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Drupacine, Cephalotaxine(s)   

23 August 2007 9,759 views 25 Comments


Stoltz, Liu and Ferreira. JOC, 2007, ASAP. DOI: 10.1021/jo0710883.

An awesome read, this paper is a smart bit of work by the Stoltz group, looking at the synthesis of two members of the Cephalotaxus alkaloid family. They state that the members accessed in this route are biologically inactive, but point out that other members of the family are a bit more pokey (and can presumably be constructed using similar means.

The synthesis begins with one of my favourite reactions, a Johnson-Claisen rearrangement. This uses triethyl ortho acetate (which smells like sweaty shoes) to add two carbons to the allylic alcohol, and then does the [3,3]. I’ve done several, and it’s a top reaction (and quite amenable to microwave chemistry…).

Some straight-forward transformations then give them either the primary amide or the amine, which under aerobic conditions, does an oxidative cyclisation to give the 5,5 fused spiro compound in rather decent yield. I’m especially impressed with the amide case, as I’d imagine that system to be rather stubborn. However, the reaction is not enantioselective, and thus generates a racemic mixture. They state, however, that this inability is useful in this synthesis…

A few more steps, and it’s palladium time again (this time using a rather exotic catalyst). This heck reaction builds that seven member ring rather nicely, completing the carbocyclic skeleton of the natural product, except in a racemic fashion.

However, using a derivative of mandelic acid as the starting material, they were able to do a separation of diastereomers. The stereogenic hydroxyl group that was key to this was then either burned-off to make either enantiomer of celphalotaxine, or used to form the acetal linkage in Drupacine.
There’s lots to read here, and I’d be interested in your opinions about this ideology (using both diastereomers from an unselective reaction to pursue two different targets/enantiomers…)

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  • .... says:

    I’d say that an enantiodivergent route is slick if the goal of the project is to generate diverse compounds….i.e. for biological testing, proving multiple structures, etc. If the goal of the project is making a single molecule, as with most contemporary total syn., with the end goal being “Look what we can make”, then I think the more elegant approach is the one that makes a single stereoisomer. Regardless, I thought this was a nice paper.

  • Spiro says:

    I totally second #1 ‘s comment.

    The title of this article is so pompous! Had they produced the spiroamine with decent ee, the article would be 3 pages shorter, and the title three lines shorter…

  • milkshake says:

    two notes on methodology:

    The funky palladacycle catalyst used in Heck is not that exotic – it is the “Herman catalyst” that was discovered by accident (tri-o-tolyl phosphine + Pd(OAc)2 is heated in benzene, the stuff crystalizes at RT.) Strem sells it and it is fairly general for high-temperature Heck with aryl bromides but not much for anything else. Please note lots of things will work for Heck, even in extremely low loadings, the only trick is to keep the Pd catalyst from dying prematurely. The palladacycle is just a resrvoir of underligated Pd species, and tetrabutyl ammonium helps to keep Pd nanoparticles from clumping together.

    The reason why Stoltz is probably doin it is to demonstrate the usefulness of Pd(II) oxidative cyclizatation methodology. (He sometimes complains that the trnsformation is underused). Stoltz best system is Pd(II) trifluoroacetate with pyridine as a LIGAND, not base. (usually Na-carbonate is added together with sieves). It is done in toluene/O2. This system did not work for amide cyclization and the alternative was to do DMF+DMSO+NaOAc+O2 with Pd(II) trifluoroacetate without pyridine. This converts it just to Pd(OAc)2 in DMSO system used by Larock and Anderssen. This older system is actually milder and more broad in scope, does not use sieves or base and proceeds almost entirely without C=C migration (contamination with the migrated isomer can be a bit of complication with Pd-trifluoroacetate/pyridine system.) There is lots of fine mechanistic details that need to be worked out – but it is a nice catalytic version of ArSeX cyclization/oxidation/elimination.

    With using separated two diastereomers of late intermediate for 2 different targets is probably something of a fall-back option that was taken because the dr was poor – but this is not a drawback in my opinion.

  • Tot. Syn. says:

    Thanks, Milkshake. You really are a font of chemical knowledge! I knew I’d seen the Herman Catalyst before, but I had no idea it was so easy to make (or buy). Thanks again.

  • willyoubemine says:

    Agreed 1,2…its like Baran, Stoltz, and MacMillan are in a pissing contest for most pompously exaggerated work. I mean after all, this is science, not salesmanship.

    Still, its a nice piece of work, though I agree with 1.

  • synthon says:

    Milkshake….I really didn’t appreciate how easily these metallacycles form. Hartwig just lectured yesterday at ACS on his iridacycle catalyst for allylic substitution which forms by metallation of the Feringa phosphoramidite ligand in the presenece of [Ir(COD)]2 and a simple amine base!

  • cjdquest says:

    Milkshake and other Pd enthusiasts – There are a couple of very nice papers from Reetz on the effects of tetraalkyl ammonium salts on the size of the Pd particles that form the catalyst resting states in these “Jeffery’s” conditions: Pd(OAc)2, NBu4OAc, base, heat. In those cases, I guess the nano-particles are small enough that enough Pd leaches into soln’ to catalyze Heck rxns. Check out the following by Reetz:

    ACIE 2000, 39, 165 – esp footnote 9.
    Chem Comm 1996, 1921
    Adv. Mater. 1999, 11, 773.

    You can see the seeds of last year’s Science paper by Lukas Goosen (s should be beta) on decarboxylative cross coupling in these papers and perhaps understand why Reetz is thanked for “helpful discussions” in that paper. There is some relevant work by Andy Myers too on the Heck reaction starting with aryl carboxylates rather than halides or triflates.

    As for the oxidative cyclization here – its beautifully utilized in the synthesis – but here’s a “mechanistic detail” to chew on. Since Reetz has shown that thermolysis of Pd(OAc)2 at temps as low as 80 C can form Pd (0) nano-particles along with CO2, CH4 and C2H6 (see refs above) – is the added NaOAc in Stolz’s reaction just a base, or is some sort of decarboxylation also somehow involved in the catalytic cycle? Occam’s razor would suggest not, but can Reetz’s results be swept aside?

    Side note – I think Herman’s catalyst is best drawn with the OAc’s as bridging ligands, not with a Pd-Pd bond! The undergrads might get confused. “trans-di-mu-acetato…”

    Enough for the picking of nits, back to work.

  • milkshake says:

    cjd: I have seen the Reetz heck papers – He was the first one to propose that the palladacycle “catalysts” actually work by slowly bleeding Pd nanoparticles – and he was proven right.

    On the oxidative cyclization: The Pd(OAc)2 in DMSO/O2 system is fundamentally different from the Pd(OTFA)2.(py)x in toluene/O2 + base + sieves. I think some kind of Pd(II) nanoparticles is very likely in the DMSO system – in fact, Anderssen proposed just that whereas for Stoltz, addition of metallic mercury does not shut down the reaction – and that’s a good indicator that the nanoparticlecles may not be the main catalyst.

  • cjdquest says:

    Ah – the good old Hg drop test – thanks for the reminder – I think I had read that was done in the Stoltz case but forgotten.

    Perhaps decarboxylation could still be involved in the turnover? Presumably in the Reetz Pd nano particle rxns, a Pd(II)-CH3 type intermediate is formed on the way to Pd(0). Could this be the involved in the turnover in the oxidation chemistry without leading to Pd(0) particles? A labeled acetate might be a quick experiment to try. Probably there’s nothing to see – I’m clearly stretching here – but I do think there is more to learn about the mechanism in these Pd oxidation rxns to learn. Shahl seems to be seeing quite divergent mechs based on fairly subtle changes in conditions. Hopefully he and others will do more work on the mechanism.

  • Taylor says:

    Agreed with milkshake. Hermann’s catalyst is sufficiently non-exotic that it features in J. Chem. Ed. 2000,77,92-95 as a preparation from PCl3 and the requisite Grignard for “fourth-year undergraduate students who are particularly interested in organometallic chemistry” or for grads with a supervisor on a restricted budgets.
    The article is by Mr Herrmann himself.

  • TWYI says:


    Have we actually reached the point where we look so far beyond the nice chemistry involved in the publication to the point of scrutinising the wording of the title?

    Almost as bad a journal snobbery.

  • willyoubemine says:


    I think the issue is perception v reality. Its nice chemistry, but the “Convergency and Divergency as Strategic Elements in Total Synthesis:” is a book title, not a research report article. The title should jsut read:
    The Total Synthesis of (-)-Drupacine and the Formal Total Synthesis of (±)-Cephalotaxine, (-)-Cephalotaxine, and (+)-Cephalotaxine.

    Why do these profs feel the need to “sell” something that isnt there? Cant the work, which no one is putting down, stand on its own?

  • radiochemist says:

    “Agreed 1,2…its like Baran, Stoltz, and MacMillan are in a pissing contest for most pompously exaggerated work. I mean after all, this is science, not salesmanship.”

    I don’t think these three are the only culprits of being the chemistry equivalent of second hand car dealers, “A nice little runner sir, 90% yield everytime..”. Peter Seeberger is another, his work on automated carbohydrate synthesis has produced some amusing papers including my favourite where he set out to make an alpha linkage and got beta and still published. He also gave an “evangelical” talk to a room full of carbohydrate chemists on his solving of all the fields problems with his wonderful machine.

  • pi* says:

    one thing to have a pompous title
    another to have a title that is actually wrong, recent jacs article…
    DOI: 10.1021/ja073351n

  • lemi says:

    i am also a carbohydrate chemist working on reactivity-based and pre-activation One-Pot Oligosaccharides synthesis, first time to hear such rumor about Peter Seeberger, haha interesting…

  • .... says:

    Maybe I’m behind on this one but I read in today’s C&EN that Jeffrey Bode is moving to U. Penn.

  • Liquidcarbon says:

    There is a triallylborane route for this, presented on the ASMC as well :) I’ll check the reference.

    Triallylborane + pyridine = 2,6-diallyl-1,2,5,6-tetrahydropyridine. Isn’t this crazy?

  • Liquidcarbon says:

    It is based on allylation of lactams, which converts carbonyl into СAll2 group, then RCM. Basically, they make N-phenethylazaspiro[4,4]nonanol, and cyclize it with acid into the polycyclic core.

  • Thomas K. says:

    Hi there,

    Can anyone give me the Rf of cephalotaxine in CH2Cl2/MeOH (or any other) system?
    Many thanks in advance for the help.

  • Avinash says:

    Hey all,

    I am an undergrad, and i was hoping someone could help me understand the mechanism of the Herman Catalyst. I am not sure exactly what is happening, and what does the n-Bu4-NOAc do? Does this go through the mundane oxidative addition-> reductive elimination type of a cycle?



  • TheEdge says:

    The Herman catalyst is a fancy Pd species used for Heck reactions. You break up the complex to generate a Pd(0) species (does anybody want to take a stab at what the ligands are that are left on the Pd?). The Pd oxidatively inserts into the Br-C bond to make a Pd(II) species that is also bound to the olefin. The olefin (effectively) inserts itself into the Pd-C bond (think of it as a fancy retro-beta-hydride abstraction). This forms the new carbon-carbon bond and leaves the Pd bound to the 5-membered ring. The complex then does a beta-hydride elimation to generate the new olefin and a Pd(II) species with an H and a Br ligand. Note that the olefin that forms is the only one that can. The olefin insertion is syn, so the C and the Pd end up on the same face of the ring. The Pd eliminates with the only H it can. The product leaves and a base deprotonates the Pd complex to regenerate the Pd(0) complex. A number of bases can be used for this, but in this case the basic amine in the product probably acts as the terminal base, probably via the acetate.

    Milkshake points out above that the tetrabutylammonium acetate is used to break up the Pd aggregates to provide active Pd species.

  • Avinash says:

    Thank you very much for the prompt reply, This has to be one of the best papers i have ever read, i must say.

  • LH08 says:

    Don’t want to be overly correct, but it is Herrmann’s catalyst (two r, two n).
    You might even call it the Herrmann-Beller catalyst.

    Angew. Chem. Int. Ed. Engl. 1995, 34, 1844.

  • Will-Ramesh says:

    Just a comment to say that these Heck conditions (Herrmann & Beller Palladacycle, nBu4OAc, DMF/ACN/H2O=5/5/1) were developped by Tietze and Shirock in their synthesis of Cephalotaxine (both racemic and later enantiopure), and used on the same substrate, so it is fair to say that the credit is theirs.
    I would encourage anyone interested to check out their synthesis of (-)-Cephalotaxine which is the most efficient to date.

  • Will-Ramesh says:

    And here are the refs:

    JACS 1999, 121, 10264.