ChemInform Abstract: Total Synthesis of Coralloidolides A, B, C, and E.

Abstract

The furanocembranoids are a steadily growing family of natural products that beautifully demonstrate how nature generates complexity and biological activity through oxidative diversification of low-oxidation-state precursors. The biosynthesis of these diterpenoids involves the formation of a 14-membered cembrane ring from geranylgeranyl pyrophosphate, followed by oxidative transformations that initially install furan and the butenolide moieties. These heterocycles often engage in further oxidative processes, which underlie the remarkable skeletal and biological diversity of the furanocembranoids. In previous publications, we and others have identified rubifolide (1) (Scheme 1) as a possible biosynthetic precursor of bipinnatin J (2) and numerous other complex diterpenoids, such as intricarene and bielschowskysin. We have now expanded this proposed set of biosynthetically related molecules to include the coralloidolides, a family of diterpenoids isolated from the alcynoacean coral Alcyonium coralloides by Pietra et al. As such, they were the first furanocembranoids to be found in a Mediterranean organism, in contrast to most other members of the family, which are of Caribbean origin. It is intriguing to speculate that the coralloidolides are naturally derived from rubifolide (1). Rubifolide (1) has been found in other tropical corals, such asGersemia rubiformis, as well as in a nudibranch, Tochuina tetraquetra, but it has not been isolated from A. coralloides. In the biosynthesis presumably epoxidation of the electrophilic D double bond yields coralloidolide A (3). Oxidative cleavage of the furan ring of 3 then affords coralloidolide E (4), which features a prominent 2,5-diene-1,4-dione moiety (Scheme 1). This functional group lends itself to several alternative reaction pathways, resulting in the formation of other members of the coralloidolide family. In the first of these, hydration of the dienedione functionality and transannular opening of the epoxide in 4 would give the tetracyclic coralloidolide B (5). It is conceivable that this intricate bisacetal could rearrange to yield coralloidolide D (6). Alternatively, selective tautomerization of 4 and double-bond isomerization could afford dienone enol 7, which could undergo transannular aldol addition to the C6 carbonyl to afford coralloidolide F (8). Finally, a second mode of tautomerization and aldol addition (via 9), followed by shifting of the double bond to the thermodynamically more stable position, would afford coralloidolide C (10). We have recently described a short synthesis of racemic bipinnatin J (2) and its near-quantitative transformation to rubifolide (1) (Scheme 2). Our efficient synthetic approach puts us in a position to test the proposed biosynthetic relationships in the laboratory in depth and identify conditions for the selective interconversion of the coralloidolides. Scheme 1. Rubifolide and its proposed biosynthetic relations with bipinnatin J and the coralloidolides.