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Pseudolaric Acid B   

8 November 2007 15,278 views 50 Comments

Trost, Waser and Meyer, JACS, 2007, EarlyView. DOI: 10.1021/ja076165q. Article PDF Supporting Information Group Website

I think this natural product can be considered different enough from the Amphidinolides that were the subject of the last synthesis, manifesting in some pretty exotic key steps. But let’s not get too far ahead of ourselves, as this isn’t a particularly well known beast. Antifungal, antifertility, cytotoxic and activity against multidrug resistant cancer cell lines sums up the biological activity in what appears to be a potent little target; appealing enough for lots of work towards it’s synthesis. Only one synthesis so far, though, and that’s of Pseudolaric Acid A, the slightly less complex analogue.

Trost’s approach was to use the [5+2] metal-mediated cyclisation he’s pioneered with Wender to build the 5,7-ring system. The key cyclisation substrate was produced using some pretty cool chemistry, involving a Noyori reduction and a Charette cyclopropanation. But it’s the cyclisation that we’re here for! They tried it first with a ruthenium catalyst, [CpRu(CH3CN)3]+PF6-, but with only a modest yield. They attribute this to insertion of the catalyst into the bis-allylic C-H bond (the one with the proton indicated), and shut-down of the catalytic cycle. Boo. However, a change of metal did the job – and delivered a decent yield of the product.

Manipulation of the product from this reaction (including an interesting TBAF-mediated isomeristion) led to the next cyclisation substrate, ready for a bit of radical action.  You’ll notice that they’ve used VASO in this case – for the uninitiated, it’s a surrogate for AIBN, which is now quite hard to get hold of. I like this cyclisation a lot – it’s not often you see such an interesting radical being generated, and with such success. This completed the polycyclic ring system, and set them up nicely for the appendage of the sidechain.

Not a long paper, but a nice synthesis.

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50 Comments

  • hrmm says:

    saying that trost pioneered the [5 2] with wender implies way more friendly collaboration/community than exists. trost does the [5 2] with Ru and wender with Rh; each quite prefers to stick to their own metal. the fact that trost let the paper go out with Rh having the best result is pretty surprising.

  • Jose says:

    Is AIBN really that tough to order? I just ordered 500 g a year or two ago. I had heard bad things about it (along with DEAD) and put a pipette tip of both into a Bunsen flame. DEAD was, in fact, dead: absolutely nothing. AIBN was a little excited, but nothing even approaching explosive.

  • excimer says:

    I don’t think you can airmail AIBN due to its blow-uppy potential, but it’s still easy to get it in the states. Since a majority of addition polymers (PVC, PS, etc) are made industrially by free-radical polymerization, it’ll still be easy to get. As far as I know, the two free-radical polymerization initiators that industry uses all the time are benzoyl peroxide and AIBN. (that is, unless you want to do controlled polymerization, in which case you’d not want to use these, but the majority of polymers are made via free-radical polymerization.) It’s not going away anytime soon.

  • excimer says:

    er, that’s not to say that there aren’t lots of free radical initiators out there (DuPont’s ABCN is another example), but I don’t think any are as ubiquitous as AIBN and BP.

  • random says:

    I’ve actually seen a few presentations recently (in the UK, of course) where VASO was used *because* the researchers couldn’t get AIBN. Or at least that’s what they said when the audience asked…

  • TWYI says:

    I like this one, at first glance I did think it was carboplatensimycin though!

    Pleasantly relieved after a couple of blinks.

    We have a 2.5 kg container of AIBN that arrived sometime in the late 80′s. I am guessing that when it runs out we will have to order something else?

  • Potstirrer says:

    I must say that I find this to be an absolutely beautiful synthesis. Very unintuitive retrosynthesis, but quite elegant. The way they put together the 5 2 cyclization precursor is incredible. TMSdiazomethane alkynlyation followed by a homologative Schlosser Wittig. SWEET!

  • Radical Fun says:

    Has anyone seen an acyl radical used to do a 6-exo trig cyclization to form a [2.2.2] bicycle?

  • Pete says:

    I like how they isomerize the double bond to the 1,3 diene, then opxidation and basic opening to install the tertiary alcohol…Demonstrates complete control over the molecule…Very nice stuff.

  • stone says:

    Tot. Syn., is that poosible to put carboplatensimycin in this blog? The paper has some pretty nice chemistry, especially the SmI2 step, even though it is NOT tot syn.

  • ZZZZZ says:

    zzzzz

    Yeah, please, more platensimycin stuff – it is the longifolene of our generation…

    zzzzz

  • Sherry says:

    Great synthesis

  • Dude says:

    The [5 2] is usually pretty tough to get to go with functionalized substrates, it’s nice that Trost was able to apply it to a total synth. The acyl radical cyclization to form the quat center is nice too… good thing it’s 6-exo, though – when attempting a 5-exo to form a quat center using this chemistry, sometimes it goes 6-endo instead (Boger)

    Stone, you’re kidding, right? They publish platensimycin in JACS. Then, using the same precursor, and basically the same stategy, they eventually replace a single oxygen with a carbon and publish the synthesis in JACS. What a joke. That is exactly the type of paper that should NOT get into JACS, but flies because of the lab it’s coming from.

  • TWYI says:

    It does has some biology though. :lol:

    Virtually the same synthesis as already published some activity related to the natural product = JACS communication :lol:

  • Chembert says:

    How does the alkynylation of the aldehyde takes place with TMS diazomethane? Can anybody suggest any report where the mechanism is discussed.

  • ZZZZZ says:

    zzzzz

    Hello Chembert; I’d have to post a chemdraw scheme for the full alkynylation mechanism, but check out Synlett.1994,107 for an early paper on this reaction (note the key 1,2-shift at the end)…

    zzzzz

  • gilgerto says:

    Chembert, check for Seyferth-Gilbert homologation on Wikipedia. Same mechanism but do a peterson type elimination insteas of a HWE type elimination ad you’re there…

  • TMS says:

    It is actually known as the Colvin Rearrangement.

  • WestCoast85 says:

    No news from totallysynthetic ???

  • TWYI says:

    Not sure I would have had time to regularly update a website when writing my thesis!

  • ZZZZZ says:

    ZZZZZ

    The site is as sleepy as I am…

    ZZZZZ

  • jimbo says:

    You should get a guest blogger to fill in. I’d hate for this blog to go away.

  • TWYI says:

    I’m sure if you forward a post on a recent TS you like he would consider posting it!!

  • greg says:

    How about Baran’s enantioselective haoamine synthesis in angew?

  • willyoubemine says:

    Its in angew? Does it have experimental worth a darn? No knock on baran, but it seems that Angew is gaining a reputation for work with unsubstantial experimental (see Hexacyclinol, Mulzer’s Platensimycin and: “http://pipeline.corante.com/archives/2007/11/29/neat_wish_it_were_true.php”).

    Topical question, is that a reviewers fault for not demanding better expt o is it the primary author’s responsibility to provide as much data as necessary for reproduction of the results?

  • PotStirrer says:

    Yes, he has an extensive experimental section. Baran’s papers always do. His enantioselective interception of an intermediate from his racemic haoamine synthesis is fine, but not as exciting as we are used to with Baran. The real meat of the synthesis comes later with the formation of the core and the cyclophane. Perhaps he has us expecting so much that when he publishes a perfectly nice synthesis, but one that doesn’t involve XeF2 or something ridiculous like that, we are slightly disappointed.

  • antiaromatic says:

    Quick question for willyoubemine or anyone else who may know. What’s this about Mulzer’s platensimycin lacking experimental? Are people wondering if the synthesis is suspsect? Any info on this would be appreciated.

  • willyoubemine says:

    Antiaromatic:

    no one is suggesting it is suspect, please dont start any rumors. There is simply no experimental supporting info. I mentioned it only because of the fact that all of the recent entries on Totally Synthetic (top right corner) including those in ACIEE have “Additional Information” except Mulzer’s Platensimycin work. I was making a point about ACIEE, not about Mulzer.

  • antiaromatic says:

    Oh okay, I gotcha. I appreciate the clarification. But I definitely agree that it is often times frustrating to read a paper from ACIEE with your perfect reaction only to find no supp. info.

  • TWYI says:

    the issues with Mulzer’s synthesis of Pasteurestin A was that it had effectively been done before years ago.

    Read the comments section of Tot Syn’s own post on Pasteurestin A and all the comments have links to the original paper etc…

  • ZZZZZ says:

    zzzzz

    …4 weeks and counting since last post…

    zzzzz

  • Tot. Syn. says:

    Sorry for the lack of blogging. Normal service will resume fairly soon, but it might be at the start of next year… Thesis… I don’t want to half-arse some blog posts, so I’m waiting until I can devote some proper time to it. Thanks for reading!

  • earth23 says:

    Get some friends to help ya out. Adding 2-3 ppl will definitely make the updates quicker!

  • TWYI says:

    Haouamine may be a good idea considering the retractions have begun

  • PAY says:

    Hi, guys! Are anybody know mechanism of TBAF-MS-mediated double bond migration? What is reason of this transformations?(Scheme 3, step a)

  • Tool says:

    Has a Haouamine paper been retracted ?

  • Gilgerto says:

    PAY: This is just a simple deprotonation-protonation mechanism. Fluoride ion when unsolvated is fairly basic, and seems to be able to deprotonate the bis allylic proton. You then protonate to get conjugated system as well as a tetrasub olefin.

  • willyoubemine says:

    wow, so they must have retracted it when they saw Baran’s work showing the incorrectly assigned Chichibabin products. Scandalous

  • TWYI says:

    Still don’t understand how anyone could mix up the Chichibabin products.

    Puzzling

  • willyoubemine says:

    yeah, thats what makes Barans paper so nice. Its unambiguous.

  • WestCoast85 says:

    Bonne année à tous !!!

  • ZZZZZ says:

    zzzzz

    …8 weeks and counting since last post…

    zzzzz

  • aaaa says:

    The old discussion about AIBN. It is actually hard to get it, but to my experience it is much harder to buy VAZO. Vazo is only made by DuPont and it is dirt cheap, but the problem is no one sells it, except them, and the delivery times are long and they want to sell a lot. Why AIBN is abandoned is not the explosivity (VAZO is also explosive), rather the highly toxic by-products from AIBN (tetramethylsuccinonitrile, TMSN) that is hard to get rid of. Industry wants to change AIBN for VAZO, because the TMSN stays in the plastic products and is highly toxic, also volatile (although a solid). Actually had it myself – did a radical reaction and had to distill the product, which was a colorless liquid. Surprisingly – the first fraction of the distillate contained a nice amount of colorless crystals. Isolated them, analysed them by NMR and…bingo, it was the TMSN shit.

  • Radical says:

    It has also been my experience that AIBN is really easy to get and it isn’t even that expensive. But what exactly do people refer to when they talk about VAZO? After all, a quick search on the Sigma-Aldrich website will reveal that AIBN is also known as VAZO 64 and the other two VAZO compounds are numbered 67 and 88 (the 2-methylbutyl and the cyclohexyl compounds respectively).

  • milkshake says:

    If you care about an organic peroxide catalyst that leaves no obnoctious residues you may consider Boc-OO-Boc, it is a nice crystalline solid that is made in one step from Boc anhydride and diluted aqueous hydrogen peroxide. It generates tert-butyl radical at very mild conditions, from 40 to 70C. I used it for generating CCl3(.) radical from CCl4.

    A simple procedure for BocOOBoc was posted in Org Prep Daily on September 7, 2006

  • ZZZZZ says:

    zzzzz

    …10 weeks and counting since last post…

    zzzzz

  • sjb says:

    Not being horrible, but I think Paul has more important things at the moment to do with his time than blog. Why not start up an offshoot of TS if you’re that worried we’re missing things?

    S

  • milkshake says:

    the sense of entitlement of a reader who demands to be entertained but is too busy to produce anything of himself is best to be conveyed in the form of anonymous comments. Because there is nothing more serious than morally-outraged anonymous post.

  • ZZZZZ says:

    ZZZZZ

    …get off your soapboxes sjb and milkshake. I was just anxious to see the blog up and running again; I wasn’t saying anything bad about Paul…

    ZZZZZ