Asymmetric synthesis of chiral chromanes and exploration on their pharmaceutical activities

Abstract

Chiral chromanes are a significant class of heterocyclic compounds possessing a benzopyran hexagonal ring as the core structure. These compounds are widely distributed in natural products and pharmaceutical compounds, demonstrating remarkable biological activities. They play a crucial role in the treatment of various diseases such as cardiovascular diseases, diabetes, obesity, hypertension, central nervous system disorders, endocrine diseases, and infectious diseases. The asymmetric synthesis of chiral chromanes and their derivatives has been an area of great interest in organic synthesis and pharmaceutical applications.

This study aimed to develop a CuCl/(R, R)-Ph-BPE-catalyzed enantioselective hydroallylation reaction using allylic phosphate electrophiles for the synthesis of chromanes and thiochromanes. Additionally, the antioxidant and anti-inflammatory activities of these compounds were explored.

Optimal reaction conditions were determined for the copper(I) hydride-catalyzed hydroallylation of chromene and allylic phosphate electrophiles. The catalysts used were CuCl and the chiral bisphosphine ligand L1, while LiOtBu served as the base, phenylsilane as the silane reagent, and THF as the solvent. With the optimized reaction conditions in hand, investigations were carried out to examine the applicability of chromene reactants bearing diverse substituents, thereby expanding the scope of the study. Substituents at the C6 position of chiral chromanes and thiochromanes, ranging from electron-donating to electron-withdrawing groups, were found to be well-tolerated, thus enhancing the versatility of these compounds. Moreover, smooth transformations were observed at the C2, C3, C7, and C8 positions of chiral chromanes. The substrate scope of allylic phosphates was also significantly broadened, accommodating various groups at position 2. These findings underscore the adaptability and potential applications of chromanes and thiochromanes in diverse chemical contexts. The absolute configuration of chromane 153A was confirmed as R through X-ray crystal structure analysis. Furthermore, the newly developed methodology was successfully employed to convert chromane 106A into two valuable chiral intermediates, namely 174A and 175A.

Subsequently, in vitro experiments were conducted to evaluate the antioxidant and anti-inflammatory effects of template chromane 3aa in RAW 264.7 macrophages. The newly synthesized chromanes and thiochromanes were screened to explore their structure-activity relationship. The results indicated that chromanes and thiochromanes possessing electron-donating groups (-Me and -OMe) exhibited superior antioxidant activity compared to those with electron-withdrawing groups (-Br, -Cl, and -Ph). Additionally, chiral thiochromanes demonstrated better antioxidant potential than their oxygen counterparts. Regarding anti-inflammatory studies, chromanes and thiochromanes exhibited significant inhibitory activities against the secretion of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Chromane 116A emerged as the most potent inhibitor among the compounds tested.

In conclusion, this study presented a novel synthetic methodology for the efficient synthesis of chiral chromanes and thiochromanes, providing valuable building blocks for the preparation of biologically active compounds containing oxygen and sulfur functional groups. The developed methodology enabled the construction of complex molecular architectures. Moreover, the experimental findings established a solid scientific foundation, supporting the potential of the newly synthesized chromanes and thiochromanes as promising lead candidates in the development of pharmaceutical agents targeting antioxidant and anti-inflammatory pathways.