Theoretical insights into the enantiodivergence induced by chiral phosphoric acid catalysis with a Lewis acid for the synthesis of N–N axially chiral atropisomers

Abstract

A detailed theoretical mechanistic investigation on chiral phosphoric acid (CPA)-catalyzed Paal–Knorr reactions, in the presence and absence of a Lewis acid, for the synthesis of N–N axially chiral atropisomers is described herein. Density functional theory (DFT) studies elucidate that in the absence of a Lewis acid, CPA catalyzes both the initial cyclization and the subsequent dehydroxylation processes, ambiguously identified as the rate-determining step in the reactions. Conversely, when a Lewis acid participates in the reaction, it facilitates the second dehydroxylation process with a significantly lower energy barrier, thereby reversing the rate-determining step to the initial cyclization step. It is noteworthy that in the case of N-aminoindoles, both the S-configurational transition state TS1 in the cyclization step and TS2 in the dehydroxylation process are favourable. In contrast, for the synthesis of a bispyrrole, the R-configurational TS1 and the S-configurational TS2 are dominant. Therefore, the enantiodivergence observed is essentially induced by the reversed rate-determining steps in the absence or presence of a Lewis acid in the case of a bispyrrole. Furthermore, the non-covalent interaction (NCI) and atoms-in-molecules (AIM) analysis of the TS structures reveal that the non-covalent interactions play a pivotal role in determining the enantiodivergence observed in these reactions.

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1 Introduction

Axially chiral compounds are commonly found in natural products and bioactive molecules.¹ In recent years, axially chiral biaryl skeletons have found versatile applications as ligands and organocatalysts.² Consequently, the catalytic atroposelective construction of such frameworks has garnered significant interest within the chemistry community, leading to remarkable achievements.³ While there has been considerable progress in the synthesis of axially chiral molecules with C–C⁴ or C–N⁵ axes, the synthesis of N–N axial chiral molecules, integral to the core structures of numerous important natural products and bioactive molecules,⁶ poses specific challenges. The exploration of properties associated with N–N axially chiral molecules, such as their rotational barriers and stability, remains limited. Despite earlier efforts by Cirilli and Higashibayashi in achieving N–N biaryl atropisomers through HPLC resolution,^7,8 the atroposelective construction of N–N atropisomers remained unexplored until recently.⁹ Researchers have addressed this gap by developing novel approaches (Scheme 1a). For instance, Lu/Houk and Li performed an asymmetric N–H functionalization to access N–N axially chiral 1-aminopyrroles and 3-aminoquinazolinones.^10,11 A N-Heterocyclic carbene-catalyzed amidation reaction for the atroposelective synthesis of N–N axially chiral 3-aminoquinazolinones was demonstrated by Biju's group.¹² Additionally, Liu and Lu synthesized 1,1′-bipyrrole atropisomers through a desymmetrization strategy via an asymmetric Cu-catalyzed Friedel–Crafts alkylation reaction.¹³ Very recently, Liu's group realized a Pd-catalyzed transient directing group enabled atroposelective C–H functionalization such as alkenylation, alkynylation, allylation, and arylation reactions of pyrroles or indoles for an efficient synthesis of indole–pyrrole atropisomers.¹⁴ Meantime, the construction of indole–pyrrole and bispyrrole atropisomers through Ir-catalyzed asymmetric C–H alkylation with acrylates was achieved by You and co-workers.¹⁵

Scheme 1 Profile of the synthesis of N–N axially chiral atropisomers.

Significantly, the Shi group and the Zhao group have independently disclosed the atroposelective construction of N–N axially chiral N-pyrrolylindoles and bipyrroles, respectively, via a chiral phosphoric acid (CPA) catalyzed asymmetric Paal–Knorr reaction for de novo ring formation (Scheme 1b).¹⁶ In the latter study, the introduction of Fe(OTf)₃ or FeCl₃ resulted in an enantiodivergence of the bipyrrole atropisomers. The proposed reaction mechanism is succinctly depicted in Scheme 1c. Initially, the condensation of the N-aminoindole/pyrrole 1 with 1,4-diketone 2, in the presence of (R)-CPA, gave rise to the imine-type intermediate A, which readily isomerized into the enamine-type intermediate B. Subsequently, activated by the formation of two hydrogen bonds with (R)-CPA, enamine B underwent enantioselective intramolecular cyclization to give intermediate C, featuring central chirality. Ultimately, CPA facilitated dehydration to generate the pyrrole ring and the axially chiral product 3. To the best of our knowledge, the following key mechanistic issues still remain obscure. 1. How does chiral phosphoric acid induce chirality? 2. What is the rate-determining step of the reaction? 3. Why does the conformation change after the addition of a Lewis acid? To address these inquiries and offer insights into enantiodivergent reactions, we present a comprehensive computational study on the mechanism of CPA-catalyzed Paal–Knorr reactions, both in the presence and absence of a Lewis acid. Answers to these questions will not only provide a thorough and profound understanding of these Paal–Knorr reactions,¹⁷ but also guide the rational design of new strategies for the catalytic synthesis of N–N axially chiral biaryl atropisomers.

2 Computational details

In the present study, all density functional theory (DFT) calculations were performed with the Gaussian 09 program package.¹⁸ The geometry optimization of all the minima involved was performed at the M06-2X level of theory with Grimme's D3 empirical dispersion correction and the def2-SVP basis set for all atoms (keyword 5D).¹⁹ To obtain accurate energies, single-point energy calculations were performed at the M06-2X//def2-TZVP level,²⁰ based on the optimized structures. The structures of the reactants, intermediates, transition states, and products were fully optimized without any restriction. The vibrational frequencies were computed at the same level to check whether each optimized structure is an energy minimum or a transition state and to evaluate its zero-point vibrational energy (ZPVE) and thermal corrections at 298 K. Solvent effects were computed using the SMD model²¹ in CCl₄ or hexane. The 3D structures of the optimized intermediates or transition states were demonstrated using the CYLView software.²² Noncovalent interaction (NCI) analyses were carried out using the Multiwfn 3.8 program.^23,24 Atoms-in-molecules (AIM) analyses²⁵ were used to explore the origin of stereoselectivity. Additional computational details and results are provided in the ESI.†

3 Results and discussion

In this section, we present the calculated results pertaining to the CPA-catalyzed Paal–Knorr reaction of N-aminoindole 1a and 1,4-diketone 2, which was used as the model system (Fig. 1). Based on a previous report that identified the key intermediate as an imine type,²⁶ the condensation of 1a with 2 initiates the formation of the imine-type intermediate INT1a as the starting point. Subsequently, INT1a undergoes facile isomerization into an enamine-type intermediate INT2a. Activation by the formation of two hydrogen bonds with CPA propels the intramolecular cyclization of enamine INT2a through transition states TS1a, affording INT3a with axial and central chirality. Facilitated by CPA, the subsequent stepwise dehydration of INT3a through TS2a and TS3a generated the pyrrole ring, thus yielding the N–N axially chiral product 3a. Given that the intermediates possess one axial (R/S) and one central (r/s) chirality, four distinct configurations need differentiation: Rr, Rs, Sr and Ss. The initial intramolecular cyclization step through the S-configurational TS1a-Ss and TS1a-Sr requires a free energy barrier of 12.4 kcal mol⁻¹ and 15.6 kcal mol⁻¹, respectively, yielding the intermediates INT3a-Ss (−7.6 kcal mol⁻¹) and INT3a-Sr (−1.8 kcal mol⁻¹). On the other hand, the free energy barriers of the R-configurational TS1a-Rs and TS1a-Rr (14.2 kcal mol⁻¹ and 23.0 kcal mol⁻¹, respectively) are notably higher than those of TS1a-Ss and TS1a-Sr. Consequently, the intermediate INT3a-S becomes more thermodynamically stable than INT3a-R. It is noteworthy that the subsequent dehydroxylation step through TS2a-Sr and TS2a-Ss exhibits a free energy barrier of 14.9 kcal mol⁻¹ and 21.2 kcal mol⁻¹, respectively, while TS2a-Rr and TS2a-Rs require free energy barriers of 21.6 kcal mol⁻¹ and 19.5 kcal mol⁻¹, respectively, which are 4.6–6.7 kcal mol⁻¹ higher than that of TS2a-Sr. This dehydroxylation step is exergonic, forming INT4a. Lastly, the concluding deprotonation step viaTS3a, characterized by a low free energy barrier, facilitates the generation of product (S)/(R)-3a. Reviewing the whole energy profiles, we observe that the second dehydroxylation process emerges as the rate-determining step for the R-configurational pathway, whereas the first cyclization step serves as the rate-determining step for the S-configurational pathway. The critical control of axially chiral N–N atropoisomers hinges on the energy difference between TS1a-Sr and TS2a-Rs (15.6 kcal mol⁻¹vs. 19.5 kcal mol⁻¹), ultimately favoring the prominent formation of product (S)-3a.

Fig. 1 Free energy profiles of the CPA catalyzed Paal–Knorr reaction of N-aminoindole 1a and 1,4-diketone 2.

To elucidate the origin of stereoselectivity, we conducted a non-covalent interaction (NCI) analysis to qualitatively analyze the types of weak interactions in the key transition states. As depicted in Fig. 2a and b, the NCI analysis revealed that the weak interactions featuring electrostatic repulsion between the trimethylphenyl group of CPA and the benzene ring moiety in the substrate in TS2a-Rs are markedly more robust compared to those in TS2a-Sr. This distinction predominantly contributes to the observed free energy difference between TS2a-Sr and TS2a-Rs.

Fig. 2 NCI and AIM analyses of the transition states TS2a-Sr/Rs and Laplacian electron density values (∇²ρ, a.u.) at the bond critical points (BCPs) in TS2a-Sr/Rs (distance in Å).

In addition to the qualitative NCI analysis, we conducted a more detailed examination using atoms-in-molecules (AIM) analysis to quantitatively identify the key weak interactions (Fig. 2c). Further quantitative analysis of the bond critical points (BCP) of the transition states TS2a-Sr and TS2a-Rs, which play a crucial role in controlling stereoselectivity, was performed. The details regarding distances, types of interaction, and the Laplacian of electron densities (∇²ρ) are summarized below. The strength of the weak interactions is evaluated by examining the Laplacian electron density values and the corresponding distances. In TS2a-Sr, there is one C–H⋯π (3.36 Å), one C–H⋯O (2.11 Å), one O–H⋯O (1.60 Å) and one O–H⋯π (2.33 Å) interaction. Conversely, TS2a-Rs features two O–H⋯O (1.86 Å and 1.63 Å) and two C–H⋯π (2.98 Å and 3.31 Å) interactions (see the ESI† for details). The hydrogen-bond interactions in the more stable S-configurational TS2a-Sr exhibit substantial strength. Consequently, TS2a-Sr displays a significantly lower energy barrier compared to the pathway associated with TS2a-Rs, leading to the formation of the prominent product (S)-3a. Both the qualitative NCI and quantitative AIM analysis provide in-depth chemical insights into the favorable characteristics of TS2a-Sr, consistent with the experimental observation of the predominant formation of product (S)-3a.

In the Paal–Knorr reaction of N-aminopyrrole 1b and 1,4-diketone 2 (Fig. 3), the reaction process resembles that of 1a, as depicted in Fig. 1. Following the isomerization of the in situ generated imine INT1b, the resulting enamine INT1b undergoes CPA-catalyzed intramolecular cyclization via the transition states TS1b-Sr, TS1b-Rr, TS1b-Ss and TS1b-Rs, each associated with energy barriers of 21.7, 21.5, 18.3, and 16.8 kcal mol⁻¹, respectively, leading to the formation of INT3b. Notably, the S-configurational TS1b-Sr and TS1b-Ss exhibit higher energy barriers compared to the R-configurational TS1b-Rr and TS1b-Rs. Subsequently, INT3b undergoes dehydroxylation through TS2b-Sr and TS2b-Ss, necessitating free energy barrier of 22.7 kcal mol⁻¹ and 19.8 kcal mol⁻¹, respectively. In contrast, TS2b-Rs and TS2b-Rr require free energy barriers of 27.2 kcal mol⁻¹ and 20.4 kcal mol⁻¹, respectively, with the latter showing a free energy barrier that is 0.6–7.4 kcal mol⁻¹ higher than that of TS2b-Ss. Finally, the concluding deprotonation step viaTS3b, characterized by a low free energy barrier, facilitates the generation of product (S)/(R)-3b. Reviewing the whole energy profile, it is evident that the second dehydroxylation process serves as the rate-determining step for the S-configurational pathway, while the first cyclization step is the rate-determining step for the R-configurational pathway. The control of the axially chiral N–N atropoisomers is contingent upon the energy difference between TS2b-Ss and TS1b-Rr (19.8 kcal mol⁻¹vs. 21.5 kcal mol⁻¹), ultimately resulting in the formation of (S)-3b with a high ee.

Fig. 3 Free energy profiles of the CPA catalyzed Paal–Knorr reaction of N-aminopyrrole 1b and 1,4-diketone 2.

Additionally, we conducted further NCI and AIM analysis to assess the strength of the weak interactions. As depicted in Fig. 4a and b, NCI analysis revealed that the weak interactions, particularly the electrostatic repulsion between the trimethylphenyl group of CPA and the phenyl moiety in the substrate in TS2b-Rr are more pronounced than those in TS2b-Ss. The AIM analysis results of TS2b-Ss/Rr, along with the values of the Laplacian electron density at the bond-critical points along the bond paths, are summarized in Fig. 4c. There are one C–H⋯O (2.34 Å) and one C–H⋯π (3.04 Å) interactions in TS2b-Ss, while one C–H⋯π (2.72 Å) and one C–O⋯π (3.01 Å) interactions can be identified in TS2b-Rr. Notably, the hydrogen-bond interactions in the more stable S-configurational TS2b-Ss exhibit greater strength, resulting in a lower energy barrier compared to TS2a-Rr, ultimately leading to the formation of the prominent product (S)-3b.

Fig. 4 NCI and AIM analyses of the transition states TS2b-Ss/Rr and Laplacian electron density values (∇²ρ, a.u.) at the bond critical points (BCPs) in TS2b-Ss/Rr (distance in Å).

To elucidate the role of the Lewis acid catalyst in the intramolecular Paal–Knorr reaction, we utilized FeCl₃ as a representative Lewis acid to illustrate how the axial chirality of the product changes upon the addition of Lewis acid (Fig. 5). It is noteworthy that in the Paal–Knorr reaction of 1b and 2, the formed INT3b could undergo catalyst exchange, wherein the CPA dissociates and FeCl₃ coordinates with the hydroxyl group to form the more stable INT4c. Subsequently, the release of the hydroxyl group with the assistance of FeCl₃ through TS2c, characterized by a low energy barrier, affords INT5c, which readily delivers product (S)/(R)-3b. Therefore, after the addition of FeCl₃, the dehydroxylation process through TS2c is no longer the rate-determining step; instead, the cyclization step viaTS1b takes precedence. In this context, the atroposelectivity is controlled by the cyclization step, wherein TS1b-Rs is favored over TS1b-Ss by 1.5 kcal mol⁻¹, leading to the formation of (R)-3b with good ee.

Fig. 5 Free energy profiles of the CPA catalyzed Paal–Knorr reaction of N-aminopyrrole 1b and 1,4-diketone 2 in the presence of a Lewis acid catalyst.

The NCI and AIM analysis were also carried out on TS1b, and the results depicted in Fig. 6 revealed that TS1b-Rs benefits from π-stacking attraction between the ester group attached to the pyrrole ring and the branched chain of CPA, resulting in a lower energy barrier. In comparison to one C–H⋯O (2.56 Å) and one C–H⋯π (2.75 Å) interactions in TS1b-Ss, TS1b-Rs exhibits a greater number of interactions, including two C–H⋯O (2.58, 2.76 Å) and two C–H⋯π (2.65, 2.79 Å) interactions. Overall, NCI and AIM analysis implied that the weak interactions existing in TS1b-Rs are more pronounced, significantly contributing to the stabilization of the TS structure. Consequently, these weak interactions are likely responsible for the energetic favoring of the R-configurational TS1-R and the formation of the axially chiral product (R)-3b.

Fig. 6 NCI and AIM analyses of the transition states TS1b-Rs/Ss and Laplacian electron density values (∇²ρ, a.u.) at the bond critical points (BCPs) in TS1b-Rs/Ss (distance in Å).

Upon comprehensive examination of all the energy profiles, the computational results reveal that 1a preferentially undergoes the S-configurational cyclization and dehydroxylation process through TS1a-S, which is energetically favored over the R-configurational TS2a-R (ΔΔG^‡(R–S) = 3.9 kcal mol⁻¹), leading to the formation of (S)-3a with a computed 99% ee. This aligns well with the experimental observation of 94% ee (Table 1). In the case of 1b, the S-configurational cyclization and dehydroxylation process through TS2b-S prevails over the R-configurational TS1b-R (ΔΔG^‡(R–S) = 1.7 kcal mol⁻¹), resulting in the 89% ee of (S)-3b, in good agreement with the experimental result of 90% ee. In contrast, the addition of FeCl₃ tends to facilitate the dehydroxylation step as a facile process, and the R-configurational pathway through TS1b-R becomes advantageous (ΔΔG^‡(R–S) = −1.5 kcal mol⁻¹) for the formation of (R)-3b in 85% ee, once again consistent with the experimental 92% ee of (R)-3b.

Table 1 The energy barriers and the gaps of rate-determining steps, and the ee of products

Sub.	Lewis acid	ΔG^‡(S) [kcal mol^−1]	ΔG^‡(R) [kcal mol^−1]	ΔΔG^‡(R–S) [kcal mol^−1]	ee (cal.)	ee (exp.)
1a	w/o	15.6	19.5	3.9	99%	94%^16a
1b	w/o	19.8	21.5	1.7	89%	90%^16b
1b	w/	18.3	16.8	−1.5	−85%	−92%^16b

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Conclusions

The mechanisms and origin of enantioselectivity in the CPA-catalyzed Paal–Knorr reaction for the synthesis of N–N axis compounds were investigated computationally. The results indicate that in the absence of a Lewis acid, the CPA catalyzed both the initial cyclization step and the subsequent dehydroxylation process as the rate-determining step in the reactions. In contrast, when a Lewis acid is involved, it readily catalyzed the second dehydroxylation process with a significantly lower energy barrier, thereby reversing the rate-determining step to the initial cyclization step. Notably, both the S-configurational transition state TS1 in the cyclization step and TS2 in the dehydroxylation process are favourable in the reaction of N-aminoindoles, while for the synthesis of bispyrrole, the R-configurational TS1 and the S-configurational TS2 are dominant. Therefore, the observed enantiodivergence is essentially induced by the reversed rate-determining steps in the absence or presence of a Lewis acid in the bispyrrole case. Furthermore, the NCI and AIM analysis reveal that the H-bonding and π-stacking interactions are the critical features of the proposed TS structures that determine the stereoselectivity. The present theoretical calculations provide important insights into these reaction mechanisms and are expected to inspire the design of catalytic reactions.

Author contributions

All authors made contributions in writing the manuscript. All authors approve the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the National Natural Science Foundation of China (No. 22101168) and Shanghai Pujiang Program (No. 21PJ1403700) for financial support. We are thankful to the High Performance Computing Center of Shanghai University, and Shanghai Engineering Research Center of Intelligent Computing System (No. 19DZ2252600) for providing the computing resources.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3ob02011h

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