Totally Synthetic by Paul H. Docherty, 23 March 2010
Total Synthesis of Coralloidolide A, B, C & E
T. J. Kimbrough, P. A. Roethle, P. Mayer, D. Trauner, Angew. Chem. Int. Ed. 2010, 49, 2619-2621.
Back in 2006, Dirk Trauner (still at Berkeley back then) completed a rather neat total synthesis of Bipinnatin in just nine steps (including a very nice Alder-ene reaction…). This synthesis was actually a means to an entire series, as Bipinnatin can be converted into a whole-load of natural products in a biosynthetic fashion. This was also published in 2006, and resulted in Intricarene (using a 1,3-dipolar cycloaddition), as well as Rubifolide and Isoepilophodione.
The most recent work in Angewandte takes this further, turning Rubifolide into the Coralloidolide family, again using biosynthetic principles. I’m not going into the Bipinnatin J synthesis, but I’ll mention that reduction of Bipinnatin J into Rubifolide needs only triethylsilane, selectively removing hydroxyl in almost quantitative ease. Now to the new stuff - starting with an oxidation. Using hydrogen peroxide, a nucleophilic epoxiation selectively oxygenates the furanone, entirely diastereoselectively, and yielding the first Coralloidolide, A. Switching to mCPBA, the furan is oxidized to a 1,4-diketone (a rather suspicious-looking dienedione). This is a further Coralloidolide - E this time. I’m amazed that this molecule is stable enough to be isolated.
Finding reliable conditions for transformation of Coralloidolide E was an effort, with Trauner describing loss of much of their material to ‘a large number of intractable products’. Instability is the key, though, as treatment of this with scandium triflate resulted in a double transannular ring closure, producing a dihydrofuran and a tetrahydropyran oxepine, along with a pair of stereocenters. Bizarrely, only dioxane is good enough for this reaction - other polar-aprotic solvents such as DMF don’t do the trick. Trauner believes the mechanism is distinctly stepwise, with a hydration of the dienedione first, and then closure onto the epoxide, and that the scandium triflate is required for both steps. Trauner also manages to effect a total synthesis of Coralloidolide C, using DBU to perform a transannular aldol reaction on Coralloidolide E, rounding off a rather neat bit of work.