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Paecilomycine A   

22 February 2007 6,122 views 8 Comments

Danishefsky and Sun-Joon Min. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200605058. Another top synthesis from the Danishefsky labs this month (is that four published this year so far? He must be cracking the whip!), this time of the biologically exciting terpeniod, paecilomycine A. The biological profile is well documented in the paper, but the headlines are 10 nM neurite outgrowth activity in PC12 cells, and significant nerve growth factor stimulation.

Their retro-synthesis is simplicity itself, using a intermolecular DA to construct the initial cyclohexane, then a Pauson-Khand to complete the decalin and fused five-member ring. The synthesis, then, relied upon getting that DA to go in both a good yield and diastereomeric ratio.
Of course, for this to happen, the group had to use the correct coupling partners. Indeed, when they started, a 6:1 d.r. was obtained using the silyl enol ether and the aldehyde dieneophile. Whilst this went in cracking yield (87%), they weren’t happy with the diastereoselectivities, so proceeded to use the enyne ester as the diene partner. Along with the similar yield, they obtained an improved selectivity, but whilst moving to the aldehyde analogue of the enyne gave an even better d.r., the yield was reduced to 58%.

I can’t see mention of which to the latter partners they used on scale, but either product allowed them to continue to the Pauson Khand reaction (I’m sure you all know that horrific mechanism!):


Okay, the yield isn’t great, but the outcome is fantastic! Cyclopropanation allowed introduction of the remaining methyl group from the top-face, and an epoxidation remaining hydroxyl group, all via substrate control, allowing completion of the synthesis in a pleasing sequence.

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  • tired by chemistry says:

    What about the nice biomimetic synthesis of Stephacidin A by R. M. Williams in Angewandte (early view)

  • Anom says:

    You got the d.r. switched in your scheme. It’s 20:1 in aldehyde and 10:1 in ethyl ester.

  • poisoned says:

    You left out the oxygen in the six membered ring in the first two drawings of the natural product.

  • cheyanimal says:

    sorry to be a pain but your arrows imply that the final two products are made with out a diene

  • Tot. Syn. says:

    That’s right, everybody get at me :(

    Nah, that’ll teach me to write posts when I’m too tired. I think I’ve fixed everything, but I probably haven’t…

    And “tired by chemistry”: You’ll find that this paper was published a little earlier, so hold your horses for now!

  • Pete says:

    This synthesis is reminiscent of most Danishefsky syntheses I have read…Not overly massive, but definitely a complex molecule pieced together in an exceptionally efficient and elegant way. Reading his papers are a joy.

  • buyproduct says:

    I like the science but Danishefsky writing is the most enjoyable to me. He says simple things in dramatic ways. Here are a couple of zingers that made me laugh.

    “… the possibility of a Diels-Alder stategy to reach 6 virtually imposed itself.”

    “While the gestalt implied in Scheme 1 seemed appealingly concise, some significant difficulties arose in the more demanding world of experimental reality whose solution, in the end, enhanced the teaching dimension of the experience.

  • Floyd McFloyd says:

    Speaking great quotes from articles, Baran wrote the following in one of his papers:

    “Several unanticipated events have conspired to delay this total synthesis.”

    Unanticipated events like the planned reactions didn’t work, the grad student keep losing product, etc, etc That is a line I am going to try to work into all of my future papers.