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Totally Synthetic by Paul H. Docherty, 19 February 2007

Total Synthesis of Papulacandin D


S. E. Denmark, C. S. Regens, T. Kobayashi, J. Am. Chem. Soc. 2007, 129, 2774-2776.

DOI: 10.1021/ja070071z

Papulacandin D and the rest of the family represent an interesting synthetic challenge, as well as a powerful antifungal treatment. The first and only total synthesis of this natural product was completed by Tony Barrett, back in ’96, using not entirely different disconnection, but I guess that is no surprise. However, the implementation of the chemistry used by Denmark is quite different.

The retrosynthetic analysis perhaps doesn’t give too much away, other that the rather nice allylation chemistry. Incidentally, I wasn’t sure how to represent it on a retroanalysis, but the C14” stereocenter was introduced via an asymmetric hydrogenation, meaning that they could construct the bulk of that lipophillic sidechain from geraniol. They were able to extend the sidechain with a bit ozonolysis, and then a Wittig to put in the more removed diene. The oxygen functionality was then reduced/oxidised to the aldehyde, with which they did a rather interesting allylation, providing a decent amount of diastereomeric control.

The key transformations, at least for me, were those assembling the spiroketal. Just a few steps, leading to impressive complexity. So, starting with a chiral THP protected differentially, but with three silyl groups, they were able to oxidise the free silane to the silanol using a ruthenium catalyst and water. This gave them a synthetic handle, allowing a Hiyama-type coupling to the aryl iodide. With this inplace, they removed the pivolyl protecting group, and performed a tandem epoxidation/opening on the THP, returing the desired spiroketal in an impressive 77% yield. Good work!!

Completion of the target then required some careful protecting group manipulations, and a Yamaguchi esterification to unify the two fragments, and finish this top paper.