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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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November 23, 2009

K. C. Nicolaou, Call Your Office

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Posted by Derek

While I'm putting up odd chemical structures today, I thought I'd add this one, Alasmontamine A, from the latest Organic Letters preprint stream. Natural products scare me:
Anyone who wants to take a crack at this one synthetically, you just go right ahead without me. It is pretty much a dimer, though, so it's only about half as awful as it looks. Which is still enough. It doesn't seem to have much biological activity, but if you can sell it as something to do with green chemistry, nanotech, or alternative energy, you should be able to round up some money, right?

Comments (39) + TrackBacks (0) | Category: Chemical News


1. David P on November 23, 2009 12:57 PM writes...

I think I'll pass on this one too.

Sure it is almost a dimer, but a horrendous place to link together, into an iminium?!

You could spend many years on this only to find out that they got that initial assignment wrong.

But you would probably find some pretty interesting chemistry along the way...

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2. startup on November 23, 2009 1:04 PM writes...

You had me at "crack".

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3. Hap on November 23, 2009 1:06 PM writes...

I'm thinking Overman might be interested, or maybe Smith, if they're still working.

By the standard theory, this is at least eleven years of thesis work (three years + one per nitrogen). Better get cracking.

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4. Maks on November 23, 2009 1:31 PM writes...

Anyone looked at the article in Org Lett?
As one of my professors once said "so many people, so few results". Isolation, structure determination and one half-hearted cytotoxicity assay. Sure, it was work to elucidate the structure but still....

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5. RB Woodweird on November 23, 2009 1:44 PM writes...

I have elucidated a truly marvelous synthesis of this, which this blog is too silly to contain.

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6. BACE on November 23, 2009 1:49 PM writes...

K. C. Nicolaou, Call Your Office Sweatshop.

There, fixed it for you. You're welcome.

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7. BACE on November 23, 2009 1:52 PM writes...

Damn...the tag does not seem to work here. It should have been "K C Nicolaou, Call Your Sweatshop". Anyway, you get the idea.

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8. MTK on November 23, 2009 1:54 PM writes...

It's actually a near-tetramer isn't it, which the authors recognized by the numbering of the carbons.

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9. Chemjobber on November 23, 2009 2:02 PM writes...

Baran will have it figured out by Monday; Thursday if there wasn't a half-holiday.

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10. Common on November 23, 2009 2:06 PM writes...

What's the counteranion of this iminium cation? Am I missing something here?

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11. Acac on November 23, 2009 2:08 PM writes...

Yeah, Derek. Go ahead and make fun of academic projects once again. Your bias is slowly starting to seep through the cracks. You keep on pointing out the flaws of academic projects and leaving out the atrocities that BigPharma and other large companies (P&G, Dow, Dupont come to mind) commit. The only difference is that in academia, your results are part of the public domain. In industry, they will never see the light of the day and be scrutinized by others. I have heard of so many stories from friends that work in companies where a ton of money is wasted for no particular reason. These projects are just as bad as projects related to "green chemistry, nanotech, or alternative energy".

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12. Sili on November 23, 2009 2:22 PM writes...

Once upon a time, I'd have taken a crack at naming the thing (the only job I was ever really good at), but these days I can't even remember the elements.

I'd have loved to fiddle with the crystal structure, though.

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13. MolecModeler on November 23, 2009 2:40 PM writes...

Pretty boring molecule if you ask me. I wish academics did not use biological activity as an excuse for making things. Just say it's interesting and we want to make it; that's the truth.

As MTK said, this looks like a tetramer, and presumably you'd want a highly convergent route that mimics the biosynthetic pathway that led to this beast. Looks like it's derived from tryptophan.

I'm sure Baran could do it.

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14. Doubja on November 23, 2009 2:46 PM writes...

Typo in the headline...

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15. RB Woodweird on November 23, 2009 2:50 PM writes...

This thread has become so pointless that I am going to reinvigorate it with a special announcement:

A Novel and Efficient Synthesis of Cadaverine, S. A. Scoggin's new novel about chemistry, graduate school, ghosts, revenge, particle physics, politics, natural product synthesis, and high explosives, is now available from Amazon:

The perfect holiday gift for that chemist in your life!

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16. Hap on November 23, 2009 2:55 PM writes...

Um, sure, because forty-step total syntheses are likely to be scrupulously verified, right? You know, like hexacyclinol was, or any of the taxol total syntheses, or palytoxin? (Particularly hexacyclinol, since the original "synthesis" had very little SI and no data on nearly all of the intermediates.) Even if the authors actually provide full data (which I wouldn't bet the house on, or even much of the furniture), the likelihood of the synthesis actually being validated by repetition is zero, and the likelihood of the synthesis being validated by a formal synthesis is close to zero (it does occasionally happen).

Heck, most methodology papers are unlikely to be either substantially validated by others or be substantially explored and delimited by...anyone. Only in the rare cases of easy-to-perform reactions with readily available substrates and an author who doesn't threaten to sue or a reaction that becomes very popular and useful are the reactions likely to be checked by others (such as the NaH-mediated oxidation of benzylic alcohols).

That also assumes that there's some sort of point in the total synthesis of heinously complex and mostly useless natural products - total synthesis may or may not be the most effective way to train future synthetic chemists, though it has worked in the past, but it is pretty expensive. Even if your ugly NP has bioactivity, almost no total synthesis produces enough material to prepare analogs (and is hence rarely validated for that reason as well).

So, most of the syntheses of molecules such as the above can't be verified (and in some cases can't even be reasonably questioned), can't achieve their stated purposes, and require lots of money to even try. I like reading TS papers (though the idea of going back to lab to make alkaloids makes me shiver), but to call them shining examples of independently validated and open research (in contrast to drug research) seems to be a FAIL in at least three dimensions, and maybe more.

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17. CRH on November 23, 2009 3:04 PM writes...

#10 - Chemjobber

Baran takes holidays?!?

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18. gyges on November 23, 2009 4:14 PM writes...

17 @Hap

Some very good points made by Hap. Added to which, yields in syntheses are never validated and blind alleys are rarely reported.

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19. HOMO-LUMO on November 23, 2009 5:57 PM writes...

Indeed not a tetramer but two dimers-fused by a spyrocyclic joint.

The tougher task is to construct the two units setting the right stereochemistry relationships, which is extremely interesting on its own right. Afterwards, to come across with a synthetic strategy to link the units.

Not as uninteresting as it looks. Terrific from a atom-economy point of view..Looks like Baran´s bussiness, who definetely would make it if he wishes.

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20. Mooner on November 23, 2009 6:05 PM writes...

#16 - Hap:

Has anyone actually reproduced that JACS NaH oxidation paper yet? I was going through the ASAP's yesterday and saw that it was still kicking around in there, despite being accepted back in July or something. Was there sufficient concern from the community that they're holding off on actually giving it an issue / page number? If it hadn't been for the majority of the heterocycles needed to try it I would have tossed together a test rxn in my hood yesterday.

Incidentally, I pointed this Org Lett paper out to my bench-mates when it hit the ASAP's and said the same thing Derek did. I've got friends just back from A*star, probably rejoicing they didn't get stuck with this.

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21. Chemjobber on November 23, 2009 6:29 PM writes...

#17: Note I said half-holiday. Enough time for turkey and then back to the hoods!

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22. Steve on November 23, 2009 6:56 PM writes...

This does look like a tetramer, if you don't think of a tetramer as four exact pieces. Nature, quite fond of symmetry, would probably synthesize four rather small similar pieces and find a way to join them together. Other than the spiro-fused six-membered rings in the center of both "halves" of the molecule, each half contains a five-ring array that looks rather similar. The connectivity of the two halves of the molecule is reminiscent of the union between two molecules of avainvillamide to make the stephacidin B architecture. Baran has prepared the latter two molecules, but so have Williams and Myers.

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23. Hap on November 23, 2009 7:12 PM writes...

Totally Synthetic had reported that he had performed under anaerobic conditions and gotten roughly 15% yield, and other people blogging reported that they had run the reactions under o2 and gotten good yields. I don't think anything has been published by anyone, though, so it depends how much you trust the people who have reported on it whether you can consider it (partially) validated or not. I mostly do, so I think of it as at least partially validated, though not as the original authors propose (with NaH as catalyst). (The oxidation would also consistent with references brought up when the paper first came out, in which people have seen similar things.)

I believe it was actually pulled from the JACS website and only recently put back.

Part of it looks like the core of strychnine, minus the strained bottom rings and plus the spiro segment (and dimerized). A biomimetic synthesis would be neat, but I don't know where to start (I can't even see the functionality needed to form the product from two equivalent pieces - an enamine looks insufficient without oxidation). This could be a lot of work for somebody.

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24. chiraljones on November 23, 2009 7:17 PM writes...

Considering the otherwise demanding chirality of the molecule, this is just picking nits, but I'm less than sold by their assignment of the axial chirality around the C5-C6'' bond...

A proper crystal structure would be the bees knees.

With regards to synthesis: It looks beefy, but not impossible.

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25. The Dimer Dimeriser on November 23, 2009 7:37 PM writes...

It's a dimer of vobtusine - follow references 6 and 7 in the paper and you'll see that this is in turn a dimer of something called vandrikine. Google says there are no reported syntheses of either of these - a gap in the market for some enterprising academic.

I suspect the dimerisation-dimerisation route from vandrikine is feasible, though the first "dimerisation" would really have to be a rather mad spiro-hetero-diels alder of two differently functionalised components.

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26. synbio on November 23, 2009 7:48 PM writes...

Am I alone in suspecting that synthetic biology will kill the field of natural product synthesis within ten years or so?

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27. milkshake on November 23, 2009 7:58 PM writes...

no, the pharma downturn in US and the US (and Japan) government funding cuts will stifle it. As much as I like total synthesis, the field grew beyond what is sustainable and it will have to go on in the future in more modest scale.

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28. Jose on November 23, 2009 8:42 PM writes...

Re: cool but not bioactive, see Baran's chartellamide work.

And then just replace "Chuck" with "Phil" :

Chuck Norris doesn't read books. He stares them down until he gets the information he wants.

Chuck Norris can lead a horse to water AND make it drink.

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29. realmad on November 23, 2009 9:19 PM writes...

Forget chartelline or even vinigrol.

If the rumor is true and he finished palau'amine, then he is bruce lee + norris + UFC champ undisputed...

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30. donde on November 24, 2009 2:06 AM writes...

So why does that iminium not tautomerize to give the presumably more stable enamine? A quirk in the conformation? Or maybe decades of enamine chemistry is wrong? I'll need to see an xtal structure before I work on this bad boy....

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31. David Bradley on November 24, 2009 4:08 AM writes...

Stupendous structure! But, why does the name alasmontamine make me think of John Denver...sounds like a rocky lament of some kind...

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32. Tot. Syn. on November 24, 2009 4:13 AM writes...


If natural products scare you, sometimes Med-Chem targets are scarier:

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33. Little Miss Process on November 24, 2009 5:02 AM writes...

You know, I wonder... the point about pharma's structures being a bit... unvaried is floating around here quite a lot. And what I'm wondering is, has our time in the sweatshops of academia slaving over nightmarish NP syntheses given us a psychological aversion to them? So now "we're out in the big wide world of pharma, and we're just going to stick to the nice easy stuff that works, more or less"? Several people have mentioned how much they wouldn't like to work on that bad boy above.

So... if our training in academia is leaving us with this aversion - is it really a good training at all? How much use is our skill in making these things if we're just going to step away from the tricky stuff as soon as we get the chance? Maybe a more pastoral supervisory approach than I certainly experienced in academia would have helped....

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34. nemo on November 24, 2009 9:37 AM writes...

I'd go with Pat Harran on this one

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35. nemo on November 24, 2009 9:38 AM writes...

I'd go with Pat Harran on this one

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36. anon the II on November 24, 2009 9:51 AM writes...

To #32 Tot. Syn.

It looks ugly but I'll bet you could toss in a 1:1 mixture of Wortmannin and Rapamycin followed by a slow drip of bis acid chloride of that diacid and get a decent (>15%) yield of the product.

What's scarier is the career prospects of all the authors.

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37. WuXi Pharmatech on November 25, 2009 9:34 PM writes...

Pleases continue the bashing of the KCNs and Barans, and the trashing of natural product synthesis....We love them here in China, and we are taking your jobs too, and there is nothing you can do about it!

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38. InfMP on November 27, 2009 7:59 PM writes...

Not just taking our jobs, you are taking our original ideas, doing an extension and then scooping us.

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39. anchor on December 1, 2009 2:58 PM writes...

#1-linking to dimeric structure should not be a problem. Many of the the dimeric indole alkoloids have propensity to oxidatively dimerize, when you make the monomeric piece. KCN and Baran have already won the half-battle !

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