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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.

DOI: 10.1002/anie.200604053

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.

Selected Comments

10 December, 2006 at 22:27, Ch_in_TS says:
It is Strange and at the same time impressive that C11, C25 and C27 carbons don’t epimerize during that Dieckman-like cyclisation stage
13 December, 2006 at 15:48, Sterics are a B*&%# says:
Ch_in_TS, yeah the empimerization problem is nicely handled with the bulky base, which opts for kinetic deprotonation needed for the Dieckman. This is another excellent use of this awesomely simple transformation. Just a reminder of the best use of the Dieckman in the Shair et. al total synthesis of CP.