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Milbemycin ß³   

10 August 2006 9,712 views 24 Comments


O’ Doherty and Li. Org. Lett., 2006, ASAP. DOI:10.1021/ol061439k.

A very succinct paper by O’Doherty (no relation…) in Org. Lett. this week, showcasing his work on asymmetric hydration in a total synthesis of Milbemycin ß3. This macrolide has a huge range of activity, from antibiotic to pesticidal, so is a tempting target, exemplified by the previous syntheses by Amos Smith, Tony Barrett and Phil Kocienski amongst others. The principle disconnection left them with a spiroketal unit and a remote stereodefined methyl group to consider, which they tackled with some interesting methodology.

Very early in their work, they create a diene via a ynoate isomerisation simply using triphenyl phosphine in phenol, delivering the diene in 97%. I hadn’t seen this procedure before, so was quite impressed. The cited literature for this is a Trost paper from the last decade. With this unit in hand, they were able to use their own ideas for asymmetric hydration to establish the stereochemistry in four steps, commencing with SAD, followed by carbonate formation and Pd-catalysed reduction, and finally diastereoselective hydration with benzaldehyde to generate the 3,5-benzylidene actetal. Good work!


Further elaboration of this fragment eventually led to the desired spiroketal, with the remaining methyl group the last stereocentre to consider. They completed this by using chemistry originally developed by Scott Nelson; a alkene isomerisation and Claisen rearrangement. This approach is very similar to the route used by Amos Smith, who used an Ireland-Claisen, but is still impressive:


Then ready to couple with the less complex bottom-fragment (again, previously made by Amos Smith) via a Wittig olefination, and lastly a Mitsunobu macrolactonisation previously used by Tony Barrett in his synthesis. This process, as the name suggests, inverts the stereochemistry of the hydroxyl partner in the macrolactonisation, potentially removing a laborious inversion protocol.

Altogether an impressive piece of work, containing a lot of cool chemistry!

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  • secret milkshake says:

    The PMP/benzylidene/ethyl ester intermediate obtained in four steps from the diene (which has to be made by extra 3 steps) happens to be exactly the protected Lipitor side-chain, with the right stereochemistry. Companies like Kaneka and Takasago are now manufacturing the triol-ester-acetonide in tonn amounts by enzymatic methods/fermentation for the statin market. We have a 1kg bottle of the (3R,5S)-t-Bu ester acetonide sitting on the shelf here…

  • HOMO-LUMO says:

    Secret Milkshake,

    Sorry for my ignorance, but would be possible to buy building blocks/expensive ligands to pharmaceutical companies, in particular japanese, from an university, is that a common practice?

  • secret milkshake says:

    Probably not, although I am in nominaly academic institute and we used government funding to buy the stuff. Also, Kaneka was nice enough to airmail us first a 10g sample free of charge.

    Any tot-synth professor worth his reputation would hate to buy and then re-protect an advanced piece (and have this in his publication). Medicinal chemistry approach is different – we were not in it for glory and we also did not have extra manpower to expend 2 man-months for scaling up the piece. We paid 10k (USD) for 1kg, (100g would be 5k). With the lab overhead and salary, it was not a such a bad deal. Also we had deadlines, there were provisional patents runing out of time.

    I just wanted to point out that the problem of synthesizing this piece has been solved – that when some underpaid undelings were scaling up gram quantities of the stuff from acetylene, some other (japanese) underlings were already churning out 100kg batches of it.

  • HOMO-LUMO says:

    Secret Milkshake,

    Thanks a lot.

  • Don B. says:

    I wondered how long it would take someone to notice the resemblence/identical chirality to the optically active portion of Lipitor(TM). I imagine it can also be purchased from a number of Indian pharmaceutical companies. They supply generic atorvastatin calcium to much of the world.

    Don B.

  • Tot. Syn. says:

    So folks, you’ll have noticed that I drew the main disconnections onto the target; is this useful, or am I wasting my time? It doesn’t take long, though…

  • HOMO-LUMO says:

    It’s useful to me.

    Thanks a lot.

  • HOMO-LUMO says:

    Probably you have seen this already in the literature, if not, take a look to the last Org. Lett of Raymond Funk:


  • Tot. Syn. says:

    Yeah, I saw that today. Damn nice paper; I might well do a post on it over the weekend. Also, I noticed that the Furstner group have nearly finished Spirostrellolide; two papers in the latest issue of Angewandte. I’ll wait until it’s finished before I blog it, though.

  • Christian Kuttruff says:

    how can I write an email to you? I would like to ask you a question.

    Thanks in advance

    C. Kuttruff

  • ddd says:

    C-C bond in alkines is 180 degrees and not 120 as drawn in that Org Lett paper. Why would you drew “trans” alkine? That is what differentiates people from top schools and from the “bottom schools”…sorry to sound bad, but I just hate that this kind of drawing

  • secret milkshake says:

    there is an easy way to make “cis-alkyne”: coordinate it into a cobalt carbonyl complex

    I think the realy good chemist would worry more about ingenuinty and practicality of the transformation and find a satisfaction in purity of his own products, rather than in how some triple bond is drawn. If you are any good, you won’t have to stroke yourself 3 times-a-day about how more’leet you are than other guys who published a paper.

  • Klug says:


  • Christian Kuttruff says:

    Can anybody tell me how I can contact the author of this blog?

  • secret milkshake says:

    ts (at) totallysynthetic … c0m

  • HOMO-LUMO says:

    Discriminating people by the school of procedence and not by talent or ability to work hard is what might irritate me…

    Milkshake, your knowledge is simply amazing.

  • HOMO-LUMO says:

    We used to say when we were kids, once I will be grow up I want to be…and then we used to say the nae of the best football player at that moment..

    Well know I should say, once I will be grow up I want to know as much as secret milkshake…just kidding! :)

  • Ochemist says:

    That last paper by Raymond Funk is very nice, very beautiful

  • Vince says:

    For your information, I was at a conference in Canada (Latest Trends in Organic Synthesis #12, a sort of poor man’s Gordon Conference) where O’Doherty (the author of the paper, not the blog) was presenting this work as a poster. It turns out that the (E,E)-olefin is formed from the alkynoate using 1.0 equiv of phenol and 50 mol % PPh3. He told me that phenol is a proton transfer agent (he says, either you wait for PPh3 to do the trick in about 2 weeks or you speed it up, and PhOH is the optimal H-swapper) and that PPh3 is just a nucleophilic catalyst. They worked it up by washing phenol off with aqueous base, and turned PPh3 into the Wittig salt using MeI in the work-up! Clever.
    So TotSyn, you may want to update the info in the blog.


  • Vince says:

    Oh yeah, I forgot. The solvent was CH2Cl2 for the ynoate isomerization.
    And that O’Doherty is quite an entertaining guy. Sure loves his beer, too!

  • Allenylmetal says:

    Ol’ George is a blast. Conferences would not be nearly as fun without him!

  • rb says:

    I think people at top schools know how to spell alkyne.

  • European Chemist says:

    I don’t know if anybody is still reading this, but how do you feel about the length of this synthesis? I personally feel it’s waaay too long, specially given the enormous precedent on this natural product. I’m also a bit skeptical on the so-called “enantioselective hydration methodology” that the authors have developed. It really didn’t flash me as being something fundamental. And when it was time to apply it to a trisubstituted double bond, oh trouble….. am I just being too demanding?

  • DH says:

    Is there anyone aware of a “commercial” source or potential source for Milbemycin active ingredient???