Totally Synthetic by Paul H. Docherty, 10 December 2006
Total Synthesis of Rapamycin
M. L. Maddess, M. N. Tackett, H. Watanabe, P. E. Brennan, C. D. Spilling, J. S. Scott, D. P. Osborn, S. V. Ley, Angew. Chem. Int. Ed. 2007, 46, 591-597.
It’s been in the works for quite a while, but Steve Ley’s synthesis of Rapamycin has just been published. This complex molecule has a multitude of biological activities, including an interesting immunosuppressive profile, resulting in clinical usage following organ transplantation. So, unsurprisingly, it’s been the target of many projects, with complete total syntheses published by Smith, Danishefsky, Schreiber and KCN.
So what makes this one different? Well, it does have one of the most interesting macrocyclisations I’ve seen since Jamison’s paper, and a very nice demonstration of the BDA-aldol methodology. The overall strategy is also impressive, so on with the retroanalysis:
First stop is the BDA-aldol reaction; this type of chemistry is interesting, because the protecting group for the diol is also the stereodirecting group. The stereochemistry for this comes from a glycolic acid, and has been used in this manner by the group before. The result is as impressive as ever, with a high yield, and presumably a very high d.r. (no mention of actual numbers).
The rest of the fragment synthesis was completed in a succinct and competent manner, but using relatively well known chemistry. However, I was especially impressed with the macrocyclisation I mentioned:
Tethering the free ends of the linear precursor with a simple etherification/esterification onto catechol gave then a macrocycle holding the desired reaction centres together. Treatment of this with base then induces a Dieckmann condensation type cyclisation to deliver the desired macrocycle. Of course, at this stage, only a few more steps were required to complete the molecule, and end an era of the Wiffen Lab.