Synthesis of 2-phosphorylchromone with anti-inflammatory activity via stereodispersive phosphine hydrogenation controlled by catalyst aggregation state

Professor Jun Wang's team from the Department of Chemistry at Hong Kong Baptist University reported a rare stereodispersive phosphine hydrogenation reaction. Using nonlinear effect theory and DFT calculations, they proposed a reaction mechanism regulated by the aggregation states of different catalysts, confirming the important application of nonlinear effects in asymmetric synthesis. Furthermore, novel compounds with different stereoconfigurations synthesized through these reactions were applied to anti-inflammatory activity studies. A subset of the obtained 2-phosphorylchromones exhibited potent anti-inflammatory activity, inhibiting the production of macrophage cytokines in vitro and improving therapeutic efficacy while maintaining good safety in an in vivo model of inflammatory bowel disease (IBD). These bioactivity studies further demonstrate the necessity of single in drugs. The article was published as an open access Research Article in CCS Chemistry, the flagship journal of the Chinese Chemical Society.

Background Introduction:

Organophosphorus compounds have established an important and unique position in biochemistry, agriculture, and medicine. Despite the promising biological activities exhibited by compounds containing phosphine oxide, their clinical applications remain limited. Brigatinib, a targeted drug for treating ALK-positive metastatic non-small cell lung cancer (NSCLC), is derived from crizotinib: the introduction of a phosphine oxide group into brigatinib provides a novel hydrogen bond acceptor, increases water solubility, reduces protein binding, and improves metabolic stability, resulting in superior efficacy compared to its prodrug, crizotinib. Such precedents for optimizing drug activity through the introduction of phosphorus-containing groups have inspired the authors to design novel phosphine oxide compounds and explore their biological applications. On the other hand, the specific configuration of enantiomers often influences physiological processes in vivo. The opposite enantiomers of a target molecule can be obtained by switching the configurations of the chiral components used in the reaction system (typically a chiral catalyst and a chiral ligand). Divergent asymmetric synthesis, on the other hand, allows for the construction of different chiral isomers through simpler and more efficient pathways (such as changing reaction temperature, time, and additives). This is of great significance for drug development.

The Wang research group has long been dedicated to the research of novel chiral organophosphine compounds, flavonoids, and their anti-inflammatory activities. Recently, they reported a stereodispersive asymmetric hydrophosphineization reaction of chromones that depends on the catalyst's aggregation state. Using density functional theory (DFT) calculations, they proposed that the enantiodispersiveness of this reaction stems from different catalyst aggregation states: without pyridine, the catalyst tends to form a dimer, generating the (R)-configuration product; while the addition of pyridine inhibits catalyst aggregation (the catalyst is a monome), thus yielding the (S)-configuration product.

Article Highlights:

1.  The first stereodispersive phosphine hydrogenation reaction catalyzed by a Zn-ProPhenol catalyst system controlled by pyridine additives. The authors chose chromones as model substrates because of their well-established and well-studied biological activities and wide applications in the pharmaceutical field. Based on previous research, the authors hypothesized that the Zn-ProPhenol catalyst could simultaneously bind both reactants (substrate and reagent) through zinc coordination, thereby promoting the asymmetric hydrophosphineization of chromones. Without any additives, the optimal conditions were to use toluene as a solvent and react at -25°C to obtain the product (R)-3aa in 80% yield with an ee value of 96%. According to literature reports, pyridine as an additive can improve the yield and stereoselectivity of Zn-ProPhenol-catalyzed addition reactions and the Henry reaction. Therefore, they investigated the role of pyridine as an additive in this reaction. Surprisingly, pyridine did not improve the yield or ee value; instead, under the same conditions, it reversed the absolute configuration of the product to the (S) configuration, achieving an ee value of 96%. Encouraged by this enantiodiversity phenomenon (stereoselectivity reversal), the authors evaluated a range of substrates to examine its universality. Both chromones and thiochromones reacted readily in the presence of pyridine, although the yields decreased slightly, the enantioselectivity was almost completely reversed, yielding (S)-3aa and (R)-3ta, respectively. Next, they investigated the effect of pyridine on different phosphine oxide substrates. Diarylphosphine oxides with electron-donating groups yielded (S)-3af and (S)-3ag, also achieving the desired reaction. It is an enantiomeric reversal.

2.  Rare nonlinear effects and the proposed reaction mechanism for catalyst polymerization morphology control. Nonlinear effects were observed in both reactions with and without pyridine, indicating catalyst aggregation. Furthermore, a large amount of precipitate formed during the reaction with pyridine. The authors proposed a dimerized Zn-ProPhenol catalyst. These phenomena suggest that the dimer catalyst may precipitate from the reaction system, and the addition of pyridine accelerates this process. Further investigation into the reaction progress and the effect of catalyst dosage on the product ee value confirmed this multi-species catalytic mechanism involving different catalyst morphologies. Therefore, the authors propose that this enantiodiversity originates from a "monomer-dimer" dual-track catalytic system: the monomeric  Zn-ProPhenol complex tends to generate one enantiomer, while the dimer species primarily produces the other enantiomer. 

3. DFT provides strong evidence for the stereodispersive selectivity mechanism of catalyst aggregation morphology. To gain a deeper understanding of the reaction mechanism and the source of enantioselectivity, this study calculated the free energies of the pre-specified reaction pathways for the formation of (R)-3aa and (S)-3aa. In the absence of pyridine, the dimer Zn-ProPhenol complex likely functions as an active catalyst. From an energy perspective, the 1,4-addition of the phosphine nucleophile to the chromone was identified as the enantioselectivity-determining step. Analysis revealed that a favorable π-π stacking interaction between substrate 1a and one of the benzene makes TSA3-4R more stable (energy difference of 3.3 kcal/mol), thus explaining the (R)-selectivity observed  experimentally. On the other hand, the authors hypothesized that the involvement of pyridine (Pyr) in the system may lead to the formation of monomeric Zn-Pyr-ProPhenol species B2. DFT calculations show that the energy of the transition states TSB3-4_S and TSB5-6_S is more than 6.2 kcal/mol lower than that of their corresponding (R)-configuration transition states during the formation of the (S)-configuration product. This is consistent with the experimental results of obtaining the (S)-product in the presence of pyridin.

4.  The product possesses excellent anti-inflammatory activity and potential medicinal value. To clarify the contribution of the phosphine oxide group to the anti-inflammatory activity of 2-phosphochromone compounds, the authors screened the highly active compounds (R)-3qa and (R)-3ja as references, and designed and synthesized a series of derivatives with the same skeleton but different substituents at the 2-position (phenyl substitution: 6a, 6b; no substitution: 7a, 7b). Pharmacophore simulation analysis revealed that phosphine oxide can act as an additional hydrogen bond acceptor, contributing to enhanced binding affinity between the compound and the target receptor. Furthermore, a series of experiments showed that compound (R)-3qa exhibited significant anti-inflammatory activity both in vivo and in vitro. Incorporating the phosphine oxide group into the chromone structure, while maintaining biocompatibility, endows it with potent anti-inflammatory effects targeting specific pathways, thus meeting the urgent need for novel skeletons in anti-inflammatory drug development. These findings validate the potential of (R)-3qa for treating inflammatory bowel disease (IBD) and reveal the important role of the phosphine oxide group in drug discovery.

Summary and Outlook:

This study reports a rare enantiodivergent synthesis catalyzed by Zn-ProPhenol. As the first asymmetric phosphine hydrogenation reaction of chromones, this reaction successfully proceeded with various chromones and thiochromones, and different types of phosphine oxides exhibited good substrate compatibility in this transformation. Notably, the addition of pyridine achieved an enantioselectivity reversal, allowing direct acquisition of enantiomers with opposite configurations. The rare nonlinear effects of this reaction system support an enantiodivergent “monomer-dimer” catalytic system under Zn-ProPhenol catalysis. DFT calculations further confirmed that the dimer catalyst induced the formation of the (R)-configuration, while the monomer catalyst generated the (S)-enantiomer. Beyond synthetic chemistry, these phosphine oxide chromone compounds exhibited significant anti-inflammatory activity both in vitro and in vivo. Incorporating phosphine oxide groups into the chromone structure, while maintaining biocompatibility, endows them with potent anti-inflammatory effects targeting specific pathways, meeting the urgent need for novel scaffolds in anti-inflammatory drug development. These findings validate the potential of (R)-3qa for the treatment of inflammatory bowel disease (IBD) and reveal the important role of phosphine oxide groups in the drug discovery process.

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About the journal: CCS Chemistry is the Chinese Chemical Society’s flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem.

About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman’s Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/.