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29 September 2008 10,010 views 25 Comments

Deslongchamps, Phoenix and Reddy. JACS, 2008, ASAP. DOI: 10.1021/ja805097s. Article PDF Supporting Information Group Website

I’ve got that unsettled feeling that one sometimes gets after reading a paper, and not quite getting it.  I can’t put my finger on it, but there’s something that didn’t read right with this synthesis by Pierre Deslongchamps.  The problem is a lack of specifics in places, but we’ll get to that in a bit.  The natural product is quite interesting from a biological perspective, as it acts as an inhibitor of Na+,K+-ATPase, just like digitoxin.  However, it’s structure is pretty different, and no numbers are given for comparison.

The synthesis relies upon a swift construction of the tricycle using a trans-annular-Diels-Alder (TADA) process, where a larger macrocycle does an intramolecular Diels-Alder.  First, however, they had to make that initial macrocycle.  The synthesis kicks-off with an Evans-type aldol to fix the two contiguous stereocenters shown in the SM below.  Seven steps, using relatively well known chemistry, allowed construction of the rest of that substrate.  Then Deslongchamps used a rather neat piece of methodology developed by Magid to transform the allylic alcohol into the corresponding chloride using hexachloroactetone and triphenyl phosphine.  It’s not really very different to doing a standard Appel reaction, but works well, on a somewhat tetchy substrate.

Using this alkyl chloride, they did a displacement by treating it with a 1,3-dicarbonyl and a bit of base.  The crown ether was apparently pretty important; a 60% yield was the result its absence.  In an evolved route, this reaction was done on an allyl-ester, as in the cyclisation step, a Stille coupling, the palladium catalyst could also promote decarboxylation, resulting in an intermediate macrocycle.  This is where I started to get a little confused, as I can’t see any mention of the ‘catalyst’ loading in either the full paper or in the supporting information.  Nothing; all other reagents get a weight and mmol value, but not the Pd…

Here’s a snippet from the SI:

The next problem is a lack of clarity as to what they actually did next.  They note that at 90-odd degrees, the formation of the macrocycle also resulted in a little Diels-Alder reaction, so warming to 123 °C did the business and gave the product.  However, I’m not entirely sure if this was done immediately following the Stille coupling, or whether the intermediate was isolated, then heated…

Either way, they got their tricycle in the end.  Elaboration of this compound into the target is summarised in the partial retro above; some smart chemistry used to finish the work.  Hydroboration of the cyclohexenone was facilitated after a bit of screening using thexylborane (a bit like disiamylborane).  The configuration of the macrocycle seemed to be enough to steer the boron reagent to complete selectivity, and also helped methylation at the C-14 position.  Lastly, there was some nice chemistry in the penultimate step, as they were able to do a carbonylative coupling of a vinyl triflate to give the conjugated ester, and epimerise the acidic C-8 position to the desired face in one step.  Pretty cool stuff, but I’m still ill-at-ease…

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  • anniechem says:

    Nice chemistry indeed…..but very weird about the palladium. In several steps described in the SI, the actual amount of palladium catalyst is not mentioned. Only in the last Pd-cat step in the SI is there a mention of the quantity used.

  • milkshake says:

    the reference to the macrocycle goes back to their Org Lett paper published in 2000 – and even there they don’t have the Pd loading numbers in the supplementary – and they used three different Pd catalysts for the Stile coupling if I count correctly.

    I found the paper convoluted, they should have discussed the diastereoselctivity of the intramolecular DA reaction step first, then desribe the sequence of steps used to make the macrocycle DA substrates, then finish the paper with the endgame.

  • pdf says:

    That’s weird. I think that before submitting my next paper, I will post here for proofreading.

  • anon says:

    milkshake – that Org. Lett. has a table with Pd loadings – they consistently use 5 mol % of Pd2(dba)3. The stoichiometric use of triphenylarsine is a little unsettling – not up there with thallium salts, but not pleasant…

  • Pete says:

    Probably being a little nit-picky, but I never like having to resort to epimerization in a synthesis. Of course, that trans-annular is pretty great and builds an immense amount of complexity, but I guess it would have been even better if that stereocenter was set appropriately in the process.

  • antiaromatic says:


    I don’t always believe that epimerization is a bad thing, especially if it doesn’t cause you any extra steps. A classic example of a synthesis full of epimerizations is Woodward’s strychnine. It’s absolutely one of the most elegant syntheses ever published, but there are a number of stereocenters that are epimerized along the way. The beauty is that by having an initial stereochemistry, there becomes a high level of substrate control that allows for high diastereoselectivity in subsequent reactions. indeed, in many of the cases, this would not be observed. Just imagine the difference between a cis and trans fused decalone. It can make all the difference in facial approach.

  • UBChem says:

    You said facial.

  • shin says:

    By the influence of two chiral centers, four new chiral centers were generated in D-A step (economical stereoinduction). Impressive but it take multisteps for the preparation of the precursor of D-A.

  • Pilky01 says:

    I agree with antiaromatic, I like to see an epimerization used in a synthesis of a natural product. Its potentially the easiest way to get a desired stereocentre and its definately a biomimetic process, similar to taking advantage of the anomeric effect .

  • Pete says:

    Well, I’m not completely convinced but you bring up some good points…I think we could argue for days on good vs. bad examples of epimerization used in synthesis, but in this case, maybe it’s not so bad.

  • milkshake says:

    Economy/elegance affictionados: Please lets have the next discussion topic: “The Issue of Feminine Monstrosity – A Reevaluation of Grendel’s Mother.”

  • shin says:

    Particularly for the ring system it is very easy to estimate the difference of energy of compound before and after epimerization by molecular mechanic calculation just in minutes accurately. Thus I think that the author rationally perceived the epimerization before the launch of the synthesis and thus it is a good tactic that can overcome the wrong stereoinduction one chiral center in trans D-A rationally.

  • the dude says:

    shin: If you like these sort of things (i.e. induction of stereocenters in transannular reactions), you should check out Evans’ synthesis of salvinorin A (also discussed on TS) and of a molecule that starts FR(then some numbers). Both beautiful pieces of work. One is based on Micheal additions the other on D-A.

  • Liquidcarbon says:

    You will find the molecule tortured if you draw the TS leading to the other diastereomer in TADA, so that’s not too surprising.

    The palladium loading must be superstoichiometric to operate at 2 mM in the presence of morpholine…

  • GYA says:

    Its FR182877 and it was really the work of the Sorensen lab

  • Madforit says:

    UBChem:you’re a genius…

  • Madforit says:

    anyone else that can see the acetylcholine like moiety on the C ring!?probably too much S.A.R in my last exam of med.chemistry went to my head…

  • milkshake says:

    The diMe-ethanolamine ester sidechain moiety is in tetracaine, for example – and it is a local anesthetic with unrelated mechanism of action (Ca2+ channel blocker)

  • Chemist says:

    To GYA:

    Re: it was really the work of the Sorensen lab

    And Evans paper in ACIEE?

  • GYA says:

    Sure, which followed two Sorensen publications on the subject (one which came much earlier than either total synthesis).

  • Chemist says:

    Evans never publishes “Studies Toward…” until the synthesis is completed (when the first paper of Sorensen appeared they almost finished the precursor for DA). Intramolecular DA idea was coming from the cochleamycin project that was started in the late 90s.
    Moreover, there are “rumors on the street” that Evans has a little bit more credit for the cascade.

  • GYA says:

    Not any rumors I’ve heard. Evans started working on WS9885B well after Sorensen.

  • Madforit says:

    to milkshake:you ‘re right it s not ach like ’cause is not an ammonium salt but i’ve seen that these kind of compounds effectively inhibits acetilcholineeseterase…probably the enzyme recognize the ach like protonated moiety…

  • Chemist says:

    Evans started the FR project in early 2001. Right from the beginning he proposed to do the cascade DA (yet in 2001 Sorensen used a different approach).

    Let’s not talk about the rumors (nobody needs to dig out all this dirt). The bottom line is that both the Big Man and Sorensen had a good idea that was succesfully realized in the same time. I assure you that Evans does not steal his ideas from other people.

  • TWYI says:

    My Deslongchamps book needs a new cover, if that is any help? :oops: