Nat. Commun, Professor Tan bin and Assistant Professor Wang Jun, South University of science and technology: Construction of axially chiral aryl pyrrole catalyzed by CPA

Axial chiral arylpyrrole is the core framework of a series of natural products and drugs, which is widely used in organic synthesis due to its special stereostructure For example, the arylpyrrole framework exists in a large number of chiral phosphine ligands, which can be applied to a variety of transition metal mediated reactions (Figure 1) More importantly, optically pure aryl pyrrole derivatives can also be used as chiral resolution agents, chiral ligands and chiral catalysts in asymmetric reactions (source: Nat Commun.) however, in the past, the conventional method to obtain optically active aryl pyrrole was to use chiral resolution agent or chiral column for optical resolution of racemates, which not only requires stoichiometric chiral reagents, but also limits the range of substrates Recently, Professor Tan bin and Assistant Professor Wang Jun of South University of science and technology established the first asymmetric Paal Knorr reaction to prepare enantiomeric rich axially chiral arylpyrrole, but its application is limited by the complex catalytic system and narrow substrate range Recently, the enantiomeric enrichment of axially chiral aryl pyrrole has been successfully prepared by the selective desymmetrization and kinetic resolution of enantiomers catalyzed by chiral phosphoric acid (CPA) In this strategy, a series of aryl pyrrole compounds were obtained with high yield and high enantioselectivity under mild conditions by remote control of chiral catalysts Relevant research results were published in NAT Commun (DOI: 10.1038/s41467-019-08447-z) (source: Nat Commun.) recently, bencivenni group reported a remote control method for the chirality of succinimide axis, which was realized by Michael addition reaction of asymmetric intercalation of arylamides catalyzed by amines (Figure 2a) The key of this method is the recognition of the symmetry plane of maleimide by catalyst The hydrogen bond between the carbonyl oxygen of the substrate and the protonated quinine ring in the catalyst is very important for the excellent stereoselectivity of the reaction Inspired by this work, the authors assume that 2,5-disubstituted aryl pyrrole, which is easy to obtain, will be a suitable prochiral substrate for enantioselective desymmetry or kinetic resolution under the remote stereo control of organic catalysts, so as to obtain the desired axial chiral framework Then, at room temperature, using 10 mol% spinol derived CPA (s) - C1 as catalyst, 1 - (2-tert-butylphenyl) - 2,5-dimethyl-1h-pyrrole 1a and keto malonate diethyl ester 2A as model substrate, the feasibility of the above hypothesis was studied It is gratifying that the desired axially chiral arylpyrrole 3A was successfully obtained in 74% yield, but the EE value of the reaction was only 22% (Table 1, entry 1) After that, the author found that CPA with large steric substituents can significantly increase the stereoscopic control of the reaction The (s) - C8 derived from h8-binol with 2,4,6-triisopropylphenyl at 3,3 '- position is the best, and the target product 3A can be obtained in 93% yield with EE value of 90% In the presence of 5 mol% of (s) - C8, the reaction of 1.5 equivalent 1a and 2A in cyclohexane was successful at room temperature, and the yield of 3 A was 96% and EE was 95% (source: Nat Commun.) after determining the optimal reaction conditions, the author first investigated the substrate range of symmetric arylpyrrole (1a-1r) Most of the substrates can react completely in 64 hours, and the target chiral aryl pyrrole (Table 2, 3A - 3R) has high yield (82% - 99%) and excellent enantioselectivity (83% - 97% ee) The excellent enantioselectivity (3S - 3U) can also be obtained by changing the ester part of keto malonate In addition, the absolute configuration of the axial chiral product was determined to be (AR) by single crystal diffraction analysis of 3S (source: Nat Commun.) in order to further expand the range of substrates, the feasibility of kinetic resolution of asymmetric racemic arylpyrrole was explored In this paper, asymmetric aryl pyrrole Racemates with aromatic substituents on pyrrole rings were prepared and reacted under standard conditions Results as shown in Table 3, all the reactions were carried out smoothly, and had a good and high selectivity factor (s = 32-69, 5a-5l) Regardless of the space and electronic properties of the substituents on the substrate, the corresponding products can be obtained in 42% - 47% yield and 87% - 94% ee In addition, the absolute configuration of 5A is determined as (as) by X-ray diffraction (source: Nat Commun.) based on the above experimental results and literature reports, the author proposed the single function activation mode of asymmetric transformation (Figure 4b) The hydrogen bond between keto malonate and CPA is the key to the formation of chiral pocket to induce chirality The second carbonyl group of keto malonate is necessary to fix the whole system in the rigid structure (source: Nat Commun.) conclusion: the author has successfully developed a highly efficient method for the synthesis of axially chiral aryl pyrrole derivatives by using two complementary asymmetric conversion strategies (desymmetry / kinetic resolution) In this method, CPA is used as chiral catalyst, the yield of product is high and the enantioselectivity is excellent The key of this method is to realize the axial chirality of the product by remote control, which makes the stereochemistry of the chiral catalyst transfer along the C-N axis of arylpyrrole.