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Phorbasin C   

13 January 2009 9,598 views 18 Comments

Micalizio and Macklin. JACS, 2009, ASAP. DOI: 10.1021/ja809491b. Article PDF Supporting Information Group Website

An interesting test-case for new methodology, this family of diterpenes has a pretty novel architecture. The unsaturated sidechain is the bit I find intreguing, as skipped-conjugation is tricky to keep that way. Oh, there’s some bio-stuff to provide a little rationale (including a bit of bacteria growth inhibition, and some cytotoxicty), but nothing startling. Micalizio is in it for the chemistry, and concern about the C-11 stereocenter, which was unassigned when they started their work…

As they didn’t know which way that methyl group was going, they designed a route where the sidechain could be appended late-stage, and thus easily varied. This left them with the cyclohexenone as the initial target, and they decided to start with the ring already in place.

The SM is cyclohexadiene bearing an asymmetric glycol and vinyl bromide; pretty handy for their route. However, it comes at quite a price – £174 (that’s $254 in colonial cash) for five grams – quite a pretty penny. The other problem is instability – I quote from the Sigma Aldrich website:

To recover the pure product from the suspension:
(1)Thaw the frozen suspension and filter the solid. (2) Rinse bottle with a few milliliters of base-washed (aqueous Na2CO3) ethyl acetate. (3) Use the rinsing to wash the solid. (4) Collect solid. (5) To further collect more product from the filtrate: extract filtrate with equal volumes of base-washed (aqueous Na2CO3) ethyl acetate (repeat three times). (6) Dry the ethyl acetate extract over MgSO4. (7) Evaporate the solvent – DO NOT HEAT! (8) Combine solids collected from the suspension and the filtrate. Pure crystals should be stored at -78° C. A suspension of the product in phosphate buffer is stable at 0° C.

Hmm… so quite a start then! But from a chemistry point of view, it leads straight (well, a few steps later) into their synthetic centrepiece – a titanium mediate coupling of teeemess propyne. This allows direct coupling (or rather metallo-[3,3] rearrangement) of an unfunctionalised alkene with the silyl acetylene with control over the stereochemistry (‘exquisite selectivity…‘). Damn neat coupling, with more on the goods here.

From a damned complex reaction to a damned simple; deprotect an acetate. Should be simple, but there’s two in this system, so they had to be careful. A bit of scandium triflate did the job, providing site-selective deprotection. Presumably the rationale is neighbouring group participation…

Unfortunately, things take a turn for the ugly in the last few steps – but it doesn’t appear to have been avoidable. To complete their work, a pair of Suzuki couplings with the enantiomeric sidechains was required; however, this reaction seems to have have given the group a bit of a head-ache, as they needed to use several (20) equivalents of thalium carbonate. I’m sure I don’t need to describe the nastiness of this reagent in any detail… But this only goes to emphasise how crap incomplete our understanding of such coupling is; in my PhD I did several Suzuki couplings using similar substrates, and got away with 5% Pd(OAc)2, 10% PPh3, THF / 2M LiOH = 90% yield. I was probably just very lucky (those were the first conditions I tried too…), but where’s the rationale? Regardless, the student in question has my permission to print out this image as a badge.

However, their approach was ultimately successful, as one of their products bore an exactly opposing optical rotation to the isolate, meaning this was the enantiomer. So their synthesis may have been of ent-phorbasin C, but they did all the hard work for the group that makes the natural enantiomer.

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  • UBChem says:

    You could spend $254 (hard earned American (in a southern-white trash accent)) or just talk to the T-Hud lab who makes this molecule via microbial dihydroxylation of bromo-benzene on the kilo scale. T-Hud’s applications of this diol are pretty badass.

  • bad-ass pot-stirrer says:

    Thanx for the post and the badge but my bad in the SI, I only used 2 equiv of Tl2CO3 for the Suzuki. I picked up the cyclohexene-diol for much cheaper from my buddy THud.

  • milkshake says:

    Yeah, Hudlicky gets the start material stuff from bacterias fed with bromobenzene. It would get much cheaper if there was a big-scale application for it. (Fully-protected Lipitor homochiral sidechain costs only few USD thousands per kilo, even though it is made by a 5+ step sequence)

    ACS journal sites are currently down but I speculate thalium is there to eat I(-) that normally complexes to Pd(0) strongly. If I remember correctly from Heck chemistry Pd hydrides such as L(n)PdH are rather stable in presence of iodide and are slow to disproportionate to Pd(0), Pd-hydride species can cause C=C migration, leading to the thermodyn most stable olefin. To prevent this they would add thallium or silver salt into their Heck system. Potstirrer, what was the rationale?

  • bad-ass pot-stirrer says:

    I would agree with you milkshake, thallium pulls iodide right out of reaction making it the far superior choice for this type of mild Xcoupl.

    I’m sure the Thud prep could be kilo-scaled if you have the patience and a bioreactor big enough- not for me tho..
    Organic Syntheses, Coll. Vol. 10, p.217 (2004); Vol. 76, p.77 (1999).

  • Help with my OCD says:

    Sorry to hijack this thread, TotSynth, but I was wondering if anyone new the best way for getting rid of the annoying new download page ACS stamps on all of their papers now? I don’t like how it looks in my .pdf archives!

  • ch3mical says:

    You can delete the front page and resave if you have adobe acrobat, not adobe reader

  • Liquidcarbon says:

    Why wouldn’t they just sell acetonides of these cyclohexenediols?

  • InfMP says:

    yeah, cool idea, i bet if you tie it off it would be more stable. I love it when the person in the synthesis arrives in the forum.

  • optional says:

    A dessymetrizative cross-metathesis could be anther nice option for installing the side chain followed by a simple CM for the addition of isopropylmethylene group. Any thoughts on that?

  • f ng says:

    stability of the acetonides could be an issue

  • sjb says:

    Erm, can’t seem to access the “more on the goods here” link, we aren’t all (ex)Oxonians ;)

  • t says:

    allylic alcohol is missing in the reductive coupling scheme..

  • optional says:

    Who doesn;t believe the Arizona cardinals now? They are for real, and its great to see Warner doing his thing. Fitzerald was also superb.

  • Jose says:

    What the hell is up with the new side banner ads on the ACS wesbsite? Are subscriptions expensive enough to cover the servers? arrghgghhghgh.

  • earth23 says:

    Lol, Cardinals comments on totsyn.

    Go CARDS!

  • Tot. Syn. says:

    Is this that rounders game you USians play? Or is it the rugby- for-mummy’s-boys game?

  • jass says:

    a lot of steps… vide my idea on orgsite

  • […] First up scheme-wise is a rather nice Suzuki coupling.  Taking a standard boronic acid, mixing in a vinyl-gem-dibromide, they achieved a selective E,E- product in cracking yield.  However, this came at a price, as they had to use thalium carbonate in the mix; not a pleasent compound.  Quoting directly from the SI, ‘Tetrakis(triphenylphosphine)palladium (1.54 g, 1.30 mmol, 8.00 mol%) and thallium carbonate (15.7 g, 33.0 mmol, 2.00 equiv) were added sequentially…’ – urgh!  I’m sure Movassaghi tried several sets of conditions, but I’d have used quant. tetrakis before I touched the thalium bottle!  However, the student in question get permission from me to use the Bas-Ass Pot-Stirrer badge in this post. […]