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Totally Synthetic by Paul H. Docherty, 17 June 2010

Total Synthesis of Fastigiatine


B. B. Liau, M. D. Shair, J. Am. Chem. Soc. 2010, 132, 9594-9595.

DOI: 10.1021/ja104575h

The target of choice today is Fastigiatine, a member of the Lycopodium alkaloid family, a popular target these days. Two reason for that: 1. an interesting biological activity is beneficial for grant applications and 2. a complex, strained ringsystem makes for high impact publications. What’s not to like? Fastigiatine in particular is a tough challenge, as additional complexity has resulted in a tightly-packed pentacyclic ring-system - something Matt Shair hoped to solve with a biosynthetically inspired synthesis.

The first reaction to catch my eye is the mixed cuperate addition into a malonyl cyclopropane. The cyclopropane takes four steps from epichlorohydrin, so isn’t too bad, whilst the masked cyclohexenone was produced from the corresponding vinyl iodide (itself a five-step procedure). See the SI for full details on these. Combination of the two fragments resulted (unsurpisingly) in opening of the cyclopropane to generate most of the substrate for the next important step.

The substrate in question certainly looks reactive enough, with two olefins along with that rather sensitive looking ketal. Surprise (!) - acid unmasks the ketone, promoting a formal [3 + 3] cyclisation. I’ll leave it to Matt to explain their thoughts: “…7-endo-trig intramolecular conjugate addition to form the C6-C7 bond, tautomerization to secure the C12 stereocenter, and finally a transannular aldol reaction to form the C4-C13 bond.” A very interesting work.

Impressive as this was, the group actually targeted an even shorter route - one in which the nosyl protecting group was removed prior to cyclisation. They hoped that this would be free to react with the ketone, resulting in an initial iminium ion formation, completing the whole ring system in one cascade. However, the free amine was a too reactive, preventing them from following this plan. This left them with the final pyrollidine ring to install - a plan dispatched by firstly methylating the now-free amine.

The group speculate that this process occurs firstly by retro-aldol reaction to cleave the C4-C13 bond, then iminium ion formation and transannular Mannich reaction, using much of their original ideas. To complete the target, the group were left with just a carboxylation of the tert-butyl ester and an acetylation to finish a really sweet synthesis and a fine read.