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8 November 2008 12,599 views 30 Comments

Chen, Gao and Wang. JACS, 2008, ASAP. DOI: 10.1021/ja808110d. Article PDF Supporting Information Group Website

Now that’s an interesting architecture! I’ve always had a soft-spot for homosteroids like this (and cortistatin), as their construction can often include that brilliant mid-20th century chemistry that folks like Corey and Woodward made their names with.  However, for this particular natural product, Chuo Chen of the UT Southwestern Medical Center has used a real mixed bag of impressive reactions.

The target, a C-nor-D-homosteroid to be precise, is actually isolated from that marine goo that seems so prolific.  And like a few of its neighbours in the goo, it’s pretty poky, with some mighty-fine P388 murine leukemia cell line busting moves.  However, synthesis, in this case, was not enough, and and a bit of a stereochemical refinement was also required as the positions numbered in red.

The key to the construction was of course finding a suitable bisection point (of course it’s not a point, it’s a ‘line’, but I can’t think of the correct word…), and in this case, it’s about the cyclopenatone.  That gives us a pair of chunks to get cracking with.

First up is the LHS, with its neat bicyclic ether feature.  How to do that?  A furanyl Diels-Alder is quite an obvious idea, but for some reason I didn’t expect it to work as well as it did.  So attack of the Weinreb amide with isoprenyl grignard gave them the precursor for an intramolecular Diels-Alder (IMDA), generating the required stereochemistry about the cyclohexene rather neatly.  This was controlled, of course, by the free hydroxyl, installed earlier by doing a Noyori reduction.

However, that hydroxyl is actually not in the natural product, and needs to be ess-en-two’d by bromide to give the required functionality.  This was done by forming a sulfonate and displacing with lithium bromide, but isn’t as simple as this may sound.  The sulfonate used was actually methyl 2-(chlorosulfonate)benzoate, a particularly electron withdrawing beasty.  This may have been required to ensure inversion, as these aren’t as straight-forward as one might imagine.

Turning focus to the RHS, I was impressed at how early Chen installs the (what I would presumed to be sensitive) gem-dichloride.  This was done by simply treating an aldehyde with chlorine gas (urgh…), base and phosphite (to capture that chlorate?).  I’ve done the reverse reaction – aldehydes from gem-dibromides using silver nitrate – but never this, and I’m quite impressed with the result.

Exchange of the aryl bromide for the correspoding stannane gave them RHS partner, so it was time to crack out the palladium.  No screening data is given, but the conditions are fairly standard, resulting in the ever impressive incorporation of carbon-monoxide, unifying the fragments.

Nice reaction, but there’s still quite a lot to be done – and several somewhat sensitive groups present, which always makes the chemistry tricky.  First-up was to complete the cyclopentane, using a photo-Nazarov reaction – a classical method of forming cyclopentenones from dienones.  The regioselectivity of the reaction (in terms of which side of the five-member ring has the unsaturation) is controlled by the ‘cation’-stabilisation ability of each side – and the phenyl ring is better (and also wants to remain aromatic), so results in a beautiful rearrangent and generation of a pair of stereocenters.  The base was required to improve the stereoselectivity of the reaction, as the ‘α position’ was ill-defined (1:1).  A bit of deprotonation allowed the natural stereochemical bias to be revealed in the desired manner.  Super-smart stuff.

The last reaction I’m going to mention is the ring-expansion of the bridged cyclohexane into a caprolactol.  Going back to the cyclohexane formed in the IMDA, the diol was formed by dihydroxylation (which also prevented reverse DA chemistry).  This was protected-up as an acetonide, and sat inert for most of the synthesis.  Freeing it up, and oxidising with a bit of hypervalent iodide resulted in an insertion of oxygen between the diol, and ring-expansion to generate a bis-hemiacetal.  Selective reduction of the less-hindered bis-hemiacetal with lewis-acid mediate silane then gave the required functionality present in the natural product.

Just brilliant stuff.  I loved reading this paper, and hope to read a full-paper on it in the near future.

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  • mr tin says:

    I dont really see how does the base help in the stereoselectivity (both protons) of the Nazarov cyclisation…

  • The Next Phil Baran says:

    the base could have been added after? seems to me that it is thermodynamic stability of the final product that matters. I’m sure the epimerization would have occured in a subsequent step

  • The Next Phil Baran says:

    never mind, it was added in a subsequent step. just epimerization

  • grad student says:

    read the SI. they used superstoichiometric Pd (1.5 eq). i need to do this kind of coupling as well actually and when i saw that they used 1.5 eq Pd i decided against doing it this way.

  • RBW says:

    ‘Treating an aldehyde with chlorine gas (urgh…), base and phosphite…’ Is this an accurate description? I would have taught chloride reacts first with phosphite to generate Cl2P(OPh)3, followed by a Mitsunobu-type process similar to using PPh3I2 to make iodides. Having the gem-dichloro early in the synthesis is not that surprising as such compounds are not so reactive (think CH2Cl2).
    The first total synthesis of cholesterol (modesty prevents me from citing the paper) also featured a Diels-Alder and protection of the alkene by an acetonide and later oxidative unmasking…
    I too have a fascination with homosteroids although I would prefer to see a biomimetic rearrangement of the steroid skeleton.

  • HPCC says:

    All I can say is that Supp Info is top banana!

  • Jose says:

    Sweet synthesis! Carbonylative Stille rxs are never good, but 150 mol%, I guess they do go.

    Matt Shair to a Schreiber postdoc, then synthesis in a biochem dept? Interesting.

  • earth23 says:

    UTSW has been trying to develop a top notch organic program for awhile now.

    Fantastic paper.

  • optional says:

    Yeah…….remember Brabendar and his Psymberin and Palmerolides before Nicolaus.

  • Jose says:

    Someone has to make this work in an r.b.- Rose Bengal, anyone?

    J. Org. Chem., 73 (21), 8635–8638, 2008. 10.1021/jo801564c

  • GYA says:

    Harran is the guy who initially brought attention to UTSW. His work on diazonamide is some of the nicest synthetic work in the last 10 years.

  • SiO2lungs says:

    that dichloromethyl formation is pretty interesting!
    by the way, I wonder how often you find three halogen atoms or more in a natural product??

  • Jose says:

    For some serious madness, see
    Angew. Intl. (2002), 41(10), 1740-1743

    Heptachloro-(!) and heptabromo (!)-1′-methyl-1,2′-bipyrrole isolated from marine sources.

  • InfMP says:

    Last week I asked one of the authors of azaspiracid whether there would ever be a full article. He said that there should be because he proofread the manuscript 1 year ago!!!

    Well I was certainly waiting for this one for a while. Hopefully Paul will consider sifting through this 15 page monster to highlight some amazing chemistry.

    The conclusion to the arrow clearly states the difference between Evans and Nicolaou. Often they finish the synthesis and then go back and do it better (ive heard this is true first hand). Elegance is often worth the wait.

  • Pete says:

    Azaspiracid is definitely worth the wait…Not only does it put any of the previous syntheses of that molecule to shame, but it also showcases numerous methods developed within the Evans lab. Really great stuff.

  • optional says:

    hey guys,
    Is paraformaldehyde soluble in THF?

  • Cat Herder says:

    no. If you need a soluble formaldehyde source, use trioxane, which is also commercially available.

  • cheminlove says:

    to SiO2lungs: for info halomon is a polyhalogenated monoterpene with citotoxic activities (cf Mioskowski and al. Angew.1998, 2085)

  • shin says:

    Halogenated natural product is very common in MARINE natural products. Why??? I do not know.

  • Tot. Syn. says:

    One of the contributing reasons is the fact that there is quite a bit of chloride (urgh… salty water) and bromide floating around in the marine stew. Biosyntheses that have electrophilic intermediates (such as epoxides) are the susceptible to attack of halide and those interesting natural products.

    An example is the biosynthesis of the Laurencia family, which have featured on this blog a few times, and also in the round-bottomed flasks in my PhD supervisor’s lab.


    Chris Braddock’s done a lot of work in this area.

  • Mike says:

    As well as halide ions acting as nucleophiles, a lot of marine sponges have haloperoxidase enzymes which oxidise X- to X+ or equivalent. This means that electrophilic halogenation of alkenes, pyrroles etc. is feasible in marine organisms.

    There’s a nice (although ten-year old) review in Acc. Chem. Res.

  • Scolnick says:

    There’s also a very helpful 2006 review by Chris Walsh regarding electrophilic halogenation in biosynthesis:

    DOI: 10.1021/cr050313i

  • SiO2lungs says:

    to Jose & cheminlove, thanks for the references.
    Damn it, halogens make up for 66 % and 64 % of the MW of these natural products (halomon and the heptachlorobipyrrol).
    Are they still ‘organic’ molecules?? :P

  • optional says:

    And what about the lipophilicity of these halogenated NP’s… Must also be the reason for there prevelance?

  • Jose says:

    By the by, there are also a few F containing NPs from terrestrial sources, but these are little beasts like fluoroacetate. I am not aware of any alkaloids, terpenes, etc. that are fluorinated.


  • Tot. Syn. says:

    And as if to illustrate the Laurencia family, Deukjoon Kim (a veteran of this field) drops this today! I’ll be writing this one up soon. http://pubs.acs.org/doi/abs/10.1021/ja806304s

  • InfMP says:

    I think that the new ACS webpage is cool, except that when you download a pdf, you get a stupid page at the front that shows when you downloaded it.
    AAAS Science does that too, and it’s annoying because to print you have to avoid page 1 and It’s annoying to have to scroll down every damn time you open a pdf.

    what is with top 5 on the asap page. they should do everything from a given day,

  • amal's alchemcy says:

    I am very unhappy with the new ACS page, especially with the format of the ASAPs. Now only does it require extra downloads to see the thumbs, the pdf’s now have this useless title page which also takes longer to download. Needless to say, the high-def pdf doesn’t seem any different from the original/regular pdf.

  • Martyn says:

    It’s unnecessarily flash and a bit crashy. Thumbs down from me.

  • sravanthi says:

    plz send old stracture spectra data