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11 April 2007 11,289 views 16 Comments

Snider, Zou, Chen and Taylor. Org. Lett., 2007, ASAP. DOI: 10.1021/ol070563g.

Another publication of this popular beastie, though with less drama than the Nicolaou paper, which I covered back in October. This is a formal synthesis, working towards an intermediate in the afore mentioned paper, using methods I feel are quite old-school, though completed in style. To help figure this one out, I’ve shown the target intermediate as drawn in both papers, with a quick retro on the enone.

The synthesis started quickly, completing the dione in good yield, although as a mixture of diastereoisomers. However, the group quickly realised that this decalin could epimerise easily, converting from the desired cis form to the trans. As luck would have it, the cis isomer was the more thermodynamically stable, and even though they only isolated 57% from the reaction, they were able to recycle/equilibriate the trans product. However, punching numbers into the big calculator lead them to realise that the target tricyclic product (also prone to epimerisation) was in a converse ratio. Thus, any thermodynamically-driven reaction would tend to give the wrong product. Fortunately, they were planning a radical reaction, and thus generated the desired product in 84%. A quick experiment with hydroxide showed that the computery thing was correct…

With this dione complete, reduction and closure of the conformationally closer hydroxyl onto the alkene generated the THF, leaving the other hydroxyl to triflate and eliminate. All that was remaining was to perform an allylic oxidation – but this was a bit more traumatic than one might expect. Efforts with chromium trioxide were unsatisfactory, as the allyl cation produced could oxidise on either end. They then moved to selenium dioxide, which either reacted too much, to produce the dienone, or the allylic alcohol. However, a little manganese dioxide allowed the latter to be converted to the desired enone in good overall yield.

I liked the paper a lot, and it certainly seems to be a better route than Nicolaou’s to that intermediate (Nicolaou did it in 10 steps, with considerably smaller yield). However, credit must go to Nicolaou, as his route did look great on paper, and had some top ideas (as well as being a good read). Both papers, however, deserve props for great writing and for explaining the full story. Snider gave several variations for this route, and explained their preferences in detail, which to me, is top :).

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  • Liquidcarbon says:

    No samarium?..

    SeO2.. what about 5 equivalents?

    *off* what do you do with selenium waste after oxidations? They won’t let you flush it down the drain, will they?

  • singlet says:

    this is definately an improvement on nicolaou route becuase
    the samarium reaction so low yielding

  • TWYI says:

    Nicolaou was first though, this is all that matters in the synthetic world for some reason.

  • pi* says:

    Nicolaou is always first, that is why other groups usually have a better synthesis, he only cares about publishing first…
    The over-oxidation is super-sexy, there must be an application for that

  • American chemist says:

    Well, I heard that Nicoalou puts two graduate students on the same project and let them compete. So getting finished first is “the survival of the fittest” I think.

  • Tot. Syn. says:

    Hmm… seems to have some very similar steps…

  • TheEdge says:

    It’s amazing how much more selective the reduction of the bicyclic ketone is in Snider’s synthesis than in Nicolaou’s. The unsaturation KCN has must significantly alter the conformation, which I guess isn’t unexpected, and something that is admittedly hard to plan for. Sometimes the bear gets you.

  • Tot. Syn. says:

    I’ll write a quick post-lett on this this evening / tomorrow…

  • alex says:

    hi nice site.

  • TWYI says:

    Chem Comm have incredibly fast submission to publication times. Even for a name like Nicolaou, was the gauranteed promptness of publication an issue when submitting here?

  • TMS says:

    Part of KC’s desire not to be beaten comes from being scooped very early in his independent career by Wolfgang Oppolzer in intramolecular cycloadditions to give estrone. KC and Wolfgang both went to Cambridge and gave essentially the same talk. Oppolzer came back to Geneva to find his co-worker on vacation. However, he was able to round up the students who were still in town and get the lab notebooks. Legend has it that the synthesis was finished in the absence of the vacationing English post-doc. Oppolzer as a member of the editorial board of Helvetica was able to get it into print at light speed and left WO/DA Roberts and Bird far ahead of KC and his graduate student W. Barnette.

  • European Chemist says:

    #11: ChemComm is a great journal for speed. We’ve had a communication accepted in 10 days and published online in less than 3 weeks. Even when the result is refusal, you receive the outcome really fast (rarely more than 20 days). The downside is that, unless you’re English or from a top-notch US lab, the demand for creativity and innovation in all Organic communications is only slightly lower than Angewandte. But I do love ChemComm for the professionalism of the people working there.

    As for this synthesis: personally I didn’t find it that interesting, but I must confess it’s nice that Snyder tells all the details “full-paper-style”.
    This last CC paper from KCN at least has an innovative intramolecular Stetter reaction. And probably beats the Snyder approach (don’t have online access to RSC journals!)

  • TWYI says:

    Good post EC, agree mainly due to the fact that ChemComm is not just restricted to synthesis. Therefore the stuff that does get in tends to be of high quality (I would say that!).

  • stone says:

    i feel it’s really annoying to read snider’s paper, since so many transformation mixedup in one scheme. just not as straightforward as KC’s style.

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