Synthesis of dihydrobenzofuran natural products that modulate immune response

The National Institute of General Medical Sciences awarded the California State University Long Beach Research Foundation $146,819 on August 10, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to develop synthetic approaches for preparing arylated bioactive dihydrobenzofurans that modulate immune response.

The project synthesizes five natural products—maceneolignan A, maceneolignan B, licarin A, licarin B, and acuminatin—and their structural analogs through optimization of a nickel-catalyzed cross-coupling reaction using bench-stable N-hydroxyphthalimide esters and aryl iodides as coupling reagents. This divergent synthetic strategy reduces the number of steps required to prepare structural analogs and enables late-stage diversification. The dihydrobenzofurans exhibit anti-inflammatory, anticancer, antiviral, and antifungal activity, with maceneolignan A demonstrated to inhibit chemokine receptor signaling implicated in allergic reactions, asthma, arthritis, inflammatory bowel disease, multiple sclerosis, and Alzheimer's disease. Synthesized compounds will be evaluated for their potential to modulate immune response in macrophage cell lines through collaboration with the Fraser Lab at California State University, Long Beach.

Performance occurs in Long Beach, California, with a period of performance ending March 31, 2030. The assistance type is a Project Grant.

Abstract

Dihydrobenzofuran natural products, such as maceneolignan a, are small heterocyclic molecules that exhibit a variety of bioactive properties including anti-inflammatory, anticancer, antiviral, and antifungal activity. Maceneolignan a has demonstrated efficacy in inhibiting chemokine receptor signaling, which plays a role in diseases characterized by inflammatory response such as allergic reactions, asthma, arthritis, inflammatory bowel disease, multiple sclerosis, and alzheimer's disease. While some natural products can be easily isolated from natural sources, the ability to prepare the same molecules in the laboratory can allow for structural modifications to improve potency. The goal of this project is to develop and implement a new synthetic approach to prepare arylated bioactive dihydrobenzofurans that is amenable to late-stage diversification. Our strategy will rely on optimization of a key NI-catalyzed cross-coupling reaction that appends the aromatic ring at the final step in the synthesis, ultimately providing a divergent approach that significantly reduces the number of steps required to prepare structural analogs. To address this objective, we will investigate the use of bench-stable n- hydroxyphthalimide (NHP) esters and aryl iodides as cross-coupling reagents. This type of cross-coupling reaction is quite robust but has not been demonstrated on dihydrobenzofurans. We will first optimize the required cross-coupling reaction using various strategies, and will then apply the optimal conditions to the synthesis of five natural products (maceneolignan a, maceneolignan b, licarin a, licarin b, and acuminatin) and synthetic analogs. Through collaboration with the fraser lab at csulb, synthesized dihydrobenzofuran compounds will be evaluated for their potential to modulate immune response in macrophage cell lines. IT is expected that this study will provide new knowledge in the application of cross-coupling reactions towards the synthesis of bioactive dihydrobenzofurans and begin to answer questions about how dihydrobenzofuran natural product analogs influence immune response. This interdisciplinary project is expected to provide enhanced research opportunities for undergraduate students at csulb.