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Totally Synthetic by Paul H. Docherty, 25 February 2010

Total Synthesis of Communesin F


P. Liu, J. H. Seo, S. M. Weinreb, Angew. Chem. Int. Ed. 2010, 49, 2000-2003.

DOI: 10.1002/anie.200906818

Quite a congested little molecule, isn't it? I felt that a 3D representation might help show the almost cage-like structure. I haven’t seen many molecules with this skeleton before, so I was surprised to see that it was isolated in Penicillium mold; however, this was found growing on a marine algae, so I guess that makes for some pretty special biosynthetic machinery. This makes for a target with an appealing biological activity - microfilament disruption leading to cytotoxicity, so it’s clear why there’s been quite a bit of synthetic action here.

The synthesis starts with a pretty large fragment, but it was easily made using a Suzuki coupling to produce the styrene (o-nitro phenyl boronic acid), and an acid chloride amide formation to couple the left part. However, that aryl iodide looks like it’s there for a reason - a Heck coupling. Treatment of the starting material with a fairly standard catalyst system results in a 5-exo closure to give the quaternary center, and provide the tetrahydropyridine as a neat functional handle.

A couple of steps later, and it’s time to close a second intramolecular system to form a further ring, using an alane amine complex to do a rather neat reductive amination. The diastereoselectivity here is fairly impressive - no numbers quoted, so I assume it’s complete. Right after, the enamine is used in a [3+2] cyclisation with an azide. In this case, the azide is cyanogen azide; not a molecule I’d have thought to be particularly stable! It turns out that this is a pretty nasty compound, having featured in Derek Lowe’s famous Things I Won’t Work With list… To quote Derek:

Cyanogen azide is trouble right from its empirical formula: CN4, not one hydrogen atom to its name. A molecular weight of 68 means that you’re dealing with a small, lively compound, but when the stuff is 82 per cent nitrogen, you can be sure that it’s yearning to be smaller and livelier still.

To be fair to it, though, it reacts really nicely here to give an intermediate product from the [3+2], and then expel nitrogen (surprise!) to give the amidine - a neat handle for installing a carbonyl, or amide in this case. However, I’d like to know if more routine methods were tried, such as a Wacker oxidation…

A few steps further on, and quite a bit has happened. Alkylation of the benzylic position was done by simply forming the enolate and trapping the allyl iodide, and a few functional group transformations delivered the pendant azide. I’m surprised how resilient the primary azide is, as it remained intact during all their attempts to olefinate the benzaldehyde. Unfortunately, the aldehyde did too, requiring a different strategy to install the enone. It turns out that the world’s simplest aldol system was required - a bit of caustic and some acetone. That's it!

The last bit of chemistry I really liked was the formation of the soon-to-be-bridging piperidene system. This was done by stirring up the amine in the presence of an allylic alcohol and PPTS, allowing a conjugate addition/elimination to complete the ring, and engender some diastereoselectivity.

It didn’t take much more to complete this elegant synthesis - a complex and effective route.