3.5. Stabilization of axial chirality

To elucidate the factors responsible for maintaining the high axial chirality, the racemization process of products was investigated. As shown in Fig. 5, the energy barrier for the racemization process through the transition state TS9 is 31.1 kcal mol⁻¹, making the racemization reaction unlikely to occur under the experimental conditions. In other words, the product exhibits stable axial chirality. In addition, we also calculated the energy barriers and the buried volumes of different substituents (Fig. S10, SI). The results indicate that the larger buried volumes of substituents lead to higher energy barriers of racemizations.

Fig. 5 Energy barrier and optimized structures of the racemization transition state TS9.

3.5. The role of the catalyst

To understand the role of the catalyst, we conducted global reactivity index (GRI) analysis.^89–93 As shown in Table 2, the values of the nucleophilicity index of R1, re-M1 and re-M2 are 2.453, 3.373 and 4.824 eV, respectively, indicating that the nucleophilicity of R1 is strengthened after coordination with the NHC. Subsequently, the nucleophilic re-M2 will convert to electrophilic M3 through an oxidation process. The nucleophilicity and electrophilicity indexes of M3 are 2.118 and 2.477 eV, respectively. At this point, M3 serves as an electrophile to react with R2.

Table 2 Electronic potential (µ, a.u.), chemical hardness (η, a.u.), global electrophilicity (ω, eV), and global nucleophilicity (N, eV) of R1, re-M1, re-M2, M3 and R2

Species	η	µ	ω	N
R1	0.242	−0.166	1.542	2.453
re-M1	0.253	−0.126	0.860	3.373
re-M2	0.194	−0.102	0.737	4.824
M3	0.208	−0.195	2.477	2.118
R2	0.173	−0.117	1.079	4.707

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4. Conclusions

We conducted a comprehensive DFT study on NHC-catalyzed [3+3] cycloaddition of cinnamaldehyde with 2-aminomaleate. The most preferred mechanism involves eight steps: (1) nucleophilic addition of NHC to cinnamaldehyde, (2) DBU·H⁺-assisted 1,2-proton transfer forming the Breslow intermediate, (3) Breslow intermediate oxidation, (4) Michael addition of acyl intermediate to 2-aminomaleate, (5) protonation mediated by DBU·H⁺, (6) deprotonation mediated by DBU·H⁺, (7) ring-closure process, and (8) NHC dissociation. The Michael addition step determines the stereoselectivity of the entire catalytic cycle, affording the R-configured product. The calculated enantiomeric excess value of 89.3% aligns well with the experimental observations (90% ee). Further NCI analysis revealed that weak interactions involved in the stereo-controlling transition states should be responsible for the observed stereoselectivity. Further calculations of the racemization energy barriers for the axially chiral products with different substituents revealed that the buried volume is crucial for maintaining high axial chirality.

Conflicts of interest

The authors declare no conflicts of interest.

Data availability

The data underlying this study are available in the published article and its supporting information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d5cp03567h.

Acknowledgements

DFT computations were carried out on the cluster at USTL.

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