It’s not surprising that a natural product with promising therapeutic activities will quickly become a target for total synthesis by academics and medicinal chemists alike. Furthermore, it’s no longer surprising that if the natural product in question contains a macrocycle, it will be made by ring closing olefin metathesis (RCM).
I recently came across the papers by the groups of Fürstner at the Max-Planck Institute (1) and Postema at Eisai (2) outlining their efforts toward the ipomoeassin family of natural products. What struck me is not that they both used RCM to make a macrocycle, but that both groups targeted the same bond within the macrocycle. Considering all those methylenes in that part of the molecule, why would that be? The answer is in either the supporting information (1) or the footnotes (2), and comes down to the necessary chiral secondary alcohol fragment.
How would you make the chiral alcohol shown? The best method I can think of is the one both groups used, a vinyl cuprate addition to an enantiopure epoxide. Epoxides of alpha olefins can be made in high enantiomeric excess, and the vinyl cuprate additions work well. That process dictates the fragments that both groups used, and therefore the bonds that were made by macrocyclization. At least that’s my take…
(1) Fürstner, A.; Nagano, T. J. Am. Chem. Soc., 2007, 1906-1907.
(2) Postema, M. H. D.; TenDyke, K.; Cutter, J.; Kuznetsov, G.; Xu, Q. Org. Lett., 2009, 1417-1420.