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Totally Synthetic by Paul H. Docherty, 31 July 2007

Total Synthesis of Azadirachtin


G. E. Veitch, E. Beckmann, B. J. Burke, A. Boyer, S. L. Maslen, S. V. Ley, Angew. Chem. Int. Ed. 2007, 46, 7629-7632.

DOI: 10.1002/anie.200703027

G. E. Veitch, E. Beckmann, B. J. Burke, A. Boyer, C. Ayats, S. V. Ley, Angew. Chem. Int. Ed. 2007, 46, 7629-7632.

DOI: 10.1002/anie.200703028

The completion of Azadirachtin, like Rapamycin, marks the conclusion of a lengthy chapter in the Ley group. It must be very odd to have these groups of natural compounds complete, published and no longer a hot topic in the lab…

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 an interesting insect antifeedant. Basically, Azadirachtin causes growth-disruption and antifeedation 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. The more attractive (or terrifying) aspect of the target to us organic chemists are the sixteen contiguous stereogenic centers!

I promised a retrosynthetic analysis, 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 an interesting 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 and a previous Ley paper. Either way, the chirality transfer goes well, and they have the desired allene. Now, to generate the radical, they use some Barton/Motherwell chemistry, forming the xanthate ester from a free alcohol, and were set to cyclise:

Now that’s a nice cyclisation! The methodology might not be new, but the yield shows how useful a well-planned radical cyclisation can be.

The decalin fragment is certainly a challenge all by itself, containing ten contiguous stereocenters, and complex oxygenation. Most of the work on this fragment was referenced back to previous papers by the group, and from what I read, most of the information is in this Perkin 1, and this Tetrahedron paper.

Their synthesis of this portion is well envisaged, starting with generation of four stereocenters from an intromolecular Diels-Alder reaction. Importantly, the endo/exo control comes from their use of a silane precursor, which gave them the endo product in a 5:2 ratio. Without this functional group, the ratio was reduced to 1:7, so was fairly important.

It was also the control element in the next transformation, an intramolecular aldol, which created a further three stereocenters with good control. The desired diastereoisomer was received in a reasonable yield, along with a further 10% of the methyl ketal, which was converted to the hemiketal easily. The silyl group was transformed into the required hydroxyl with retention of stereochemistry using mercuridesilylation, (a modified Tamao-Flemming oxidation).

Also noteworthy in the Perkin 1 paper was the chain reduction of an aldehyde by formation of the corresponding silyl enol-ether and ozonolysis. Such a simple method, it must have been done before - but this is the first time I’ve seen it.