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Palmerolide A   

16 July 2007 15,051 views 43 Comments

palmerolide_a.jpg

Nicolaou, Chen, Guduru, Sun, and Banerji. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200702243.

I didn’t manage the macrolide spectacular I promised in the last post, but here’s a gem I missed in the ASAPs from a few weeks back. The target is a landmark for several reasons, but the more aware of chemical politics will have noticed that this is the first (of many I imagine) publication from the Nicolaou/Chen labs at the A*star institute, Singapore. This venture is one that has captured a lot of interest, and I think many of us know people involved in this (Hi, Frankie!). As an aside, it’s also interesting to note that David Chen did a post-doc his PhD (probably) for Ian Paterson, so certainly knows his macrolides!

Anyway, enough politics – more chemistry! Many of you will recognise the target, even though this is only the second synthesis (the first being that by De Brabander), as quite a bit of noise was made on it’s isolation. This is because of its impressive biological profile, as well as its geographical location in the Antarctic! As I mentioned in the last post, the retrosynthesis of this type of target gives away much of the game, and in this case, provide few surprises. I guess the enamide coupling will have raised some eyebrows – we’ll discuss that shortly. Otherwise, RCM/Yamaguchi/Stille are fairly par-for-the-course.
palmerolide_a_1.jpg

The synthesis of the partners for the Stille coupling is what first caught my attention, where they used an interesting allylation reaction to impart two stereocentres in good enantio- and distereoselectivity from a diisopinocampheylborane species. The carbamate was then formed, and they were set to hydrostanylate the free acetylene. Although they don’t discuss their reasons, they use some neat chemistry by Gerry Pattenden to do this. Presumably, the silver nitrate is basic enough to deprotonate the acetylene and cause bromination. This bromo acetylene can then be stereo- and regioselectively hydrostannylated using catalytic palladium and tributyltin hydride. Neat.

palmerolide_a_2.jpg

[However, this brings me to a point of consideration - why are Stille coupling more common in academic publications, and Suzuki more so in an industrial/commercial context? When it came time for me to make some dienes, I decide to use Suzuki chemistry, and found that disiamyl borane did the hydrometallation very nicely, and that the coupling was quite straight forward, but perhaps I was rather lucky...]

And now to a bit more catalysis, and some Buchwald chemistry (who gave an excellent talk here earlier this year). This time we’re working with catalytic copper (I’ve heard that copper (I) iodide can be a bit of a pain to work with due to disproportionation – anyone want to clarify?), achieving an impressive coupling, ableit is somewhat modest yield. Importantly, however, most of that mass balance is returned starting material – an important consideration in such an advanced reaction! That’s it – job done well (including a stereochemical reassignment I didn’t mention)!

palmerolide_a_3.jpg

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43 Comments

  • jimbo says:

    “why are Stille coupling more common in academic publications, and Suzuki more so in an industrial/commercial context? ”

    I can tell you why industry -doesn’t- use Stille, but I, for the life of me, can’t explain why academics continue to use it. I think much of it might come down to fear of isolating boronic acids/esters.

  • HB says:

    Why is any of this intellectually noteworthy? In my opinion, it’s a toss-up between macrolides and peptides as far as the most dull types of synthetic targets are concerned. Now, I can understand why peptides need to be pieced together in repetitive, boring manipulations. I think macrolides could be done more artfully, but fail to see any excellent examples.

    Both of the “feature reactions” listed here are fairly nice, but nothing I ended up scratching my head over.

  • accurate says:

    The first total synthesis by this group is GE2270A :
    http://www3.interscience.wiley.com/cgi-bin/abstract/113440460/ABSTRACT?CRETRY=1&SRETRY=0
    I think you also missed this one (towards Haplophytine):
    http://www3.interscience.wiley.com/cgi-bin/abstract/114278211/ABSTRACT
    More politics !!!

  • milkshake says:

    Nitpicking: In the last scheme describing the grand finale step you are missing an iodine on the C=C and one H on the amide. Otherwise it is quite remarcable they can do Ullmann-type amidation at room temp and that the main side-product is carbamoyl-cleaved material. I would worry about lots of other stuff but not this.

    Stille vs Suzuki: in this case they could not use alkyne hydroboration because there is the vinyl sunstituent in the molecule. Charlie Brown of the KAPA zipper fame has a paper on hydroborating C=C in the presence of alkyne. Unhindered boranes are not selective but 1 equiv of BBN prefers terminal alkene over terminal alkyne in 6:1 ratio. The ratio is higher than 25:1 with internal alkene and internal alkyne.

  • wiggum says:

    my experience has been that stille couplings work better for vinyl and some heterocyclic substrates while suzuki is better for aryl and other heterocyclic substrates. By better I mean the yields are higher. The toxicity of organotin makes it a no-no in an industrial setting, that and there are hundreds if not thousands of commercially available boronic acids/esters.

  • ArrowPushingMonster says:

    I use CuI a lot … whats this about disproportionation problems?

  • Mike says:

    A couple of points about the bromination-hydrostannylation step.

    First, although Nicolaou cites the Pattenden paper, the latter makes it clear that the methodology was invented by Zhang (J. Org. Chem. 1990, 1857). Pattenden added a further 9 examples to the 3 that Zhang had reported.

    As for the bromination itself, this is a reaction we’ve used a few times, and the mechanism is a bit of a mystery. Is silver nitrate really basic enough to deprotonate an alkyne? I’ve certainly never thought of it as a base. Is it more likely that (maybe via initial pi-complexation???) you make a silver acetylide , which is sufficiently nucleophilic to pluck the Br off NBS? Any thoughts, anyone?

  • itastallion says:

    In the last step of the synthesis (Buchwald chemistry) you might require to have a vinyl iodide on the side chain terminus..

  • synthon says:

    For some reading on the formation and use of silver acetylides, see the work of Partrick Pale at CNRS: http://dx.doi.org/10.1016/j.tetlet.2006.02.067

  • bibi-p says:

    how about yamamoto`s platensimycin formal syn?
    very nice key reactions..

  • bibi-p says:

    sorry i do not know link the DOI
    ..was last saturday ASAP. enjoy it..

  • ChemicalProcrastinator says:

    Dave Chen did his PhD with IP, not a postdoc.

  • The Canadian Chromatographer says:

    Hmmmm… not that I want to throw any gasoline on the red ashes, but David Chen has done his Ph. D. with Nicolaou, I’m 98% positive.

  • Jose says:

    In industry, I recently did some couplings with a benzylic stannane (which I made) and there were *lots* of raised eyebrows and tedious discussions at meetings, even though it was a small med-chem scale reaction. i think it just really freaks people out, the chemists even get chemophobic there. RSnMe3 species are pretty scary, but RSnBu3 are pretty happy and well-behaved.

  • Hap says:

    I thought that Stille reactions tended to be more reliable in complex substrates such as macrolides (I read this, not from experience) – so though they can’t be used for industrial/pharmaceutical settings, they are going to be used a lot in total synthesis. Of course that would seem to beget a legitimate complaint – if you can’t use Stille couplings for anything other than academic natural product synthesis, it seems like developing Suzuki variants for complex substrates should be more emphasized.

  • Giagan says:

    David Chen: Paterson PhD student, Nicolaou post-doc

    http://www.ices.a-star.edu.sg/ices/research_and_development/researcher_profile/detail.do?id=15466504

    Also, Palmerolide A is not the first Nicolaou/Chen synthesis published:

    http://www3.interscience.wiley.com/cgi-bin/abstract/114278211/ABSTRACT

  • Atompusher says:

    Sometimes Suzuki reactions just don’t work as well (or at all) in comparison to Stille couplings. In my experience 2-halo pyridines are one such case.

    Many industrial med chem types avoid Sn because they are weenies. Yes it is toxic and makes your fingernails fall out and all of that, but come on. If your technique is that bad you shouldn’t be doing chemistry in the first place.

  • ChemicalProcrastinator says:

    Maybe its the boiling in aqueous base that makes the Suzuki a bit of an issue for natural product people? Just a thought….

    Anyway, I am 100% sure that Dave Chen did his PhD with Ian Paterson, I was in Cambridge at the time.

  • hetchem says:

    No sorry Canadian Chromatographer

    You are wrong check out this

    Chem Eng News

    http://pubs.acs.org/cen/coverstory/84/8409singapore.html

    And even better his CV

    http://www.spms.ntu.edu.sg/CBC/Research/documents/ChenDavid_000.pdf

  • HR says:

    Pretty sure David Chen did his PhD in Cambridge and then post-doc for Nicolaou working on diazonamide

  • HB says:

    Dear Quibbling Retards:

    A quick Google check precludes an unnecessary volley of “no, I am pretty sure that …”

    Witness: http://www.spms.ntu.edu.sg/CBC/Research/documents/ChenDavid_000.pdf

    Cambridge!

  • jerry says:

    why r people so interested in David Chen not in his work? He is just a smart Chinese guy,right?

  • The Canadian Chromatographer says:

    There’s only one thing to reply:

    D’oh!!!

  • Tot. Syn. says:

    ChemicalProcrastinator:
    Boiling in aqueous base is a bit of a generalisation – I found that 40C with a little 2M LiOH was suitable for my system. And it wasn’t trivial either – vinyl iodide/vinyl alkyl borane…

  • milkshake says:

    There is also anhydrous Suzuki, with CsF as a base (protecting groups, doh!)

    Industry folks usualy do not do tot synthesis. If they do then they are likely to address scalability and othes issues so they would naturally shy away from tin-based reagents.

    In many vinylic coupling cases the Stille is more reliable and uses milder conditions. You try first what you think has the biggest chance to work, not what is most enviro-friendly or chapest. When working on a tot synth thesis project, one has rarely the time and motivation to look for alternatives if a particular Stille coupling performs fine. Pushing the material through to solve problems with some difficult late stage messy step should be the priority – otherwise one would never graduate.

  • commonli says:

    I am wondering why KCN don’t publish the experimental procedures in his communications..

  • yepyep says:

    Industry people probably don’t like Stille coupling because in the real world you actually have to get rid off of all the impurities? Reviewers in the JACS or ACIE aren’t as bitchy as the reviewers in FDA or EMEA :p

    And as this is another macrolide synthesis, I don’t really know what to comment… RCM just isn’t as sexy as she used to be a few years ago.

  • ArrowPushingMonster says:

    In my experience Stille’s are cleaner and give better yields than the corresponding suzuki’s. The stannanes are also generally more stable than the boronic acids. Pharma just don’t want horrendous amounts of toxic tin hanging round the place or being carried through to their drug

  • Spiro says:

    Check this:
    http://www.fda.gov/ora/science_ref/lm/vol4/section/14.pdf

    A priori there is only one order of magnitude of a difference between the oral lethal dose of boron and tin cpds.
    My guess is boron is cleared better than tin and does not accumulate, so there is less of a problem with its use in pharma chem.

    I would be very intererested if someone could provide me with a link to the FDA expectations of what the max contents of tin and boron are in approved drugs.

  • Hap says:

    Milkshake,

    It makes sense to use Stille couplings based on what the graduate student needs to do (complete the molecule), but it also means that the field has less meaning to anyone else. Making big natural products is intellectually stimulating but it’s awfully expensive to do if the intellectual stimulus is all that people are getting for their research money. Using techniques that aren’t going to fly anywhere else seems like a way to ensure irrelevance for total synthesis in the long run. It seems like it would be primarily a methods development task to find Suzuki couplings that work on complex substrates, one that total synthesis/methodology groups would be suited to (and which ould be worthy of funding as well).

  • ZZZZZ says:

    zzzzzzzz
    Summary: Tin is bad for you, boron is not as bad
    zzzzzzzz

  • TheEdge says:

    Hap-
    I agree. I think the problem is that most of us set out on our total syntheses with a couple different key bond constructions we want to try based on chemistry our lab is already doing, and we’re willing to use whatever we have to in order to get to them. Some of us get there more elegantly/ efficiently than others, but there is rarely an applicability-to-others factor considered. We need some catalyst lab (who rarely publish syntheses. how often do we see a complex synthesis out of the buchwald or fu labs?) to step up and assemble some highly functionalized polyene beast and the rest of the community needs to avoid the “ZOMG they would have gotten ten percent better yield with a stille” response we’re so likely to have.

  • [...] written by sks [...]

  • [...] at the post – yes, you have seen it before. Originally described in an Angewandte paper last year (which was discussed on this blog), Nicolaou and Chen achieved a smart, logical synthesis of the marine macrolide. The main problem [...]

  • Doghead says:

    You guys total need to grid the fact that Sn residue is highly toxic in the biological testing in the pharmaceutical settings. It is extremely difficult to remove and WILL mess up the results. This is why industrial folks don’t like Sn reagents at all.

  • The Next Phil Baran says:

    This doesn’t show an improvement in synthesis of any kind! It’s old chemistry that just happens to fit a really important molecule medically/commercially. Why is this JACS and not medicinal chemistry? So he changed some functional groups and the potency increased – this has been happening for years. He just got lucky on a really good compound medically. Who cares.

  • TWYI says:

    More analogues today in JACS – LOL

  • milkshake says:

    looks like you are suffering a bad case of JACS envy – IMHO that journal is heavily over-rated, the same goes with Nature. I would sooner read Org Process R&D, JOC and Org Lett than the self-important JACS overflowing with irrelevant crap.

  • mark says:

    I bookmarked this site, Thank you for good job!

  • zachhhh says:

    I am a student at University of Louisville and am having a terribly hard time finding what exactly an -olide group is can someone please explain?

  • Kay Veit says:

    You made some good points there. I did a search on the topic and found most people will agree with
    your blog.

  • Leone says:

    Good to know

  • CindyChou says:

    Hi, I’m a student in organic chemistry and I picked this publication to explain the total synthesis of the Palmerolide A. There is one thing that I don’t really understand in the publication…
    It is the “unstability” of vinyl iodide aldehyde 7 in the Evans aldolisation conditions explaining the low yields of the reaction. (JACS, 130, 3637 on the scheme 2)

    I don’t if you could help to understand this point!

    Have a good day, and thank you for the job you’re doing for this website I really appreciate to read it!