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5 April 2007 11,113 views 30 Comments


Maier and Varseev. Org. Lett., 2007, ASAP. DOI: 10.1021/ol070049a.

Although the biological profile of this zwitterionic target is sparse to say the least, it’s thought that it might have an interesting med-chem role, as the parent compound, symbioimine, has a very interesting activity. Even though it is non-toxic at 100 μg levels, it inhibits differentiation of precursor osteoclast cells (RAW264) into mature osteoclasts, and also slightly inhibits COX-2. However, need I say that the architecture is very appealing? Martin Maier did..
Their synthesis hangs on one particularly effective transformation – creation of a IMDA subrate via a HWE on a conjugated aldehyde, which, after a bit of warming, does it’s thing and out-pops the transdecalin core. Nice, if perhaps not so novel.

So now I’ll take a step back, and do a retro on the HWE-IMDA substrate, which was built pretty quickly, starting with natural citronellol. Most of this is self-explanitory, but the organocatalysis/HWE was done in a pretty fashion.

So, to elaborate, the chemistry they used was taken from MacMillan’s work; α-hydroxylation, followed by HWE, then cleavage of the O-N bond all in one pot gave the chiral allylic-alcohol in a respectable 55% yield. Top banana.

From the IMDA-transdecalin, elaboration to the natural product looks straight-forward enough, but when I read homologation I thought we were in for a somewhat messy finish. I couldn’t have been more wrong… Reduction of the ester to an alcohol, mesylation and displacement with cyanide gave the 1-C homologation nitrile, which was methylated with nice substrate-control. Then, reduction of the nitrile and trapping onto a free ketone gave the final ring! Very tasty.

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  • European Chemist says:

    As usually happens, you can always find something of interest even in the most simple of syntheses.
    I don’t have access to Org Lett (and don’t think I’ll give this one a read, especially after the nice summary on this post, Paul) but I’d be interested in knowing more about that alpha-hydroxylation. A friend of mine tried it in an advanced intermediate in our lab and complained that MacMillan’s work actually involved using EXCESS aldehyde relative to nitrosobenzene or else yields were compromised. He also mentioned long reaction times…
    Also, although the endgame features this very nice diastereoselective methylation, 8 steps to elaborate to a target close to the final product (or it’s the final product itself?) sort of tarnishes the beauty of the thing. Sometimes you get that feeling in a total synthesis, “the key-step is rather elegant but then they take ages to finish because of FG transformations and homologations”.

  • Jan says:


    here you can find the literature, discribing the method of a-hydroxylation und an Scrrenshot of the scheme 1 from the publication.

    i hope this is no rights violation. Otherwise please remove this Link!

    (13) (a) Zhong, G. Angew. Chem. 2003, 115, 4379-4382; Angew. Chem.,
    Int. Ed. 2003, 42, 4247-4250. (b) Brown, S. P.; Brochu, M. P.; Sinz, C.
    J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808-10809. (c)
    Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003,
    44, 8293-8296. (d) Co´rdova, A.; Sunde´n, H.; Bøgevig, A.; Johansson, M.;
    Himo, F. Chem.-Eur. J. 2004, 10, 3673-3684. (e) Hayashi, Y.; Yamaguchi,
    J.; Sumiya, T.; Hibino, K.; Shoji, M. J. Org. Chem. 2004, 69, 5966-

  • Tot. Syn. says:

    Well, that’s the problem – I think it is a violation of copyright, and one that would get me in trouble with Wiley, or indeed any other publishing house. That’s part of the reason I spend so much time redrawing the schemes above. In particular, this image is of the entire scheme, so really gives away the paper…

  • willyoubemine says:

    what if you rewrite the references? is that a copyright problem…stupid John wiley. Good friend of mine, but can be real jerk when he gets drunk.

    Question: They do the enantioselective hydroxylation only to oxidize and lose stereochem!!! So why do it enantioselectively, was it only to have a diastereoselective D-A? If so, okay, that is actually quite clever.

  • TheEdge says:

    re: hydroxylation: The supp mat. claims they use a 1:1 ratio of aldehyde and nitrosobenzene with a concentration of 0.26 M and the reaction is done in 25 minutes. I wish they commented on the yield, if it’s due to decomp or separation of diastereomers/olefin isomers. EC, FWIW, one of my labmates had problems running one of these on late stage material as well. He claimed it was the worst reaction he’d ever run. It’s probably a concentration issue for late stage material. Operationally, getting your 100 mg into 100 microliters is tough.

    The D.A. is nice, but both previous syntheses of symbioamine use the essentially same D.A. I really like the diastereoselective methylation. That was gutsy, and a nice use of substrate direction. I believe the sulfation procedure is significantly higher yielding than earlier reports as well, although it is surprising no one else discovered it before now

  • WillisWill says:

    Whether you cut and paste or redraw/rewrite the original material doesn’t really make a difference in the eyes of copyright law – you’re essentially reproducing the copy-protected material. Although, I think the extent to which you reproduce would not constitute an infringement

    I doubt Wiley is in the business of gunning after grad students (Elsevier, on the other hand…) so no need to shut down the blog yet!

  • JustAChemist says:

    There was another synthesis of Symbioamine in ACIEE early view (by Thomson and Kim). Check it out. It seems a bit shorter than this one.

  • Liquidcarbon says:

    Will it be very-very original if I say “information must be free”?

    Let me guess, another part of the reason you redraw the schemes is because you think they look better and are more clear than those in papers? (e.g no abcdefghijkl steps) I’d say you’re thinking right!

  • Giagan says:

    Sorry about the off-topic post, but there is a BBSnider formal synthesis of platensimycin in OrgLett that might be interesting to address.

    Personally, I found the symbioimine structure to be a bit of an obvious one. But then, there is always a lot to learn even in these cases, and the payoff is more likely (something to seriously to consider) than with something more complex like, say, ingenol or haplophytine.

  • Jan says:

    Yes, the schemes look very nice an so i would like to know the name of the application, which are you using for drawing these beautiful structures. So next time i do not need to copy a scheme from the original paper, because i can draw it by myself.

    Thx Jan

  • Giagan says:

    In comment #10, I didn’t mean to trivialize the efforts of those who carried out this total synthesis. The completion of any synthesis is quite a nice accomplishment.

    The “payoff” that I mentioned refers to meaningful publications, such as those describing a total synthesis.

  • TheEdge says:

    Jan: He uses ChemDraw. It’s on the F.A.Q. page:


    Giagan: Yeah, the D.A. is pretty obvious, but the challenge here is making the synthesis convergent. The authors found one powerfully simplifying transformation, but they never really found a second. It’s still a nice synthesis. The Thomson route is shorter, and they use a more “biomimetic” D.A., but they also don’t have the extra methyl stereoceneter.

  • European Chemist says:

    #10: The Snider Platensimycin synthesis is a formal one and not really introducing anything new for the sake of it (many stuff taken from the previous Nicolaou paper in ACIE), in my opinion. But it’s up to Tot. Syn. to decide….

    And #12: I wouldn’t dare saying that all the publications describing a total synthesis are meaningful: excellent examples come out in almost every Org Lett issue…. the meaningfulness of a publication is something different to each one of us, but I could hand you a long list of Total Synthesis papers which add nothing new to the field.

  • Giagan says:

    #14: I actually wasn’t trying to say that all publications describing a total synthesis are meaningful, and this is part of why I felt the need to clarify. In part it depends on your definition of meaningful. You are right in saying that many total synthesis papers add nothing new to the field. We could, but probably shouldn’t list examples. ; ) But what I was getting at in comment #10 with regard to the “payoff” and meaningful publications has more to do with interviews. Right or not, interviews are much smoother when you have publications and your role in the project(s) is clearly defined. Such publications are more likely with a target manageable enough to be completed in your grad student/post-doc tenure. I’m not saying I agree with this–you can become a fantastic chemist by hammering away at an insanely complex target for several years. But this is the reality of the job hunt. I apologize for not being clear about what I meant from the outset.

    “And #12: I wouldn’t dare saying that all the publications describing a total synthesis are meaningful: excellent examples come out in almost every Org Lett issue…”

    Your statement about Org Lett actually addresses your disagreement with the converse statement; namely, all meaningful publications describe a total synthesis. Like you, I completely disagree with this. As you mention, Org Lett regularly provides excellent examples of important papers that do not describe total synthesis.

  • Ryan says:

    I have a question to pose to the commenters at this site. I am headed into grad school next fall. I will be doing total synthesis work. Right now, I am having a hard time figuring out the best way to increase my knowledge in modern synthetic methods. Do you think that I should be reading total syn papers, synthesis textbooks, reviews, or methodology papers?

    What would some of you suggest might be an excellent way to broaden my knowledge? I was thinking of going through some total synthesis papers and then when I hit a transformation I am not clear on, try to find some literature precident (and follow the paper trail).

    I have some excellent books at my disposal as well as access to the literature. Any other ideas would be greatly appreciated.

  • willyoubemine says:

    the best resource initially for strategy and achievements is the Classics in Total Synth books…The Nicolaou ones.

    From there, I would recommend doing a lit search on other total synth of the same targets and comparing strategies in your own mind. The things I always think about are a) is the approach novel, and not a rehash of old chem (i.e. imo: polypropionate assembly nowadays, though the early work is just beautiful). b) is the approach THE BEST way to make it (i.e. the Johnson cascade approach to steroids, why do it any other way. or more recently Baran’s Chartelline C work).

    Though the steps may not be ideal bc of PG’s or low yields, if the approach is elegant, taking the molecules inherent structure and reactivity into account, then the synthesis will be terrific.

    just my buck, two pounds, and a shekel.

  • TheEdge says:

    I’m with willyoubemine on the nicolaou books and the subsequent follow-up. If you’re going to the lit to learn, you should try and find full papers, as opposed to communications. They tend to cover failed routes and explanations of why things work the way they do. Synthesis communications, especially in JACS, can be kind of cursory.

    The Kurti and Czako book, Strategic applications of named reactions in organic synthesis, seems pretty comprehensive in terms of raw reactions. The Evans 206 notes are very informative in kind of a boot-camp, this is why things work kind of way, and are similar to the Boger book. They can be found here, although you may need to be on a Harvard network to get to them:


    It’s also a link off of the DAE homepage.

    Perhaps most importantly, you should slog through the publications of any PI you’re interested in working for. They are as good a starting point as any and should give you a good feeling for how the group does chemistry.

  • The Dude says:

    In the words of Robert Burns Woodward, “A tough molecule is the best teacher”. It’s always good practice to try and look at targets and figure out how to disconnect them. You become more sensitized to things like functional group tolerance, chemoselectivity, and stereocontrol once you delve into the mucky details of planning the synthesis of a specific target. Reading the literature and practicing synthetic planning form a powerful feedback loop.

  • Mike says:

    Another good place to read up on synthetic planning is the series “Strategies and Tactics in Organic Synthesis” – kind of like the Nicolaou books, but with each chapter written first-hand by the authors of the original literature rather than being Nicolaou/Sorensen/Snyder’s take on it. I think there are 5 or so books in the series.

    To be honest, I think the best way to learn about tot. syn. techniques is to read the original literature. The advantage of using any of the books mentioned (or this site) is that you have to wade through rather less dross before getting to the interesting chemistry… but the disadvantage is that you’re relying on someone else’s opinion of what’s interesting!

  • milkshake says:

    while reading all fancy stuff about tot synth, it helps to learn something about metodology too. The usual problem of tot synth is that that chemistry is full of surprises and you are likely to get stuck at around step number 22, with few migs of material available. You better be able to make the reaction work (the alternative is to postpone your graduation by another year, go back and re-design the entire scheme and bring all material through)

    Good place to start reading about methodology/reaction/catalyst optimisation are papers of Evans and also Org Process Research R&D journal, for the scale-up angle.

  • Giagan says:

    What if you read every single E. J. Corey paper? I imagine that too would be instructive.

  • HR says:

    “Every single EJ Corey paper” will actually include his papers on the invention of various protecting groups like TBS etc… My personal favorites from Corey will be aspidophytine and ecteinascidin 743.

  • TWYI says:

    I love reading through Corey’s Tett. Letts. over the years. I think there was a pdf summarising them all on Baran’s website.

  • Mitch says:

    Happy b-day Paul. :)


  • Tot. Syn. says:

    Ah! Not quite – wherever I you read my birthdate (presumably on your wonderful forums), I wrote it in non-American format. So it was on the 04/10/1980 – the 4th of October! However, I did celebrate the 10th of April when I was living in the US, as it marked the day that my Driving Licence made me 21…

  • Giagan says:

    #23: ““Every single EJ Corey paper” will actually include his papers on the invention of various protecting groups like TBS etc… My personal favorites from Corey will be aspidophytine and ecteinascidin 743.”

    Precisely why I think it would be so instructive. Also, how many named reactions contain “Corey”?

    I’m with you on your picks, but I’d also add neotripterifordin and the prostaglandins as favorites of my own, off the top of my head.

  • Tynchtyk says:

    Corey-Kim Oxidation
    Corey Fuchs
    What else?
    (Woodward-Hoffmann-Corey Rules :)))
    BTW, Today is Woodward’s Birthday, we had a lecture by his daughter Crystal Woodward on his honor this morning. He would be 90 if he was alive now…

  • WillisWill says:

    The old stand by from my sophmore orgo class: the Corey-House

  • Eddie says:

    Yes Corey-papers are great! Especially, the papers with the steps with 99% yield after crystallisation and column chromatography!!! I wonder what industry is saying to Corey-yields….but they are at least good for mechanisms and strategy