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Lycoflexine   

24 October 2010 58,221 views 116 Comments

Ramharter, Mulzer, Weinstabl. JACS, 2010, 132, 14338-14339. DOI: 10.1021/ja107533m Article PDF Supporting Information Group Website

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.  (However, on closer inspection, the starred author is one Juergen Ramharter, even though Mulzer is also named…)  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.

To say that this synthesis is concise would be a massive underestimation; eight steps is all it takes for fruition.  Starting with a fairly simple cyclohexenone (bearing a single stereocenter in the form a methyl group in the 5 position), a pair of Lewis-acid catalysed additions (Sakurai / aldol) 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 just a sniff of Grubbs’ second generation catalyst.  However, the group only achieved in the region of 30% yield, so clearly needed a re-think.  On consideration, they suspect that the diene product is unstable – and that their best move would be to reduce it.  They did this by simply pushing in a bit 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.

Having reduced to the single olefin, it was time to functionalise it, and the cyclopentene was converted to a cyclopentanone by simply hydroborating / 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 final cascade leads directly to the product.  A little acid was 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!

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