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Daphmanidin E   

30 October 2011 19,279 views 38 Comments

Carreira, Weiss. ACIEE, 2011, EarlyView. DOI: 10.1002/anie.201104681 Article PDF  Group Website

Now that’s a busy polycyclic ring-system!!  Three five-membered rings, two six-membered rings and one seven (depending, of course, on how one counts the ring sizes.  Anyone read the IUPAC Gold Book last night?) – adding up regardless of maths to one hell of a synthetic challenge.  And there’s even some token biological activity to aim for – this bad-boy has some moderate vasorelexant acitivity next to rat aorta.  (When the paper mentions ‘moderate’ activity, we can be pretty sure it does very little indeed…) But who knows – perhaps one of it’s derivatives or intermediates could be more biologically interesting.

What we’re interested it is of course the synthesis – and it’s a one-man job in this case. That man by the fumehood is Matthias Weiss, and he started the chemoenzymatic or chromatographic separation of a diethyl succinate derivative.  With no Supporting Information to hand, I’m unsure how he went about that – it’s always a disappointment when leading PIs like Erick Carriera neglect the scientific process… Lets just hope that it was high-yielding and amenable to scale!  A bit of mono-protection of this C2 symmetric intermediate, followed by enol triflation gave them a partner for a rather neat B-alkyl Suzuki cross-coupling, appending the silyl-protected propanol side-chain.  Unfortunately this reaction require the use of Triphenylarsine – not the most pleasent of additives – required to suppress reductive detriflation.

The product was then treated with an array of Group-13 organometallics, firstly diastereoselectively hydroborating the alkene, and then reducing virtually everything to give a triol product in excellent yield.  What I like about this procedure is the apparent simplicity in functional group transformation.  A few steps manipulating protecting groups lead them to an intermedate that was O-alkylated with the corresponding tosylate then took them to the precursor to two Claisen rearrangements.  The first is perhaps the more obvious – the alkenes are sitting the perfect place to be tickled with a little heat to encourage carbon-carbon bond formation, and diastereoselective formation of a congested tertiary – tertiary system.  Next, they treated the resulting ketone with base and 18-crown-6 to O-alkylate again, this time with allyl bromide.  Again, heating was used to simulate rearrangement, neatly forming the quaternary centre in three steps.


Eight steps further on (including a neat Henry condensation and a stereoselective methylation), and the team were ready for a spectacular formation of the octahydroazulene domain.  Working from an alkyl-iodide and looking for coupling with the cyclopentenone, the group had a lot of possible conditions to consider.  However, what they went forward with was rather unusual – a cobaloxime-mediated Heck cyclization, requiring irradiation to proceed in good yield.  Carreria states that this method development will be published in another paper, but I haven’t seen anything just yet.  Looks very interesting though –  and delivers a stunning yield in this challenging system.

With the medium ring closed, the (one-man) group were pretty close to the finish.  An intramolecular aldol codensation was used to install the remaining cyclopentene (requiring two reaction cycles to achieve a 77% yield), whilst de-BOCing the amine with TFA was enough to enough to prompt imine formation, and completion of the final ring. Removal of final protecting group completed the synthesis – one that cleverly balances new methods with classical techniques.

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  • Sathiya says:

    Awesome… Great job… kudos to the “one man” group… great post totally synthetic,

  • K-Y says:

    The catalytic, cobalt-catalyzed Heck reaction was actually published a week before this paper came out in Angewandte: DOI: 10.1002/anie.201105235, although they make no mention in the text of this methods paper of any relation to this synthesis.

  • stir_bar says:

    It was a pretty awesome synthesis! It is a bit strange for ACIEE to not have supp info… I’m excited to see posts again, too.

  • fng says:

    the molecule is attractive (and certainly challenging) and cool transformations are showcased in the synthesis but the number of protecting group operations is up there – i don’t mean to take anything away from the hard work of Weiss.

  • Industry Chemist says:

    The Lipshutz ad on the right is creeping me out. The penetrating gaze, the playful smirk…

  • LOTIONchemist says:

    Lipshutz is a handsome devil. That smirk juxtaposed with that sassy dirty blonde hair is saying: I am one clever son-of-a-bitch and you know it. That is style. He would make an outstanding manager in Pharma.

    • krest17 says:

      He is an outstanding and very supportive PI indeed. It was a truly great time in his group. My recommendations.

  • Bruce Lipshutz says:

    I’ve successfully impregnated metal catalysts on solid support (Pure Appl.Chem., Vol.78, No.2, pp.377–384, 2006) and now I’m ready for Paul’s mother!

  • sss says:

    Off topic, but… See nature chem ASAP – taxadiene by Baran. I have huge respect for the guy, but how did it make it to nchem?… I just hope this is only me not getting something…

    Again, sorry for off-topic…

  • gubbs says:

    Are you kidding SSS? This guy is going to make a gram of taxol and trolls like you will still say “not jacs quality” or whatever.

    • sss says:

      I didn’t say that… And this is exactly the kind of comment I was afraid of…
      See, I think Phil is the best out there, end of story. And when he makes taxol by oxidation of taxadiene he should submit to nature at least, and he will be accepted, in my opinion.
      All I was talking about was this particular work, that’s all. So please, gubbs, be adequate.

  • Trewson regal says:

    I think you should read the paper. The argument is quite convincing for why this is at nature or science level.

    • sss says:

      I did. I think it’s a terrific synthesis of taxadiene (and I wouldn’t expect anything less from Phil) and a great contribution to the project which, upon completion, will be a true science level publication.

      • stir_bar says:

        Are people really arguing that Nature Chemistry is on the same level as Nature and Science?

        On another note: “A.M., Y.I. and P.S.B. conceived the synthetic route, conducted the experimental work, analysed the results and wrote the manuscript.”

        Baran still works in lab?

  • OtherSideOfTheDesk says:

    I am well off topic here, but this is the best place to ask this question. I am developing notes for my natural product synthesis class, my first as a PI. This class is for 4th year undergraduates, and I intend to stress synthetic strategy, and its evolution over the years. I am looking for examples of less complex natural product targets that have been made several times over the years, preferably with increasingly complex routes. I am hoping my fellow readers can suggest some gems that I have overlooked. Thanks!

    • brian says:

      histrionicotoxin and kainic acid.

    • Tot. Syn. says:

      Hmm. I’d consider Prostaglandin E2 & F2a (which I worked on) – Corey alone has about five syntheses. Then there are the macrolides like Leucascarolide and Discodermolide… Strychnine’s had a few syntheses…. I’ll have a think about some more.

      • gippgig says:

        B.R.S.M had an entry about “Progress In Strychnine Synthesis” (Oct. 9; brsmblog.com/?p=811#more-811).

    • OtherSideOfTheDesk says:

      I like histrionicotoxin and kainic acid. I have already thought about strychnine and the prostaglandins, but I haven’t made up my mind yet.

      The WMK-derived ones like sativene and longifolene look pretty good, but I am a fan of the old-timey syntheses…

    • Ninja says:

      what about those dimeric cyclobutane natural products.. Maybe you cant find one that has been done over and over but there are several of them and if you are trying to emphasize strategy, there is nothing more state-of-the-art than Baran’s recent synthesis of the Piperarborenines. Simply impressive.

      • TMSOTf says:

        Agreed, that wacky route gets my vote for most creative synthesis of the year. just stunning.

    • rhodium says:

      I enjoy all the biotin syntheses.

    • Matts Chair says:

      Huperzine A? From Kozikowski in 91 to Herzon this year.

    • derek says:

      As an undergrad (4th year, 2006) I took a similar class as to what you are developing; the class was split into groups, and we were charged with comparing synthetic routes to their target molecules, those targets usually being slightly different in structure. I recall one group presenting on Johnson’s progesterone synthesis, and for the next class the other group presented on Vollhardt’s estrone synthesis; for a class discussion we compared the two (e.g., would Vollhardt’s route be valid for progesterone?), with the professor simply acting as mediator. We also touched on beta-lactam antiobiotics (penicillin V, the landmark Sheehan synthesis; also Merck’s thienamycin) and the tetracyclines, Masamune/Sharpless assembly of L-hexoses, and the multiple routes to Tamiflu (it might be obvious at this point that one of the primary texts was Nicolaou/Sorensen’s “Classics in Total Synthesis I”, a function of Sorensen being the professor’s Ph.D. advisor). Regardless, I definitely agree with histrionicotoxins, prostaglandins and a survey of strychnine syntheses (esp. the Reissig synthesis….simply nasty) as classic targets, though perhaps their complexity could wait til the latter part of the course…..

    • Ron says:

      The carbapenams (thienamycin in particular).

  • HPCC says:

    Dysidiolide is something that was first made by Corey (1997), but made a few more times thereafter, and each approach teaches something about making carbocycles. We covered it in my natural products grad course, and that’s where the power of the Diels-Alder reaction was introduced.

  • toluene says:

    for a good overview of syntheses of natural products, especially for the ones that have been made several times, you might want to check out this website:


  • 3 says:

    OtherSideOfTheDesk: ‘Camptothecin’ would make a very good case study-it has lots of syntheses, and the complexity that is good enough.

  • Hap says:


    There is a review of histrionicotoxin syntheses [Nat. Prod. Reports 24(2007), pp. 298-326] up to 2006. (Google “histrionicotoxin synthesis review Stockman”)

  • brian says:

    quinocarcin/cyanocycline is another very interesting target that has been prepared by several groups; reviewed in chem. soc. rev. by mulzer in 2008.

  • Anonymous says:

    @OSOTD: You state you are looking for…”examples of less complex natural product targets that have been made several times over the years, preferably with increasingly complex routes.”

    Why would you want to highlight “less complex natural products” being made by “increasingly complex routes”? Isn’t that counterintuitive? Shouldn’t you be teaching aspects of “increasingly complex targets” being made by “less complex methods”. This simply seems like over-engineering, so, why teach that? Isn’t that what’s wrong with OChem now? I know everyone on this side will (more than likely) disagree with me, but if you are teaching this, you are setting the discipline back several years. We should be making things easier, not harder.

  • Hadriel says:

    Probably complex means fewer steps but achieving more in each step. More to highlight current techniques and capabilities.


  • 3 says:

    what is the cheaper source of disposable syringes? What brand is good for Organic Chemicals? Sorry for the distraction.

  • K-Y says:

    Not sure if this is too off topic, but has everyone seen this?


    The most interesting aspect is the “quiz mode,” which hides the reagents and/or product. It’s surprisingly engaging in terms of quizzing yourself to predict reactivity or conditions, and a good tool for anyone learning synthesis…

  • Young Padawan says:

    BTW: Now that it’s out of the early view, SI are up.

  • [...] 30/10/11: Also, Tot. Syn. now has a post on [...]

  • MTBE says:

    I wonder why they use MTBE so often as the extraction solvent. Is it very cheap?