Shair, Liau, JACS, 2010, ASAP DOI: 10.1021/ja104575h.
After wading through the Heathcock paper last week, I’m glad that today’s topic of discussion is a little shorter and easier to read. (Seriously, part of me hates reading paper older that the 90’s as the style used in the schemes and figures is so difficult to follow. Some of those 1960’s JACS papers are a real slog to get through – but worth it, normally….)
The target of choice today is Fastigiatine, a member of the Lycopodium alkaloid family, a popular target these days. Two reason for that – 1. tasty biological activity checks the right boxes on the grant applications and 2. a complex, strained ringsystem makes for high impact publications. What’s not to like? Fastigiatine in particular is a tough cookie to crack, as additional complexity has resulted in a tightly-packed pentacyclic ring-system – something Matt Shair hoped to crack with a biosynthetically inspired synthesis.
The first reaction to catch my eye is the rather busy mixed cuperate addition into a malonyl cyclopropane. I haven’t checked, but you can be fairly sure that Aldrich don’t carry these particular species, so it’s a good thing that their syntheses are fairly short. The cyclopropane takes four steps from epi-chlorohydrin, 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 resulted (unsurpisingly) in opening of the cyclopropane to generate bulk 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 (!) – a bit of 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.” Damn neat 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 reactive little beastie, preventing them from following this plan. This left then with the final pyrollidine ring to install before retiring to the pub – a plan dispatched by firstly methylating the now-free amine, the using the tried-and-tested method of heating the crap out of it.
The group speculate that this process occurs firstly by retro-aldol 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.