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Totally Synthetic by Paul H. Docherty, 30 March 2009

Total Synthesis of Vincorine


M. Zhang, X. Huang, L. Shen, Y. Qin, J. Am. Chem. Soc. 2009, 131, 6013-6020.

DOI: 10.1021/ja901219v

Vincorine has already been completed by Vollhardt, Overman and Levy in the past, but Qin’s got quite a background in this family too - exemplified by a total synthesis of minfiensine (and by Overman too). Qin has improved the first few steps in the synthesis by altering the conditions for formation of the β-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…

It only took a few steps to get to the next intermediate (using pretty interesting conditions for the Appel reaction: Cl3CCN, PPh3, base). Looking back at the previous synthesis, they used a pretty neat Heck-style coupling developed by Cook. Hoping to do something similar here, they tried out a few catalysts, but to no success. Qin doesn’t suggest what went wrong, probably because they couldn’t assign the byproducts they actually isolated.

A Johnson-Claisen rearrangement, which is a more traditional approach, provides for excellent control over stereochemistry and 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. A d.r. of 4:1 is reasonable too…

From here, the total synthesis is straightforward…