Home » Still In The RBF

Trichodermamide B   

27 July 2008 9,722 views 28 Comments

Zakarian and Lu. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200801652. Article PDF Supporting Information Group Website ResearchBlogging.org

I think his group are probably still unpacking the boxes after a move from FSU to Santa Barbara, but they’ve had enough time to finish (or at least publish) a short but sweet synthesis of trichodermamide B.  From a biological activity perspective, it’s a reasonable human colon carcinoma beater, and ‘moderate antimicrobial’ agent, so of some interest, but one of the more interesting facets is the inactivity of the related trichodermamide A.  The only difference between these two beasties is that trichodermamide A has a third hydroxyl group in place of the chlorine – interesting that it turns around the activity so dramatically.

Anyway, we can pretend that that’s why we’re interested in the synthesis, but that’s basically a lie – on with the synthesis.  The first reaction is a DA between a cyclohexadienone and vinylene carbonate, resulting in a bridged, bicyclic carbonate.  Treatment of this with lithium hydroxide resulted in the expected saponification – with a twist.  An actual twist, in this case, of a bond, resulting in ‘virtually complete inversion of stereochemistry at C7′.  Zakarian invokes a retro-aldol, aldol mechanism in which the product is the more stable trans isomer.  Neat.

The acetal was binned using samarium diiodide (is there anything that stuff won’t do?), protection and we’re set for the pièce de résistance – a nitrosation/oxaza-Cope rearrangement.  This seems to be a fairly straight-forward bit of chemistry, with the yield dropping into the eighties due to debenzylation.  I wonder if they could use a bit of NMP to mediate the lewis acidity of the tickle-four – worked for Crimmins (and me).  Not that it matters – the yield is great; no mention of d.r., so it’s presumably good.

So what’s left?  The right-hand fragment isn’t a challange, so it’s all about functionalising the cyclohexane with some degree of synthetic elegence.  This is often the point where this type of tot. syn. goes tit’s up, as the group flail around trying to force the functionality in.  Not so in this case…  A Grieco Mitsonubo inversion of stereochemistry gave them an allylic selanide in there steps from the last scheme.  Then, treatment with peroxide resulted in in situ [2,3]-sigmatropic rearrangement leaving them with the required stereochemistry.  Not new chemistry by any measure, but still a nice sequence.  (I wonder if they could have formed an an allylic acetate instead; then, a bit of palladium to form the Ï€-allyl complex.  The Pd would be on the top face, so addition of summat like p-methoxyphenol might be expected to come from the bottom face at the less-hindered side and give a simlilar product… with less smell)

Completion of the molecule was expedient; esterification went well, leaving them with deprotection of the acetal (zinc triflate in the presence of ethanethiol… interesting), and displacement of an allylic mesylate (that’ll be a reactive little beastie) with chloride in a surprising good yield.  Nice work!

Lu, C., Zakarian, A. (2008). Total Synthesis of (±)-Trichodermamide B and of a Putative Biosynthetic Precursor to Aspergillazine A Using an Oxaza-Cope Rearrangement. Angewandte Chemie International Edition DOI: 10.1002/anie.200801652

1 Star2 Stars3 Stars4 Stars5 Stars (No Ratings Yet)
Loading ... Loading ...

28 Comments

  • antiaromatic says:

    The bioactivity difference is interesting. I wonder if it has something to do with the fact that in the case of the chloride, you have two hydroxyls poised to possibly form an epoxide. The alcohol adjacent to the chloride is anti to it, and so epoxide formation isn’t a crazy idea. Then again, the the allylic alcohol could just as easily undergo vinylogous epoxide formation, shifting the double bond and kicking out the chloride. Since Zakarain installs the chloride at the penultimate step, there really isn’t any opportunity (i.e. basic chemistry) for him to run across that kind of an instability. Just a though, tho.

  • Paul, I am testing out a new capability on ChemSpider previously outlined here: http://www.chemspider.com/blog/beta-testers-of-rich-text-editing-capabilities-required.html

    based on your license here: http://creativecommons.org/licenses/by-nc-sa/2.5/scotland/ I copied this article into the ChemSpider record and acknowledged you and linked back to your site.

    However, despite the license I still like to ask permission. Are you okay with me doing this for your postings. Acknowledgment will be made to you at all times of course.

    Please contact me at antonyDOTwilliamsATchemspiderDOTcom to discuss. Thanks

  • Oops…the record ID is: http://www.chemspider.com/Chemical-Structure.555058.html or you can simply search on the name of the compound

  • milkshake says:

    allylic primary (and secondary) mesylates are OK but the usual way is to make them at -20C or 0C in THF and convert them in situ by adding LiCl or LiBr excess.

    The Pd allyl transfer that you mentioned is interesting because one can conceivably use asym Pd ligand (like Trost or Stoltz) to resolve the piece kinetically, although the piece is somewhat too elaborate for a late-stage resolution.
    I would rather try asym DA at the beginning.

  • alex says:

    I agree whith antiaromatic, the anti position of the OH and Cl suggests the hypothesis about epoxide formation, which could be an instability cause of this molecule. So in this way we can explain the installation of the chloride at the end of the synthesis.

  • InfMP says:

    “that’s why we’re interested in the synthesis, but that’s basically a lie…” oh man that made me laugh out loud. But seriously though, i am going to do a talk in front of the dept and i wish i could say that about the target…..!

  • [...] is hosting the comments but the post does point back to the original post here: “From the TotallySynthetic.com Blogpost on Trichodermamide B by Paul Docherty“ addthis_url = [...]

  • antiaromatic says:

    Baran’s ASAP is pretty sweet.

  • whistling Kitty Chaser says:

    Damn skippy

  • buyproduct says:

    I dont know, whenever I read Baran paper I feel like I am reading an infomercial. Its good stuff, but I dont want to be aware that you are trying to sell me something.

  • InfMP says:

    friends of mine always come down on Baran. they say he is not modest.
    I saw him speak, I didn’t notice this trait; I thought he was hilarious and entertaining.

    But I think the people who just put down his syntheses are retarded and jealous. they are wicked. my favorite is Cortistatin A

  • odum says:

    He visited our school last year and we went to dinner. he was funny, polite, and self-depricating. very modest guy. He gave a great talk and presented the work fairly. I wonder who he pissed off – or maybe InfMP is right they are just jealous.

    I think that his syntheses are as exciting as woodwards and give a sense of wonder. I am always left asking “how in the world did they think of that??” I read the latest alkaloid one – I thought it was incredible. Many other syntheses these days look like engineering or a demonstration of some stupid in-house method. But noone on this blog says it.

  • 'Newhouse' Wannabe says:

    InfMP, my favorite is psychotrimine

  • HPCC says:

    Newhouse, are you posting from the 1st floor of a Scripps lab, near the NMR?… ;)

  • milkshake says:

    I had personally a very good (brief) Baran impression also.

    The problem mentioned here – a salesmanship – has been unfortunately a disease that has been in organic chemistry for a long time. It starts with “improving” the yields and selecting for the table only the most impressive examples, sweeping problems with a limited scope or poor diastereoselectivity, using “enantiomeric ratio” instead of ee, reporting “a readidily available starting material” as something that takes 8 steps to make and “commercially-available starting material” a natural material-derived synthon piece that costs $800 per gram.

    All produced data should be provided for the reader to make his own mind, not just steer him towasrds the most favorable direction.

  • . says:

    Milkshake:

    I agree on almost all your points, save one -

    ee is an archaic term, the reminants of measuring enantiomer composition via optical rotation. It makes compound enantiomeric calcultations difficult, and reveals little to the organic chemist when compared to enantiomeric ratio. In my opinion, ee is much less useful than er.

  • ... says:

    I disagree that salesmanship is a bad thing. Most of my favorite papers (e.g. Baran’s Nature paper, MacMillan’s sugar paper, Toste’s counterion chemistry) are all pretty heavy on salesmanship. A seasoned practitioner of chemical synthesis would be unlikely to reproduce a result without first consulting the Supporting Information and following up on references to see how long making that starting material is going to take. I don’t always love Baran’s flavor of salesmanship, but I think it’s a fine skill for a supervisor to have.

  • ZZZZZ says:

    zzzzz…

    ‘reporting “a readidily available starting material” as something that takes 8 steps to make and “commercially-available starting material” a natural material-derived synthon piece that costs $800 per gram.’

    For an example of this, see: Baran, J. Am. Chem. Soc. (asap).

    …zzzzz

  • reality says:

    zzzzzz.

    read the SI, it is available in 2 steps if you dont want to buy the commercial bromotryptamine.

    They make 2.5 grams of the natural product so the argument that this is a case of BS salesmanship doesnt really fly here. Nice try.

    zzzzzz.

  • ZZZZZ says:

    zzzzz…

    Hi reality, check the SI even more carefully:the 2 steps to make the tryptamine compounds require 7-bromoindole (price: 345$/g).

    …zzzzz

  • flaming Bung Hole says:

    ZZZZZZ you dont see shit. 7-Bromoindole is available in multi kilo quantities from several sources. You fools just look for the highest prices you can find.

  • Tok says:

    Gotta side with flaming Bung Hole (bad choice of name) on this one, TCI sells the 7-bromoindole for $78/g, or $55/g if you buy 5 grams. The places listed on Scifinder that sell 100g-1kg lots will be much cheaper. The point is, the route is short and sweet and if anyone wanted to make multi-kilo quantities of this stuff, they’d just outsource the tryptamine and get it for pennies per gram anyway.

  • Jose says:

    Even if the tryp is $800/g, with only a handful of steps to make multi grams of natprod, who cares? Think of the silica, CDCl3, and time the other published route uses (16 steps, 13.2% overall yield, milligram quantities), they probably burned through several $900 kegs of silica to crank that one out.

  • ethyl benzene says:

    Really nice synthesis of trichodermamide Zakarian and Lu. I really thought the oxaza-cope rearrangement was cleaver. The final thiol cyclization is an interesting reaction. I wonder weather or not the cyclization would have worked in water.

    On a side note did you guys see that synthesis of Pinnatoxin A in ACIE by hashimoto?

  • ale says:

    Yes, I see the synthesis of Pinnatoxin A in Angewandte….a good job, in particular very cool the the formation of the seven membered cyclic imine by auto-catalyxed dehydration

  • ethyl benzene says:

    The ruthenium-catalyzed cycloisomerization was a very unique approach for both macrocyclic formation as well as formation of the exocyclic methylene. It is interesting to compare both zakarian’s and hashimoto’s approach to this molecule.

  • Tot. Syn. says:

    Psychotrimine tomorrow (done the schemes, need to add text…), and Pinnatoxin over the weekend. Remember, Zakarian’s synthesis is back here:
    http://totallysynthetic.com/blog/?p=894

  • TWYI says:

    Step 52 conducted at 120 C for 18 h.