Research Projects

Natural products have long been foundational to drug discovery, offering treatments for cancer, infectious diseases, and more. Although their prominence declined in the 1990s with the emergence of high-throughput screening (HTS) and combinatorial chemistry, these synthetic approaches failed to replicate the structural complexity and diversity of natural compounds, yielding only one FDA-approved drug (sorafenib) since the 1980s. Renewed interest—fueled by advanced analytical techniques—has reaffirmed the value of natural products, with over 50% of approved small-molecule drugs (1981–2019) derived from or inspired by them.¹ Lignans, a major class of plant-derived polyphenolic compounds, hold significant therapeutic potential, particularly the aryl tetralin and aryl naphthalene subclasses.² Podophyllotoxin (I) is a key precursor to clinical topoisomerase II inhibitors such as etoposide (IIa) and teniposide (IIb), used in anticancer therapies.³⁻⁴ Other derivatives, including GL-331 and NK-611, are in various stages of clinical evaluation. Podophyllotoxin itself is topically used to treat HPV-induced warts, while its stereoisomer, picropodophyllin (III), is a clinical-stage IGF1R inhibitor with demonstrated efficacy against glioblastoma and rhabdomyosarcoma.⁵ Recent oxygenated analogs—erlangerins C & D (IV & VI) and 3α-O-(β-D-glucopyranosyl)desoxypodophyllotoxin (VII)—exhibit promising activity, especially against breast and ovarian cancers.⁶⁻⁷ However, synthetic access to such oxygenated lignans remains underexplored. Aryl naphthalene lignan lactones, by contrast, offer rigid, stereocenter-free frameworks with diverse substitution patterns, including retro-lignans and 7-oxygenated/glycosylated derivatives.⁸⁻⁹ Notable examples include patentiflorin A, justiprocumin A, diphyllin, and daurinol, which show strong antiviral activity (anti-HIV, anti-Ebola, anti-influenza, anti-COVID) and anticancer properties. Daurinol has also demonstrated anti-metastatic effects, improved radiotherapy responses, and potential in autoimmune arthritis treatment. Despite the structural diversity and therapeutic promise of lignans and related polycyclic scaffolds, no unified synthetic strategy currently enables the efficient generation of both natural and unnatural derivatives. Most existing approaches are highly target-specific and overlook principles of atom-, step-, and pot-economy.¹⁰⁻²³ To address this gap, the proposed research aims to establish a concise, unified, and sustainable synthetic platform for constructing diverse lignan cores (tetralin, dihydronaphthalene, naphthalene), butyrolactone natural products (e.g., paraconic acids, sesquiterpene lactones), and functional (hetero)polycyclic arenes from simple, readily available starting materials—advancing both drug discovery and materials science. Building on the PI’s extensive background, this work identifies alkylidene succinates—especially the Stobbe adduct (easily accessed) and itaconate (commercially available, inexpensive)—as promising substrates, contingent on overcoming challenges in α-selective C–C bond formation. The proposal aims to design and optimize mechanochemical strategies for α-selective alkylation/acylation of these substrates and explore subsequent transformations to access structurally diverse lignans and related frameworks. Moreover, the development of catalytic enantioselective protocols will enable the asymmetric synthesis of oxygenated tetralin lignans—an area yet to be explored. For structures I–XI and references 1–23, see Figure 1 and references in Part B.