Azadirachtin Pt. I
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!
I promised a retro, and here it is: the main disconnection between the two largest fragments are discussed in this post.
Their plan (which hasn’t changed too much over the years) was to split it into two large fragments – the “Decalin” component and the “Pyran” component. The decalin fragment has been the focus of several papers by the group over the years, and is covered in the following post, with the pyran unit was made with apparent ease from a galactose derivative.
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:
I find it interesting and useful that they give two sets of conditions for this reaction, and also slightly surprised that the results are identical, but the conditions couldn’t be more different. The gold chemistry references a Toste paper (no suprises! – and, as an aside, the Boss always refers to gold as being “A big proton”, which explains to me how this works), and a previous Ley paper (with my previous supervisor). Either way, the chirality transfer goes well, and they have the desired allene. Now, to generate the radical, they use some Barton/Motherwell chemistry (old-school), forming the xanthate ester from a free alcohol, and were set to cyclise:
Now that’s a nice cyclisation! (Though I am somewhat predisposed to like a good radical cyclisation…) The methodology might not be new, but the yield goes to show how useful a well-planned radical cyclisation can be.