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Totally Synthetic by Paul H. Docherty, 24 July 2006

Total Synthesis of Tetronolide


R. K. Boeckman, Jr., P. Shao, S. T. Wrobleski, D. J. Boehmler, G. R. Heintelman, A. J. Barbosa, J. Am. Chem. Soc. 2006, 128, 10572-10588.

DOI: 10.1021/ja0581346

An impressive total synthesis of tetronolide in this JACS article, concerning this interesting spirotetronic acid type natural product. The biological activity of this target is particularly interesting, but I won’t go into it just now. Let’s just say this is an appealing target. Indeed, there have been other efforts towards it, including a total synthesis by Yoshii, and a formal by Roush.

Using a chiral auxiluary to derive much of the stereochemistry in the components, the first point of interest is the tethered intramolecular Diels-Alder reaction to create the cyclohexene. Proceeding in a 5:1 d.r., heating at 155C for more than four days, this is certainly a time-consuming approach. However, the reaction provided two quaternary centres and three stereocenters and a yield of 65%. A few more steps then completed the upper-half of the target.

The lower half was produced using a chiral auxiliary again, developing the desired tetraene in 11 steps. They then coupled this with the top fragment, heating a very dilute solution with 2,6-di-tert-butyl-4-methylphenol (BHT). However, they were unable to get the reaction to go to completion, as the product decomposed under the reaction conditions. They got around this by stopping the reaction early, isolating the product, and resubmitting the recovered starting material to the reaction conditions. It might sound annoying, and probably was, but this is an impressive transformation!

Elaboration of the adduct to the macrocyclisation precursor was completed after several failed attempts, allowing them to use a strategy similar to that of Yoshii with a Julia olefination, then macrocyclisation with NaOtAm (sodium tert-pentoxide), using the sodium ion to template the cyclisation. A stereoselective reduction with selectride and deprotection then delivered the target in 27 steps (longest linear sequence - LLS), concluding an ambitious and thoroughly impressive total synthesis.