Biomimetic Approach to Diverse Coral Diterpenes from a Biosynthetic Scaffold

Abstract

Thousands of coral terpenes originate from simple scaffolds that undergo oxidative tailoring. While corals are excellent sources of drug leads, the challenge of supplying structurally complex drug leads from marine organisms has sometimes slowed their development. Making this even more challenging, in comparison to other organisms such as plants and microbes where the terpene literature is substantial, very little is known about how the unique coral terpenes are biosynthesized and elaborated in nature. Here, we use a semisynthetic strategy to produce at gram‐scale in yeast the eunicellane scaffold that underlies >200 coral compounds. Synthetic oxidation reactions were explored, generating key scaffolds that reflect three of the four structural classes derived from eunicellane. This includes the first asymmetric syntheses of the natural products solenopodin C and klysimplexin Q. Biomimetic methods and detailed mechanistic studies of synthetic reactions shed light on potential enzymological reactivity, including the role of epoxide rearrangement in eunicellane biosynthesis. Several of the oxidative rearrangements were mechanistically unique. The results enabled a unifying scheme of eunicellane biosynthesis in the corals, define novel oxidative rearrangement routes to complex terpene scaffolds, and pave the way for creating new and known bioactive isoprenoids for applications such as pharmaceutical development.