Using Singlet Oxygen to Synthesize Polyoxygenated Natural Products from Furans

Abstract

[Reaction: see text]. Singlet oxygen is a powerful tool in the armament of the synthetic organic chemist and possibly in that of nature itself. In this Account, we illustrate a small selection of the many ways singlet oxygen can be harnessed in the laboratory to aid in the construction of the complex molecular motifs found in natural products. A more philosophical question is also addressed: namely, how much do singlet oxygen oxidations influence the biogenesis of these natural products? All the synthetic examples surveyed in this Account can be characterized as belonging to the same class because they all involve the oxidation of a substituted furan nucleus by singlet oxygen. Readily accessible and relatively simple furans can be transformed into a host of complex motifs present in a diverse range of natural products by the action of singlet-oxygen-mediated reaction sequences. These reactions are highly advantageous because they frequently deliver a rapid and dramatic increase in molecular complexity in high yield. Furthermore, an unusually wide structural diversity is exhibited by the molecular motifs obtained from these reaction sequences. For example, relatively minor modifications to the starting substrate and to the reaction conditions may lead to products as variable as spiroketal lactones, 3-keto-tetrahydrofurans, various types of bis-spiroketals, 4-hydroxy cyclopentenones, or spiroperoxylactones. In addition, two more specialized examples are discussed in this Account. The core of the prunolide molecules and the chinensine family of natural products were rapidly synthesized using effective and short singlet oxygen mediated strategies; this adds weight to the assertion that singlet oxygen is a very effective moderator of complex cascade reaction sequences. We also show how our synthetic investigations have provided evidence that these same strategies might be used in the biogenesis of these molecules. In the cases of the chinensines and the litseaverticillols, an entire and diverse family of natural products was synthesized beginning from known naturally occurring furan-bearing terpenes. Additionally, in several cases, intermediates in our syntheses have been isolated from natural sources, which suggests that we have followed the same synthetic paths as nature. Certainly, the limit of the synthetic potential of singlet oxygen has not yet been reached, and we can look forward to seeing the boundaries expand in the future in a slew of new and interesting ways.