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Histrionicotoxin 285A… and some history…   

23 September 2008 12,024 views 65 Comments

Holmes, Macdonald,  Horsley,  Ryan and Saubern. Org Lett, 2008, ASAP. DOI: 10.1021/ol801604z. Article PDF Supporting Information Group Website

I’m thoroughly glad I took a little more time to dig through ASAPs I’d missed, as I’d somehow neglected this Org Lett published by Andy Holmes.  Y’see, some of the work towards the natural product was conducted in the lab I started my PhD in, back in 2004 in Cambridge.1 However, I’ll leave the reminicing for later in this post.

The target, histrionicotoxin 285A, was (like the rest of the family) isolated by blending poison-arrow frogs, and turns out to be a pretty potent inhibitor of the nicotinic acetylcholine receptor.  Although there’s been loads of work on HTX 283A (including a synthesis by the group back in 2004, and even further back in 1999…), this is the first synthesis of 285A, using a strategy familiar to the group.  This utilises a key nitrone dipolar cycloaddition:

The substrate took a fair-few steps to make (mostly through acetylide additions / reduction), but this is a pretty nice was to construct a ring and two stereocentrers.  However, after a deprotection of the masked aldehyde and Wittig olefination, they open the ring and destroy the recently installed stereocenters… only to reinstall them again, using a second nitrone dipolar cycloaddition.  This is because the reaction with styrene was only actually protecting the nitrone.  Under the microwave conditions, the cycloaddition reverses, and the free nitrone is revealed to react again.  This time, however, the reaction is intramolecular, building a more important carbocyclic ring found in the target.

Transformation of this intermediate into the natural product didn’t take too long; I’ve shown a partial retrosynthesis to illustrate it.  What I did like was the allene addition; simply take one primary iodide, displace with lithiated allene, and enjoy the 99% yield.  I dunno why I was so taken with this, but I’d never have though it would have been so high yielding!

Nice work, showing the most evolved example of the group’s method for making this family.

1.  Chemistry over; time for a bit of my life!  I started my PhD studies with Jon Burton back in 2004, working in lab 287 at Cambridge University.  This is where I met one Helen Horsely, one of the authors of this paper, as the Burton groups shared 287 with the Holmes group (Jon Phd’d and post-docd with Andy Holmes).  It was a cracking lab, but a little dated (circa. 1950 I think!); everything was made from teak.  However, at the end of my first year, Holmes moved to his current position in Australia, and the Burton group got it’s own (more modern) lab.  287 was emptied (by us students), and the lab transformed into some chemical-biology suite.  Emptying that old lab was an experience in itself; we found several flasks with the initials “IF” on the side – Ian Fleming!  We also found a half-case of champagne, a half-kilo of brucine and a bottle of hexamethylditin that was built into the framework of the teak benches… Nice!

However, of late I’ve felt a bit of nostalgia for the old-days, so here’s a couple of photos of the old lab.  Mmm, I can almost smell the silica in the air, and DCM on the varnish.  If you squint a bit, you can see the column I was running in the first photo, with the yellow netting on the outside.  I only had one accident during my PhD, and it was with that column; twisting the gas-quick-fit adaptor on the top resulted in a sliced thumb, and a few stitches.  I’ve got to thank Helen for her first-aid skills that day!

The fume-hood on the left in the second photo had a THF still in it; but it wasn’t over sodium.  No, sodium was for wimps – we ran ours over potassium.  Cards-on-the-table – I was terrified of that thing, and I was extremely glad it was decommissioned before it became my responsibility!  However, that THF was dry.

Working in a huge lab like that, with loads of students and post-docs was a fantastic experience; I learnt loads in that lab just by walking past other students working.  I don’t think that more modern labs (often smaller), with their individual bays, offer the same experience.  But the health & saftey does count for something…!

It’s a bit of shame that 287 isn’t a synthetic lab anymore, but times move on and I guess teak isn’t where it’s at anymore…

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  • treesap says:

    @ pdf : I assume you were at La Clair’s talk at the ACS meeting. 40 minutes of gibberish, but not on the subject of hexacyclinol. It’s a bit unseemly to ask questions following a lecture about a paper that’s completely unrelated to the work presented. The reason no-one asked a question about the presented work (I’m guessing) is that it was unintelligible. Even the session Chair sad: In the absence of questions I know I’m supposed to ask something but I’m at a loss to think of anything.

    BTW, you not actually defending La Clair are you? His hexacyclinol paper was pure fabrication and everyone knows it.

  • Tot. Syn. says:

    KCN: My Take.

    Personally, I’ve got a fair amount of respect for the man. Mostly because if it wasn’t KC doing these enormous syntheses, and ‘being first’, someone else would take that role. And he does it rather well. Taking the example of MTX, the challenge was set down when it was isolated – and there’s something about human nature that means we have to make these things. Can anyone really think of someone better suited to the task? Sure, better syntheses of beasts like Brevetoxin come along, but the fact that KC got one out-there alters the landscape, and shapes the syntheses that follow; others can learn from the (quite often) ‘brute-force’ approach.

    As for the books, yes, they lean a bit to his work. But they make for a fantastic resource, and I found them invaluable, especially at the beginning of my DPhil (remember I was working on prostaglandins…). And to be completely frank, this blog probably wouldn’t exist without the books.

    Lastly, we all hear about the conditions of working in the labs – totalitarian regimes, manacled to the fumehood. Not true, but it’s a competitive game, this being first. And every student in those labs knew what they were going in for. Does that stop the applications? Not a chance. In my final year at Cambridge, I knew five PhD students who were planning to work for him. That says a lot. And sure, a good chunk of those students will simply (!!!) get the work done, get their names on a couple of papers and reap the rewards of a career door-opener. And then there’s the guys that really go for it and make a career out of it. Makes a difference for these people…

    @treesap: The most amazing thing is the fact is that La Clair keeps getting funding and hasn’t been shamed out of a career! I think people keep giving him money just to see what the next car-crash might be…

  • thezorro says:

    Personally, I dont see the point on critising KCN on that way.

    Sometimes there is not much innovation on his work, sometimes there is, and a great deal of it. Plus the fact of the great credit that he/they deserve for making that monsters of molecules. Remember that molecules move, and often, chemistry on paper doesnt´t have to do much with chemistry on the flask/vial.

  • milkshake says:

    It has become fashionable to criticise KCN for doing things quick and dirty (especially within the other high-profile groups that ended up scooped by him). The other irritant is KCNs presentation style, (cheezy fonts and colors), and the overtly self-promotional style of some of it. I think this has been blown out of proportion and there has been useful methodology coming out of his grop (IBX oxidations etc) so I don’t see a good reason why people keep repeating the same stuff about him I have been hearing since 90s.

    I have a good friend who did postdoc in KCN group few years ago, finishing some godawful marine monstrosity, and he had pretty good things to say about the man. Not mentioning, this postdoc helped him to get a very good pharma medchem position afterwards.

  • pdf says:

    @ treesap. Of course La Clair is a pathological liar. It was just an example of bashing someone. La Clair is a disgrace and we all should be ashamed of “researchers” like him. And what the hell is Xenobe? For money laundering? He proved that all piece of crap is possible to publish, even in high impact journals. He needs psychiatrical attention urgently or worse. Can´t say here.

  • pdf says:

    Scroll down for more KCN bashing…

  • Hap says:

    I don’t know who’s more suited to doing maitotoxin than KCN – I just don’t see the point. There are skills hard to get otherwise about working on monsters like that at on the small scales required, but I don’t know that the skills are useful elsewhere, worth the money and time to attain them, or worth more than the skills generated with an equivalent amount of money on smaller targets (or doing something else).

  • treesap says:

    I’m not sure this is just KCN bashing so much as questioning the value of total synthesis by routine brute force, of which KCN has become somewhat of a poster boy (maybe unfairly). What’s the value of a many-step total synthesis by pedestrian retrosynthesis and well-known methodology? Not much… good hands-on training for some grad students, proof that it “can be done”, and maybe some spin-off benefits in analog synthesis along the way. In contrast, total synthesis that includes (requires!) the invention of new methodology, or introduces new techniques (e.g. first use of microwaves, flow microreactors, ultrasound etc.), or is just so elegant or beautiful in conception and execution that your shake your head in awe…. That’s what makes a great chemist for me.

  • PMB says:

    if you guys so curious about how KCN runs his groups, why not apply to him. If you are in, you will know the truth but not heard the news.

  • Dien Toast says:

    We need to distinguish a few things here; just because KCN can be a nice guy, just because lots of people still apply to him, just because people from his lab get good jobs, just because he has introduced some new methodology, just because he is the first to synthesize new molecules…just because all these things are true does NOT automatically mean he is in a Woodward/Corey/Brown class and worthy of a Nobel Prize. I think KCN without a doubt is an excellent and prolific organic chemist, but I also equally strongly think that his work does not deserve a Nobel Prize. He has not fundamentally changed the field like RBW or EJC did.

  • TWYI says:

    ..and that above is a great definition.

    The future of the field is not ploughing bodies onto molecules for the sake of making them first.

    At least try and do something worthwhile along the way. New methodology or (dis)proving possible biomimetic hypotheses.

    No more macrolides by aldol, wittig/HWE and RCM/Yamaguchi to snap it all up. Please :cry:

  • TTX says:

    You’re all stupid people . I personally admire Nicolaou because he is a great organic chemist. He has synthesised lot of molecules. DON’T uh forget, never ever about calicheamycin. I just can believe it. I think you’re jealous…yes…you certainly are. Of course he deserves the Nobel prize…Nobel prize is not enough to describe hid unique intelligence so…please !!!!

  • Tot. Syn. says:

    Hmm… I’ve seen that IP address somewhere else – yes, it’s that Romanian wanker again. Your Romanian-English dictionary might not be up to the task, so I’ll help you:


  • KCN says:

    Tot. Syn. I think you’re a wanker. What language is this? Who are you? What education you have? 2 years of elementary school? Spare me !!!!! Any comments? anestezin@yahoo.com

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