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. 2024 Jan 24;26(4):922–927. doi: 10.1021/acs.orglett.3c04261

Atroposelective Synthesis of Axially Chiral Naphthylpyrroles by a Catalytic Asymmetric 1,3-Dipolar Cycloaddition/Aromatization Sequence

Ian Maclean †, Enrique Gallent †, Oscar Orozco †, Alba Molina †, Nuria Rodríguez †,‡, Javier Adrio †,‡,*, Juan C Carretero †,‡,*
PMCID: PMC10845160  PMID: 38266629

Abstract

graphic file with name ol3c04261_0008.jpg

A straightforward methodology for the enantioselective preparation of axially chiral 2-naphthylpyrroles has been developed. This protocol is based on a CuI/Fesulphos-catalyzed highly enantioselective 1,3-dipolar cycloaddition of an azomethine ylide followed by pyrrolidine alkylation and pyrrolidine to pyrrole oxidation. The mild conditions employed in the DDQ/blue light-mediated aromatization process facilitate an effective central-to-axial chirality transfer affording the corresponding pyrroles with high atroposelectivity.

Axially chiral molecules are key structures in organic and medicinal chemistry, present in numerous natural and biologically active compounds,1 and considered privileged chiral ligands for transition metal catalysis and organocatalyzed procedures.2 Therefore, the development of new methodologies for their efficient preparation has become a hot research topic, and many strategies have been recently described to fill significant gaps and expand the chemical space of this class of compounds. However, most contributions focus on the preparation of atropisomeric biaryls (6,6-ring systems), while the enantioselective assembly of five-membered heteroaryl atropisomers has been much less documented.3 This situation could be attributed to the lower conformational stability caused by the modified bond angles of the five-membered ring that increase the distance between substituents, therefore decreasing the rotation barriers.4

Pyrrole cores are present in a variety of natural products and are valuable building blocks for the preparation of pharmaceuticals and new materials.5 Consequently, strategies for the catalytic atroposelective synthesis of axially chiral arylpyrrole derivatives are highly appealing. In the past few years, several catalytic asymmetric procedures for the preparation of axially chiral pyrroles have been reported. However, most of them allow access to only pyrrole-derived atropisomers with a C–N6 rotational axis. The preparation of pyrroles with N–N7 or C–C8 bonds has been much less studied (Scheme 1). In fact, to the best of our knowledge, only three procedures describe the enantioselective preparation of axially chiral C2-arylpyrroles. In 2019, Tan and co-workers9 developed an elegant direct chirality transfer strategy by cyclization of enantioenriched atropisomeric alkenes synthesized by organocatalytic asymmetric N-alkylation reactions (Scheme 1a). More recently, Wang, Xu, Mei, and co-workers10 have reported a direct phosphoric acid-catalyzed asymmetric Attanasi reaction, between 1,3-dicarbonyl compounds and azoalkenes, to afford C2 naphthylpyrroles in high yields and excellent enantioselectivities (Scheme 1b). Finally, during the completion of this work, Ullah, Lu, and co-workers11 have described the atroposelective synthesis of CF3-substituted 2-aryl pyrroles by the phosphine-catalyzed cycloaddition of aldimines with allenoates and subsequent oxidation (Scheme 1c).

Scheme 1. Synthesis of C–C Axially Chiral 2-Arylpyrroles.

Scheme 1

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The 1,3-dipolar cycloaddition of azomethine ylides with olefins offers direct access to highly functionalized proline derivatives.12 Since 2002, numerous well-defined catalytic systems capable of giving rise to excellent enantioselectivities have been developed. On the contrary, several research groups have reported different protocols for the dehydrogenative oxidation from pyrrolidines to pyrroles.13 Thus, in connection with our previous work in 1,3-dipolar cycloaddition and pyrrole synthesis,14 we envisaged that a metal-catalyzed asymmetric cycloaddition of azomethine ylides and subsequent oxidation of the resulting pyrrolidine could provide an expeditious route to a new class of axially chiral C2-aryl pyrroles, via a central-to-axial chirality transfer strategy (Scheme 1).15 Nonetheless, to achieve this objective, two main issues had to be addressed: (a) the development of a robust asymmetric 1,3-dipolar cycloaddition leading to the preparation of highly enantioenriched pyrrolidines decorated with suitable groups around the C–C axis to avoid free rotation in the final pyrrole core and (b) the achievement of a mild pyrrolidine to pyrrole oxidation process that would allow the efficient central-to-axial chirality transfer.

We began our investigation by exploring the cycloaddition between iminoester 1a (obtained by condensation of 2-methyl-1-naphthaldehyde and methyl glycinate) and methyl maleimide (2). On the basis of our previous work,16 a Fesulphos (4)/CuI complex was initially used as the catalytic system. To our delight, using Et3N as the base and THF as the solvent, the corresponding pyrrolidine endo-3a was obtained as the only detectable diastereoisomer in 87% yield and 83% ee (Scheme 2a). This ee could be increased to 87% by performing the reaction at 0 °C. The use of other metal complexes, bases, or solvents did not bring any further improvement.17 A significant decrease in conversion and asymmetric induction was observed when the catalyst loading was reduced to 5 mol %.

Scheme 2. Synthesis of C–C Axially Chiral 2-Arylpyrroles by a 1,3-Dipolar Cycloaddition–Aromatization Sequence.

Scheme 2

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At this point, our next purpose was to evaluate the pyrrolidine to pyrrole dehydrogenative aromatization process. We were pleased to find that racemic pyrrolidine endo-3a was easily oxidized to the corresponding pyrrole 5a using benzoyl peroxide (BPO) in DCE at 110 °C (Scheme 2b).13 Unfortunately, all attempts to separate the mixture of enantiomers by HPLC with different chiral supports failed, and pyrrole 5a prepared from enantioenriched pyrrolidine 3a (87% ee) showed null optical rotation, suggesting that 5a is not configurationally stable. However, the straightforward benzylation of 5a led to N-benzyl pyrrole 6a, which was easily resolved by chiral HPLC using standard conditions (CHIRALPAK IA-HPLC column) (Scheme 2b). Hence, to develop an oxidation process with central-to-axial chirality transfer, we focused on evaluating the oxidation of N-benzyl pyrrolidine 7a. This reaction using BPO as the oxidant proceeded in good yield (65%) but with a severe erosion of the enantioselectivity [87% to 10% ee (Scheme 2c)].

Therefore, on the basis of literature precedent, we proceeded to evaluate other possible oxidants (Table 1).13 The use of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as an oxidant led to the formation of 6a in high yield but with low enantioselectivity (entry 1). In an attempt to improve the enantiomeric excess, the reaction was then carried out at −15 °C (entry 2). However, at such a low temperature, starting material 7a was recovered unaltered. This lack of reactivity was also observed when CuCl/TEMPO/O2- or MnO2-based systems were used as oxidants (entry 3 or 4, respectively). Considering that the oxidizing ability of DDQ improves significantly upon visible light excitation, we decided to perform the oxidation of 7a with DDQ under blue light irradiation.18 Using this system, and under strictly anhydrous conditions,19 we were able to obtain 6a in 98% isolated yield and 60% ee (entry 5). The ee could be improved to 72% by decreasing the temperature to −15 °C (entry 6). Finally, pyrrolidine 8a with the bulkier 2,4,6-trimethylbenzyl moiety provided the best result, affording the corresponding pyrrole 9a with 84% ee (entry 7). However, the oxidation with N-acyl- and N-tosyl-protected pyrrolidines did not occur, affording the starting material unaltered (entries 8 and 9, respectively).20

Table 1. Optimization of the Aromatization Conditions.

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entry oxidant R T (°C) t (h) yield (%)a ee (%)b
1 DDQ Bn rt 24 98 50
2 DDQ Bn –15 24 ndc –
3 CuI/TEMPO/O2 Bn 80 24 5 –
4 MnO2 Bn rt 24 ndc –
5 DDQ/blue light Bn rt 1 98 60
6 DDQ/blue light Bn –15 1 98 72
7 DDQ/blue light CH2Mes –15 4 98 84
8 DDQ/blue light Ac –15 4 ndc –
9 DDQ/blue light Ts –15 4 ndc –
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a

Isolated yield after chromatographic purification.

b

ee determined by HPLC.

c

Not detected.

After establishing the optimal reaction conditions,21 we set out to study the structural generality of this cycloaddition dehydrogenative aromatization sequence. First, we evaluated the scope of the 1,3-dipolar cycloaddition regarding the substitution at the azomethine ylide. As shown in Scheme 3a, aromatic iminoesters with different electron-donating and electron-withdrawing groups furnished the corresponding pyrrolidines in high yields and excellent enantioselectivities (3b–g). After reaction with bromomethylmesitylene using standard conditions, 2-naphthol pyrrolidines with different O-protected groups (3b–d) were tested in the subsequent aromatization process, affording the corresponding pyrroles (9b–d, respectively) in moderate yields and high enantioselectivity [85–97% ee (Scheme 3b)]. Thus, aromatization of pyrrolidine 8e, bearing a phenyl group at position 2 of the naphthyl moiety, led to the corresponding pyrrole derivative 9e with moderate enantioselectivity (70% ee). Likewise, N-(2,4,6-trimethylbenzyl)-2-bromonaphthyl pyrrolidine 8f was also compatible with the aromatization conditions, affording pyrrole 9f with excellent enantioselectivity (99% ee). No enantioselectivity was observed when pyrrolidine 8g was subjected to the aromatization conditions, confirming that the presence of a substituent at position 2 of the naphthyl moiety is essential to achieve an effective central-to-axial chirality transfer. The absolute configuration of pyrroles 9 was unequivocally established by X-ray diffraction of bromo derivative 9f (see the Supporting Information for details; Scheme 3).22

Scheme 3. Scope of the Cycloaddition–Aromatization Sequence Using 1-Naphthyl Iminoesters,

Scheme 3

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Isolated yield after chromatographic purification.

ee determined by HPLC.

Next, to expand the scope of the reaction, we applied this methodology to the case of 2-naphthyl iminoesters (Scheme 4). Remarkably, under similar reaction conditions, the cycloaddition dehydrogenative aromatization sequence using iminoesters 10a–c led to pyrroles 13a–c respectively, with high yields (70–92%) and enantioselectivities [90–99% ee (Scheme 4)]. The presence of a halogen or alkyl substituent at position 2 of the naphthyl moiety allowed for effective central-to-axial chirality transfer. However, aryl-substituted derivative 13d was obtained as a racemic mixture. Finally, the presence of less hindered substituents such as OMe or OiPr in the naphthyl moiety led to not configurationally stable derivatives (13e and 13f). In this series, the absolute configuration of pyrrole type 13 was established by X-ray diffraction of bromo derivative 13a (see the Supporting Information for details; Scheme 4b).23

Scheme 4. Cycloaddition–Aromatization Sequence for 2-Naphthyl Iminoesters,

Scheme 4

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Isolated yield after chromatographic purification.

ee determined by HPLC.

We next studied the compatibility of the procedure with other dipolarophiles (Scheme 5). N-Phenylmaleimide (14a) was an effective partner for the cycloaddition providing the corresponding pyrrolidine 15a in 99% ee. Linear diactivated (E)-alkenes such as fumarate (14b and 14c) or fumaronitrile (14d) also proved to be excellent dipolarophiles affording the corresponding pyrrolidines with almost complete endo diastereoselectivity and excellent enantioselectivity [adducts 15b (88% ee), 15c (81% ee), and 15d (98% ee)].24N-2,4,6-Trimethylbenzyl pyrrolidine 16a with a phenyl substituent in the maleimide moiety successfully participated in the aromatization reaction to generate pyrrole 17a with low yield (47%) but high atroposelectivity (86% ee). However, the aromatization of pyrrolidine 16b resulting from the cycloaddition with dimethyl fumarate and subsequent benzylation took place with good yields (71%) but lower atroposelectivity (60% ee) (17b). This loss of effectiveness in the central-to-axial chirality transfer could be explained by steric effects. When di-tert-butyl fumarate was used, a higher chirality transfer efficiency was observed [17c (69%, 78% ee)]. Remarkably, the central-to-axial chirality transfer is almost complete in the case of pyrrolidine 17d owing to two cyano groups at positions 3 and 4 of the pyrrolidine ring (56% yield, 99% ee).

Scheme 5. Cycloaddition Aromatization Process Using Different Dipolarophiles,

Scheme 5

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Isolated yield after chromatographic purification.

ee determined by HPLC.

To shed some light on stereochemical stability of naphthyl pyrrole derivatives, racemization experiments were conducted in xylene at 130 °C for 8 h (Figure 1). After 10 measurements of the enantiomeric excess had been taken, the values obtained for the energy barrier for compounds 17a and 9c were 33.6, and 33.8 kcal/mol, respectively, confirming the configurational stability of these atropisomers at room temperature. A lower energy barrier was obtained for 13a (29.1 kcal/mol at 110 °C).

Figure 1.

Figure 1

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Determination of rotation barriers.

In conclusion, an innovative procedure for the preparation of C–C axially chiral naphthylpyrroles was developed using a 1,3-dipolar cycloaddition/oxidation sequence. Excellent yields and enantioselectivities were obtained in the 1,3-dipolar cycloaddition using the Cu(I)/Fesulphos complex as the catalyst system. Other key features of this approach are the proper N-alkylation of the pyrrolidine adduct and the final low-temperature DDQ/blue light-mediated pyrrolidine to pyrrole oxidation process for effective central-to-axial chirality transfer.

Acknowledgments

The authors thank FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (Grants PGC2018-098660-B-I00 and PID2021-1248553NB-100), for financial support. E.G. thanks MINECO for a FPI predoctoral fellowship. The authors also thank MINECO for financing (RED2022-134331-T).

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.3c04261.

  • General experimental procedures, characterization data, and NMR spectra (PDF)

The authors declare no competing financial interest.

Supplementary Material

ol3c04261_si_001.pdf (5.8MB, pdf)

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  22. CCDC 2297239.
  23. CCDC 2297242.
  24. In contrast, the cycloaddition with dimethyl maleate, under similar conditions, provided a mixture of diastereomers with low yield.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ol3c04261_si_001.pdf (5.8MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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