ACS catalyst: Professor Chen Yingchun's research group of Sichuan University constructed the axial chiral framework containing 3-pyrrole by asymmetric Barton zard reaction

Pyrrole is a kind of electron rich heterocycle, which widely exists in natural products and materials The Barton zard reaction of α - isocyanoacetate with Nitroalkenes is one of the classical methods for the direct construction of highly functionalized pyrrole (scheme 1b) However, the reaction has not yet been used for asymmetric transformation because there is no stereocenter in pyrrole skeleton Recently, Professor Chen Yingchun's research group of Sichuan University has developed the enantioselective Barton zard reaction by using the central axial chiral transfer strategy A series of axially chiral 3 - (hetero) arylpyrrole derivatives were synthesized by the reaction of α - substituted Nitroalkenes with (hetero) aryl groups and α - isocyanate catalyzed by Ag 2O and the phosphine ligands derived from cinchona base Relevant research results were published on ACS Catalysis (DOI: 10.1021 / acscalal 9b00767) (source: ACS catalyst.) will produce three-dimensional center in the Michael addition step in the early stage of Barton zard reaction Therefore, the author proposes to introduce appropriate ortho substituents into β - aryl - α - substituted Nitroalkenes through the center to axial chiral transfer strategy After continuous cyclization and removal of HNO 2, the axial chiral 3-arylpyrrole framework can be constructed（ Scheme 1c ）。
In order to verify the above conjecture, in the presence of excess K 2CO 3 and chiral phase transfer catalyst (PTC) C1, the author first carried out the Barton zard reaction of nitroolefin 1A containing α - methyl and β - 1 - (2-toluenesulfonyloxy) naphthyl with α - isocyanoacetate 2A (Table 1) The product 3a of 3 - (1-naphthyl) - 1h-pyrrole can be obtained in high yield, but its enantioselectivity is poor Subsequently, the author tried the catalytic system developed by Dixon group (j.am.chem.soc 2011, 133, 1710 − 1713), which has been successfully applied to the asymmetric reaction of α - isocyanoacetate It is gratifying that the combination of Ag 2O and quinine derived amino phosphine ligand L1 significantly improves the EE value of axial chiral 3a In addition, the enantioselectivity of the corresponding products can be further improved when α - isocyanoacetate tert butyl 2b is used as the substrate The results showed that phcf 3 was the best solvent for the reaction, and the enantiomeric product 3A (entries 13-17) was obtained with 92% yield and 94% ee The asymmetric reaction can also be carried out well at the scale of 1mmol (entry 21) (source: ACS catalyst.) under the optimal reaction conditions, the author investigated the applicability of the substrate (scheme 2) Nitroalkene 1 derived from 2-naphthol with different O-protecting groups has good enantioselectivity and high yield The naphthyl ring containing other functional groups is also compatible with the reaction, and the axial chiral product 3G - 3P can be obtained in excellent yield, and the reaction has excellent enantioselectivity In addition, the α - substitution of nitroalkene 1 can significantly affect the enantioselectivity of 3q and 3R Nitroalkene-1 with other aromatic rings (such as quinoline, 7-indole and phenyl) is also a suitable substrate, and its blocking isomer 3s-3v is successfully obtained However, the activity of 4-toluenesulphonylmethylisocyanide is low, and the target product 3W is obtained only in medium yield and enantioselectivity When diethyl α - isocyanomethylphosphonate or α - isocyanomethyldiphenylphosphine oxide reacts with appropriate nitroalkene 1, the corresponding axial chiral product 3x - 3Z can be obtained with high enantioselectivity In some cases, DBU or CsOH is needed to promote the final aromatization process (source: ACS catalyst.) in addition, even indole substrates with different substituents can be successfully converted into the target product 5A - 5J (scheme 3) with good yield and good to excellent enantioselectivity 3-benzofuran and 3-benzothiophene can also be obtained with high yield and excellent enantioselectivity (source: ACS catalyst.) in order to further understand the catalytic mechanism of the asymmetric Barton zard reaction, the author carried out the reaction of indole derived nitroalkene 4A and α - isocyanoacetate tert butyl 2B (scheme 6) Under the catalysis of Ag 2O and ligand L1, 5aa [3 + 2] intermediate was separated in medium yield and 95% ee value Its structure was confirmed by X-ray diffraction It is important that the axial chiral product 5A was obtained after the aromatization of 5aa at DBU, and the enantiomeric purity was retained Based on the above results, a reasonable catalytic mechanism is proposed The phosphine group of ligand L1 binds with silver, and the nitro group is coordinated in ethyl α isocyanate 2B and 4a, forming an additional hydrogen bond between the protonated quinine ring and nitrooxygen atom, resulting in the transition state ts-i Michael adduct is preferentially carried out from re face, and then through the intramolecular cyclization of transition ts-ii, the chiral cycloadduct 5aa with rotation blocked structure is obtained, which is the key to the center axial chiral transfer (source: ACS catalyst.) conclusion: a series of axially chiral 3-aryl or 3-heteroaryl pyrrole have been constructed by classical Barton zard reaction In the system of Ag 2O / cinchona base derived phosphine ligands, various Nitroalkenes with β - ortho substituted (hetero) aromatic groups react with α - isocyanoacetate or α - isocyanomethylphosphonate diethyl ester to form a series of highly enantiomeric hindered isomers with good yield and excellent enantioselectivity The separation of [3 + 2] cyclized intermediates shows that the enantioselectivity depends on the center to axial chirality transfer The authors of this paper are Professor Chen Yingchun and Associate Professor Du Wei, Huaxi pharmaceutical college, Sichuan University.