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29 April 2008 13,413 views 33 Comments

Dake and Kozak. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800522. Article PDF Supporting Information Group Website ResearchBlogging.org

A complex little target, this natural product is related to fawcettimine, which we looked at last year. However, fawcettidine has attracted far less synthetic attention than the latter, and this synthesis constitutes the first. Like it’s cousin, drawing a retrosynthesis onto the structure is quite tricky with such tight constraints, so we’ll go straight into the forward synthesis.

The key reaction, developed from some of the groups methodology (in this Org. Lett.), was a palladium mediated enamide annulation. Of course, they had to build the starting material first, which conveniently came in enantioenriched form – natural pulegone. The elaboration of this into the desired precursor was smart and efficient, but uses routine chemistry (nice cuperate addition…), so I’m not covering it here…

The annulation itself was sweet – cracking yield, and apparently only one diastereoisomer. They suggest that they were concerned about the thiocarbamate group – specifically that sulfur atom’s propensity to knacker palladium platinum (technical term), but encountered no such problems. (They did mention that at low catalyst loadings, the reaction was slow – I wonder if the reaction is faster with a carbamate analogue?)

An allylic oxidation later, and they were ready for the next cyclisation – conjugate addition of a freshly liberate thiolate. This delivered the eight membered ring in great yield, but I’m a bit confused about the stereochemistry, as their figure is inaccurate. (I’ve drawn what I think they made below.) Still, I’m impressed with the yield, considering the ring size and potential for competing processes.

Then comes a reaction I was very pleased to see – a Ramberg-Bäcklund reaction. This little beauty extrudes sulfur dioxide from the eight-membered ring to give the desired ring contraction as an olefin. The two step process (involving formation of a three-membered cyclic sulfone and then a separate decomposition step) failed, however, so I bet they were chuffed (and rather relived) when Chan’s one-pot procedure did the business. One reduction later – natural product.

Kozak, J.A., Dake, G.R. (2008). Total Synthesis of (+)-Fawcettidine. Angewandte Chemie International Edition DOI: 10.1002/anie.200800522

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  • TWYI says:

    Platinum mediated…? ;-)

  • pmgb says:

    SI gives useful prep for triethylamine washed silica gel and pH 8 buffer

  • Billy says:

    Jennifer Kozak is an All-Star…go UBC!

  • gilgerto says:

    Et3N washed silica gel is a must when you have to deal with alkaloid or any amine. I usually saturate a slurry with Et3N and then wash the packed silica gel with my eluant. You can also spray Et3N on TLC plates and let them dry. You can keep these plates for many months without problem.

  • pmgb says:

    Thanks gilgerto, I will try this for quinuclidinol derivatives..

  • gilgerto says:

    Yeah should work fine. For TLC plates, you cannot use KMNO4 stain. I find Dragendorf, Mo/Ce and iodine very useful. Let me know how it worked!

  • Radical says:

    I found that any acidic stain, even Mo/Ce gives poor results with Et3N deactivated TLC plates.

  • milkshake says:

    Alternatively you can use chloroform-methanol-ammonia mixtures both on TLC and colums, they work fine and the absorbed ammonia interferes only with ninhydrin stain.

    ANd you can get triethylamine off a developed TLC plate, by heating it over a heat gun (glass side up) andsniffing at the hot TLC peridically, to see if the fishy NEt3 odor is gone. Of course other volatiles will be to, but this is a good thing, ususally.

  • pmgb says:

    Milkshake-The ammonia you mentioned is NH4OH or NH3 in methanol..

  • gilgerto says:

    Milkshake: I don’t put Et3N within the eluant, I just drawn TLC in Et3N and let it dry for few hours. Excess Et3N is evaporated and only Et3NH+SiO2 stays on the plate. I must say that I have’nt try to heat the plate up to remove this Et3N…

  • gilgerto says:

    Another point: I can get a primary amine off a column using let’s say 20% EtOAc/n-hexanes within the first 20 fractions. With this method amines just dont stick to silica gel, so no need to use very polar DCM-MeOH based eluant which I find less effective for difficult purification…

  • pi* says:

    some of the discussion in the paper was a little immature, no? Like 6-8 lines spent on how the thiol might be a problem, but wasn’t.

  • Liquidcarbon says:

    Methyl methacrylate on the scheme – methyl acrylate in the text. Tsk-tsk.

  • J says:

    Creative synthesis. I’m most intersted in the enone formation; in the paper they claimed to use classical conditions (SeO2, 1,4-dioxane–Riley-type oxidation). It’s too bad that the yields on that step were dismal, but I can’t think of another way to effectively make that particular functional group (best guess would’ve been allylic bromination, selective alcohol formation, followed by a Swern or PCC).

  • antiaromatic says:

    gilgerto–You can get a primary amine of a column with 20% EtOAc/n-hexanes? The molecules you must be referring to must have a lot of other greasy functional groups attached. In that case, I’d buy it, but I’m not sure how else. Is it the fact that you use n-hexane as opposed to hexanes (which is a mixture of different hexane isomers)?

  • milkshake says:

    There is actually a catalytic version of SeO2 allylic oxidation that uses 5-10 mol% of SeO2 and anhydrous tBuOOH 4-5 eqivs as a reoxidant, at RT to 40C, in a concentrated DCM solution, with about 10 mol% of salicylic acid as a co-catalyst. It was published by Sharpless group a long time ago. The advantage is that you have much less crap from Se to remove in work up from your sensitive enone. The disadvantage is that the reaction often stops as a mix of allylic alcohol and enone.

    I have been playing with this reaction about a decade ago and it works quite nicely on geranyl acetate (you get aldehyde on trans Me at the terminal prenyl group opposite to acetyl). I found out that the salicylic acid co-catalyst gets eaten which is one reason the reaction stops, the other one is accumulation of water – 1 to 2 mol% of water actually accelerates the reaction but more of it inhibits it, which turns out to be a problem at higher conversions – but you can add activated sieves. An alternative improved co-catalyst is simple tetrazole because it does not get oxidized away.

    Since the reaction uses lots of anh tBuOOH, on scale it is cheaper to buy 70% aq. tBuOOH, dilute it with 3 volumes of DCM, saturate with MgSO4, filter and re-dry with fresh MgSO4. Then use as-is undiluted as a reaction medium.

  • gilgerto says:

    Antiaromatic – You’re right, I have a OTIPS group on the molecule that kind of help… But I can assure you that without Et3N, it takes much more than 20% EtOAc/Hex to get it out of the column…My mistake, I’m using hexanes and not n-hexanes, altought I don’t think it makes any difference at all. We were supplied in n-hexanes and switched to hexanes and I didn’t even realized it.

  • gilgerto says:

    Milkshake – There is also a nice procedure to get anhydrous tBuOOH as a PhMe solution from 70% aq. in this JOC from Sharpless
    JOC, 1983, 48, 3607.
    I’m using this solution for hydroxy directed Mo catalyzed epoxydation and it works like a charm.

    this solution is stable for months at room temp and shows no sign of reduced efficiency.

  • Madforit says:

    Tot.synth:what do you think about the total synth.of callipeltoside from evans group?tetrahedron 64,21 2008….

  • gilgerto says:

    Madforit – This a full report from previous syntheses…

  • Madforit says:

    ok…my fault..thanks anyway..Gilgerto could you send me that report?

  • gilgerto says:

    Madforit – Sure give me your email and I’ll forward it to you.

  • TheEdge says:

    The original Evans Calli paper (and all of his publications) are available on his website.

  • PJ says:

    Anybody check out the two Carreira papers on synthesis of an amphotericin analogue? That’s some impressive stuff! What do you say Tot.Syn.? Are you going to blog it?

  • Madforit says:

    Gilgerto:claudio.zambaldo@studenti.unipr.it thank you so much!!

  • Madforit says:

    The edge: thanks for the link…

  • Tot. Syn. says:

    Folks, thanks for the blogging suggestions. It’s been a busy past-week, but I’m writing up the Carreira papers for now. Should have it up tomorrow evening. Thanks for the Evans suggestion – what’s it doing in Tetrahedron?

  • TWYI says:

    Special Total Synthesis issue of Tetrahedron.

  • HPCC says:

    Well, T.S., the (+)-Hirsutene by Benjamin List in JACS is, as you would call it, Top Banana. FYI. :D

  • Madforit says:

    Gilgerto-don t send me the Evans post, i m coming back at the university,i can see the full paper,but thanks anyway…sorry for the english.

  • milkshake says:

    The (+)Hirsutene is very nice indeed; Finding a hidden symmetry in molecules is very powerful trick and here it comes naturally, the methodology was fine-tuned for a better ee but not forced on the target.