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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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« That Schering-Plough Lawsuit Isn't Going Away | Main | The Ideal Synthesis »

June 28, 2010

Maitotoxin: It's On, All Right

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Posted by Derek

Earlier this year we had a paper from the Nicolaou lab on the synthesis of the ABCDEFG ring system of maitotoxin. Now I see that a synthesis of the QRSTU domain has arrived. That's what, twelve rings down? Only twenty more to go, guys. This piece is ". . . appropriately functionalized . . . for further elaboration and coupling with suitably activated neighboring ring systems of maitotoxin for the purposes of constructing larger domains of the natural product." My deepest sympathies to all concerned.

Comments (28) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. anonymus on June 28, 2010 10:24 AM writes...

Probably another pointless synthesis.

It is of high probability that the Maitotoxin synthesis will bring absolutely nothing to the declining field of total synthesis.

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2. Student on June 28, 2010 10:43 AM writes...

Well, they got 3 mg of product so whoever is in charge of coupling the fragments better have a sure and steady hand!

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3. LNT on June 28, 2010 11:22 AM writes...

What a waste of research dollars... You'd be better off just flushing that cash down the toilet. At least then you wouldn't have 4 or 5 additional jobless synthetic chemists on the market at the end of the process.

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4. Evorich on June 28, 2010 11:28 AM writes...

Why are they doing this again??

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5. MLBpitcher_and_MedicinalChemist on June 28, 2010 11:49 AM writes...

@LNT

But they are from KCN's lab? Are you sure those synthetic chemists will be jobless since they are deemed to be the best and are from Scripps?

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6. Arjun on June 28, 2010 11:50 AM writes...

Total Synthesis: Doing slowly and at great cost what nature does quickly and cheaply.

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7. Hap on June 28, 2010 12:05 PM writes...

I don't think nature makes these things either cheaply, quickly, or in great supply. It can't make analogs, either, which is where synthesis comes in - of course, since there won't probably be any analoging from this (unless someone gets lucky and one of the fragments has substantial activity), and not enough product to do anything with, then this synthesis doesn't have that point, either.

You can make almost any target in a worthwhile manner if you can make it rapidly or in away that no one could do before, or give access to things you couldn't have gotten otherwise. This synthesis, however, doesn't seem likely to do that - making a very large target in a way that's been explored before doesn't really seem to have much point. Considering my poor experiences trying to work with reactions on small scale (and failing miserably), I can have only sympathy for someone working lots of steps with small amounts of invaluable intermediates, but torturing graduate students and postdocs doesn't seem like appropriate training for their futures (I hope) and doesn't seem to be worth the money and effort.

The synthesis of gargantuan targets and the synthesis of smaller targets seem to have the same relation to one another as do manned and unmanned space travel, except manned space travel has a point (utility to humanity other than being cool).

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8. Anonymous on June 28, 2010 12:47 PM writes...

What strikes me is that there is no mention of the number of steps required to complete this target anywhere in the paper.

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9. anchor on June 28, 2010 12:55 PM writes...

#8 (anon) - It is not the steps, but end justifies the means! At his rate I wonder as to when we will have enough target molecule so that they can start to derivatize in order to complete SAR.

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10. anonymus on June 28, 2010 1:42 PM writes...

@ MLBpitcher_and_MedicinalChemist

Many postdocs (including some from KCN) could not find a job in recent years.

You do not impress too much people anymore by showing that you have been part of a team of 15 chemists achieving the total synthesis of 0.5 mg of a useless natural product, especially when you're using other groups methodologies.

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11. processchemist on June 28, 2010 1:50 PM writes...

I worked on the scale up of some total sytheses and semisynthetic coumpouns, and it's a tough and fascinating chemistry but the meaning of this project is totally beyond my understanding.
Some SAR on the fragments would be more interesting. I still think that the screening and the medicinal chemistry of natural compounds should be a resource of this industry, because if you start "omics" or with cutting edge proprietary platforms and end with a natural compound undergoing clinical trials (Merck/Ariad with ridaforolimus, Sirtris/GSK with resveratrol, NeurogesX with capsaicin) maybe you're out of tune (or focus or whatever).

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12. Anonymous on June 28, 2010 3:02 PM writes...

I won't necessarily apply this comment on this particular target or the lab performing the work however I may be out of tune as still think there is a place in the world of science for such complex natural product synthesis ventures. Total synthesis as a demonstration of new or obscure reactions can be of value to spreading procedures, and likewise in training of people to work on such challenges (although agree prospects for job are not generally as enhanced as once were for doing projects of this type), particularly is part of a true team effort. Sure it would be nice if applicability was always considered and the potential for some SAR or getting to useful fragments are bonuses but much could be lost if academic labs are not encouraged to take on such beast. Obviously the literature would be even duller.

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13. BZ on June 28, 2010 3:56 PM writes...

Why not do something more practical?

Maybe because Intent and Outcome are almost never the same.

I would be disappointed if KC changed his modus operandi based on a popular opinion. Then again, in a perfect world, we would have experts to tell us how to conform and what we all should be doing. Viva La Difference!

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14. Hap on June 28, 2010 5:21 PM writes...

Unfortunately, being different doesn't make you right - sometimes you're right, and sometimes you're just wrong in a different way. Being stubborn and wrong is not brave, just stupid.

MTX's synthesis is likely to be expensive and mind-numbing (if it were different, that would be something). If it were a movie, it probably will be Waterworld, though the Final Fantasy movie is also a possibility.

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15. HK on June 28, 2010 6:16 PM writes...

KCN strikes me as the kind of guy who would do this strictly for the purpose of showing that humanity can do what Nature does. Maybe not as well, but with current technology, this is what we can manage... not that I'm supporting this notion (or arguing against it - I like the idea of it) but if that's his philosophy, then so be it. He has trained some great chemists, so he must be doing something right. That's worth the research dollars right there, eh?

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16. Jose on June 28, 2010 7:24 PM writes...

"I'm just as good as Papa Kishi! I'm just as smart as Papa Kishi! And dammit, people *like* me!"

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17. McChemist on June 28, 2010 7:51 PM writes...

Okay, since everyone is whining about how this is a useless project: What exactly should academic synthesis groups be working on, then? Yeah, a total synthesis of maitotoxin has a 99.9% chance of being totally useless, but you could say that about most any academic project. Maybe you could work on methodology, but most methodology projects end up just as useless, too (here's a catalyst that takes 9 steps to make and does this boring transformation in 85% ee! Yay!) Everyone here makes fun of academic med. chem. projects, as well, so what should these grad students be doing?

There's no way in hell I'd ever want to work on this kind of synthetic slog, but the students who do will have been exposed to a variety of synthetic methods, and they'll gain some valuable experience in structure elucidation and such. You'll end up with some reasonably well trained chemists, and 0.1 mg of a natural product in a freezer somewhere. But isn't this really a best-case scenario for most academic projects?

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18. weirdo on June 28, 2010 8:14 PM writes...

#18
"so what should these grad students be doing?"

Maybe they shouldn't be working on anything. What is the point of wasting the best years of these bright students lives to train for a job that doesn't really exist, atleast not in this country anymore. Do we really need this oversupply of talent?

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19. Kugelrohr on June 28, 2010 9:19 PM writes...

MTX might be a strange choice for a total synthesis project- but overall total synthesis is a venerable discipline. First and foremost it is a very effective way to train young chemist and expose them a broad repertoire of reactions. It’s a great opportunity to learn the concept of retrosynthetic analysis and leaves room for creativity since there are many ways to reach the target. The best synthetic chemists come out of natural product total synthesis… and in fact they are often disappointed when they end up in Pharma and have to do simple & trivial MedChem. How can you even compare synthesizing a complex chiral alkaloid with making another round of Me, Et, Pr analogs?

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20. Rich Rostrom on June 28, 2010 9:55 PM writes...

Not to be a complete noodge -

but in the posting title, maitotoxin is misspelled "maitoxin".

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21. startup on June 28, 2010 10:55 PM writes...

I don't know, I think we should be grateful to KCN group. Total synthesis is a dirty job, but it's there and someone has to do it. So better them than me.

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22. Anonymous on June 28, 2010 11:10 PM writes...

Why are people always so negative abut KCN. He is a very bright and talented guy who takes on big challenges and drives his people hard to accomplish them.

There are lots of other synthetic chemists who make compounds for the sake of making them. You can spin and say that we are developing methodology or whatever else, but the objective is still the same.

Regarding the point of utility, it is well established that natural product chemistry has been largely reduced to an exercise for training students. It is a dying field and career prospects are going to slowly diminish, at least in the US. So whether you make a natural product with 5 rings or 40, the point is still the same.

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23. A stickler on June 29, 2010 12:03 AM writes...

#17

(sorry for the cross-post from Tot. Syn., but its relevant)

There are a multitude of justifiable reasons to pursue a total synthesis. Here are the main ones:

1) Interesting bioactivity (you need to make >5 mg. of product to justify any rudimentry biological studies, however)
2) Highlight a new methodology by its application to kung fu a complex molecule in half.
3) Highlight a strategy that enables access to an *entire class* of natural products, and not a shoehorned approach.
4) Confirmation of structural analysis.

The only other reason I can think of climbing such mountains (pardon the analogy) is the challenge to innovation. Sometimes you hit a brick wall, and need to come up with a completely new and useful solution to circumvent it. Other times, entirely unexpected results can present unique opportunities for new methods, disconnections, etc. Academia is engaged in basic science. They're tasked with charting undiscovered country, boldly going where no one has gone before (pardon the Star Trek analogy). Unless KCN can contribute something useful, this will merely end up being another trophy to his ego.

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24. Rock on June 29, 2010 12:40 AM writes...

#22
As someone who had interviewed dozens of KCN students, working on these massive projects do not train them well (or at least, they do not interview well). All too often you get someone from a very large team working on the same natural product. They typically make a 20-30 step fragment of the molecule, along with five others which makes it difficult to pull apart their individual contribution. They then spend the remaining year or two of their time bringing up more of the fragment to feed later stages of the total synthesis. Over the years, we never hired a single KCN chemist.

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25. Jose on June 29, 2010 2:09 AM writes...

"Why are people always so negative abut KCN. He is a very bright and talented guy who takes on big challenges and drives his people hard to accomplish them."

The very fact that he is directing his massive resources (cough cough) towards MTX refutes everything about this statement. If he was truly bright, creative and inventive, he'd be doing projects like Baran's that leave you gasping for air at their audacity.

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26. Anonymous on June 29, 2010 9:23 AM writes...

#25 - Baran got his Ph.D with KCN. Look at his before and after steroid pictures

#24 - Most of KCN's co-authors are asian. Many foreign scientist tend to be somewhat one-dimensional. They work harder but are not great communicators. In any case, you do not want all rock stars on your team.

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27. Aspirin on June 30, 2010 1:55 PM writes...

-You do not impress too much people anymore by showing that you have been part of a team of 15 chemists achieving the total synthesis of 0.5 mg of a useless natural product, especially when you're using other groups methodologies.

Spot on. If I were a recruiter, I would be far more impressed with someone who has a three-man paper in JACS where he applied a novel methodology to the synthesis of a modestly complex alkaloid than with someone who is part of a 20-member team who is cracking MTX with hammer-and-tong chemistry just to prove that it can be done. In the first case the individual's contribution clearly stands out while in the second one it's hard to distinguish his work from that of the 20th person on the team (unless he is first author)

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28. jekbradbury on July 1, 2010 2:38 PM writes...

In 2008, the same group synthesized GHIJKLMNO: http://pubs.acs.org/doi/abs/10.1021/ja801139f
for a total of 20 rings synthesized out of 32 total...

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