Syntheses and Photoreactivity of Chromene Natural Products

Plants with high phytochemical diversity produce an abundance and varietyof secondary metabolites which increases their chance of producing potent compounds or precursors to combat herbivory. Phototoxins are light activated secondary metabolites that plants can produce for defense against herbivores. Chromene compounds are naturally occurring phototoxins that serve as precursors to toxins that aid in a plant’s defense. Piper kelleyi is a phytochemically diverse species that contains an abundance and assortment of natural products including compounds 1 – 3. Jeffrey Research Group isolated compounds 1 – 3 from Piper kelleyi in 2014 and hypothesized that there is a biosynthetic connection between the three compounds. This hypothesis led to investigations into the biosynthetic relationship between these three compounds as well as an investigation into how the photoactivity of chromene 2 contributes to the phytochemical diversity of Piper kelleyi. The indication of a biosynthetic connection between 1 – 3 gave inspiration for further studies that were conducted with various chromene natural products. 2H-Chromenes are light-activated pharmacophores that form ortho-quinone methide intermediates upon irradiation with UV light. The short-lived, highly reactive ortho-quinone methide intermediate can be utilized in a variety of reactions to produce a library of natural products. The research presented throughout this dissertation demonstrates that the reactivity of the chromene is differentially related to its structure in all the reactions that were explored including nucleophilic trapping, dimerization, and electrophilic aromatic substitution. The nucleophilic trapping and subsequent dimerization reactions presented suggest that the addition of a phenol group on the benzopyran ring changes the reactivity of the chromene. In addition, various 2H-chromene compounds were utilized as electrophiles in light mediated electrophilic aromatic substitution (EAS) reactions. The total syntheses of piperaduncin A and piperaduncin B, isolated from Piper aduncum, were achieved through light mediated EAS. This achievement demonstrates the utility of the OQM intermediate and its ability to serve as an intermediate in natural product synthesis. EAS reactions with various chromenes and electron-rich aryl groups demonstrate that the reactivity of the OQM intermediate as an electrophile is dependent on the structure of the chromene. Herbivory of Piper kelleyi leads to oxidation products and increased compositional diversity. Due to this conclusion, oxidation reactions were performed to determine possible oxidation products present in Piper kelleyi. As series of oxidation reactions utilizing prenylated benzoic acid 1 and chromene 2 produced various oxidation products. These reactions demonstrated the labile nature of compounds 1 and 2 and give insight into potential oxidation pathways occurring in Piper kelleyi. The oxidation reactions presented could be relevant to the phytochemical landscape of Piper kelleyi