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Totally Synthetic by Paul H. Docherty, 24 October 2010

Total Synthesis of Lycoflexine

Ramharter, Mulzer

J. Ramharter, H. Weinstabl, J. Mulzer, J. Am. Chem. Soc. 2010, 132, 14338-14339.

DOI: 10.1021/ja107533m

I love the fact that one can just look at a molecule and then guess the author of the synthesis. And when I first glanced at Lycoflexine, the name Johann Mulzer was at the top of my mind. This makes me smile for two reasons - firstly, Mulzer always works on small, yet interesting targets. Secondly, I routinely learn something new in his work. However, on closer inspection, the corresponding author is Juergen Ramharter, even though Mulzer is also named…

To say that this synthesis is concise would be a massive underestimation; eight steps is all it takes for completion. Starting with a fairly simple cyclohexenone (bearing a single stereocenter in the form of a methyl group in the 5 position), a pair of Lewis-acid catalysed additions (Hosomi-Sakurai Reaction / aldol addition) append both the allyl group and an ethanol group (converted into an acetylene later). Not content with two stereocenters and 2 carbon-carbon bonds in as many steps, they then did a further alkylation to create the quaternary centre.

Next was their planned metathesis cascade, initially using Grubbs' second generation catalyst. However, the group only achieved aprox. 30% yield. On consideration, they suspect that the diene product is unstable - and that their best move would be to reduce it. They did this by using an atmosphere of hydrogen - something I always suspected might work, but this is actually the first time I’ve seen it done. Interestingly, the precedence cited is a Grubbs paper from back in 2001 - so I’m surprised it isn’t done more often.

The cyclopentene was converted to a cyclopentanone by a simple hydroboration / oxidation. What’s special is that they did the oxidation in-situ, reacting IBX directly with the organoborane to get the desired ketone. This is actually the final intermediate isolated - a cascade leads directly to the product. Acidic conditions were used to remove the Boc group, allowing isomerisation of the acidic stereocenter, and more importantly, a transannular Mannich reaction to complete the ring-system.

Very tidy work - and lean too!