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Erinacine E   

21 January 2008 10,828 views 15 Comments

Nakada and Watanabe, JACS, 2008, EarlyView. DOI: 10.1021/ja7102795. Article PDF Supporting Information Group Website

And it lives!!! Yep, I finally managed to write another post for this blog, and haven’t forsaken the interweb. I don’t have time to go through all the exciting chemistry that has been published in the last ten weeks (thanks for counting the weeks, days minutes and seconds, Andrew…), so I’ll stick to describing new publications and selected highlights. However, I’ll ask you lovely readers to suggest what you feel most merits blogging from those past 10 weeks.

Focusing on relatively recent work, this ASAP by Nakada leapt out with the complexity of that molecule! The group has quite a bit of experience with this family of natural products, having previously completed a synthesis of erinacine B, which allowed them to start with an advanced precursor from that synthesis. This precursor contained the entire 5,6,7-fragment (LHS); I’m not going to discuss that synthesis today, but focus on the amazing elaboration of this structure to the target.

The first step was installing the glycoside bond. Not an easy transformation, but the demostrated excellent control by using a thioglycoside starting material and MeOTf to give the desired anomer in 84% yield and 14:1 d.r. Protecting group manipulations generated the starting material for the scheme above, which after a double oxidation performed the first cyclisation in situ (probably promoted by triethylamine from the Swern oxidations).

Interestingly, they couldn’t get the key intramolecular aldol reaction to go at all using standard metal-cation bases (e.g. t-BuOK), but got a fantastic yield with an organic base. I guess the metal cation chelated the highly oxygenated RHS of the molecule in an unfavourable conformation, preventing reaction or even favouring decomposition. Also note that the benzoyl group has migrated; this prevents retro-aldol condensation, and is something they apparently planned. Completion of the synthesis required four further steps, including an inelegant but effective epimerisation of one of the secondary alchohols, finishing an amazingly complex molecule.

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15 Comments

  • Just to let you know that I deposited this structure onto the ChemSpider database tonight using the new single structure deposition system. I have pointed the link back to your site…scroll to the bottom of this link and you will see the association with TotallySynthetic.com. I will do this for all of your new postings so help direct people to your postings.

  • milkshake says:

    even if one can dream up this kind of aldol disconnections with concomitant elimination or migration, on this highly finnicky substrate, the advisor is going to say “get real young man, you cant risk and hope this will work – so late in the synthesis”

  • Big C says:

    Short, smart synthesis of an interesting metabolite by Overman:

    http://dx.doi.org/10.1021/ol702518t

    Nice selective oxidation thrown in there, blog-worthy IMO.

  • Dude says:

    One request: no more platensimycin!

  • UBchem says:

    Just not completely sold on the benzoyl migratiion as “planned.” I haven’t seen too many examples which would say otherwise. It seems like a very, very fortunate accident.

  • stone says:

    Nice work posted!

    Total Syn. How about Nicolaou’s recent synthetic studies on the Sporolides in Angew Chem? Beautiful molecules!

  • pi* says:

    good to see you back!
    migrations like this arn’t so rare. a very common, not unrelated example is epoxidations of silyl enols

  • Spiro says:

    I agree with you, UBchem.
    Furthermore what the authors needed was a regioselective aldolisation, and the benzoyl group happens to do the trick ; the migration is totally optionnal, who cares about its migration since it is removed almost immediately?

  • UBchem says:

    It’s not a matter of ‘not caring,’ I think it’s a pretty funky maneuver and could have some synthetic utility. Pi* is right about the silyl shift in the Rubottom reaction, but silicon has that ability with low energy anti-bonding orbitals. The benzoyl group is a completely different system.

  • milkshake says:

    Simple acetyls are notorious for traveling around on a carbohydrate becayse of OH inreamolecular participation – so people tend to use benzoyls (or p-toluoyl for more crystalline product) to supress the migration. In that respect it is funny benzoyl migrated here just the same.

    Also if you have 1,3-diacyl glycerols and you try to do some base-promoted reaction on it, you have to be very careful as not to get a mix with the 1,2-diacylglycerol-derived product in it.

  • albert says:

    Glad to see you’re back in business.

  • TheEdge says:

    Spiro: The pKa difference between the two acidic protons in the final aldol (the one they want and the gamma-position of the a,b unsat aldehyde) would be pretty significant even without the benzoate. I think it’s there because it’s easy to get off in the presence of the other functionality present and it’s small enough to allow the aldol to proceed. I’m surprised the other one goes with a TES on it. Those suckers are huge.

    Milkshake: The tricycle is an intermediate in another synthesis (as mentioned by Paul), so they probably had the precursor sitting around and decided to just try it. The thing that gets me is that the earlier synthesis was derived from an intermediate in an earlier synthesis, too. If you go back and count all of the linear steps, it works out to 40 to make this one. I really like their late stage stuff, but there has to be a better way to make the tricyclic portion, and a lot of “formal” syntheses of Erinacine by other groups are going to appear.

    It’s good to have you back, Paul.

  • rosko says:

    Hey, another non-nitrogen containing kappa opioid agonist, in fact one that I didn’t know about!
    http://www.jstage.jst.go.jp/article/antibiotics/51/11/983/_pdf

    (You covered salvinorin A, a better known and more potent such compound, in a previous post)

  • JewlerAZonq says:

    Though I am far from the topic, but still I liked it