Totally Synthetic by Paul H. Docherty, 2 June 2009
Total Synthesis of Ricciocarpin A
A. Michrowska, B. List, Nat. Chem. 2009, 1, 225-228.
This total synthesis is rather short and features an interesting organocatalytic step, which is Ben List's niche. The target of the synthesis is a isolate of a liverwort, and possesses “potent molluscicidal activity”. Ricciocarpin A is indeed active against Biomphalaria glabrata water snails, which are vector of schistosomiasis, a nasty tropical disease. So it’s worth working on a treatment for the cause, rather than the symptoms.
Several syntheses have been published in the past by Takeda, one by Liu, and another by Audran. As short as some of those are, this is something special. A mostly linear precursor was built quickly using an aldol condensation, followed by cross-metathesis. Initially, they used Grubbs G2, but found that the nitrated version helps to decrease the loading whilst increasing the yield.
With the precursor complete, List peformed an organocatalytic reductive Michael addition, which produced a cyclohexanal intermediate. The yield was great, but the diastereoselectivity was very low - 2:1, with the wrong diastereomer as main product. However, the enantioselectivity was very good, so the group tried to improve the situation. It turned out that addition of samarium triisopropoxide for the Tishchenko reaction had a very impressive effect: epimerisation of the errant stereocenter, and then reduction to give the desired diastereoisomer, and the product, in a good yield. List explains this complete diastereoselectivity by invoking chelation of the catalyst by both carbonyls, which leads to the product.
A very nice total synthesis!