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Coraxeniolide A   

19 February 2008 8,168 views 22 Comments

Corey and Larionov. JACS, 2008, ASAP. DOI: 10.1021/ja8003705. Article PDF Supporting Information Group Website

This article was mentioned in the comments for the previous post, and contains some quite remarkable chemistry. Corey himself has had quite a fascination with this class of natural products, having already completed (amongst others) Antheliolide A back in 2006. However, this work takes a somewhat alternative route to the trans-cyclooctene moiety, starting with a bit of primordeal organocatalysis – the Hajos-Parrish-Eder-Sauer-Wiechert reaction (see the Org. Syn. too)! Not only is this a nominee for the longest named reaction, it’s also (probably) the first enantioselective organocatalytic reaction. The result of the reaction, a hydroxy dione, was reduced selectively with triacetoxy sodiumborohydride, achieving excellent selectivity. What was required next was a selective elimination of the secondary alcohol; this was achieved by Mitsunobu activation in a transformation I personally haven’t seen before. Nice result!

However, a spot of trouble was had next – a stereoselective reduction of the remaining ketone was required, but sodium borohydride was found to be “nonselective”. Interesting how a subtle change in functionalisation of the 5,6-ring system has overturned the previous selective approach of the reducing agent.

After completing the reduction using CBS catalyst (I bet the group have an entire fridge of them!), and tosylating, it was time for the pièce de résistance. An elimination of the tosylate group via carbonyl formation and loss of the bicyclic bond left the desired trans- trisubstituted olefin. Most interestingly, this relatively simple molecule is actually chiral, as demonstrated by its optical activity. In fact, many trans- substituted medium rings are endowed with this feature, and have been isolated enaniomerically pure form by both resolution and synthesis. (Both the papers linked to are worth a read!)

The group then took both this material and the enantiomer (produced separately) forward through to two natural products, coraxeniolide A and caryophyllene. The former was produced using some smart transformations – starting with a trityl perchlorate mediated conjugate addition of a silyl ketene acetal. Nice! Next was a selective enolisation using sodium tert-pentoxide (that old gem…?!!), trapping with formaldehyde and ring closure gave the required lactone with the desired trans- ring junction.

The natural product was complete shortly thereafter using only a few more steps, but again there’s quite a bit to consider. Installation of the exo-cyclic methylene was slightly troublesome as some standard conditions were ineffective; however, salt-free methylenetriphenylphosphorane did the job, which they attributed to enhanced reactivity of the salt-free ylid. (I wonder if Tebbe’s or Petasis’ reagent worked? Perhaps they knackered the lactone…). After this, the sidechain was appended by a relatively simple alkylation; unfortunately, the undesired epimer was favoured. This selectivity was overturned by treating the product mixture with Schwesinger phosphazene P2-Et – again, not a reagent I’m familiar with, but is basically an organic, non-ionic super base

A really nice synthesis, which also demonstrates that the Corey lab is the place to steal obscure reagents…

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  • earth23 says:

    It will be interesting to see the experimental section when it comes out…

    I’ve recently been attempting an E2 elimination and used modified mitsunobu conditions, I wonder how they got it to work and I didn’t! Also, the enolate formation and addition to formaldehyde, on paper it looks easy but I’m wondering how they generated their formaldehyde without the presence of acid.

  • antiaromatic says:

    A wonderful example of a well-designed Grob fragmentation. Maybe it’s just me, though, but it seems that Corey has problems letting go of a problem. This is oddly reminescent of the prostaglandins. I’m pretty sure Corey’s made B-Carophyllene before, but not in a “satisfactory” way. I think this one may put the nail in the coffin for this project, though.

  • Potstirrer says:

    I propose that the first ketone reduction is so selective because the tertiary alcohol acts as a directing group with the in situ generated Na(OAc)3BH. In the second ketone reduction, that alcohol is a TMS silyl ether and would direct the wrong way anyway. They then have to rely on reagent control to get the proper diastereomer.

  • Tot. Syn. says:

    I considered that too, but I did a Chem3D model of the first structure and couldn’t quite convince myself that the reductant would be held with sufficient proximity to the carbonyl group…

  • Madforit says:

    I can ‘t understand the stereochemical course of the Mukayama/Michael addition step,is the enentiomerically enriched substrate that control the reaction?
    Thanks in advance.

  • Elimconfu says:

    I was impressed by the regioselectivity of the Mitsunobu elimination. Anyone have thoughts on why it eliminated in that direction and not the other?

  • Spiro says:

    Tot.Syn & Potstirrer: I don’t see what’s the issue about the carbonyl reductions: both are attacked from the convex face with standard borohydrides.

    earth23: formaldehyde = ref. 14

  • Tot. Syn. says:

    Spiro, are you sure? I just checked the paper again, and whilst the first reduction is performed using in situ generated triacetoxy sodium borohydride, the second was performed with “Me2S-BH3 in the presence of 10 mol % of the (S)-oxazaborolidine” – CBS conditions, which are reagent controlled.

  • gilgerto says:

    Corey always amazed me by using very rare and unconventionnal reagents. I wonder how long it took to the student who performed the synthesis to get to theses conditions. Anyway, nice chemistry and a nice application of the grob fragmentation to access larger ring.

  • antiaromatic says:

    Gilgerto: I am pretty sure that Corey doesn’t take students anymore. This work was done by a postdoc, but nevertheless, it certainly had to suck to screen all of the different reagents. It is interesting, however, that the Mitsunobu elim. has that regiochemistry. At least from steroid chemistry, this isn’t an altogether suprising result, as it is known that in cis-fused systems, the double bond prefers to be next to the junction as opposed to parallel to the junction.

  • milkshake says:

    Mitsunobu complex is both quite hot activating group and base, similar to Burgess reagent. If you do Mitsunobu ether formation with a secondary alcohol and phenol and forget to add the phenol before DEAD, you end up with lots of eliminated product. I made this mistake once, with N-benzyl-3-methyl-4-hydroxypiperidine (cis trans, 2:1). I ended up with lots of elimination product, about 3:1 ratio of regioisomers (with the less substituted olefin being the major one).

    If you build a model of this hydrindane diol, there is one quite reasonably-looking cyclohexane boat conformer which has both OH groups equatorial and the only beta proton available for syn elimination of the secondary OH is the one that actually gets eliminated here. (The paper does not give an explanation).

  • milkshake says:

    actually it was Mitsunobu on (2:1 cis/trans) N-Boc-3-methyl-4-piperidinol, sorry

  • suprafacial says:

    The alkene-ketone before TMS protection was made before with same condition.

  • Hap says:

    If you’re not a very smart graduate student, you can try Mitsunobu substitution on a protected cyclooctanediol with azide to get lots of elimination product. I couldn’t figure out what all those peaks at 5 ppm were – oops.

  • Malcolm says:

    you are right, Corey does not take grad-students anymore. He still takes undergraduate students though, the Org Lett from last week first author is an undergrad.

    Totsyn: I love the comment about obscure reagents in the Corey lab. I wouldn’t want to work there though. The lab hasn’t renovated since, correct me if i am wrong, the mid-70s to 80s? The rotovaps are antiques. I love the lab I work in, brand new everything.

  • Spiro says:

    #8 Tot. Syn.

    I confirm what I previously said : standard borohydrides (NaBH(OAc)3 , NaBH4) are non-hindered and expected to attack from the convex face. CBS is not “standard” as it is highly hindered and chiral interactions are also to be considered. Note that the yield of the reaction is 60% (2 steps), and that the other face (convex one) may reasonably have been reduced with as much as 30% yield.

  • Tool says:

    Man, I need to go back and study my name reactions. See, I thought that the “carbonyl forming elimination of the tosylate” implementted in this synthesis was a Grob fragmentation. But I must be wrong, because the references in the paper associated with this transformation don’t cite any of Grob’s work. Actually, they only reference Corey’s work.

    While I’m at it, I will also review the Corey-Woodward-Hoffman rules !

  • [...] kinda thing interests me. Y’see, after blogging the Danishefsky synthesis last week, and the Corey synthesis on Monday, I was intregued by the differences in graphical representation of structures. Both were [...]

  • chemist says:

    Dear Tool,

    Grob was a person that actually classified this type of reactions (e.g. introduced the terms “electrofugal” “nucleofugal”, etc.). However, his “unifying theory” unified several already known rearrangements (Warton, Eschenmoser, Marshal, etc.). Grob himself was responsible for the alkaloid fragmentations, 1,4-dibromo-2-alkenes, etc. If you look at his ACIEE Review (ACIEE, 1967 (6), 1-106) when he talks about the “carbonyl forming elimination of the tosylate” he references Warton and Corey!!!

    The bottom line is that EJ is somewhat better with the name reactions than all of us here (including you):(

  • Tool says:

    “Chemist” – Maybe you should adopt my moniker. ACTUALLY, you may want to have a look at Grob’s 1955 Helv. Chim. Acta that describes these reactions (along with experimental details). It’s a Grob fragmentation. Period.

    I should certainly hope that EJ is better than I with the name reactions !!!!! I’m not an authority, but it doesn’t really take one in this case.

  • chemist says:


    1) Grob did not develop the discussed fragmentation. Neither did he develop the fragmentation of 1,3-tosyl alcohols. In his 1963 Caryophyllene paper Corey has a detailed discussion of the fragmentation and cites the 1955 Helv. Chem. Acta paper where Grob gives an overview of fragmentations and talks about his own work–the fragmentation of 1,4-dibromides (and gives the experimental for the fragmentation of 1,4-dibromides). However, Corey cites the paper during the discussion of 1,4-dibromoalkane fragmentations.

    2) Corey cited his earlier paper because there is a precedent for the fragmentation he used in the current work. Why should he cite Grob who did not work with this particular reaction? Just because Grob studied these reactions later?

    3) You may use the name reactions or you may not. How often do you call olefin epoxidation “Prilizhaev reaction” and cite Prilizhaev’s paper? Since “Grob fragmentation” is too general, a number of chemists are totally fine with not calling every fragmentation “Grob fragmentation”

    4) No. I shouldn’t adopt your moniker. I am totally fine with mine. Although I am sometimes a crappy chemist, at least I read the papers before talking about them on the forums.

  • J says:

    Props to EJ, but I thought the Mitsunobu was a little odd and somewhat uneconomical.

    Forget Corey and Grob. I call it a Molander fragmentation (J. Org. Chem. 2001, v. 66, 4511-4516). What do you think of them apples?

    Oh yeah, read my blog.