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ent-Abudinol B   

13 May 2008 20,331 views 50 Comments

McDonald and Tong. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800749. Article PDF Supporting Information Group Website ResearchBlogging.org

An intriguing approach to this molecule, McDonald has decided upon a biosynthetic route, in which the ‘molecular zipper’ idea is employed. This idea has been pondered upon and used for years (with a notable paper by Jamison in Science last year). However, impressive as the biomimetic transformation is, quite often the synthesis of the substrate is a lengthy and drawn-out affair. Not so in McDonald’s work. This is actually a second generation synthesis – a first attempt was published in JACS last year, and uses the same principles, but with a slightly clunky implementation.

The two main fragments in this synthesis are derived from natural sources. The top number resulted from an impressive chemoselective bis-epoxidation of farnesyl actetate under Shi conditions, whereas the bottom piece came from alkylation of geranyl bromide (and some other stuff…). That allyl silane certainly looks conspicuous, and those of you with a good named reaction knowledge will be ready for the funky Brook rearrangement / alkylation that generates the silyl enolether in moderate yield.

And bosh – ready for a bit of biomimetic chemistry. A bit of TMS-triflate, some bulky base and watch it go. (They suggest that the TBAF is only there to mop up a silyloxonium ion intermediate, but according to the supporting information isn’t strictly necessary – but does give a better yield.)

Next up – more epoxidations using the Shi catalyst, and a Wittig methylenation. Then we’re set for the final biomimetic cyclisations, but unfortunately in a less impressive yield. Several other isomers of the final target were also produced, both of which I believe could be converted to the desired product… thoughts? However, let’s not detract too much from what is an impressive achievement none-the-less.

I’d like to leave it there, but I can’t because of the supporting information. Or, rather, the lack of it. Why no spectra of the final synthetic sample compared to the isolation sample? They compare this with the data for their first generation synthesis, and I’m sure the work is kosher, but I would have though Angewandte would like some spectra in the SI…

It’s also worth noting their explanation for an ‘ent-’ synthesis – and it’s all about the Shi catalyst. This reagent (as you all know) is derived from naturally available fructose, but only as the abundant enantiomer. To get the correct stereochemistry for the natural product, they need to epoxidise with the catalyst derived from L-fructose, which is pretty damn expensive. However, Shi himself sought to rectify this situation with a short synthesis of the requisite catalyst a few years ago.


Tong, R., McDonald, F.E. (2008). Mimicking Biosynthesis: Total Synthesis of the Triterpene Natural Product Abudinol B from a Squalene-like Precursor. Angewandte Chemie International Edition DOI: 10.1002/anie.200800749

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50 Comments

  • Diego says:

    Mimicking Biosynthesis, that´s awesome..
    i really like this paper..

  • SMILES says:

    Very beautiful synthesis.
    I like this double epoxidation without touching the allylic acetate…
    I have never saw this kind of Brook rearrangement, if someone has other examples, it will be wellcome.
    And concerning the support. info, your link is wrong ;-)

  • SMILES says:

    And sorry for the mistake…I have never seen…

  • Tot. Syn. says:

    fixed, thanks!

  • antiaromatic says:

    SMILES,
    Concerning that Brook rearrangement, I could very well be mistaken, but I am pretty sure that the seminal idea for this type of a Rearrangement is due to Corey in his 2002 synthesis of Onocerin (http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/2002/124/i38/abs/ja027373f.html). Corey actually upped the anti, though, by doing the whole thing in one pot from an acyl silane.

  • gilgerto says:

    Two papers based on biomimetic polycyclisations within the last month, including this Angew and last Corey’s JACS. It is also interesting to see that both synthesis took advantage of a brook rearrangement to introduce a silyl enol ether. This is nice work, and I’m totally comfortable with low yield for cyclisations (which is rarely higher than 50% for such a cascade) considering the rapid increase in complexity accessed…

  • gilgerto says:

    Quick question: what is a Abderhalden???

    ”It is a good practice to store it in a Alberhalden at 56 C over KOH (speaking of CuCN)”

  • SMILES says:

    For the Abderhalden, I have found this,
    http://www.wilmad-labglass.com/group/1041,
    I have already seen this before but i don’t how it works exactly, and probably they are talking about the central part of this apparatus.

    THX antiaromatic for your very instructive referenc , I was not aware that this double bound can migrate to form the enol ether, I was stayed on the addition of alkyl anion on acyl silane.

  • milkshake says:

    1) TBAF quench also provides 3 equivs of water per 1 eq. of TBAF (the commercial stuff is approx trihydrate)
    2) Since they built the exo methylene substrate for the second cyclization by Wittig, they could have looked into r C=CHX as an alternatives to C=CH2, even if it would then require removing the X from the product. These cyclizations often work better with a stabilising group on the C=C accepting the carbocation, such as silyl or a halogen. Also, MeAlCl2 is often higher-yielding than TMSOTf for this kind of cyclizations but I suppose it may be somewhat less stereoselctive as a reagent (so one ends up separating the epimers next to the carbonyl and equilibrating the undesired one with a base). This is something that EJ tends to gloss over in his papers but separating and re-equilibrating the epimers is a nuisance

  • Chris says:

    Just a note on the synthesis of “ent-Shi ketone,” derived from unnatural L fructose – that prep, from L-sorbose, is a bit of a mess, as it involves lots and lots of hot water. Sort of throwback to the midcentury golden era of synthesis, I guess, with cauldrons of boiling acid and base solution, but trying to fine-tune a solution to pH 7 with 9 M NaOH is a little annoying, as is boiling off liters of water. and then it’s into the Soxhlet…

  • milkshake says:

    I wonder if it would be feasible to optimise the second step, with sulfuric acid selective hydrolysis of the acetal and the base-promoted cyclization, by swiching from water to wet methanol for easier evaporation of the mix. Also if you alkalise with Ca(OH)2, all sulfuric acid is gone as CaSO4 and the residual alkalinity is minimal because Ca(OH)2 is so poorly soluble…

  • dude says:

    I have a question about the polyepoxide cascade. Let’s take the first cascade as an example. Why under these conditions is the 6 endo then 7-endo cyclization path favored over a 5-exo then 6-exo path? I thought that most polyepoxide cascades went 5-exo in organic solvents, and this was the importance of the Jamison Science Paper. Why are Baldwin rules not well-applied in these cases? Cationic intermediates??

  • Sulfonic says:

    Just look for the more stabilized cations

  • gustaf says:

    Hi dude, I think this has to do with the fact that the most stable bicyclic epoxonium ion is formed. If you want you can check this earlier work of McDonald: http://pubs.acs.org/cgi-bin/searchRedirect.cgi/jacsat/2005/127/i13/pdf/ja050013i.pdf

  • gilgerto says:

    James. J. Laclair strikes again this morning in JACS… Not as the sole author though…

  • laclair says:

    How about Baran Lab strikes again?

  • Madforit says:

    hi guys,i need to put a clorine atom on a butanol with a piperidine ring on the other side of the alkil chain!!SOCL2 did not work at all!I need help..Thanks,sorry for the english.
    p.s The same reaction works on the same compound with just one more carbon atom on the alkil chain…

  • TheEdge says:

    Is this the paper you’re using as a referernce?
    DOI: 10.1021/ja01578a022
    Their conditions aren’t necessarily harsh, but they are forcing, with a concentration of 1.8 M, and stirring overnight at rt, and they use thionyl chloride.

  • A joke? says:

    gilgerto: I put the address of the Xenobe Institute into google maps and the picture it gave me was quite interesting….

  • gilgerto says:

    Don’t worry, I did that already. This is the less serious web site I have ever seen…

  • gilgerto says:

    (speaking of xenobe web site)

  • milkshake says:

    stop hitting on JJ – his crazy hoax hurt no-one and it perhaps even helped to improve the journal editing standards. No students or grant money were wasted in the process, only his credibility.

  • gilgerto says:

    Acetali: That’s F…… amazing…

    Milkshake: It makes feel good hitting on Dr. la Clair because one of our paper submitted to Angew was refused recently:P

  • InfMP says:

    Just look at the spectra. No satelitte peaks again. it looks drawn. It’s funny because I was just reading the old tender button posts with him last night. What a funny guy. This is my favorite quotes:
    -My mental image of the Bionic Brothers is 5 guys in matching Adidas track suits with a ghetto blaster, breakdancing on a big piece of cardboard. Who are these people?….I just wonder what N. Voss and his Get Fresh Crew are doing with their NMR in Germany
    -natural product isolation and structure confirmation using only the services of the evil N. Voss, keeper of the Magic NMR, that cannot produce 13C spectra. Oh, and also quite handy at adding solvent peaks to spectra when they become annoying absent. I personally HATE when my chloroform peak goes missing and I have to draw it in in crayon).

    Speaking of Brook rearr, it was cooincidently brought up today at school, and I totally tuned out because it looked random and obscure…I guess not. I wouldn’t credit Corey though, I guess it was discovered by Brook in Toronto.

  • gilgerto says:

    InfMP: What, you don’t get NMR that clean after a 30 steps synthesis…get back to work:P

  • Dude says:

    Look, “dude” – I’m the Dude, man. I’ve been the Dude for well over two years around here, there, all kinds of places. Places you haven’t been. You’re – you’re some guy who just – some kind of impostor or Johnny come lately or what-have-you. Well, you just entered a world of pain, “dude”. Because this will not stand. This aggression will not stand, man! Get your own fuckin’ handle, asshole! Fuckin’ amateur!

  • Potstirrer says:

    An aberhalder can be a very useful piece of equipment. In the lower flask you place a solvent with a boiling point that you desire to heat your substance to. In the curved pot on the left you can place some sort of dessicant. This is directly connected to the middle, horizontal tube where you place your sample, usually in a vial. That chamber is then evacuated under reduced pressure and the solvent below is heated to reflux (the solvent flask is not directly connected to the evacuated flask…it is under atmospheric pressure). The warm vapors will then rise around the evacuated chamber, warming it, and eventually condense above.

  • Tot. Syn. says:

    Dude(s); ‘Your name’s Lebowski, Lebowski. Your wife is Bunny.’
    Or Possibly:
    ‘The Dude abides. I don’t know about you but I take comfort in that. It’s good knowin’ he’s out there. The Dude. Takin’ ‘er easy for all us sinners. Shoosh. I sure hope he makes the finals.’

  • antiaromatic says:

    InfMP:
    I guess I wasn’t as clear as I could’ve been, but I wasn’t trying to insinuate that Corey came up with the Brook rearrangement. Corey made it useful as a way to transform allylic, silyl alcohols into silyl enol ethers in a single step. That’s all I was referring to.

  • ZAL says:

    Well, clearly it’s Corey who gave Brooks the idea to try that rearrangement…(OK, obvious joke, I know…)

  • GiVi says:

    dude (not Dude),

    the cyclisations that are taking place are infact exo and not “6 endo then 7-endo” as you called them.
    the bonds breaking are outside of the formed ring. even the cyclisation on the nearer side of the epoxide leads to exo products.

    as jamison was pointing out a couple of papers ago, the terms exo / endo are not the right ones for discussing this kind of cyclisations.

  • TWYI says:

    Baran’s 1,3-diol synthesis is very nice. TWYI says thumbs up, especially with some of the dr’s

  • Madforit says:

    The edge-thanks a lot for the reference…

  • TheEdge says:

    Madforit-Did it work? FWIW, that’s the only ref you get from Beilstein for the exact structure you want. Scifinder is great for subject searches, but for reactions, Beilstein Crossfire is definitely the way to go.

  • milkshake says:

    Beilstein has nicer interface for searching structures + reactions but their database does not cover the recent patents (a problem for a medicinal chemist) and it has lots of mistakes because at one time they were paying people in East Europe in universities to catalogue literature for them. The database entries were rarely re-checked and the people who were entering them were paid by the number, and a pittance at that. It was just a side-job like waiting tables in the restaurant.

  • Madforit says:

    The Edge-problem fixed,it was just an elimination of the clorine atom,my fault…what do you think about tetrahedron number on natural product syntheses?

  • Achem says:

    Do you guys really think that Baran’s 1,3-diol stuff is cool? Isn’t that the old good radical insertion?(Ton of examples on steroid chemistry) What is exactly new about it?

  • TWYI says:

    jealous

  • agreed says:

    You’re right Achem. Its all known and all useless. Sure. I can think of dozens of ways of making diols from alcohols…

    umm… Why don’t you read the paper because what is new and what is not is clearly stated there.

  • milkshake says:

    Barans hydroxylation paper: It could be useful for functionalizing things resistant to bromination – that limits lots of things in the molecule – but the application of old principle is nice, EJ published something very similar on aminoacids recently. I would still prefer a method catalytic in metal though.

  • agreed says:

    the EJ org lett paper is referenced there.

  • GYA says:

    Baran conquered cortisatin. Just search the two together. Its not on ASAP yet, but it is available from JACS. Very nice!

  • bad wolf says:

    milkshake–is that why SciFinder coughs up the same reactions/citations so many times? Wading through the same citation referenced multiple times seems to have increased lately.

  • Tot. Syn. says:

    Yep, I’ll have an article on cortisatin tomorrow… sorry for the delay- I’ve been out-of-town over the weekend.

  • milkshake says:

    As far as I understand it the problem is that Scifinder searches products across several reaction steps so when you have a eight-step scheme Scifinder will reference it eight times. Very frustrating.

  • TWYI says:

    just hit the one reaction per reference option, surely?

  • bad wolf says:

    Until you mentioned it i hadn’t found that tab. A little obscure–thanks for the tip!

  • MCC says:

    What an elegant synthesis. I found the cascade transformations truly impressive. A really novel approach to a very structurally challenging NP.

  • [...] with the goods; a poly-epoxide cascade to build a poly-ether.  He’s not the only one – Frank McDonald crafted a nice synthesis last year using the same principles.  However, Jamison has upped the epoxide count, controlling [...]