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23 June 2007 6,759 views 11 Comments


Danishefsky, Krauss and Mandal. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200701837.

Yes, it’s another macrolactone, but this one’s a bit special, and there’s not an aldol in sight! Danishevsky and his group have been working with the Migrastatins for some time now, and have made several analogues, promoting that impressive cell-migration-busting activity. However, an isomer, the snappily and originally titled Isomigrastatin, has also been isolated, and Danishefsky quickly set to work.

I guess it’s no real surprise that that one of the key reactions was a diastereoselective Diels Alder reaction, and even less surprising that it was with a derivative of his diene, but I really like the synthesis of the dienophile, which comes from some previous work. It’s based on a protected tartaric acid, which was reduced and alkylated with vinyl grignard. The alcohol was then methylated and the acetonide removed, allowing cleavage of the diol to the desired aldehyde. Nice!

The hetero-Diels Alder went well with a spot of lewis-acid catalysis, and removal of the TMS group gave the desired pyrone. This was then reduced, and treated with acid to effect a Ferrier rearrangement, one of my favourite reaction :), and the olefin epoxidised with mCPBA. This epoxy lactol was presumed to be suitable for a Wittig reaction; however, it was a stubburn beast, and they had to perform the olefination upon the open-chain aldehyde analogue (requiring reduction-protection-oxidation).


They then set about a conjugate addition to the unsaturated epoxide; work by James Marshall suggested that the stereocontrol for this reaction would be determined by attack anti to the epoxide. However, in this paper, Danishefsky found control from the C-15 silanol.

Thus, a distereoselective reduction of the C-15 ketone with CBS catalyst gave them this control element, and addition of the methylcuperate went with good yield (~13:1 d.r.).

Completion of the synthesis from this point required esterification to provide the lactone unit, and RCM. However, the final olefin in the macrocycle was still absent, and by design. Y’see, the major decomposition products of the natural product remove the strain from the ring by expanding it and/or isomerising one of the E-olefins. Thus, by leaving this strain-building step to last, they hoped to keep it intact. However, to my eye, this was a calculated risk – they knew that the target was unstable, and this unsaturated ester motif was prone to isomerisation. Could they put it in?

Ultimately, they decided to used a selenide elimination to put it in – and the pheynyl selenyl group was already in place in the final fragment. Oxidation then cause the elimination – and (no doubt to some relief) a cracking yield of the target. Interestingly, they noticed that treatment of the target with isomerising conditions showed complete conversion to the Z-isomer, which says something about these reaction pathways.

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  • Spiro says:

    Thumbs up to the guy who carried the phenylselenium cpds through all those steps!

    I frowned at the 12 -> 15 transformation, and taking a look at the supporting information confirmed it was some scam…

  • Zinc says:

    Considering that the three step 12->15c sequence as well as the coupling of 15c to 17 were higher yielding than the route described in the text, I think it’s odd that this issue wasn’t raised in a footnote, at the very least.

  • kiwi says:

    Its very similar to their own migrastatin synthesis in JACS a while ago (unsurprisiingly i guess). The step i remember from that was the same diers-alder/luche reduction/aqueous ferrier sequence given here, quite a clever and non-intutitive way to make a chiral linear aldehyde

  • albert says:

    Just a stupid question from a non-organic chemist: isn’t that diene the Danishefsky-Kitahara one?

  • spottospot says:

    Albert you obviously don’t know diddly squat.
    Only the name with the star is the star.
    Google it before you ask it!
    POOR OLD Schuda, he is a nobody.
    Danishefsky, S.; Kitahara, T.; Schuda, P. F. Org. Synth. 1983, 61, 147.

  • around the corner and down the hall says:

    careful who you insult spottospot, Sam himself refers to it as the Kitahara diene or Danishefsky-Kitahara diene. Of course this is later in his career, but he is quick to give credit to Takeshi, who is more than happy to accept. I’m sure there is a paper in which Sam says this, but I’m too tired to look it up, maybe tomorrow…

  • The Canadian Chromatographer says:

    Hey! Looks like Dylan Stiles’ synthesis with Trost has been accomplished. As a tribute to a key player in the organic chemical blogosphere, I think Totally Synthetic MUST blog this one! ;-)

    Look up Org. Lett. ASAP, June 26, 2007. I know I can’t post the web page link here…

  • Tot. Syn. says:

    It has indeed – well spotted. Good job, Stiles; I’ll blog it soon.

  • wisemanleo says:

    Okay, why not just let the phenyselenium group fly off in the first place to make the olefin? Or does that route end up with loss of control as to which pair of olefins undergo grubbs metathesis?

  • metathesizer says:

    according to footnote 16, the ring system containing all double bonds is unstable and decomposes under metathesis conditions, so it is difficult to obtain dienolide directly by metathesis