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Oasomycin   

14 December 2006 5,617 views 12 Comments

oasomycin_a1.jpg
Evans, Nagorny, McRae, Sonntag, Reynolds, Vounatsos, Xu. ACIEE, 2006, EarlyView. DOIs: 10.1002/anie.200603652, 10.1002/anie.200603653, 10.1002/anie.200603654.

No biological data given as a raison d’etre, so we’ll focus on the fact that this is one bad-ass structure, ripe for a bit of aldol-bashing. Indeed, over the three communications outlined above (why not one article?), Evans et al go seriously aldol-tastic in the synthesis of this 41-member macrolide. So, to the retro (and probably the most complex I’ve drawn so far:

oasomycin_1.jpg

Now that’s what I call a disconnection approach! It’s all in the execution from here, and for the most part, it’s known chemistry. Their methods and retro ensure that the synthesis is very convergent, but I’m not going through much of it. However, two steps caught my eye:

oasomycin_2.jpg

Using a HWE, they built the diene SM, and were ready to hydrog the less-substituted alkene (the “trans Δ4 olefin”). However, various methods, including use of Lindar’s catalyst, resulted in over-reduction and inseparable byproducts. But they did get success using Crabtree’s catalyst (this JOC), which chelated to the free hydroxyl, allowing reduction of only the desired alkene. This did require deprotection of a TES group to free the hydroxyl in question, and then reprotect, but the managed an 80% yield over those three steps. Not new chemistry, but new to me…
oasomycin_3.jpg

Lastly, I really liked this aldol (one of the many), using Evan’s own methodology; a C2 symmetric copper catalyst to generate the chiral product in good e.e., on the “Chan Diene”. However, I couldn’t find a yield for this?!

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12 Comments

  • PG says:

    “Why not one article?”
    Section 2.5 of the guidelines says: “The maximal length of a Communication, inclusive of all literature citations, footnotes, and tables, is 10000 characters.”
    You shall not break the rule.
    That being said, it’s nice to see total synthesis in Angewandte with full experimental section and NMRs.

  • Tot. Syn. says:

    Well, I did say “Article” not “Communication”…

  • Antediluvian says:

    Your blog is great. I was wondering though why you missed Danishefsky’s brilliant synthesis of 11-O-Debenzoyltashironin–12/08/06 JACS. Are you just really busy or was it just an oversite?

  • Tot. Syn. says:

    No, I’ll probably try and give it a mention later in the year… too much to do! I’ll actually be away from the blogosphere for about two weeks quite soon, because our research group is moving university…

  • chemist says:

    It brings up an interesting question. A person spends his/her Ph.D doing methodology and gets out 7 publications. Another person does total synthesis of a huge natural product and gets one article (full paper) as you suggest. Guess who gets the money after applying for grants.
    BTW, how many full papers did KCN published on Azaspiracide?

  • sjb says:

    It’s always been a matter of wonder to me how these moves work. Do relocation packages for academics take into account the moving of their students too, and how difficult it may be to break out of / get new housing contracts for parts of the academic year (that said, similar I guess occurs in thin sandwich degrees and to a lesser extent CASE placements.

    S

  • Tex says:

    Antediluvian

    Bear in mind that a blog is primarily on issues that the blogger (Tot. Syn.) finds interesting – not every total synthesis (however brilliant – however that is defined) can be posted. It would simply take too much time, and Tot. Syn. has dissertation research to do! I for one, just appreciate the blog (posts + comments)for what it is – a good read.

    Tex

  • Antibonding says:

    Tot. Syn.

    This aldol addition appeared in some other Evans synthesis (Phorboxazole?). I guess that’s the reason why authors did not provide the yield.

    Publishing full papers requires more time and effort than communications. I think it all depends on the style. I have never seen people just publishing a full paper on a synthesis of this sort.

  • yepyep says:

    Extra double bond between C28-C29 in the upper picture?

  • Tot. Syn. says:

    Fixed. Cheers; I take it it was the stereochemistry on the olefin that gave it away :)

  • William…

    puh i prah…