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Tetronolide   

24 July 2006 4,322 views 3 Comments

tetronolide.jpg

Boeckman, Shao, Wrobleski, Boehmler, Heintzelman, and Barbosa. JACS, 2006, ASAP. DOI: 10.1021/ja0581346.

An impressive 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 DA to create the cyclohexene. Proceeding in a 5:1 d.r., heating a 155 C for more than four days, this is certainly the big stick approach to getting it to work. However, work it did, in 65%, providing two quaternary centres and three stereocenters. A few more steps then completed the upper-half of the target.

tetronolide_1.jpg

The lower half was produced using a chiral auxiluary again, developing the desired tetraene in 11 steps. They then coupled this with the top fragment, heating a very dilute solution with BHT. However, they were unable to get the reaction to go to completion, as the product decomposed under the reaction conditions. The got around this by stopping the reaction early, isolating the product, and resubmitting the recovered SM to the reaction conditions. It might sound annoying, and probably was, but this is an impressive transformation, so we should cut them some slack!

tetronolide_2.jpg

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, using a Julia olefination, the 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 (LLS), concluding an ambitious and thoroughly impressive campaign.

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3 Comments

  • ochemist says:

    First D-A provides only one quaternary center.

  • Tot. Syn. says:

    Darn, you’re right. I really wish I could count…

  • movies says:

    If you want to get all technical about it, that’s not a quaternary center. A quat. center is a carbon bonded to four other carbons, so that is really a tertiary ether stereocenter. Think t-butanol: that’s a tertiary carbon not a quaternary carbon.