Denmark, Regens and Kobayashi. JACS, 2007, ASAP. DOI: 10.1021/ja070071z.
Definitely a target of split personalities, or at least lipophillicities, papulacandin D and the rest of the family represent an interesting synthetic challange, as well as a powerful antifungal treatment. The first and only 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 a different beast, using his own chemistry twice, and in a useful manner.
The retro-synthetic 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 retro, but the C14” stereocentre was introduced via a 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 (referenced to a Methods. Carbohydr. Chem. paper, so I’ll assume some gross sugar-bashing), protected differentially, but with three siyl 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.