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Spriolaxine Methyl Ether   

27 August 2007 7,796 views 26 Comments


Trost and Weiss. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200702637.

I wasn’t sure about this paper when I started reading it – the introduction, in which the ketone and acetylene functional groups are compared and contrasted, seemed quite out-of-place. Surely most readers are well aware of the utility of the alkyene group, and of the transformations which may be be performed on it. Hmm. Anyway, Trost’s route to this natural product is really quite nice, and, as the paper points out quite feverently, is reliant on some smart alkynylation chemistry.


As can be seen from the reterosynthesis, they planned to use a ProPhenol alkynylation twice to impart hydroxyl stereochemistry and form C-C bonds. This method seems to work rather well – in the first case, the yields and ee (shown) were very good; in the second case, a more complex addition to an unsaturated aldehyde, the result was less good but still impressive (52%, 5:1 d.r.).

Having done this trick twice, a final piece of alkynylation was used; attack into R-(+)-propylene oxide gave the final hydroxyl stereocenter required for the impressive spiroketalisation. This chemistry was first used by Utimoto, and has been investigated mechanistically by De Brabander last year. Their result speaks for itself – creation of two rings and a spiro- stereocenter in cracking yield (presumably as a single diastereoisomer).

Smart chemistry, nice read…

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  • HPCC says:

    Yahoo! First to post! :D

    Sorry to take a p!ss at a few not-so-innocent typos, but the proline-based chiral ligand is missing its nitrogen atoms. And, in your first paragraphs, there’s a new functional group named by you: “alkyene”… What’s the oxidation state of this baby? :) To your credit, you’re blogging this stuff after 12+ hours in the lab, at 1 AM, whilst I’m reading this at 4 PM, when I’m still all awake. Is it beer o’clock yet?

    All that being said, I, too, was wondering where all this babbling by BMT was leading. Not my favourite synthesis this year, but definitely some noteworthy transformations.

    I personally resent 3,5-dimethoxybenzaldehyde (Trost’s student’s starting material): pure, it’s a not-too-viscous yellowish liquid… that crystallizes at the very moment you need to use it!!! Whether it be in your pasteur pipette, syringe, needle, you name it! I’ve stored that b@stard (5-10 g) in a vial for weeks, and its metastability in the liquid state has always amazed me – I mean, p!ssed me off.

  • Karl Hungus says:

    Yawn. This would be in Org. Lett. if Trost’s name wasn’t on it.

  • Spiro says:

    After the “atom economy”, the “alkyne strategy”… Keep in mind that this strategy will work only if the carbons bearing the triple bond are not too functionnalized in the target. Spirolaxine is a molecule with a lot of “CH2″ functionnal groups next to other “CH2″ functionnal groups, therefore the possible use of so many alkynes.

  • TheEdge says:

    I think it’s a nice, short synthesis that highlights some things that should be looked into. The ProPhenol chemistry is supposed to work well on unsaturated aldehydes. What happened here? Did they ever try using Carreira’s pseudoephedrine chemistry (possibly better d.r. and shorter synthesis)? Would bronsted acid catalysis close the spiroketal? It would be more “atom economic”.

    I really like their installation of the phthalide. The bromination is beautiful, and the trapping with CO2 must have required extremely careful experimentation. Well done all around.

  • HPCC says:

    3: I agree with Spiro on both points. One’s methodology truly gets tested when it gets experimented with something else than the idealized substrate. Let’s hope there’s already a more-than-just-CH2-based molecule on the treadmill. And the new buzzword promotion is, to say the least, troubling… :)

    4: Granted, PdCl2(PhCN)2 is anyhting but the holy graal of atom economy, yet they could also have tried PdCl2 in THF/MeCN (their solvent mixture) and thus generated PdCl2(MeCN)2 in situ, and thereby have made the whole thing a lot sexier (by saying “only three atoms for the catalyst”! I think Trost has moved on from atom economy for its own sake. It’s a concept that’s worth thriving for, but it won’t always always always be implementable.

  • TWYI says:

    Agree with 4, the CO2 quench and cyclisation can be very tricky. A lot more reliable is to first convert the alcohol to the carbamate, then lithiate and cyclise with acidic conditions.

    Not as elegant but it gets you there.

  • anon says:

    not as good as Andy Phillips’ synthesis
    DOI: 10.1021/ol0710111

  • ZZZZZ says:

    I agree with #2. And as for #4, no special optimization was done.

  • petr says:

    why don’t your links to acs papers point readers to the graphical abstracts?

  • Tot. Syn. says:

    Urrr, I generally link via DOI, so it’s up to the journal house as to what the DOI links to. Read the FAQ.

  • aa says:

    i notice they use PtO2/H2 twice to reduce alkynes and alkenes.Whenever i do hydrogenation my first thought is always Pd-C, but i’ve never used another catalyst Could anyone tell me the advantage/reason for this over Pd-C? Thanks

  • TheEdge says:

    In the paper they state that Pd/C would reductively destroy the benzylic ether, which is kind of surprising because electron rich benzyl ethers are generally hard to cleave reductively. The PtO2 catalyst is a little milder, and avoids the problem altogether.

    #8 It certainly sounded like they optimized the lithiation step. Not having to screen conditions for the bromination doesn’t make it any less pretty.

    #7 The big advantages of the Phillips synthesis are that it’s convergent and not full of rhetoric about “the alkyne strategy”. Other than that, I like both equally.

  • milkshake says:

    5% Pt-C from Aldrich should work pretty darn good -and is definitely cheaper than Adams PtO2

  • .... says:

    Baran and Kock have some insights on palau’amine in Angew today

  • mevans says:

    Wow, that ProPhenol stuff looks pretty versatile!

    All about ProPhenol

  • willyoubemine says:

    PtO2 is a great alternative to Pd for hydrogenation of pi systems where selectivity is an issue, no dehalogenation or benzylic hydrogenolysis competes.

  • aa says:

    thanks all for clearing that up

    the edge: thanks, i guess i should read the paper more closely rather than falling asleep during a comparison of alkynes and ketones

  • Tot. Syn. says:

    HPCC: I forgot to say “thanks” for pointing out my typos. I’ll fix them shortly. Things are a little busy just now – finishing in the lab and writing my thesis…

  • kiwi says:

    amen #7, #12… the level of salesmanship in this paper is off the scale, now that trost has invented the alkyne i imagine all syntheses will be instantly solved ;-)

  • Metallabenzeneer says:

    Why, in the paper, does scheme 2 show the (S,S)-ProPhenol leading to the R product, but then scheme 3 shows the (R,R)-ProPhenol also leading to the R product???

  • TWYI says:

    well spotted 20

  • Jose says:

    The two Baran Angew papers are stunning! To surmise the existence of massadine chloride on purely biosynthetic grounds, and then, bingo! Isolate it? That is *scary* brilliant.

  • TWYI says:

    Very Baldwin-esque, predicting natural products before their isolation!

  • lemi says:

    did anyone see jamison’s paper in science, fantastic-i must say…

  • Liquidcarbon says:

    Jamison: nicccccce, when I first saw a biosynthetic hypothesis for polyether toxins, I knew someone will make it work.

  • Rof5 says:

    #20, the boss didn’t proofread the paper, did he?