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Cyanolide A Aglycon   

16 June 2011 24,709 views 29 Comments

Rychnovsky, Gesinski. JACS, 2011, ASAP. DOI: 10.1021/ja204228q Article PDF Supporting Information Group Website

Guest Blogger: See-Arr-Oh

When I first saw the dimeric gamma-substituted pyran motif in this molecule, I said “Gotta be Rychnovsky” (or maybe Wender).   Throughout his career at UC-Irvine, Scott Rychnovsky has been the master of the TMS-promoted diastereoselective Prins cyclization, which he has applied to the synthesis of at least 10 macrolides.  Until now, however, none have been attempted sans protecting groups!

Cyanolide A was isolated in 2010, and it’s already been the target of four total syntheses.  Perhaps this is due to its intriguing biological profile; I usually assume new natural products will be antibacterials, antifungals, or might cure cancer.  Not cyanolide A: it’s a molluscide.  Rychnovsky hopes it could one day treat schistosomiasis, a disease caused by a parasitic worm carried by snails living in contaminated water.

The authors point out that most of the syntheses to this point have been based on either Yamaguchi or Shiina macrolactonization of two identical pyrans to form the C2-symmetric compound.  Our team wants to use the double Prins here, but realize the required gem-dimethyl synthon will divert the reaction from the expected 2,3-pyran to form a THF ring instead.  So they forge ahead with a Sakurai dimerization:

The authors believe that their monomeric unit might be unstable under Lewis acidic conditions, so they opt for a dimethyl acetal instead…wait, isn’t that a protecting group?  (we’ll let it slide for now)

Troubles were afoot at the first step, when the authors tried a Ce(III)-mediated addition to a hindered ethyl ester, only to find out that they couldn’t install their desired allylsilane.  Luckily, they devised a workaround: 2-step enol triflate formation, Kumada coupling to install the allylsilane, then pTSA deprotection led to an aldehyde, where a simple aldol set them up for synthon 2.  Right?

Wrong!  All attempts to use a thiazolidinethione auxiliary with standard tin(II) or titanium(IV) Lewis acids just swapped the silane for a proton.  Using modified Sammakia conditions (sparteine, PhBCl2), the authors were able to promote their aldol without suffering subsequent protodesilylation.  Simple LiOH hydrolysis of the auxiliary provided 2.

Now, how do we append the other five carbons of the lactone?  Nucleophilic addition of a thioacetal to an epoxide, followed by oxidative methanolysis forms their desired protected pentyl alcohol.

Yamaguchi conditions unite 2 with 3, although they had to test quite a few other lactonizations first, since 2 tended to form the ?-lactone.  From here, Prins Lewis acid conditions conditions (TMSOTf in DCM) are enough to form the dimeric, symmetric backbone, and we’re only an Upjohn dihydroxylation, diol cleavage, and reduction away from the target:


A pretty clean 10-step LLS, with an overall yield at 18%, and (mostly) protecting-group free.

(Editorial – this is the first in what I hope will be series of guest-posts, written by readers who wanted to talk a synthesis up. Thanks to See-Arr-Oh for approaching me, and for writing a great post. Get in touch if you want to give it a go!)

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  • Young Padawan says:

    Nice post See-Arr-Oh. I especially appreciate the level of Detail. Thanks to TotSyn for being open-minded and keeping the Blog alive while you don’t seem to have so much time to write by yourself.

  • See Arr Oh says:

    Why thanks, Young Padawan. It’s lots of fun to write, and Paul has a good thing going here. Why not give it a try, synthetic folks? (Note Paul’s link in the italics at bottom)

  • purple says:

    Could you include yields next time? I would have no idea what these are as I have no acess to the chemical literature. Good post nontheless, nicely explained.

  • purple says:

    And maybe you dont want to include this, but curly arrows for the key/interesting steps would be helpful to people who cant see whats going on, and it would be a more informative and ‘sexy’ post! Thanks.

  • See Arr Oh says:

    I aim to please, purple: the first few steps run 87-97%. For formation of 3, it’s 62% for 2 steps. The tandem Sakurai is 76%, and 78% over two steps to wrap it up.

    I’d say the step that would best benefit from “curly arrows” is the tandem Sakurai. I don’t know if this helps, but initial generation of an oxonium (from the alcohol condensing with the aldehyde), followed by diastereoselective allylsilane trapping wraps up both rings.

  • Tot. Syn. says:

    Thanks for the input, folks. See Arr Oh – I’ll imprint the yields onto the schemes this weekend – thanks for adding the numbers. Good call, Purple.

  • nicho says:

    totallysynthetic.com/blog is truly a great forum for those of us interested in learning about current total syntheses in the literature. Thanks to both Paul and See Arr Oh for the motivation provided, great blog guys!

    Rychnovsky’s strategy nicely showcases the power of the Prins cyclization, For those of you interested be on the lookout for my PhD advisor’s synthesis of this natural product, Prof. Jennings at the University of Alabama. The lab work was carried out by a very talented undergrad, Mr. Robert Sharpe, who is now at UNC in Prof. Jeff Johnson’s lab, good job man!

  • Matt says:

    Although nice piece of work, I am little disappointed that the authors could not be more gracious to the paper which describes the first report of this methodology and the subsequent uses in total syntheses, Keck’s pyran annulation.

  • If the authors addressed every original paper for a method, the post would be 10 pages long and take a week to write! Just saying. Writing up these posts takes a lot longer than you’d think and there isn’t enough time to pat EVERYONE on the back.

    Great post, See Arr Oh!

  • gippgig says:

    I do believe there’s a dreaded pentavalent carbon in the thioacetal.
    I agree that showing the mechanism for the Sakurai dimerization (not “Prins conditions”) would be nice.

  • See Arr Oh says:

    @gippgig: Whoa, good catch! TotSyn, if you want to fix that Texas carbon, I sent you some new ChemDraws. Also, RE: Sakurai mechanism, I drew up a scheme of how I think it goes **Fair warning: the authors don’t draw the mech nor do they discuss it much.

    I guess you could view it one of two ways:

    1. two acetals on two different molecules both decompose (-TMSOMe) at the same time, leading to two oxonium species that are each caught by a neighboring allylsilane on the other molecule (the classic Sakurai reaction). This would produce a dimer that has to undergo two intramolecular TMS-promoted 6-exo-tet cyclizations of the chiral sec alcohol onto a TMS-activated methyl ether (not likely).

    OR, 2. Initial sec alcohol / acetal condensation FIRST, (-TMSOMe), TMS-promoted decomposition of this new acetal (-TMSOMe), and finally diastereoselective allylsilane trapping to form the pyran ring.

    What I’m not too sure about is whether or not the two pyrans are formed simultaneously; you could imagine a stepwise mech (on-at-a-time) and that the first pyran brings the other two reactive groups into closer proximity to form the second.

    • Tot. Syn. says:

      Thanks for that – haven’t had time this weekend, so it’ll be tomorrow before I change it.

      Texas carbon though? How do I put that in British? Norfolk carbon??

      • See Arr Oh says:

        ‘Round these parts, we call it a Texas carbon, ’cause everything’s bigger in Texas (ever been? They have donuts the size of small car tires)

        Where in the UK is everything just gigantic? Dover? Manchester? Chiswick? Maybe it’s a Cardiff carbon.

        • HPCC says:

          For Canadian reference, I’d dare rename it “Halifax carbon”.

          True anectode: I was there travelling, my girlfriend orders a “small glass” of beer (typically 12 oz.) and I order a pint. She got served a pint of (delicious, Alexander Keith’s Premium) beer, whereas I got essentially a litre mug, which made us both very happy and relaxed! :P

        • Tot. Syn. says:

          Erm… I don’t think that transfers well to the UK, not exactly. And I’m just going to offend someone here if I look for a Texas comparison.

      • Bigger in Texas says:

        It’s a reference to the 5-pointed Texas lone star, which is found on the state flag.

    • Tot. Syn. says:

      Post Updated – thanks, See Arr Oh. See, he cares about you readers more than I do… :)

  • See Arr Oh says:

    If anyone out there knows either of the authors, maybe you could help us all out and ask them to write in!

  • cdn_chemist says:

    Excellent post See-Arr-Oh! Despite the concise synthesis of Cyanolide A, I was really disappointed to see the phrase “without the use of protecting groups” included in the paper. The referees at JACS should be more vigilant as this paper blatantly uses protecting groups and the authors clearly mention “deprotection.” I fail to see how a synthesis can be protecting-group-free, yet still employ a “deprotection.” The chemistry literature just keeps getting worse…

    • Microwave says:

      They didn’t protect it, it’s from the SM.
      Probably, I’d call it protecting group free, too.
      Strictly speaking, Maybe yes. However, I don’t understand you really disappointed because of that.

    • BRSM says:

      You say ‘vigilant’ as if the reviewers overlooked the acetal in the abstract and paper… Although if I’d done this work I wouldn’t claim it as protecting group free, you can sort of see their point of view; the dithioacetal is in the starting material (and can’t be omitted), and it has to be converted to the dimethyl acetal for the Sakurai reaction – it’s no different to converting an alcohol to a tosylate for an alkylation. They do a deprotection of the diethyl acetal in the starting material, but that starting material is made from the Reformatsky reaction between the alpha-bromoketone and triethylorthoformate, so it’s again just left over from a C-C bond forming reaction. I guess they still waste steps manipulating these, though, which is a shame, but in my mind it’s another FGI. I do cringe a little at the amount of self promotion being packed into today’s journal articles, as I’m sure everyone done, but I don’t think this is too bad, and it certainly doesn’t spoil this fine synthesis.

      Incidentally, have you read T. Hud.’s book? You’d love it…

  • Red Ox says:

    Really neat synthesis very elegant. NICE job See Arr Oh. Keep it up, love reading this blog. Also do not agree with the claim that this is protecting group free synthesis, I would call it a protecting group “free” synthesis.

  • IrII says:

    I would call it a synthesis that uses not very many protecting groups.

    Hope this helps.

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