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Spirotryprostatin B   

27 June 2007 15,817 views 20 Comments

spirotryprostatin.jpg

Trost, and Stiles. Org. Lett., 2007, ASAP. DOI: 10.1021/ol070971k.

He’s done it :). Those of us who read Tenderbutton from the start will have known of Dylan’s work on this tasty little number, and he’s done it proud. Eight steps to the natural product; we’ll start with step one (or rather, the first non-literature step):

spirotryprostatin_1.jpg

We’ve looked at Otera’s catalyst before, but as a quick reminder, it’s a funky trans-esterification catalyst. It’s been known for a little while, and the mechanism is in this JOC article. Nice to see it being used; what was it like to handle, Stiles?

spirotryprostatin_2.jpg

Deprotonation of this malonate-like β-dicarbonyl allowed displacement of vinyl tosylate to append an oxindole, creating the starting material for the synthesis-defining prenylation. The concept for this reaction is that upon treatment with palladium, addition of metal to the allylic ester will allow decarboxylation and generation of a good carbon-centered nucleophile. This then re-adds to the allyl-palladium species to generate a new quaternary stereocenter.

As Trost points out, this is similar to the palladium-mediated Carrol rearrangement, examined by both Tsuji and Saegusa. However. a difficulty in this case is the regioselectivity of the prenyl addition, as the anion generated by decarboxylation is an extended enolate of a fashion, and could react in many positions. However, a bit of hard-work by Dylan resolved this in good fashion, optimising to a cracking yield and dr.


spirotryprostatin_3.jpg

Completion of the synthesis took a few more operations, using Sharpless chemistry to add phenylselenium acetate across the prenyl group, and then eliminate again by in-situ oxidation. Finally, the last ring was to be put in, but the usual suspects, palladium and copper were somewhat reluctant. However, success was had with trimethyl aluminium, attributed to it’s ability as both a “Brønsted base and a Lewis acid”. Pokey, but nice.

Good job, old chap!

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20 Comments

  • milkshake says:

    A lovely detail is that a simple oxindole was used as a starting material and the oxindole NH was left unprotected for the entire sequence. Running the synthesis naked saved 2-3 steps but it must have caused lots of grief along the way, when finding the least messy reaction conditions…

  • the dude says:

    Could someone (maybe even Dylan) comment on Otera’s catalyst? It doesn’t look like something you’d want to use if you didn’t have to. Why can’t you use any of the plethora of other esterification catalysts? Thanks.

  • provocateur says:

    just a doubt…how is otera’s catalyst superior to the usual transesterification catalyst , titanium isopropoxide?

  • Spiro says:

    #1

    Absolutely. This guy, Trost, is plagiarizing Baran!

  • Spiro says:

    #2

    This is the one-million-dollar question!

    Provocateur’s comment about the “usual transesterification catalyst” makes me laugh. There are probably as many usual transesterification catalysts as there are Synth. Commun., Tet. Lett., Chem. Commun. or Org. Lett. articles titled “XYZ, a superactive catalyst for (trans)esterification of QWERTY-acids with YTREWQ-alcohols under mild conditions”.

    IMHO Otero’s catalyst is the fanciest of all. That’s its main property.

    PS to all readers: what is YOUR usual transesterification catalyst? Mine could be PPTS for touchy componds, but the one that really saved my A** one day was diphenylammonium triflate.

    PPS: I have read Otero’s book on esterification : http://www.wiley.com/WileyCDA/WileyTitle/productCd-3527304908.html
    This is the poorest book I read from Wiley. After reading this book and many more articles on the topic I came to the conclusion that this field is a hoax.

  • kiwi says:

    #2, #3 – Oteras catalyst is a beaut, nice sparkling white crystals, stable as a rock. a shaved lab rat can make it on a scale of tens of grams – in two steps from dibutyltin oxide and dibutyltin chloride, then tin ligand exchange with a thiocyanate salt.
    Its about as mild as you can get for transesterification, and although i can’t speak for dylans case you can get the loadings down real low – from memory in one of otera papers they were sub 0.1% (i can’t quite remember of the top of my head).
    For the substrate i was doing other approaches were precluded – the methyl ester of this compound was relatively easy to make, but getting your hands on the free acid was pain. to complicate matters the alcohol was not the type of alcohol you could just throw buckets of equivs around either, so that didn’t make TsOH catalysed reactions any easier. a reactive allylic bromide painted me into a corner in so far as basic conditions went, Ti(iPrO)4 didn’t seem to want to play either, so i chose Otera (thanks to tenderbutton.com). It got the job done, but unfortunately i also saw a little exchange of the allylic bromide out to the thiocyanate, and i ended up coming from a different direction in the end.
    But i’d still consider using it again, my only moan being it’s a bit heavy, so 1 mol% can end up being quite a bit.

  • Mike says:

    OK, so I’ve forgotten how to use HTML.

    Let’s try this again:

    Check out the tenderbutton archive:

    http://archive.tenderbutton.com/?p=114

  • The Canadian Chromatographer says:

    Re: #4. Hahahahahahahaha! Way to go, Barry M.!

  • This post and many others is a great example of real discussion. BTW what is the convention on the order of authors – does the lab head always go first? Or does it matter?

  • [...] I want to show the mathematicians the vibrancy and value of the chemical blogosphere so – at random – I picked today’s TotallySynthetic. By chance it’s very fitting as it is a review of a paper by one of the blogospheric heroes – Tenderbutton (== Dylan Stiles). Dylan wrote a fascinating and idiosyncratoc blog for over a year under his supervisor and pressure of work combined to stop him – fittingly he has a regular blogging column for a chemical publisher. Here’s a flavour of the current post which I’ll show tomorrow: [...]

  • Tot. Syn. says:

    PM:

    It varies quite dramatically – usually the author/principle investigator goes last or first, with the students in order of contribution left to right. However, there is no real convention.
    There’s a great piece about this over at ChemBark:

    http://blog.chembark.com/2007/03/29/standardizing-author-order/

  • milkshake says:

    If the advisor proposes the project and micromanages the work on it, he should be first. If the main research idea originated with the student or postdoc as it often happens and their work was reasonably independent, then the advisor should be at the end. There is a large gray area inbetween and big egos of some famous PIs like to put themselves first every time.

  • dylan says:

    greetings, thanks for the accolades! nice to finally be able to talk about what i was working on with impunity.

    re: Otera’s catalyst, it is indeed a very high-quality material and I can’t recommend it enough. It’s a white powder, a little waxy, and you can weigh it out on the benchtop no problem. I’ve been keeping the same batch in the freezer for a couple of years and it doesn’t seem to have degraded at all. I’m surprised it’s not commercially available.

    It’s pretty hefty (mw = 1196), and i tried other methods to do that transesterification, but nothing else worked as well. DMAP epimerized the holy hell out of the proline stereocenter, giving me a product with 0% ee. Dibutyltin oxide worked, but it was slow as dirt. I had two reactions racing side by side, one with 3% Otera’s cat, the other with 10% Bu2SnO (both in toluene, 90 C). The reaction with Otera’s was done after 2h while the Bu2SnO only had a faint microscopic spec of product on TLC after 24h.

  • aldehyde says:

    Dylan, my hat is off to you. I sent this to someone I tutor: now you see why stereochemistry and mechanisms are important!

  • provocateur says:

    congrats dylan
    neat work!
    It did not seem tht the paper was written by Trost!was it u…

  • milkshake says:

    So what’s next for you, Dylan – another molecule?

  • TWYI says:

    Congrats on the Angewandte too!

  • [...] I’d like to think that ChemBark is doing some good things and that it is not simply a “time sink” blog, as one commenter put it. I am pleasantly surprised that the site receives a lot of Google traffic for technical questions, like the general procedure for HATU coupling. There is clearly an audience for technical information in chemical blogspace. I am also encouraged that people refer visitors to ChemBark’s discussions of cultural issues in our field, like the order of authors on papers or how to improve peer review. Where else can you find analyses of these issues that are open and accessible to all who wish to voice their opinion? And as far as humor is concerned, I would hope that people appreciate and enjoy the posts and comments on ChemBark that are made in jest. You guys crack me up, and I thank you for it. [...]

  • [...] written by sks [...]