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Tricholomalides A & B   

21 July 2009 20,011 views 32 Comments

tricholomalide-a

Danishefsky, Wang, Min. JACS, 2009, ASAP. DOI: 10.1021/ja9049433. Article PDF Supporting Information Group Website

I’m still wading through the bumper-Tetrahedron issue flagged-up in the comments, but halfway through reading Amos Smiths spongistatin epic I noticed a new Danishefsky paper in JACS.  So whilst I man-handle Amos’ tour-d’force into bite-sized-chunks, here’s a smart slice of typical Danishefsky.

Initial work on the target was published in a rather nice Tet. Lett. last year, and that’s where the synthetic action starts.  A well known Robison Annulation created a 6,5-fused enone in a racemic fashion, which Danishefsky cyclopropanated in a rather interesting way.  Enolisation and silylation gave them an activated alkene, which was treated with a carbene derived from dichloroethane.  This method isn’t new by any means, but I like how effective it was.  Treatment of the somewhat volatile chloro-cyclopropane with silver nitrate allowed an oxidative cleavage of the cyclopropane in a endo fashion to give the ring-expanded product.  Nice.

tricholomalide-a_1

A couple of steps later, and it was time to create another ring, and like the previous modus-operandi, Danishefsky firstly installed a small ring and then ring-expanded.  In this case, treatment of trichloroacetyl chloride with zinc and a bit of ultrasound cause formation of a ketene, 1 which did a [2+2] cycloaddition to give a dichloro cyclobutane as a single diastereomer.  A bit more zinc (and a few protons) allowed reduction of the gem-dichloride (without rupturing the cyclobutane, which I would have been worried about), which was ring-expanded to a gamma-lactone using a baeyer villiger oxidation.  All in a rather spiffing yield.

[However, I can't help but wonder if there might have been a faster route... using manganese triacetate and acetic acid.  A good chunk of my readers will remember that I did my PhD on this stuff, mostly doing radical cyclisation chemistry with malonates.  However, the prototype reaction is with olefins and acetic acid, in which the acetyl radical is generated, and adds to the olefin to form a gamma-lactone.  However, I think it would add to the wrong end of the olefin, resulting in a diastereomeric product.  Worth a pop, though...]

tricholomalide-a_2

Not much more needing done, to be fair.  Oxidation of the freed alcohol to the ketone and alkylation using cerium chloride and the requisite Grignard reagent appended the required sidechain for tricholomalide B, and using a spot of base, that could be converted into tricholomalide A.  Neat and efficient work, if racemic (though Danishefsky seems to favour racemic syntheses just now…).

tricholomalide-a_3

[1] I wonder if one could apply other sources of sound to get this to go.  My Pinky and Perky record (unfortunately in my Mum’s loft) gets pretty high-pitch.

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32 Comments

  • milkshake says:

    A nitpicking: if your acetic acid-derived radical adds to a wrong end of C=C the product would be a regioisomer (not diastereomer).
    Also, you write Dansihefski did this and that – I think more likely is that Danishefki proposed the initial scheme and then whispered hints like “Use the TBHP, Sun-Joon” whenever he felt a disturbance in the synthesis

    • j. says:

      That article caught my eye, too. Does anyone else want to pull a few things off the shelf and see if this actually works?

    • c says:

      I call bullshit! This seems really fishy.

      • milkshake says:

        I think it is simple air oxidation of the alkoxide that is somehow facilitated by the heteroaryl next to ONa (or OK). Allylic alcohols could be isomerized with a strong base to this one does not seem too off. Unfortunately they don’t provide any supplementary info. Some stuff in their article about “NaH is a very strong reducing agent” and “both NaH and THF could be quantitatively recovered by filtration under nitrogen and subsequent evaporation” positively sounds like baloney. I would like to know if they worked under air and how peroxide-free was their THF.

        I think referees/editors should not have allowed this communication into print without any supplementary info, and without the mechanistic proposal. I suspect it is real but done rather sloppily.

      • TWYI says:

        From what I can gather, the lead author on this worked with Zhen Yang, author of that very very iffy crisamicin synthesis reported on these very pages a year or so ago.

    • Liquidcarbon says:

      I have heard about ethylation of 2,3,5-trimethylpyrrole on prolonged reflux with EtONa in EtOH, not sure whether it was published. I tried to look it up once and couldn’t find it. In this case the acetaldehyde impurity was believed to be the actual catalyst. Since such pyrrole is extremely electron-rich, it will react like enamine, then ethoxide will transfer the hydride to the pyrroline.

      But in this JCAS there is NO apparent oxidant. Let me put it straight:
      Ar(R)CHOH + NaH = Ar(R)CO + NaH + H2. Oops, it doesn’t combine.
      Whatever the actual oxidant is, it has to be stoichiometric.

      • antiaromatic says:

        It’s even stranger than that! It’s

        Ar(R)CHOH + 2NaH –> Ar(R)CO + 2NaH + H2.

        • milkshake says:

          I think the electrons precipitated from the reaction mixture and were recovered by filtration, in quantittative yield. (Anyway, I just wrote an e-mail to one of the editors and he wrote back that he will have a closer look at this thing.)

        • My Handwavy Guess says:

          Most of the substrates in this paper are electron deficient heterocycles. My guess is that NaH deprotonates in the benzylic position to give a dianion, if it a pyridine you can put the 2nd negative charge on nitrogen and get an enolate from the first oxy anion. On workup you protonate to dearomatize the system and give the ketone and air oxidation gives you back the aromatic ring.

          But some of the reactions are downright weird, I don’t know what is going on in scheme 5.

          • TA says:

            Is this the guy (David Zhigang Wang)who came up with the “Conservation of Helical Asymmetry” theory?

          • European Chemist says:

            Scheme 5 is just an aberration of Nature :-)

            There are electron rich benzenes too! p-methoxyphenylethanol is converted to its acetophenone in 87% yield. Scheme 4 is the only one which, due to its atom-economical rearrangement character, could be really catalytic in NaH. And yet I have never seen NaH doing conjugate addition to enones!

            Is this paper bullshit or is it jut WAY ahead of its time?

          • milkshake says:

            In this case the mechanism would be C=C migration promoted by base, no redox. (Alkoxides are basic enough to isomerise allyl benzenes to beta-methylstyrenes, ie safrol to isosafrol). So I don’t think this one is wrong although it hardly makes sense to include it into a paper about ‘oxidative’ transformation.

          • European Chemist says:

            I beg to differ, oh venerable Milkshake :-)

            1- Alkoxydes are quite basic IF they are in the right solvent. A potassium alkoxyde in DMSO can deprotonate a terminal alkyne – hence allowing the addition of acetylide anion to aldehydes to be catalytic in tBuOK if done in that solvent. Don’t know how much of this can be translated to THF.

            2- If you add 2 eqs of NaH in one portion to a THF solution of an alcohol, you should (SHOULD…) get complete deprotonation of the alcohol to the alkoxyde. What you then assume is that a sodium alkoxyde, in THF, is able to aproach another sodium alkoxyde and remove a proton from the carbon closest to the negatively charged Oxygen?

            3- Just realised that probably something that could save this is the kinetics of deprotonation of an alcohol by NaH. Since NaH is really not soluble in THF I wonder how much of an “instantaneous” acid-base reaction that is. Anybody has a clue? (Milkshake?)

          • Old Timer says:

            Yes it is. This is the David Zhigang Wang who worked with Tom Katz (the should-have-been Nobel Laureate) for his Ph.D. and postdoc with Danishefsky – which I guess is the reason why it’s being discussed here

        • European Chemist says:

          Claiming that NaH can oxidise alcohols is one thing. Claiming that it can do so catalytically is another.
          Going as far as to report procedures for recovery of NaH is just, well, plain weird.

          The stoichiometry just doesn’t make sense! Also, the Supp Info reports oxidative amidation using MHMDS but here in some cases it seems that the alcohol reduction product is observed. I wonder whether some Canizzaro-like hydride transfer might be in order. This is definitely the kind of paper that should be discussed in depth; I wonder just how much careful refereeing went into it.

          • The Next Phil McGroin says:

            anyone who has ever deprotonated an alcohol with NaH knows the reaction is almost instantaneous. Solubility is not an issue, because the alkoxide is usually soluble, driving the NaH into solution as it is consumed. The vigorous evolution of H2 does not continue for hours and in general there is no induction period. Add NaH to a solution of MeOH in THF and see how quickly the H2 stops evolving.

          • wackadoo says:

            you guys should look up LADH (liver alcohol dehydrogenase), hydride transfer back to the sodium makes fine sense… just not your normal orgo stuff….

  • Martyn says:

    Some very good reading to be had in the Tetrahedron issue, though it seems to mostly be full-paper versions of previously reported work.

    Is the AgNO3 step really oxidative? looks to me like you just lose TMSCl.

    • Radical says:

      I agree, I don’t think any oxidation is taking place. The Ag+ is simply activating the Cl.

      • Tex says:

        Perhaps I am mistaken, but don’t you add a degree of unsaturation to the molecule – so it’s a net oxidation?

  • Old Timer says:

    Although this is a fantastic synthesis, I can’t help but notice it is really more than that. This paper is an example of truly outstanding scientific inquiry that results in the revision of several structures, with a versatile route to each. Definitely a top paper of 2009!

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  • Ye Tao says:

    I am responding to Liquidcarbon’s concern that there is no oxidant in the reaction.

    If one examines the balanced reaction carefully, one notices that the hydroxyl and alpha proton on the alcohol serve as the oxidant.

    equation: 2 R-CH2-O-H + –cat NaH–> 2 R-CHO + H2

    Oxidation states: LHS: C=-2; O=-2, H=1; RHS: C=0; O=-2, H in H2 = 0.

    NaH is catalytic in the above reaction. Carbon gets oxidized and the hydrogen atoms get reduced. The reaction, while most likely unfavorable thermodynamically, is irreversibly driven by entropy increase from gas evolution.

  • Ye Tao says:

    Typo: coefficients before alcohol and aldehyde should be 1.

    R-CH2-O-H + –cat NaH–> R-CHO + H2(g)

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