Totally Synthetic by Paul H. Docherty, 26 November 2006

Total Synthesis of Discodermolide & Dictyostatin Hybrid

Paterson

I. Paterson, N. M. Gardner, Chem. Commun. 2007, 49-51.

Not strictly a total synthesis, this paper discussed the synthesis of a hybrid of discodermolide and dictyostatin, both previous conquests of the Paterson group. Clearly, from the structures shown below, these molecules are intimately related in construction, and Curran has shown that a constrained macrocycle hybrid may be more potent. This led them to the structure above, containing elements of both molecules, that could be assembled in part from fragments from other work.

I’m not going into a full discussion of the synthesis, because as impressive as it is, most of the work is in the previous articles. However, the retroanalysis below shows the synthesis from the most advanced fragment. The most ambitious step is definitely the aldol reaction, utilising the groups experience with 1,6-induction in similar boron aldol reactions to gain an impressive 95:5 d.r.

The hybrid, at the end of the day, showed impressive cancer cell growth inhibitory properties, proving it to be the most active discodermolide/dictyostatin hybrid so far.