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Oocydin A   

16 April 2008 12,789 views 43 Comments

Roulland, ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800585. Article PDF Supporting Information Group Website ResearchBlogging.org

Yep, just one name. And an impressive synthesis for just one chap (and I don’t think he even had the backing of “Bioic Bros. GMBH” like La Clair). Even the target has more names – this one was independantly isolated three times, gaining haterumalide NA and FR177391as alternative monikers (albeit with different optical rotations…). No mention is made of its biological profile in this paper, but a synthesis of the methyl ester by Snider in 2003 states “Haterumalide NA is cytotoxic to P388 cells with an IC50 of 0.32 ug/mL [and] has MICs of approximately 0.03 ug/mL against phytopathogenic oomycetes”. That neatly explains the odd name, and shows a reasonable activity profile. Other syntheses of the target include one of the actual acid by Hoye and Wang, but for some reason they didn’t quote the optical rotation… Anyway – retro:

I always love a bit of sp2-sp3 Suzuki action, especially on a gem-dihalo-olefin! However, the synthetic action gets interesting with a paladium-catalysed THF formation. Starting with an easily accessible SM, derived from tartarte, he screened a range of palladium sources and ligands, finally optimising to an impressive yield and d.r.. The reaction, to me at least, is very much like a Tsuji-Trost, resulting in an easily diversified product.

Synthesis of the other main fragment was more routine, but I was interested to see how Roulland would install the dichloroolefin. Typically, he used a bit more French chemistry (it might not actually be French, but to me samarium diiodide = Henry Kagan), eliminating the acetoxy group to give the desired electrophilic partner for the Suzuki coupling.

The electropositive partner was produced by in-situ hydroboration of terminal-olefin bearing THF fragment, and then use of slightly exotic conditions resulting in an excellent yield of the desired product. (I’ve mentioned this in several other posts, but remember that the trans- halogen tends to perform oxidative addition faster than the cis-). Previous work on this modified Suzuki Miyaura reaction by Roulland can be read in this JOC.

Functional group transformation and some Yamaguchi action resulted in the macolactone, so soon he was able to do the NHK chemistry to complete the molecule. This went well, with one proviso: ‘…a special workup with sodium serinate to sequester the chromium cations was necessary to obtain [product] in acceptable yield.’. I’ve never done an NHK – anyone with experience like to comment? Also, why does Roulland speak in the plural?

Additional – I can hardly believe this – but this is blog-post number 200. That gives an approximate average of 100 per year… and I still feel entirely under-qualified for this! Thanks for reading folks – hears to the next 200!

Roulland, E. (2008). Total Synthesis of (+)-Oocydin A: Application of the Suzuki–Miyaura Cross-Coupling of 1,1-Dichloro-1-alkenes with 9-Alkyl 9-BBN. Angewandte Chemie International Edition DOI: 10.1002/anie.200800585

InChiKey Dump:
OAWOFENLLWPBEQ-VXLXENEIBB BXJWNHUXROCRCE-HMXCVIKNBS NFSYWHAEMPOEFR-RAXLEYEMBJ CUUUYLULMKBICZ-PMFPUCIMBR PJWDDPOFBZDVFJ-MULDZMIYBB NLTMGJFECAQKCM-BPLDGKMQBD UCOBGBWAOODAMK-RAXLEYEMBW

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43 Comments

  • Caustic says:

    Not so bad for a french.

  • J says:

    Cute geminal vinyl dichloride formation. Wouldn’t call it French (Zhang did the methodology).

  • Klug says:

    It’s really quite interesting to see how little B-alkyl Suzukis get deployed; they’re such a great bond disconnection.

  • Big_C says:

    Nice work! To any reader who might know– is it typical in Europe for a PI to do this much hood work?

    Also, congrats Tot. Syn.! 200 posts is quite impressive, especially considering the ever-improving quality of your entries.

    Keep up the good work!

  • Le Dude says:

    Congratulations on the 200th post Paul. You’re doing a great job and a valuable service to the organic chemistry community.

    Nice work described here. I’m a little unclear on the reason for the strong diastereoselectivity of the tetrahydrofuran formation. I wish it was discussed more thoroughly in the paper, because it isn’t obvious why a 96:4 ratio is obtained – he even says the diastereoselectivity was unexpected.
    The sodium serinate workup to sequester the chromium from the NHK is also interesting, as was the vinyl dichloride formation.

  • InfMP says:

    yeah my friends and i can not help but joke everytime we see an impressive one man paper. The ridiculousness and obviousness of the LaClair scandal made me doubt reviewers (I think about this when I get back hate comments from them! hahahha)

  • Paulo says:

    Congrats for your 200th post, homonym ! ;-)

    BTW, what is the meaning of “Not so bad for a french” ? Or maybe Total synthesis has to be from UK or US to be valuable ??? and after all, French guys are said to be arrogant…

  • Ron says:

    One thing I appreciate about the supporting information is that most of the reactions outlined in the paper are done on at least an one-gram scale. At least we know the reactions are probably scalable.

    A couple of the procedures must have typos because they didn’t make sense, though. Still, I’m impressed at the documentation of the experimentals for this synthesis.

  • Caustic says:

    What meant by “not so bad for a french” is you cannot see so many total synthesis papers coming from french lab.
    If I go further you dont see so many papers in top ranked journals (JACS, or Angewandte).

    And Paulo, maybe french people are arrogant, but concerning the research they are probably not enough arrogant and maybe that cost the nobel Prize to Henry Kagan.

    In addition, I propose you a game (for non french readers), give your top 5 French ORGANIC chemists ( who are still alive, not retired or not emeritus….and without SciFinder, Beilstein, ACS, Wiley…..research database).
    And I am sure a lot of people are not able to give me 5 names…
    If you can, so congratulations…you deserve to do a postdoc in France…lol

  • Tot. Syn. says:

    Kagan, Alexakis, Chauvin, Dixneuf, Amatore, Zard, Luche, Lehn…

  • guigui le chimiste says:

    You can add

    Janine Cossy (quite a lot of Total syntheses even if they are not so innovatives),

    Max Malacria (Radical chemistry, Pt and gold chemistry, cyclotrimerisation by Co : quite a few Angew. and JACS papers),

    Zhu (quite a few total syntheses in JACS and Angew. notably Ecteinascidin 743 (JACS 2005):competitive with the one from Corey (Fukuyama was the only other that completed the total synthesis of this beast)

    and Barton spent some times in France as head of ICSN (the institute where E Roulland is now)

    Yes I am French (did a post doc in the US) but I don’t like when caustic is saying that French chemistry is crap. I think that he only paId attention to papers coming from the US. There are no other countries where the culte of personality is so high. Only the name count, not what is actually in the paper.

    Unfortunately, there are not enough funding in France to have the same quality of research than in the US. There are no research group of 50 PhD or post doc that can be competitive with Nicolaou and others…

  • Tot. Syn. says:

    Damn. I’m annoyed that I missed Cossy and Malacria. I’ve heard quite a few stories about Barton’s time in France from a former student, Willie Motherwell at UCL in London… something to do with the term “bonding”, its translation into French, and then back again into English…

  • guigui le chimiste says:

    I forgot J. P. Genet

  • WestCoast85 says:

    Merci guigui le chimiste pour avoir remis Caustic à sa place !!!

    It’s a message from the ICSN where we make beautiful total synthesis…

  • Caustic says:

    Guigui, you misunderstand me.
    I didn’t say “french chemistry is crap”, even if I was slightly sacarstic by saying “not so bad for a french”.
    I only wanted to point out that
    - First, few groups in France dare to do total synthesis, even if you have named two well known (Cossy and Zhu).
    - And second, the french chemistry is underestimated because underrepresented in Top ranked journals (this is my opinion).
    Furthermore I completely agree with you when you outlined the lack of funds in this country, but it’s not the only problem to resolve to improve the research…
    And finally, and without sarcasm, I am delighted to see this total synthesis with a impressive tandem hydroboration-selective Suzuki-Miyaura cross-coupling, that reminds me a review of Danishefsky and Trauner in Angewandte…..

  • guigui le chimiste says:

    Maybe,

    I went a little bit to carry away after your sarcasm.
    I apologized for that.
    There are effectively few groups in France that tackle total synthesis of complexes natural product besides the groups of Cossy and Zhu. There are the only ones of the Tot. Synth. groups in France that are about 20 students or post docs and are sure to get funding.

    Other Tot. Synth. group does not dare tackle those compounds because in France you usually have funding for 3 year and then if the work is not finish, you are not sure to have funding or someone to complete the total synthesis.

    Besides those big groups they are some talented young faculty like E. Roulland (I never met him) or Jean Marc Campagne and others that do nice work but that have between one or three students, so they are not so productive. Even if they completed a nice synthesis, they stay anonymous worldwide because they got between 1 or 3 papers a year.

  • lemi says:

    as far as i know, most people, in Zhu Jieping’s group, concentrate their attention on MCRs, only a few chinese Postdocs still do total synthesis, maybe that’s why few total synthesis papers published from his Group by far, recently one of his Postdoc Yanxing Jia(already back to china and began his indenpent career) finish Complestatin and Chloropeptin I and the paper was already published online in Angew
    http://www3.interscience.wiley.com/cgi-bin/abstract/118480198/ABSTRACT

  • Scott says:

    The sodium serinate is the typical work up for the NHK… at least that is what I understand. I must have run a dozen of those in grad school, worked up every one with the serinate and never once got my desired product. Apparently the reaction works for some, but never for me! I ended up just lithiating and adding into an aldehyde. Good yield and great dr.

  • SMILES says:

    If I understand you Scott serinate is the typical work-up for NHK and If I use EDTA, citrate or tartrate instead…is it possible???

  • Paulo says:

    Thanks Guigui for answering to Caustic while i was suffering in the lab ! There is a real chemical french power ! ^^ Or is it the french touch ? :-)

    I am completely agree with Guigui, and just to answer caustic about Kagan’s missed Nobel : everybody knows that Nobel are won by a lot of work, okay, but also with a very large amount of lobbying, and then, in chemistry i mean, are usually scooped by American researchers. The last exception is Chauvin (he had the prize because Grubbs had, but why did not giving him the prize ? Mmmhh… ), who is to be said to cultivate tomatoes in his garden when he received a phone call from stockholm : “Hi, you will have the Nobel Prize in half a hour ! See you !”

    Mmhh… Thinking about tomatoes now…

  • Thanathos says:

    About funding in France, in my group, we fought for one year to have aprox. 15000 euros of funding (for a 2-year project)… and we have to deal with 1 (yes ONE) 300 Mhz-NMR-so-crappy for at least… 150 researchers… 24h are necessary to have a 1H spectrum… don’t even think about a 13C… (okay, okay, we have also a reconstituted shitty 200MHz -NMR but spectra look like HPLC…) And with only 10 graduate students who begin a PhD each year in all the Chemistry Department… How can we be competitive in theses conditions ?

  • SMILES says:

    Have you noticed the work-up for the palladium catalyzed cyclization? Only Silica, removed the solvent under reduce pressure (generally it’s better…than vaccum) and directly column, is it usual for this kind of reaction???

  • Tot. Syn. says:

    I used that procedure with Suzuki couplings. After a few attempts at doing an aqueous extraction, where I had to separate ‘black stuff’ from ‘more black stuff’, I resorted to vaccing-off the solvent, adding a bit of ethyl acetate and silica, drying the crude mixture onto silica and then running a normal column. Worked every time and boosted the recovery from 80ish% to 90ish%.

  • ER says:

    Ca vous a plu ? c’est moi qui l’ai fait !

  • Paulo says:

    Magnifique travail, Emmanuel ! Ca va faire des jaloux ! ;o)

  • ER says:

    It was fun to do it ! this is the most important thing.

  • milkshake says:

    My congrats to the author (the pluralis majestatis in the paper is well-deserved).

    I would like to point out that there is a new Wacker-like procedure (PdCl2, 6 atm O2, DMAc, AcOH, sieves; cyclic ketals survive unmolested; ACIE 2006, 45, 481-5) that takes terminal monosubst olefins into terminal allylic acetates with C=C shift in very good yields – which could be a good alternative for making the allylic acetate substrate for the tetrahydrofurane piece cyclization. (Not that there is anything wrong with the vinylcopper+cross-metathesis sequence actually used here)

  • ER says:

    Thank you very much for this piece of information ! I go and get this article

  • WestCoast85 says:

    I’ve got a question Mr Roulland !

    What do you think about the Jamison’s methodology using Nickel as transition metal for the reductive coupling of an alkyne and an aldehyde ?

    Is it an interesting alternative method to the NHK coupling ?

    Thierry

  • ER says:

    I thought about it. Nevertheless it is not certain you will obtain the right anti configuration for the alcohol function. But using the asymmetric version of this reaction (JACS 2003, 125, 3442) yes why not? but for this reaction a regioselectivity issue on the alcyne function would remain. The NHK is quite diastereoselective and gave the right stereochemistry moreover it is a straightforward manner to introduce the side chain. Even if NHK is a very capricious reaction and is not very “green”.

  • WestCoast85 says:

    Oki, thank you !

  • InfMP says:

    someone here was asking about workup for Pd type reactions. Yes, I agree that extractions are usually not the best idea because you end up with the metal kind of sitting between your two layers. On the other hand, just using a column directly sometimes ends up leaving a bit of metal in the final product. Of course, it is NMR-silent, but you will notice some line broadening. People in my group usually filter through celite and then column. I find that this is a great method.

  • ER says:

    For me the worth point is to get rid of Ru from Grubbs catalyst !

  • Tot. Syn. says:

    There was a useful discussion about getting rid of Ru in the comments here about a year ago:

    http://totallysynthetic.com/blog/?p=610

    Scroll down to the comment by “The Canadian Chromatographer”

  • PG says:

    Since Kagan is french, his firstname is Henri (not Henry).

  • PB says:

    Dave Knight from Cardiff has published a patent on removing TM residues from reactions with Hydrogen Peroxide. It works really well for Grubbs and is very simple – I normally just dilute my rxn mix down in DCM, add an equal volume of 15% aq. H2O2 (about 100mL for 50 mg grubbs) and leave it to stir on ice for a while (without cooling it gets a bit feisty as the rutile product catalyses the oxidation process). Then just separate the phases and wash the DCM with thiosulfate. There’s still a bit of brown but it sticks on a column/plug no problem.

  • ER says:

    I’ll try it next time, thank you. Is the Ru transformed onto some kind of water soluble ruthenate ?

  • ER says:

    or perrhutenate ?

  • PB says:

    It ends up as rutile (RuO2) which mostly stays in the aqueous, but any that does come through with the organic just sits on top of the column.

  • PB says:

    The patent number is WO2007091085 if you’re interested. For a patent it’s surprisingly easy to read and use too…

  • Futur epouse says:

    je t’aime Emmanuel!! Epouse moi!!!

  • Tot. Syn. says:

    My knowledge of franglaise might be my only French, but google translate suggests that yet again ‘that’s plenty…’!

  • Future epouse says:

    My heart is broken!, reponds moi Emmanuellllll