Boger, Campbell, Zuhl, Liu. JACS, 2010, ASAP. DOI: 10.1021/ja908819q.
A busy week in the Boger group; it’s been a while since I blogged papers back-to-back from one group! This target has clearly developed from their work in vindoline and vinblastine, using similar synthetic techniques. Their interest in this target in particular was to assign the absolute stereochemistry; only one synthesis has been completed so far, and they didn’t check all the boxes in the submission form…
Synthetically, the first thing of note (for me at least!) is their synthesis of a 1,3,4-oxadiazole – not a hetrocycle I’m planning to crow-bar into my syntheses. Their method was surprisingly neat, using exactly the same type of substrate for the more common furan and pyrrole analogues – a 1,4 dicarbonyl. The difference here is that the spacer groups between the carbonyls aren’t the usual methylenes but a hydrazine group. This doesn’t seem to affect the reactivity – dehydration with tosyl chloride and base does the job nicely.
So why were they making such an exotic beast? Well, if you’ve read the earlier posts (don’t tell me you haven’t?!!), it’s all about this [4+2] / [3+2] business Boger’s got going on. Y’see, heating the 1,3,4-oxadiazole up causes a [4+2] onto the alkene. At this stage, the fragile looking dinitrogen bridge decides to exit stage left, leaving a 1,3-dipole, neatly stabilised by the surrounding functionality. This then reacts with the proximal indole, completing three rings and setting five stereocenters. Not bad, then.
However, this technology actually overshoots the goal. To get to the target, we need to swap out a ring, and completely remove a stereocenter. A few steps after the cascade, the group have successfully traded the methyl ester for a nitrile. Treating this with hydrofluoric acid strips of the TBS group, and provides a sufficiently acidic environment to close onto the N,O-acetal and generate the THF necessary. They still had to bin that cyanohydrin, though, which took a bit more work.
First to go was the nitrile, removed using selectride. The hydroxyl took a bit more effort, with the group going old-school and forming a xanthate ester. This seemed to be pretty convenient, as it gave then a lovely crystal structure. Good times, as they were able to separate the enantiomers with a bit of chiral preparative HPLC, and use the resulting X-ray structures to assign the absolute configuration of the natural product. Not quite as elegant as an asymmetric synthesis, but still nice.
All that remained as this point were a pair of reductions to do a Barton-McCombie deoxygenation and cleave the benzyl group. Unfortunately these had to be done sequentially, but it did give them the target – so all’s well!