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Eudesmane Terpenes   

17 May 2009 20,370 views 53 Comments

eudesmantetraol

Baran, Chen. Nature, 2009, AOP. DOI: 10.1038/nature08043. Article PDF Supporting Information Group Website

They say that the best defence is a good offence, so I’m going to start latterly – and remind (somewhat forcefully, if necessary) all prospective commenters that the folks at Nature decreed that this paper is worthy.  That’s good enough for me, so let’s avoid the tired arguments about suitability… </pre-emptive rant>

Anyway, what we’ve got here is typical of Baran – re-examination of chemical methodology of the past, and modernisation to solve problems in an orthogonal fashion.  Breaking that down, what he seems to be really good at is picking up an idea from the past, re-examining the goals, and using modern techniques and reagents to solve problems.  This appoach often allows him to disregard common retrosynthetic failings, such as recursive oxidation / reduction and protecting group abuse – but must come unstuck quite often.  (I don’t know that it does come unstuck, but I rather hope that is the case for my own sanity…)  Today’s target are terpenes, and the old-school technique I alluded to is remote oxidation.  This one generally describes selective (and unactivated) C-H oxidation using a scaffold in which a remote group provides the impetus/selectivity.

Of course, the first requirement is a skeleton to work with, and rather than a semi-synthetic intermediate, Baran decided to make his own (and rather quickly too).  First up is a little organocatalysis, using a standard proline-based catalyst to do an enantioselective Michael addition, which following a spot of base give the cyclohexenone in great e.e. and decent yield.  Notable is the low catalyst loading (5% is pretty good for organocatalysis), and the use of a catechol to activate the enone for addition.

eudesmantetraol_1

A few steps further on, and they’d bolted another ring to the cyclohexenone, with a cross-conjugated diene and single stereocenter in place.  However, three simple reaction allowed the group to greatly enhance the stereo-complexity – cuperate addition and a pair of reductions – and now we have five stereocenters.  Nice work!  This trans-decalin is the least-oxidised (most reduced) carbon skeleton from which Baran works, and it’s a good thing he has such a concise route towards it, as he targets several natural products from here.

eudesmantetraol_2

All of these targets share one further oxidation, so it makes sense to put it in first.  This is done by firstly appending a controlling group for the remote oxidation – a carbamate featuring a trifluroethyl chain.  This choice was directed by their methodology for 1,3-oxidation published last year in JACS, and is related to the Hofmann-Loffler-Freytag reaction (used to do a 1,3-bromination via atom transfer).  Their development of this chemistry lead to the use of a trifluroethyl group to encourage N-centered radical formation, increasing selectivity.  So we’re all-set to do a bit of 1,3-oxidation, but there’s a complication – as there are three possible tertiary centers avaliable.  Their smart move was a bit of rationalisation using 13-C NMR to probe the electronegativity of the various carbons, confirming that they had a good chance of selectivity, which was bourne out.  In this case, it works really quite well, using methyl(trifluoromethyl)dioxirane – a varient of DMDO in which is more active, and selective for equitorial C-H bonds.

eudesmantetraol_3

The next most reactive position for this chemistry was dealt with accordingly, but this time doing a bromination to provide a common intermediate, 18.  In the simplest case, treatment with silver carbonate resulted in the diol, which after clevage gave pygmol in cracking yield over four steps.  It’d be interesting (but a lot of work) to see if this could’ve been stereoselecive, had the center been prochiral.

eudesmantetraol_4

Using the same intermediate, Baran was able to complete two more targets, 11-epieudesmantetraol and eudesmantetraol, by firstly eliminating the bromide with tetra-methyl piperidine (can I assume that the methyl groups are bis-geminal, alpha to the nitrogen?), and then brominating with NBS to form a cyclic carbonate.  This time we’re stereoselecitive, and it remained so when the opened the carbonate, which closed onto the primary bromide to give a terminal epoxide.  Only one step was required to access each natural product, choosing either acidic or basic condition to open the epoxide (remember your first-year org-chem?).

eudesmantetraol_5

This is a fantastic piece of work – not just smart, but well executed.  However, it’s worth remembering that this approach isn’t entirely new, as remote oxidation was a very popular technique for steroid chemists.  Use of transition-metal oxidants, such as iron coordination complexes was common, such as in this example by Paul Grieco.  However, Baran had taken this idea and modernised it considerably, with the NMR/X-ray analysis of reactivity a critical step.

eudesmantetraol_6

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53 Comments

  • GreicoP says:

    People have been talking about doing this kind of thing for years in total synthesis (not just semi-synthesis like the breslow work), and now they actually do it. This paper is a real landmark in my opinion.

  • The Next Phil Baran says:

    Was there any mention of whether they tried to oxidize the second tertiary carbon (isopropyl group) by just adding another equivalent of dioxirane? Is the problem that the second oxidation occurs at the equatorial hydrogen? I don’t have access to nature at home. It seems like a simplification.

  • OC says:

    you missed methyl group~

    • big fish says:

      in the main picture, the secondary methyl in the side chain is missing.

  • nanking says:

    you missed a methyl group

  • milkshake says:

    In respect of this controlled hydroxylation of tertiary CH bonds, it is worth looking up the latest Du Bois work in Angew Chem, – I think it beats the Christina White’ iron catalyst. Also there were two communications from Corey group where they used both radical photo bromination and Pd-metalation, to oxidatively elaborate aliphatic chain in aminoacid.

  • gyges says:

    Interestingly, the first reaction depicted shows a way towards making CC1CC(C#N)C(C(C)C)CC1 you can shed some daylight on the depiction of the molecule here (hopefully, one day, I will tire of that pun).

    Anyone know the commercial synthesis?

    ps I forget the appropriate stereo chem. I think that the required cpd has the menthol configuration including at the nitrile group which replaces the alcohol ie C[C@H]1C[C@@H](C#N)[C@H](C(C)C)CC1

  • stork naked says:

    this is a great body or work from baran, very simple and direct and highlights a lost art of strategic planning and oxidation state tactics.

  • benchworker says:

    Can somebody tell me something about Mo Movassaghi at MIT, it seems like he’s doing nice chemistry, but doesn’t know what kind of guy he is

  • India-Synthesis says:

    Very nice work of Pr. Baran et al.!
    For your information, There is another very nice total synthesis of Micrococcin P1 in Angewandte Chemie (hot papers)to my opinion deserves to be published on this noteworthy blog!

    • Tot. Syn. says:

      It’s a cyclic peptide – which I don’t write about. I’ve only covered one peptide in three years of writing this blog, and the simple reason is that they don’t interest me in the slightest. The work, especially if it’s published in Angewandte, JACS or Org. Lett. is sure to be impressive – and the completion of any target is an achievement. But if it doesn’t interest me, I’m not spending four hours writing about it. Sorry!
      BTW – no one’s ever complained…

  • poodle says:

    Baran’s mind often works in a mysterious way. But for the first time, he gave such detailed discussion about the way of his thinking and planning. I enjoyed reading the paper tremendously and would encourage anyone who’s interested to do so. The logic behind this work is as interesting as the synthesis itself, if not more.

  • India-Synthesis says:

    Dear Paul, do not worry about that it was just a sugestion, continue your nice work.

  • syn. says:

    This blog has way too much of a pro-baran bent.

    • The Next Phil Baran says:

      I think it’s more of a pro-pro-Baran slant, not so much pro-Baran. I think Baran is just the figure head.

  • Grille says:

    You must be new to this blog if you say that!!!!

  • Truth Squad says:

    Definitely no peptides in this blog, please. What I like about Baran’s terpenes is that they do not seem to have any fancy biological activity, nor fancy structures. In fact, they most likely were cherry-picked for illustrating the bioinspired general strategy. That said, the synthesis is neat and this should be enough for a fancy destination.

  • Quality Control says:

    Baran has missed typed silver carbonate in Figure 3 going from 18 to 19. It should be Ag2CO3 not AgCO3.

    • antiaromatic says:

      Why couldn’t it be Ag2CO3? I know silver usually comes as Ag(I), but there are a number of examples where silver can be Ag(II), most notably AgO.

      • Quality Control says:

        First off silver carbonate is Ag2CO3 not AgCO3. Furthermore, in his Sup. Info. he has the scheme correctly annotated as Ag2CO3. I’m not saying silver(I) species don’t exist it just is not what he used and hence he made a typo…the typo was also repeated on the scheme on this site ;).

        • antiaromatic says:

          Cool. Good catch.

          • milkshake says:

            There is such thing as Ag(2+). It is generated from Ag(+) and peroxidisufate, and it is scarier than Luca Brasi. It oxidizes Mn(2+) all the way to permanganate, and RCO2H to R radical. There is one pretty useful but obscure radical alkylation reaction of el-deficient systems that are resistant to overoxidation – like quinones and pyrimidines.

          • organicgirl says:

            Does anyone know why the silver carbonate works?

  • Nicolaou's Mustache says:

    This is complete Star Wars chemistry. I’m getting used to it, though. Nice paper, Baran.

  • Jose says:

    Not pro-Baran, but pro-damn good chemistry. And since Baran is publishing a disproportionate amount of staggering chem, the blog reflects that.

  • milkshake says:

    yea, its totally disproportionate. Hogging all available fame – I think he ought to publish some of his stuff anonymously.

  • LW says:

    That 13C comment you made Paul had got me thinking about something I’m doing in the lab….cheers for that.

    Agelastatin A…..part 4? Not read it but there’s another one that’s popped up in Org Letts.

  • GYA says:

    this one is ok. its a bit steppy and a number of the yields are quite poor. not one of my favorites.

  • Nicolaou's Mustache says:

    yo paul, check out the new JACS Aplysiatoxin synthesis. you should blog it and comment on the lack of references to Keck: the first guy that demonstrated the synthesis of a tumor promoter from an inhibitor. Bastards.

  • Liquidcarbon says:

    If anything, I’d like to suggest listing the authors as they are listed in the journal. The PI can still be bold.

    • Tot. Syn. says:

      I *do* put the authors names in journal-order, with one alteration – I always put the starred-authors name first. There is no consensus in the literature as to where the PIs name should go, so I’ve standardised it for my blog by putting it first. I don’t mean anything by that – it’s just a standard (which is more than can be said for the journals).

  • krest17 says:

    Looks like a competition who can leak Baran better. What’s new? – known, already published methodology applied to relatively simple very carefully preselected molecule. NMRs consideration – well I think they where after experiment.

    • Tot. Syn. says:

      It’s like more, not leak better… It think that’s what you were trying to say. And yes, the molecule was preselected – by the 13-C NMR analysis that you say they did after-the-fact. [It's actually very easy to do 13-C prediction, and it can be extremely accurate.] Which is it? Preselection (otherwise known as careful retrosynthetic analysis), or random oxidation?

      Please don’t troll around this blog – comments like yours need justification and/or citations. Especially when your IP address locates you in SoCal…

    • Pilky01 says:

      Krest 17
      Could you explain whats wrong with synthesising a ‘very carefully preselected molecule’? As far as i understand, synthesising a carefully selected target molecule is the bread and butter of total synthesis is it not. Non selective synthesis comes under the guise of Diverstiy Orientated Synthesis (DOS) doesn’t it? but even that is usually very carefully thought through before executiuon. What do you mean exactly?

      • krest17 says:

        Sorry, I did not want to hurt you feelings about Baran. Nothing is wrong with careful selection, nothing – I just more appreciate when scientists develop new methodology to get interesting molecule and not when they search through myriad of natural products just to find some with right OH-stereocenters that fit to their already developed and published (J. Am. Chem. Soc., 2008, 130 (23), pp 7247–7249) methodology . Tot. Syn. – Sorry again – it was just my humble opinion.

  • krest17 says:

    Finally, it is at least third paper about selective oxidation in Nature/Science for last two years – new conception?? – hardly

  • williswill says:

    Paul –

    Regarding the the trifluoro DMDO oxidation, do you mean to say that the this variant is selective for eq. hydrogens compared to reg. DMDO, or simply that it is more active?

    A nice feature of the CF3 analog is not only is it a stronger oxidant, it is also lower boiling than reg. DMDO, and thus you can prepare a high conc. solution of the stuff.

    • milkshake says:

      I wonder if there is any dioxirane that’s stable in solution in fridge indefinitely – like now increasingly popular TMS diazomethane. One of the seriously annoying aspects of running DMDO-reactions is having to make it fresh over and over again, titrating the stuff, getting few% of theory every time.

      There is a perfluorinated version of methyl-isobutylketone now available cheaply in bulk from 3M, manufactured as a fire-extinguishing liquid, and its fluorous and low-boiling. I wonder if anyone could make a storable dioxirane from that.

      • cjdquest says:

        Milkshake:

        FYI RE: TMS-diazomethane. It is stable, but apparently no less toxic.

        be sure to handle in a well-ventilated fume hood.

        http://www.canadaeast.com/front/article/666039

      • williswill says:

        Has anyone ever explored a dioxirane on a solid support? Wouldn’t help if you needed to use a percise # of equivalents, but could make the preparation of the stuff less of a pain…

      • InfMP says:

        DMDO is stable indefinately in -80 fridge. I used to keep 0.1M for months and it never changed!

  • ryan says:

    nice job,give me a doctor fellowship,en >>>

  • The Next Phil Baran says:

    I have been thinking about this paper quite a lot recently. I wonder if his rationalization about where the N-centered radical would react is correct, though I don’t doubt the result :->. To me it looks like the proton of the isopropyl group is inaccessible anyway (trans relationship, if it was cis it might happen.) Second, is it more likely that N-centered radicals would react at a carbon two bonds away or at a carbon adjacent to the carbamate group?

  • European Chemist says:

    The paper is awesome by any standards – if not for the chemistry, especially for the thinking that goes underneath. The theoretical discussion is book-like, establishing concepts and stating very strong opinions.
    Baran is the kind of chemist that annoys everyone, because he does NOT use any fancy chemistry nor exotic reagents. He just does things “a la Woodward” and relies on careful thinking rather than on pure brute force to complete his stuff. Of course, there are some students on the webpage that will probably never make it beyond 5th author on a single paper through their Ph.D. or Post-Doc, but looking at what stuff is successfully completed you can only imagine what other, wild projects are running in that group.

    Particularly love the resorting to old chemistry: the dioxirane oxidations (which nobody really understands), the Hoffmann-Loffler chemistry (in which Baran himself has a hard time justifying the abnormal regioselectivity), the dissolving metal reduction of the ketone (it must have been at least 20 years since the last paper I read that reduced a ketone that way!!). You can still do a LOT of elegant stuff in academia without having to constantly follow “fashionable” trends (as he did on occasion by realising the value of an obvious, but never attempted organocatalytic asymmetric synthesis of cryptone).

  • The Next Phil Baran says:

    I am genuinely interested in that question. I’m trying to figure it out.

  • stuffneverworksforme says:

    With regards to the Micrococcin P1, its only hot because the mystery of configuration was solved. The chemistry is well developed, the group already published the diastereomer years ago in organic letters, where the same methods where used.

  • bubu says:

    really good,thanks

  • stuffneverworksforme says:

    Baran = god haha

  • [...] concise syntheses of a family of terpenes from the eudesmane family. The syntheses in this work are cool in their own right, but make no mistake, this is a strategy paper for the Baran group. They’re thinking long [...]

  • [...] standard proline-based catalyst, aided with a bit of a catechol to boost reaction rate and yield (another example is in this Baran paper).  The remaining aldehyde was then Wittig’d to bolt-on a diene, and set them up for a bit of [...]