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(6Z)- and (6E)-Cladiellin Diterpenes   

21 November 2006 9,030 views 24 Comments

polyanthellin_a.jpg

Kim, Kim, Lee and Kim. JACS, 2006, ASAP. DOI: 10.1021/ja065782w.

Not one, two, or even three; four total syntheses in this paper, all of medium ring diterpenes, generally with a 9-member ether present in the target. Of course, all originate from a common precursor, and in Kim’s route, from his intramolecular amide enolate alkylation (IAEA) methodology. The original methodology paper was published in 2003 in JACS, followed by an Org. Lett. in 2005 describing their total synthesis of laurencin.

polyanthellin_a_1.jpg

As can be seen with the example above, their methodology is exceptional at producing that medium ring, and with an E double bond in it! This was isolated as a single diastereoisomer – really quite impressive. Some relatively straight-forward chemistry took them to a Diels-Alder substrate; reduction of the amide, followed by Corey olefination with α-lithio TMS-aldimine and methylenation. The DA itself has been done before, by my mate Ryan, and also by Crimmins (whoever he is… :)), but is still a sweet piece of chemistry:

polyanthellin_a_2.jpg

With the bulk of the natural product carbocyclic skeleton complete, they only needed five steps to finish. Notable was the conversion of the methyl ester to an isopropyl group by addition of MeLi with CeCl3 to produce a tertiary acetate. This was then binned by dissolving metal reduction.

Target natural product done, they then set their ambitious sights on three more, manipulating that Z-olefin to death:

polyanthellin_a_3.jpg

First, buckets of mercuric acetate – three different transformations in one pot, including a sequential oxy-mercuration to complete polyanthellin A in one step. A dihydroxylation with osmium tet delivered a diol to the correct face to complete (-)-cladiell-11-ene-3,6,7-triol, leaving the more complex (-)-deacetoxyalcyonin acetate to be finished in four steps including a nice Burgess salt promoted elimination to give the exocyclic double bond.
polyanthellin_a_4.jpg

Top stuff, and one of my favourite reads this month.

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24 Comments

  • kiwi says:

    the number of people called “kim” on the paper almost has a brady-bunch type ring to it

  • milkshake says:

    Lee is soon to be unmasked as a reactionary

    After self-critique he will be allowed to join a voluntary re-education program in frontier provinces

  • Prelim Passed says:

    You forgot on Kim, there are four on the paper.

  • sjb says:

    … is almost waiting for the Trumpton fire brigade to publish.

    S

  • ddd says:

    total synth is a good thing. But whether we want it or not Biology aswers much more fundamental questions by definition. I think synthesis of palytoxin carries much less value then discovery of p53 protein which is mutated in 50% of human cancers. Discovery of Human genome carries more value then natural product synthesis…Although I am total synth person and completed my target…

  • PG says:

    So the human genome has been “discovered”? No wonder it has so much value…
    There are known discoveries; there are things we know we discovered. We also know there are known undiscovered; that is to say we know there are some things we haven’t discovered yet. But there are also unknown undiscovered — the ones we don’t know we haven’t discovered.

  • eee says:

    ddd, ain’t we bitter. what happened?

  • ddd says:

    :))), well lets say I switched from synth chem lab to a biology oriented lab (at one of the top schools in USA). It is so fun to be exposed to a biology group (they do not care about mechanisms, they just need to get a compound to test even with 30% yield). And I just discover more and more things in biology that I was not aware about. p53 gene, discovery of GPCRs, nuclear hormone receptors, Ion channels….what happens in our brains when we switch from one language to another……those are really fundamental questions, and without answers medicinal chemists cannot even start their work. Those discoveries gave rise to so many drugs…And those questions are much more fundamental than chemical questions. Would cancer patient care if drug, which saves his life, is made in elegant way or in a boring way. The only diff is the cost I agree, but the bottom line is – it saves his life anyway…

  • ddd says:

    as to PG I will say: do not be a “word bot”. I agree I should have said “genome was sequenced”, because genome existence was known before :)

  • HOMO-LUMO says:

    ddd,

    To the best of my knowledge (ignorance I’d say),to understand complex biological processes, biologists need to focus ultimately on events at the molecular level, hence chemistry and particularly organic chemistry are still crucial. However, even when I am a tot. synthesis guy, I agree that 20 multi-step syntheses are not the best way to get a cure against i.e different types of cancer or neurodegenerative diseases.

  • ddd says:

    homo-lumo, this field is called chemical biology now. I agree you have to concentrate on the molecular events, but chemistry is quite simple. Nature thinks in a very SIMPLE and straightforward way.

    If sponges want to defend themselves, why bother trying to reinvent the wheel? Just target actin cytoskeleton and you will kill any predators for sure…

  • eee says:

    ddd, I’ll be concise. I think you’re missing the point on why total synthesis is done; or the meaning of the word “fundamental”. By the way, an average cancer patient would equally not care how the drug is made, or whether it’s p53 gene that’s mutated or p54.

  • ddd says:

    I know why tot synth is done, methodology, new reactions, supply problem, 50 tot synth eventually will put the whole field forward in terms of convergency, efficiency and new chemistry. Sure gold, or C-H activation are important.

    Anyway I think I am just interested more in biology then in chemistry now, and this is why I posted above posts :))). Patient would certainly care about p53 or p54. The reason is that drug based on p53 will save his life, and p54 willnot work at all.

  • Tot. Syn. says:

    I don’t think we really need a discussion about what is more fundamental; Chemistry or Biology. The bottom-line is that biologists rely on chemistry for a proper understanding of the mechanisms of action, and chemists require an understanding of the significance of the molecules they are constructing (SAR et c.). It’s called a (symbiotic) relationship. And if both parties stand and shout each other down, nothing gets done.
    (And the DMPK guys are effectively the relationship counsellors… but that might be stretching this analogy too far!)

  • HOMO-LUMO says:

    That was a good definition, I would add as well that with chemistry is possible to do biology, for example, doing click chemistry or even dynamic combinatorial chemistry (library of several compounds undergoing a reversible reaction in the presence of an enzyme is possible to identify possible inhibitors of the enzyme and hence even to get information of its active site, etc). I’m quite ignorant on this, but I find interesting as well what Bertozzi, Kjessling, Davis or Seeberger do.

    BTW, ddd, as somebody pointed out one day in tenderbutton, is it true that in chemical biology you need to pippete, use the LC-MS, and connect the hundreds of points in the high field NOESY and other 2D and even 3D NMR tech, like a demon?

  • ddd says:

    BTW, ddd, as somebody pointed out one day in tenderbutton, is it true that in chemical biology you need to pippete, use the LC-MS, and connect the hundreds of points in the high field NOESY and other 2D and even 3D NMR tech, like a demon?
    ————————————————————————————–
    ??? Well this is quite a general statement. Yes they do use pipetters and not only in chem bio field, but in all fields of biology. This is the nature of the field. They do use pipetters as they do use polyacrylamide gels on daily basis.

    They do use LC/MS all the time and not NMR. And the reason is plain simple – when you make kinase inhibitor you react amine with chloropyrimidines. LCMS of the reaction mixture allows you to monitor reaction progress providing you with HPLC chromatogram and mass spec. This takes only 10 min…fair enough. And you can predict most of the time what kind of structure your product will have. They use NMR only for proteins.

    They do not run 1,5 – assymmetric aldol reaction where you have to run NOESY for your macrolide in order to confirm the configuration of the stereogenic center.

  • Rof5 says:

    Wow! It’s another nice paper from SNU this month on the blog.
    First one is Amphidinolide E by Prof Eun Lee.

  • dockingman says:

    Hey, I was wondering if this Corey olefination is actually a well-established reaction… It seems to me that this people called it “Corey olefination” but it should actually be “the reaction performed by Corey and others” or something like that… I can’t find many other references to a “Corey olefination” (e.g., a Google search almost only yields this blog post!), and to me it looks mostly like a Peterson olefination on an imine in order to yield an alpha,beta-insaturated carbonyl on workup… Any hints on it?

  • [...] Another medium-ring ether synthesis, but using completely different methodology to last months excellent synthesis by Kim. But Steve Clark (now at “WestChem“, having moved from Nottingham) should know these species pretty well, having worked with Andy Holmes… Anyway, this is a great read, so on with the synthesis (no retro; you’ll see why…). [...]

  • [...] Continuing their fascination with natural products derived from the Laurencia family (not an uncommon fascination!), Deukjoon Kim’s group (the same team that brought you this post) has completed two more related structures, each with that eight-member ring, often found in the family. They base most of the work on an advanced intermediate, created in their synthesis of Laurencin (seven steps, 35% yield), containing that eight-membered ether ring, set for functionalisation. [...]

  • watch says:

    poopy goes in the potty pottatttooss

  • [...] final intermediates are starting to look fairly similar to those encountered by Kim; looking back at that paper, Kim was able to do a rather tasty oxo-mercuration to form both the [...]