List, Michrowska. Nature Chem., 2009, AOP. DOI: 10.1038/nchem.215.
Another rather short blog post, but why wax-lyrical when the synthesis is short and sweet? Ben List is still hammering-away at his niche in organocatalysis, this time reporting a rather nice domino reaction. The target of the synthesis is a isolate of a liverwort, and possesses “potent molluscicidal activity” – not a biological effect I’d come across before. It turns out that this natural product spells doom for Biomphalaria glabrata water snails… and we’re still at a loss. Water snails irritate me too, especially when having a bath, but the plot thickens… it turns out these slimy little devils vector schistosomiasis, a nasty tropical disease – bad news. So it’s worth working on a treatment for the cause, rather than the symptoms.
Several syntheses have been published in the past – one that I can’t see online by Takeda (Heterocycles, 47, 1, 277-282), one by Liu (10.1021/ol052638r), and another by Audran (10.1055/s-2005-871932). As short as some of those are, this is something special. A (mostly) linear precursor was built quickly using an dehydrative aldol, followed by a bit of cross-metathesis. Initially, they used Grubbs G2, but found that the addition of a nitro group put oats in the fodder-bad, and drop the loading whilst increasing the yield. And it’s probably not patented.
With the precursor complete, List did what he does best – a bit of organocatalysis – resulting in a reductive Michael addition, which produced a cyclohexanal intermediate. The yield was great, but the diastereoselectivity was a nightmare – 2:1, and in wrong direction (if you like). However, the enantioselectivity was very good, so the group hoped that they might be able to improve the situation. It turned out that dumping in the reagent for the Tishchenko reduction (a bit of samarium triisopropoxide) had a pretty impressive effect – epimerisation of the errant stereocenter, and then reduction to give the desired diastereoisomer, and the product, in a very healthy yield. List explains this complete diastereoselectivity by invoking chelation of the catalyst by both carbonyls, which leads to the product.
Damn nice work!