Qin, Zhang, Huang, Shen.JACS, 2009, ASAP. DOI: 10.1021/ja901219v.
It’s really nice to move on to a full paper this week after last weeks (lack of) communication nightmare, as it gives Yong Qin plenty of space to discuss his strategy for the synthesis of vincorine, including the missteps. The target has seen quite a bit of action, having been completed by Vollhardt, Overman and Levy in the past, but Qin’s got quite a background in this family too. In-case you’re sitting there thinking ‘I’ve seen this somewhere before…’, I’ll take you back to the synthesis of minfiensine by Qin (and by Overman too, whilst I’m at it).
Qin has improved the first few steps in the synthesis by altering the conditions for formation of the beta-keto ester, using methyl potassium malonate rather than Meldrum’s acid, but the key step is still the carbene chemistry. Using p-ABSA to form the diazo compound in the most acidic position, the same cascade reaction happens as in the minfiensine synthesis – insertion of the carbene into the enamine, opening of the three-membered ring to form an iminium ion, and trapping with the pendant sulfonamide. It’s a great way to build this complexity… but I wonder if he could impart asymmetry in this reaction by using something like a chiral lewis acid. This might chelate between the 1,3-dicarbonyl, and provide facial selectivity.
It only took a few steps to get to the next intermediate (using pretty interesting conditions for the Appel reaction: Cl3CCN, PPh3, base), but at this point they were firmly stuffed. Looking back at the previous synthesis, they used a pretty neat Heck-style coupling developed by Cook. Hoping to do something not dissimilar here, they tried lobbing in a few catalysts (I wonder how many they really used before they called it quits…!), but to no success. Qin doesn’t suggest what went wrong, probably because they couldn’t assign the guff they actually isolated.
They fell-back to a more traditional approach, and a reaction that I fell in love with years ago when I started my PhD. The Johnson-Claisen in one of the better-known variants, perhaps because it not only provides for excellent control over stereochemistry, but also because it appends a two-carbon fragment. Normally, the stereochemical control comes from the alcohol centre, but as it is primary in this case, it seems to come from the general conformation of the molecule. 4:1’s pretty reasonable too…
From here, the synthesis is fairly unremarkable (and I must say I’m surprised that it was deemed JACS worthy – though all the total syntheses seem to be going into Angewandte these days…). Nice stuff in some ways, but there’s nothing very new here.