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Manzamine A   

18 August 2010 22,167 views 17 Comments

Fukuyama, Toma, Kita. JACS2010ASAP. DOI: 10.1021/ja103721s Article PDF Supporting Information Group Website

Ah – now this is a bit of a blast-from-the-past.  I knew I’d written something about this molecule before, so I had a quick rummage in the Tot. Syn. folder on my PC – and found nothing.  So I had a look in the other Tot. Syn folder, and another place I keep stuff for this website, and then four or five other places… (yeah, great filing system here) …and it turned up in this presentation I wrote a life-time ago.  You can download the presentation here – it’s all based on a Nicolaou review that was published in Angewandte in 2005, with some mechanisms and added bits thrown in.  I quite like the idea of sharing these kind of presentations, so perhaps I’ll try to add a few more.  Anyway, I managed to find the structure of Manzamine A (no simple sketch!), along with mention of prior syntheses by Martin and Winkler.

I’m actually kinda surprised that there haven’t been many more efforts in this direction, as this is one tasty target.  As usual, I’ll quote the authors with respect to biological activity: ‘cytotoxic, antibacterial,  antimalarial,  insecticidal, anti-inflammatory and anti-HIV’ activity are the headline – you need any more?!  And that ring system is something special – two medium rings and a strained 6,6,5 core, with a tryptamine-derived unit bolted-on for good measure. Yeah, there’s a lot to be getting on with!

Going back to your first class in retrosynthesis, you’ll remember that cyclohexene = Diels Alder, and Fukuyama doesn’t disappoint.  Working with a molecule related to Danishefsky’s diene (with an alkynyl pendant chain), a Diels-Alder with a chiral-butenolide (that is allegedly readily avaliable) completed the cyclohexene, providing two new stereocenters in excellent yield.  Unfortunately, the endo/exo selectivity wasn’t amazing, with a 2:1 ratio in their favour, but a 65% yield of their desired product is still pretty respectable. Over the next few steps, the acetoxylactone was broken apart to reveal a pair of alcohols – one remained protected, whereas the other was used to build the fifteen-member ring.

To build-on the remaining 5,8-system, the group needed to append a small chiral fragment first, which they constructed in great yield by an asymmetric zinc addition.  The protocol referenced is a sole-author paper by Nugent from back in ’99.  Having done this, the group completed this small fragment by first introducing a carbamate group, and then displacing the primary alcohol with iodine.

With both fragments in hand, they did a pair of deprotonation / alkylation sequences to produce a quaternary centre with great control of stereochemistry.  Considering that there are quite a few functional groups lying around, the control of reaction is really quite impressive.  Even more impressive is that they apparently isolated only one stereoisomer; control derives entirely (and unsurprisingly) from facial selectivity – which is also presumably what controls the third step in this sequence, a nice little epoxidation.

With this done, it was the work of a moment to turn the allylic carbonate into a dihydro-pyrrole – though I’m simplifying the protocol by saying that.  Firstly, the acid and amine perform a dehydration, creating a intermediate which does a [3,3] sigmatropic rearrangement to give the product, neatly transferring the carbonate stereochemistry across the double bond, forming an intermediate isocyanate.  After a bit of experimentation, the group then found conditions to close the C-ring and form the required imine.

Another alkylation appended a greasy chain for creation of the D-ring – no prizes for guessing that this will be a bit of RCM to complete that eight-member ring.  However, the A ring is still incomplete, so it’s interesting to see how Fukuyama went about it.  Firstly, a bit of oxidation takes the ethanol group up to the aldehyde.  Then, in a protocol that must smell worse than the salad-drawer of my fridge, a little thiophenol and caesium carbonate were used to remove the nosyl protection group, forming the imine concomitantly, which was reduced with a bit of hydride.  And in a very nice yield!

The RCM did the business, and the remaining silyl group was removed the alcohol oxidised to the aldehyde.  This allowed for coupling of the tryptamine group using a modified Pictet-Spengler reaction, and completion of the target in only a few more steps.

It’s hardly a short synthesis, but the target is a phenomenal challange, so hats off to the intrepid trio who managed this.

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17 Comments

  • Mr. Nobody says:

    Corrections. The carbonate discussed is actually a carbamate. The structure of the carbamate as drawn has an additional carbon just relaxin.

    • unimpressed with the blogosphere says:

      Why are the comments always so lame these days – it’s either some loser pointing out a simple chemical typo or a jacka$$ ranting about the fact that the paper doesn’t belong in JACS. (Or, like the comments on the last post, a bunch of totally random comments/questions by knuckleheads who don’t know how to use the ACS conference calendar website…) Where have all the insightful comments gone?

      Maybe the field really is dying. Sigh.

      • acac says:

        …Or malcontents b**ching about the lack of insightful comments.

        Srsly, ‘Unimpressed’, your own comment is hardly contributing to any meaningful discussion. Seems to me that TotSyn [hearts and flowers; TotSyn for President] intends the blog for people of varying levels of interest and proficiency in org syn, and the comments just reflect that variety. Big deal.

  • antiaromatic says:

    unfortunately, I think they’ve all gotten tired of the exact comments that you mention and have decided either to read and not post or just not read all together. it becomes a real drain to see people who probably haven’t accomplished much in their careers belittling other people’s work.

  • gippgig says:

    Does anyone care whether the structures are correct?
    (If anyone does, the starting material for the deprotonation/alkylation already has the nosyl.)

    • Mr. Nobody says:

      Every scientist should be concerned with knowing the correct structure of the compounds they are using or reading about. Every aspect of chemistry stems from structure. I am sure that many people are directed to this site for another tool to keep them informed of interesting topics. It is difficult to access how many people reading this blog would be confused by a mistake.
      In my opinion if you don’t care enough to have the correct information in front of you, and always be questioning information verifying its validity, maybe science isn’t the field for you.

  • novachem says:

    unimpressed with the blogosphere, looks like you just added to all that ranting!

  • stewie griffin says:

    Anybody have comments on the choice of magnesium perchlorate? I can’t say I’ve ever come across a need to use that reagent. What exactly is it doing, and why not chose a different cation?

  • HPCC says:

    Perchlorate anion has a reputation for being absolutely inert, non-nucleophilic. And also quite ‘charge-separated’ from the Lewis acidic counterpart (Mg2+ here, often Li+).

    Personally I read the paper and was really impressed by that body of work. I was given a lecture within a Natural Products Synthesis grad course by a prof who had post-docced with Overman and worked on that b!tch of a molecule, and hence, appreciate even more those Japanese people’s achievement.

    Mr. Nobody’s comment about the extra chillin’ carbon was not totally out of place, in that I spent 5 minutes just figuring out what that never-seen-before functional group could be, and how they extruded the amide out of it. :-)

  • [...] San Francisco, Paul Docherty of Totally Synthetic was kind enough to promote my tweets from this session. Time, unfortunately, got away from me this [...]

  • rhino says:

    thanks HPCC! i suddenly remembered that important (and often forgotten) bit of information :).

  • baran_ baldspot says:

    I like Movassagi new synthesis. He is doin well…not good as Baran. young academics have best synthesis. Surpong complanadin was memorable too. Top three are those academics. I can’t wait for new Baran synthesis

  • HK says:

    Their SI doesn’t mention any special precautions (or reasons) for the use of perchlorate, but I’ve been told metal perchlorates can be pretty dangerous. I sent a message out in our department asking if anyone had zinc perchlorate, and I got a private message from our chair (really cool guy) who offered me alternatives to use so that I wouldn’t have to use something he considered needlessly dangerous.

  • ZG says:

    As already stated the perchlorate dissociates well and will therefore enhance the Lewis acidity of magnesium. This acidity is necessary in order to facilite what is arguably a [2+2] between the isocyanate and the ketone, followed by a retro [2+2] to give the imine and extrude CO2. This reaction is know to be facile in the presence of Lewis acid. Mg may be preferable since it is divalent and can help to prearrange the reactive moietys prior to the first [2+2].

  • frenchy says:

    Hi people,

    To contribute to the perchlorate discussion, I would say that I would rather use Mg(NTf2)2 – the triflimidate anion being non nucleophilic as well and the salt avoiding the risk of explosion while being a strong Lewis acid. I guess some chemists stay stuck to perchlorate or tetrafluoroborate salts because they know they will do the job, they used it before, they have it on the shelf, or they dont give a damn about changing. However, I know a guy who had a labmate blowing is face up after shaking a perchlorate … Not good … If we can change a reagent for a safer one, we have to do it …

    To also contribute to the quality of the posts discussion, I must confess that I enjoy reading this blog (congrats Paul it’s really interesting what you do here, and how you tell stories), and I dont always feel the need for posting, and particularly that I dont care about typos, mispealing or extra carbon atoms …

    Like the Phil Baran afficionado, I am impressed by the chemistry of the guy, and I hope I will attend a conference where he will be giving a lecture soon …

    Sorry for the long post … by the way the structure of Manzamine A is correct, it’s just that the 8-membered ring is E and the macro is D

  • chiaki0423 says:

    Amazing