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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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August 8, 2007

Steve Ley, Azadirachtin, and Me (Very Much in That Order)

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Posted by Derek

The latest issue of Nature has an article (subscriber-only) on Steve Ley's long-anticipated total synthesis of azadirachtin, which can be read, again subscriber-only, here and here at Angewandte Chemie. (For a open-source look at the synthesis, try Totally Synthetic). I'm quoted in the piece expressing numerous doubts about the merits of total synthesis, most of which made it into print.

I also expressed quite a bit of admiration for Steve Ley's work, most of which didn't make it into the article, so I wanted to get that on record over here. The reason I can hold both those opinions is, of course, that Ley has done a lot more over the years than just make azadirachtin. As I told Nature, if he'd been running one of the make-it-or-die total synthesis factories, he'd have no doubt been finished well before now. But he's introduced reagents and experimented with many new ideas and techniques, and those have (in my view) a greater chance of having an impact on the world than natural product synthesis does.

A lot of what goes on in that field seems to me to have about as much relevence and utility as do chess problems. It's to Ley's credit that he's made a molecule of this complexity while avoiding the large pitfalls in that part of chemistry - some of which are marked with names like "If You're Not First, You're Nothing", "You Worry About the Reactions and I'll Worry About the Yields" and "If You Can't Get This Coupling To Go, I'll Find A Post-Doc Who Will".

Back when I was finishing up graduate school in 1988, I had to put together a research proposal. I chose, like a fool, the polycyclic core of azadirachtin, and I cranked out a paper synthesis plan for it. Would it have worked? Not a chance in hell. Looking back, I can see that I was already falling out of love with total synthesis even back then, and time has not healed the rift. Steve Ley never lost the faith, but (to his credit) he hasn't let it define him, either.

Comments (18) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. Anonymous on August 8, 2007 10:04 PM writes...

I saw the story at Nature. While they were mainly using your quotes for the anti-total synthesis side of the argument, it was also clear that you admired Ley's work. I'm no organic chemist, but I'm intrigued enough now that I'll have to have take look at the structure.

Nit: you wrote "that Ley has does a lot more" rather than "does" or "has done."

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2. Derek Lowe on August 9, 2007 5:51 AM writes...

Fixed, thanks!

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3. anon on August 9, 2007 9:02 AM writes...

Guess there is now no such thing as 'Steve Ley's azadirachtin' - a failure to succeed by a big name chemist that all lesser chemists can take comfort from in the long lonely evenings in the lab. We will have to find another failed project to take comfort from...

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4. SynChem on August 9, 2007 9:37 AM writes...

My background is in classical total synthesis, and I totally admire Ley for his brilliant self-inventing transformation from just a synthetic chemist to a true innovator. I bet Derek had his "flow chemistry" in mind when he made the comments. That stuff with more development could revolutionize how we industry people or academics do chemistry! I'm sure some of the classical synthesis big names sneer at Ley's contraption, 'cause I think I know their way of thinkging pretty well.

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5. Kay on August 9, 2007 1:51 PM writes...

How about some thoughts on the WuXi IPO? I only hear good things about them (although they tend to be a bit on the expensive side).

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6. Matt on August 9, 2007 3:13 PM writes...

It strikes me as odd that work carried out in an academic setting is never thought to be an educational tool. Is it possible that total synthesis of complex targets might serve to teach students how to think about and execute synthetic transformations? No, this is ridiculous…it’s merely “a trophy grabbing exercise” designed to promote the image of the professor at large since this will never be forgotten.

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7. Stephen on August 9, 2007 5:07 PM writes...

>No, this is ridiculous…it’s merely “a trophy grabbing exercise” designed to promote the image of the professor at large since this will never be forgotten.

Then you've never heard Steve Ley speak publicly nor privately. Granted, there are some who have the "If You're Not First, You're Nothing" mentality, but he isn't one of them. You'll have never laughed harder then when he describes his synthesis of Plicamine using solid phase reagents; even going so far as to coin the 'British way' of doing synthesis by using solid phase reagents in tea bags and dipping them in the rxn mixture....

For him, its not about getting there first, but about what technology you develop along the way that makes a difference.

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8. Bioorganic Chemist on August 9, 2007 5:25 PM writes...

I'm certainly not a total synthesis jock, but I find total synthesis really valuable in defining the limits and capabilities of known reactions. It's pretty easy to make a reaction look general in a methodology paper, it's a wholly different thing for a reaction to work in the synthesis of complex molecules. Total synthesis does a really good job of validating methodology and demonstrating where our limits are as organic chemists (and justifies more reaction/protecting group methodology development despite the apparently unlimited number of reactions (e.g. LaRock)). That validation in complex targets makes those of us who do med-chemmy things much more efficient as chemists. "Oh, I'll use this combination of protecting groups and this reaction on my complex molecule because it worked in the synthesis of x." (Note also that total synthesis types typically do a better job of describing failures/alternative approaches than in med-chem/bioorganic projects. Our failures in synthesis usually don't even make it into theses, much less into papers.)

I would also argue against Wender's point: the challenge in total synthesis is making an externally defined target; choosing a simpler related target is not just easier because it's simpler, but it's easier because you can redefine the problem if an approach to one target doesn't work; just go after a related target! (Again, something that med-chem/bioorganic types do all the time.)

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9. provocateur on August 9, 2007 6:20 PM writes...

As long as NASA gets public money to get to Mars and beyond or sum lab gets public funding to tell me tht fat ppl around me make me fat , I will hv no problems in partaking and enjoying the elegance of a total synthesis done well.

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10. MTK on August 9, 2007 6:56 PM writes...

I agree with Matt. Total synthesis is a great training ground for chemists, provided you get the freedom you need from your advisor.

One other thing, I hate reading the majority of total synthesis papers, but I love hearing the majority of total synthesis talks, if that makes sense. In a paper it seems that you see a bunch of reactions and your eyes begin to glaze over. In a good talk one gets a great sense of the challenges, the thought process, and the creativity often exhibited in total synthesis.

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11. freed-all-baths on August 10, 2007 5:19 PM writes...

MTK - I agree with you wholehartedly. I guess most publs. don't offer enough space to discuss the synthesis of the seriously huge molecules the top guys go for. However, one of the best total synthesis papers you could read is an unfinished one! - Ian Fleming's studies towards ebelactone-a using only organosilicon methods to control everything in the molecule (Org. Biomol. Chem., 2004, 2, 1051-1064) is a wonderfully told story and produced more original chemistry than you could imagine!

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12. educateyourself on August 12, 2007 12:24 PM writes...

nice work on the nature commentary. i'm sure this will initiate a stream of hype-driven, baseless commentary on the lack of utility of multistep synthesis. the truth is, people have been attacking this field since the "glory days" of woodward, yet it still persists, and continues to attract the brightest, hardest-working organic chemists. so rather than looking at what you (perceive) to be wrong with this field, perhaps try to appreciate why it just won't go away!

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13. CET on August 12, 2007 3:40 PM writes...

Re: #12

yet it still persists, and continues to attract the brightest, hardest-working organic chemists

At the risk of trolling, I will point out that to the extent this is true, it may be a largely self-perpetuating phemenon.

If grad students believe that the job market requires them to spend five years making something just to show that they can, the brightest and most ambitious will often be willing to make that sacrifice.

But I might just be projecting.

Also, 'multistep synthesis' and 'natural product synthesis' are two different things.

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14. educateyourself on August 12, 2007 7:10 PM writes...

five years to "show they can"? but azadirachtin took more than twenty, and synthetic projects that span >1 Ph.D. (in series) are more the norm than the exception. so maybe it just isn't as simple as that (?)

here's a projection for you: in 50 years you'll still have the best and brightest doing synthesis, you'll still get your best academic and industrial scientists from synthetic laboratories, and you'll still have second-rate scientists with diarrhea of the mouth sitting around on these blogs trying to start a debate over the differences between 'multistep' and 'natural products synthesis' while missing the big picture entirely.

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15. Hap on August 13, 2007 12:45 PM writes...

Total synthesis seems to be a useful way to learn how to do and understand lots of reactions, and to plan syntheses. There might be better (shorter time, costing less, more effective) ways to do this, but they don't appear to have been developed or to have enough practitioners to be useful. While some of the knowledge is illusory (arrow-pushing is compact but the knowledge doesn't always work at deeper levels), the practitioners learn and understand a lot of chemistry. If pharma could develop this sort of knowledge more cheaply and effectively, I would think that they wouldn't spend the time and money courting total synthesis groups and their advisors. In addition, lots of chemistry probably wouldn't have been developed if performed only towards simple targets, while lots of chemistry that works on simple targets doesn't work with functionalized of complicated pieces - working on simple, human-imagined targets that can be changed if they can't be easily made is unlikely to illuminate such chemistry.

Finally, a recent Whitesides paper in JACS was clear that despite working with a well-characterized enzyme (structurally and kinetically)(carbonic anhydrase) with a fixed pharmacophore, the binding of ligands to the enzyme is ill-understood. If people can't understand the binding of ligands to enzyme (let alone actual drugs), how are they going to design enzyme ligands de novo? Organisms have been doing this for awhile, providing at least lead compounds, and while lots of the leads can be cultured, some cannot, and so total synthesis is the only way to get them. (Many syntheses fail in this regard, however.)

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16. CET on August 13, 2007 3:52 PM writes...


A complex target is valuable for validating a new method - but this is not an argument for natural products per se, merely for relatively complex ones.

Similarly, working through the synthesis of a complex molecule (an admittedly vague definition) is certainly essential training for a synthetic chemist. See the above point.

Wender's research strikes me as a much more useful way to explore the biological potential of natural products than having graduate students spend five (or 20) years making the whole thing.

Just to needle number 14, I'm going to propose that the dominance of (insert your preferred name for the synthesis of molcules whose size makes them industrially impractical and whose biological activity is uninspiring) has more to do with its effectiveness as a hazing process than with its utility.

I'm not sure I really believe that, but you sound like you're spoiling for an argument.

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17. Hap on August 13, 2007 4:41 PM writes...

Boger's recent work is a decent argument for the confluence of total synthesis - using it to do SAR on natural products with little or no availability otherwise. With most syntheses, there isn't enough left to do anything with it when you're finished other than an NMR, MS, etc., and even thirty years ago Boekheide was complaining about this (in his article about the synthesis of superphanes). That, the fraternity-like atmosphere of some synthetic groups, and the first-at-all-costs attitude of a lot of syntheses diminish the value of total synthesis, but it still achieves things difficult to do other ways.

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18. Halima Warsi on June 1, 2008 11:04 PM writes...

Sir,

As many Poeple knows that azadirachtin is a active constituent of Neem seed but nimbidin have good medicinal uses in case of Diabetes,antitumer etc

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