Phosphoric acid-catalyzed atroposelective construction of axially chiral arylpyrroles

Axially chiral arylpyrroles are key components of pharmaceuticals and natural products as well as chiral catalysts and ligands for asymmetric transformations. However, the catalytic enantioselective construction of optically active arylpyrroles remains a formidable challenge. Here we disclose a highly efficient strategy to access enantioenriched axially chiral arylpyrroles by means of organocatalytic atroposelective desymmetrization and kinetic resolution. Depending on the remote control of chiral catalyst, the arylpyrroles were obtained in high yields and excellent enantioselectivities under mild reaction conditions. This strategy tolerates a wide range of functional groups, providing a facile avenue to approach axially chiral arylpyrroles from simple and readily available starting materials. Selected arylpyrrole products proved to be efficient chiral ligands in asymmetric catalysis and also important precursors for further synthetic transformations into highly functionalized pyrroles with potential bioactivity, especially the axially chiral fully substituted arylpyrroles.


Supplementary Note 3 General procedure for preparation of racemic compound 3
An oven-dried 10 mL of Schlenk tube was charged with arylpyrroles 1 (0.15 mmol), 1 mL of CH 2 Cl 2 and diphenyl phosphate (0.01 mmol) at ambient temperature. Then, ketomalonate 2 (0.10 mmol) was added to the above solution and the mixture was stirred until the starting material was completely consumed. The mixture was concentrated under reduced pressure and purified by flash column chromatography (ethyl acetate/petroleum ether) to afford the corresponding racemic product 3.

General procedure for the asymmetric synthesis of compound (R)-3
An oven-dried 10 mL of Schlenk tube was charged with arylpyrroles 1 (0.
The reaction gave (R)-3h was obtained in 95% yield with 89% ee at a 0.8 mmol scale. The coupling reactions were performed with this batch of (R)-3h as the starting material.

Supplementary Note 4
General procedure for preparation of racemic compound 5 An oven-dried 10 mL of Schlenk tube was charged with arylpyrrole 4 (0.20 mmol), 1 mL cyclohexane and rac-C8 (0.01 mmol) at ambient temperature. Then, ketomalonate 2a (0.10 mmol) was added to the above solution and the mixture was stirred until the starting material was completely consumed. The mixture was concentrated under reduced pressure and purified by flash column chromatography (ethyl acetate/petroleum ether) to afford the corresponding racemic product 5. Notably, there was also by-product 5' was obtained, which is the isomer of 5.

General procedure for the kinetic resolution of racemic arylpyrroles (rac-4)
Under nitrogen atmosphere, an oven-dried 10 mL of Schlenk tube was charged with asymmetric arylpyrroles rac-4 (0.40 mmol), (S)-C8 (0.02 mmol), 2.4 mL of dry cyclohexane, and the mixture was stirred at 30 °C for 10 min. Then, a solution of ketomalonate 2a (0.20 mmol) in dry cyclohexane (2.4 mL) was added dropwise to the above solution and the mixture was stirred until the starting material was completely consumed, then the mixture was concentrated under reduced pressure and purified by flash chromatography eluted with PE/EA (10/1 to 5/1) to afford the corresponding axially chiral arylpyrroles product 5 and recovered substrates (R)-4.

Chiral HPLC spectrum of racemic 5b
Chiral HPLC spectrum of (S)-5b equiv) in H 2 O (1.0 mL) was added dropwise to the mixture, the mixture then heated at 85 °C for 1 hours. After cooling to room temperature, the reaction was quenched by addition of water and extracted with EtOAc. The organic phase was separated, washed with water, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by a silica gel flash chromatography (Hexane/EtOAc) to give compound 10 and 11.
Phosphorous oxychloride (0.6 mmol, 6.0 equiv) was added dropwise to stirred ice-cooled DMF (1.0 mL) under a N 2 atmosphere. The mixture was kept at 0 °C for 30 min and then a solution of the (R)-3a (0.1 mmol, 40.1 mg) in DMF (1.0 mL) was added and the mixture then heated at 85 °C for 3 hours.

Chiral HPLC spectrum of racemic 12
Chiral HPLC spectrum of 12

Chiral HPLC spectrum of racemic 13
Chiral HPLC spectrum of 13

Chiral HPLC spectrum of racemic 17
Chiral HPLC spectrum of 17 According to the literature, 11 an oven-dried 10 mL of Schlenk tube was charged with (R)-3h (47.1 mg,

Investigation of the Reaction Mechanism
To give more mechanistic insights for this transformation, a series of control experiments were carried out. The reactions between 1a and 2a in c-hexane at room temperature for 24 hours gave the desired 3a in more than 50% yields, indicating the strong background reaction for this transformation. Meanwhile, the reactions between 4a and 2a could also proceed in the absence of acidic catalyst, albeit lower yields.
These results clearly illustrated C3 of the pyrrole is an applicable nucleophile to attack the ketomalonate. Based on the reported literatures and the above results, we anticipated that the CPA interacts with ketomalonate via double H-bond and enhance the electrophilicity of the ketone of ketomalonate. However, it is hard to predict the possibility of the interaction between CPA and H3 of the pyrrole with these initial results at this stage.
To test the probability of the interaction between CPA and H3 of the pyrrole, a series of NMR monitoring experiments were performed. First, a solution of (S)-C8 (18.24 mg, 1.20 equiv) and 1a (4.54 mg, 0.02 mmol) was stirred in CDCl 3 (1.0 mL) at rt for 12 hour. As depicted in Supplementary   Figure 3, identical chemical shifts were observed (5.87 ppm) for H3 and H4 of pyrrole even in the presence of excess CPA (1.20 equiv). Meanwhile, a variation of the chemical shift (-0.14 ppm) was recorded as compared to the 31 P NMR of CPA as shown in Supplementary Figure 4. Subsequently, the NMR monitoring experiments were performed in c-hexane-d 12 (the developed reaction solvent is c-hexane) and identical chemical shift was detected too. Similarly, a variation of the chemical shift (+0.20 ppm) was recorded as compared to the 31 P NMR of CPA as shown in Supplementary Figure 6 with c-hexane-d 12 as the solvent.
As shown in Supplementary Figures 3-6, no variation of the chemical shift was detected for H3 and H4 of the pyrrole by the 1 H NMR spectra analysis in both CDCl 3 and c-hexane-d 12 even in the presence of excess CPA. On the other hand, inconspicuous variations of the chemical shift (-0.14 and +0.20 ppm) were observed for the CPA by the 31 P NMR spectra analysis with both CDCl 3 and c-hexane-d 12 as the solvent. The above results demonstrated the possible weak interaction between CPA and N atom of the pyrrole and then ruled out the possibility of the interaction between CPA and H3.
Finally, to verify the interaction between CPA and the other substrate ketomalonate, a solution (S)-C8