Catalyst Aggregation State Flips Chirality in Anti-Inflammatory Phosphine Synthesis

Chemists at Hong Kong Baptist University have reported an unusual asymmetric reaction in which simply adding pyridine to the reaction flask reverses the handedness of the product. Professor Jun Wang’s team, working in the Department of Chemistry, developed a stereodispersive phosphine hydrogenation of chromones in which the same Zn-ProPhenol catalyst system delivers either the (R)- or the (S)-enantiomer depending on whether the catalyst exists as a monomer or a dimer in solution. The work, published as an open access Research Article in CCS Chemistry, the flagship journal of the Chinese Chemical Society, combines mechanistic experiments, nonlinear effect analysis and density functional theory calculations to explain how the aggregation state of a catalyst can steer stereochemistry, and then applies the resulting compounds to anti-inflammatory studies.

Organophosphorus compounds occupy an important position in biochemistry, agriculture and medicine, yet the clinical applications of phosphine oxide-containing compounds remain limited despite their promising biological activities. One instructive precedent is brigatinib, a targeted drug for treating ALK-positive metastatic non-small cell lung cancer that is derived from crizotinib. Introducing a phosphine oxide group into brigatinib provides a novel hydrogen bond acceptor, increases water solubility, reduces protein binding and improves metabolic stability, giving superior efficacy compared with its prodrug. Such examples of optimizing drug activity through phosphorus-containing groups inspired the authors to design novel phosphine oxide compounds and explore their biological applications. A second consideration is stereochemistry: the specific configuration of enantiomers often influences physiological processes in vivo, and the opposite enantiomers of a target molecule can normally be obtained only by switching the configurations of the chiral components in the reaction system, typically a chiral catalyst or a chiral ligand.

Divergent asymmetric synthesis offers an alternative, allowing different chiral isomers to be constructed through simpler and more efficient pathways such as changing reaction temperature, time or additives. This flexibility is of great significance for drug development, because each enantiomer of a candidate drug may need to be evaluated separately. The Wang research group has long studied novel chiral organophosphine compounds, flavonoids and their anti-inflammatory activities. In the new work they report a stereodispersive asymmetric hydrophosphineization reaction of chromones that depends on the catalyst’s aggregation state. Using density functional theory calculations, they propose that the enantiodispersiveness stems from different catalyst aggregation states: without pyridine the catalyst tends to form a dimer that generates the (R)-configuration product, while the addition of pyridine inhibits catalyst aggregation, leaving a monomeric catalyst that yields the (S)-configuration product.

The reaction itself is described as the first stereodispersive phosphine hydrogenation catalyzed by a Zn-ProPhenol catalyst system controlled by pyridine additives. The authors chose chromones as model substrates because of their well-established biological activities and wide applications in the pharmaceutical field. Based on previous research, they hypothesized that the Zn-ProPhenol catalyst could simultaneously bind both reactants, the substrate and the reagent, through zinc coordination, thereby promoting the asymmetric hydrophosphineization of chromones. Without any additives, the optimal conditions used toluene as solvent and a reaction temperature of -25°C, giving 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, so the team expected a similar benefit here.

Instead, the pyridine experiment produced a surprise. Pyridine did not improve the yield or the ee value; under the same conditions it reversed the absolute configuration of the product to the (S) configuration, while still achieving an ee value of 96%. Encouraged by this enantiodiversity phenomenon, 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. The team also investigated the effect of pyridine on different phosphine oxide substrates, finding that diarylphosphine oxides bearing electron-donating groups yielded (S)-3af and (S)-3ag, again achieving the desired enantiomeric reversal. The ability to obtain either mirror image of the product from a single catalyst system, simply by adding or omitting one small additive, is a rare and practically valuable feature for synthesis planning.

The mechanistic clues came from nonlinear effects and from what happened in the flask. Nonlinear effects were observed in the reactions both with and without pyridine, indicating catalyst aggregation in both cases. Furthermore, a large amount of precipitate formed during the reaction with pyridine, leading the authors to propose a dimerized Zn-ProPhenol catalyst and to suggest that the dimer catalyst may precipitate from the reaction system, with pyridine accelerating this process. Further investigation into the reaction progress and the effect of catalyst dosage on the product ee value confirmed a multi-species catalytic mechanism involving different catalyst morphologies. The authors therefore propose that the enantiodiversity originates from a monomer-dimer dual-track catalytic system: the monomeric Zn-ProPhenol complex tends to generate one enantiomer, while the dimeric species primarily produces the other.

Density functional theory calculations provided strong evidence for this stereodispersive selectivity mechanism. The study calculated the free energies of pre-specified reaction pathways for the formation of (R)-3aa and (S)-3aa. In the absence of pyridine, the dimeric Zn-ProPhenol complex likely functions as the active catalyst, and 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 rings makes the transition state TSA3-4R more stable, with an energy difference of 3.3 kcal/mol, explaining the (R)-selectivity observed experimentally. When pyridine is present, the authors hypothesized that it participates in the system to form monomeric Zn-Pyr-ProPhenol species B2. DFT calculations show that the transition states TSB3-4_S and TSB5-6_S are more than 6.2 kcal/mol lower in energy than their corresponding (R)-configuration transition states during formation of the (S)-configuration product, consistent with the experimental observation of the (S)-product in the presence of pyridine.

Beyond synthetic chemistry, the products were put to work in biological experiments. To clarify the contribution of the phosphine oxide group to the anti-inflammatory activity of 2-phosphorylchromone 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, including phenyl-substituted compounds 6a and 6b and unsubstituted compounds 7a and 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. A subset of the obtained 2-phosphorylchromones exhibited potent anti-inflammatory activity, inhibiting the production of macrophage cytokines in vitro.

Compound (R)-3qa emerged as the standout. According to the report, a series of experiments showed that (R)-3qa exhibited significant anti-inflammatory activity both in vivo and in vitro, and in an in vivo model of inflammatory bowel disease it improved therapeutic efficacy while maintaining good safety. Incorporating the phosphine oxide group into the chromone structure, while maintaining biocompatibility, endows the molecule with potent anti-inflammatory effects targeting specific pathways, meeting the urgent need for novel skeletons in anti-inflammatory drug development. The authors state that these findings validate the potential of (R)-3qa for treating inflammatory bowel disease and reveal the important role of the phosphine oxide group in drug discovery, further demonstrating the necessity of single enantiomers in drugs. As with any preclinical study, the in vitro cytokine data and the animal model results will require further development and testing before any clinical use can be considered.

For the synthesis community, the study adds a rare example of enantiodivergence controlled not by changing the chiral catalyst but by changing its aggregation state under otherwise similar conditions. As the first asymmetric phosphine hydrogenation reaction of chromones, the transformation proceeded with various chromones and thiochromones, and different types of phosphine oxides showed good substrate compatibility. The rare nonlinear effects support the enantiodivergent monomer-dimer catalytic system under Zn-ProPhenol catalysis, and the DFT calculations indicate that the dimer catalyst induces formation of the (R)-configuration while the monomer catalyst generates the (S)-enantiomer. The work was published in CCS Chemistry, the Chinese Chemical Society’s flagship English-language journal, where all articles are diamond open access with no fees for authors or readers, making the full mechanistic and biological dataset available to chemists and drug discovery researchers worldwide.

Subject of Research: Catalyst aggregation-state-controlled enantiodivergent synthesis of anti-inflammatory 2-phosphorylchromones

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

Article References: Synthesis of 2-phosphorylchromone with anti-inflammatory activity via stereodispersive phosphine hydrogenation controlled by catalyst aggregation state. Original publication (Bibliographic details unavailable.)

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Keywords: asymmetric catalysis, Zn-ProPhenol, hydrophosphineization, chromones, phosphine oxide, nonlinear effects, DFT calculations, enantiomers, anti-inflammatory, inflammatory bowel disease, organophosphorus, drug discovery