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10 December 2006 9,672 views 5 Comments


Ley, Maddess, Tackett, Watanabe, Brennan, Spilling, Scott and Osborn. ACIEE, 2006, EarlyView. 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 beast 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 retro:

First stop is the BDA-aldol; this type of chemistry is interesting, because the protecting group for the diol is also the stereo-directing 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.

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  • provocateur says:

    Its interesting to see the macrocyclization…very interesting in the sense tht u wld hv to get both sides of the catechol functinalized with both ends of the macrocycle to be joined which in one way itself is challenging…
    by the way ….kongrats on a very scholarly blog ts.kip(keep it up!!!!!)

  • 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

  • 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 synthesis of CP.

  • ranfiddler says:

    en…the Dieckmann-like cyclization likes another version of the Chan reaction (1984). It’s very impressive of the application in such big macrocyclic molecule.

  • [...] The completion of Azadirachtin, like Rapamycin (blogged back in December), marks the conclusion of a lengthy chapter in the Ley group, and having been a student at Cambridge for a few years, the progress on these molecules was frequently subject to rumour. It seemed that everyone knew someone who had worked on either, going back years to the early work. It must be very odd to have them complete, published and no longer a hot topic in the lab… Also, props to Alastair and and everyone else I know on this paper. Anyway, many of you will also have met this molecule in publications leading up to the total synthesis, but for those who haven’t, it’s a complex in biologically interesting insect antifeedant. Basically, it causes and growth-disruption and antifeedation (sp?) in insect species which are detrimental to the plant in which it is found, but not to insects which aid the plant, such as lady-birds and bees. Interesting, but to us organic chemists, the more attractive (or terrifying) aspect of the target are the sixteen contiguous stereogenic centers! It’s certainly quite a beast, and I’ll attempt a retrosynthetic analysis tomorrow. To me, however, the most impressive transformation was the synthesis of the bicyclic ether via a radical cyclisation onto an allene. First, of course, they had to make the allene, which they did using a rather tasty Claisen rearrangement: [...]