Hoppe, Becker, Bergander and FrÃ¶hlich, ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200704678.
We (that is Tot. Syn. at least) met Vigulariol just over a year ago, with a nice racemic synthesis by Steve Clark, covered on these very pixels. However, a recent asymmetric synthesis by Dieter Hoppe was brought to my attention (by one of the authors, no less – any questions, just get in line…), featuring one hell of a domino reaction!
I didn’t discuss the properties of the natural product in the previous post, so perhaps it’s time for a quick resume; it’s a cytotoxic marine diterpene of the cladiellin (eunicellin) family, of which I have a little familiarity. However, the cyctoxicity isn’t particularly potent, so let’s stick to the tasty chemical structure as a raison d’etre.
The synthesis effectively stems from a three-component-coupling, with each component the product of a short synthesis. Somewhat nicely, the central cyclohexene fragment (which was originally the product of a seven step synthesis) could be derived from a component of commercial eucalyptus oil. However, it is only present as 5%, so that must be a fun column!
The excitement starts with a substrated directed deprotonation of the cyclohexenol. The carbamate moiety ligates the lithium, which is also chelated to by the trans-tetramethyl-1,2-diaminocyclohexane. They then dump in the Ti, which performs a metal exchange, and then a Ti-mediated aldol with the aldehyde fragment, returning a reasonable 83:17 d.r. The mixture of diastereoisomers was then treated with Lewis Acid to promote the condensation onto the third fragment, the diethyl acetal. This set two further stereocentres with apparent complete control. Top banana.
Although we’re only a few steps in, they finished the synthesis with another four. A key RCM reaction tied the nine-member ring together – no mean feat, as several other groups working on this type of natural product has serious problems with RCM. Their RCM went in reasonable 45%, also yielding an eight-member ring analogue in which a methylene unit had been “snipped” out. This is annoying side-reaction of metathesis catalysts, as it destroys the SM and creates a mess, particularly in cross metathesis. Any-ho, next was a substrate controlled epoxidation with DMDO, which went in good yield, preparing them for the last cyclisation.
A bit of hydrogen loosened the benzyl protecting group, allowing THF formation, completing the carbocyclic skeleton of the natural product. All that remained was a Wittig methylenation of the ketone to complete the target. Although the yields for the reactions I’ve shown aren’t fantastic, that belies an incredible strategy for the synthesis of a complex target.