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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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July 20, 2009

Everything In Its Place

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Posted by Derek

Things are pretty quiet around the industry these days, so my blogging thoughts have been turning to Big General Problems. And here's one that I know that people are working on, but which I think we as chemists are going to have to understand much better: localization.

"Say what?" is the usual response to that, but hear me out. What I mean is the trick that living cells use for their feats of multistep synthesis. Enzymes aren't generally just floating around hoping to bump into things - well, some of them are, but a lot of them are tied to specific regions. They're either membrane-bound, or they're expressed in structures where they don't get a lot of chances to diffuse out into the mix. The interior of a cell, on the whole, is a pretty intensely structured place (as it would have to be).

And that allows specific reactions to take place away from other things that might interfere, which is something that we have a hard time doing in the lab. If you have a five-step synthesis, it's a pretty safe bet that you don't dump the reagents for all five steps into the pot at the same time and hope for the best. No, we generally have to fish out the product and take it on separately. It's often a real achievement (especially on larger scale) to be able to "telescope" two steps into one flask and skip any sort of product isolation between them. Doing it with more than one step is even more rare (and more useful when you can bring it off).

There's been a lot of work on one-pot cascade or domino reaction systems, and that's a step toward what we need. But most of these cases are reaction-driven: people find chemistries that can be run in this fashion, and then try to exploit them to make whatever can be made. Nothing wrong with that, but it would be nice to have product-driven approaches, where you'd look at a particular structure and figure out which multicomponent reaction scheme would work best for it. Generally speaking, we just don't have enough worked-out systems to be able to do that.

And that's where I think that some new technologies could help, specifically flow chemistry and/or microfluidics. Instead of figuring out reactions that can exist while all stirring around together in one pot, this approach takes it as a given that many transformations probably just can't be done that way. And if you can't have one big reactor with multiple things in it, then why not make multiple reactors, each with a different thing in it? Flow systems can, in theory, send compounds through a series of isolated reactions, moving the material physically through various zones and reagents. Not every reaction is perfect of course, but you can often use scavenger reagents along the way to strip out potential interfering impurities before the next step.

I like the idea, but there are a lot of things to be done to make it work. Probably the most advanced organic synthesis that's being done is this style is in Steve Ley's lab at Cambridge. I always enjoy reading their flow papers, which make clear that there's some significant optimization that needs to be done before you can throw the switch and stand back. Some other multistep flow work can be found here and here, and the same comment applies: there's a lot of preparation involved.

My hope is that these kinds of things will eventually move toward more of a plug-and-play system, where you put in the various cartridges and choose a protocol from the list of best-general-fits for your planned reactions. We're quite a ways from that, but I don't see why it wouldn't be possible.

Comments (21) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs


COMMENTS

1. gyges on July 20, 2009 9:55 AM writes...

"My hope is that these kinds of things will eventually move toward more of a plug-and-play system,"

This 'blackboxification' has been anticipated for a while now: whether or not we are on the cusp, or another false summit, I don't know.

Your post reminded me of something that Gabriel Tojo wrote on sci.chem, way-back-when.

Someone posted a general question about synthesis and he gave a description of two sorts of synthesis that goes on in labs. He pointed out the glamorous end - discovery of new reagents; new reactions etc which everyone wants to get into ... but (from memory) he also wrote about the development end of research (if you'll excuse the supposed contradiction). The stuff that no-one wants to do. Finding optimal conditions and discovering the limits of bog-standard reactions.

He likened (again from memory) the process of chem synthesis research to map making. Everyone has heard of the explorers discovering new continents etc and everyone wants to do that but nobody hears of the people who draw detailed maps of towns and cities which are vital for efficiently getting from A to B.

I think that this lack of mapping of the towns and cities, the detailed mapping of mundane chemical transformations, is holding back this area of work very much to our detriment.

Apologies in advance if I've misrepresented GT.

Permalink to Comment

2. gyges on July 20, 2009 10:00 AM writes...

"My hope is that these kinds of things will eventually move toward more of a plug-and-play system,"

This 'blackboxification' has been anticipated for a while now: whether or not we are on the cusp, or another false summit, I don't know.

Your post reminded me of something that Gabriel Tojo wrote on sci.chem, way-back-when.

Someone posted a general question about synthesis and he gave a description of two sorts of synthesis that goes on in labs. He pointed out the glamorous end - discovery of new reagents; new reactions etc which everyone wants to get into ... but (from memory) he also wrote about the development end of research (if you'll excuse the supposed contradiction). The stuff that no-one wants to do. Finding optimal conditions and discovering the limits of bog-standard reactions.

He likened (again from memory) the process of chem synthesis research to map making. Everyone has heard of the explorers discovering new continents etc and everyone wants to do that but nobody hears of the people who draw detailed maps of towns and cities which are vital for efficiently getting from A to B.

I think that this lack of mapping of the towns and cities, the detailed mapping of mundane chemical transformations, is holding back this area of work very much to our detriment.

Apologies in advance if I've misrepresented GT.

Permalink to Comment

3. gyges on July 20, 2009 10:01 AM writes...

"My hope is that these kinds of things will eventually move toward more of a plug-and-play system,"

This 'blackboxification' has been anticipated for a while now: whether or not we are on the cusp, or another false summit, I don't know.

Your post reminded me of something that Gabriel Tojo wrote on sci.chem, way-back-when.

Someone posted a general question about synthesis and he gave a description of two sorts of synthesis that goes on in labs. He pointed out the glamorous end - discovery of new reagents; new reactions etc which everyone wants to get into ... but (from memory) he also wrote about the development end of research (if you'll excuse the supposed contradiction). The stuff that no-one wants to do. Finding optimal conditions and discovering the limits of bog-standard reactions.

He likened (again from memory) the process of chem synthesis research to map making. Everyone has heard of the explorers discovering new continents etc and everyone wants to do that but nobody hears of the people who draw detailed maps of towns and cities which are vital for efficiently getting from A to B.

I think that this lack of mapping of the towns and cities, the detailed mapping of mundane chemical transformations, is holding back this area of work very much to our detriment.

Apologies in advance if I've misrepresented GT.

Permalink to Comment

4. gyges on July 20, 2009 10:02 AM writes...

"My hope is that these kinds of things will eventually move toward more of a plug-and-play system,"

This 'blackboxification' has been anticipated for a while now: whether or not we are on the cusp, or another false summit, I don't know.

Your post reminded me of something that Gabriel Tojo wrote on sci.chem, way-back-when.

Someone posted a general question about synthesis and he gave a description of two sorts of synthesis that goes on in labs. He pointed out the glamorous end - discovery of new reagents; new reactions etc which everyone wants to get into ... but (from memory) he also wrote about the development end of research (if you'll excuse the supposed contradiction). The stuff that no-one wants to do. Finding optimal conditions and discovering the limits of bog-standard reactions.

He likened (again from memory) the process of chem synthesis research to map making. Everyone has heard of the explorers discovering new continents etc and everyone wants to do that but nobody hears of the people who draw detailed maps of towns and cities which are vital for efficiently getting from A to B.

I think that this lack of mapping of the towns and cities, the detailed mapping of mundane chemical transformations, is holding back this area of work very much to our detriment.

Apologies in advance if I've misrepresented GT.

Permalink to Comment

5. El Selectride on July 20, 2009 10:11 AM writes...

The Lectka group at Johns Hopkins also did some target-oriented multi-step flow chemistry, with what they called a "synthesis machine."

http://www.jhu.edu/chem/lectka/Research%20Pages/synthesis%20machine.html

http://www.jhu.edu/chem/lectka/Pubs/Synthesis%20Machine.pdf

Permalink to Comment

6. Justmakethedamncompound on July 20, 2009 10:53 AM writes...

If half as much time was spent on actual synthetic chemistry as it was on things like combichem and whatever, we might have fuller pipelines. Oh, but that would require rolling up ones sleeves and doing some work....

Permalink to Comment

7. CMCguy on July 20, 2009 11:02 AM writes...

I have been involved in several attempts at "telescoping" reactions and the experience was mixed: as might be anticipated when it works out well one wonders why its not done more often, however when its fails can lead to god-awful mess. In cases its not so much about if can do the different reactions in sequence but without an effective purification in between the impurity profiles and yields can suffer to a point of lack of utility.

per gyges comments I also like an "Explorer Analogy" where med chemists are doing the initial trail blazing, followed by trafficking paths/routes and initial roads by process people, then the engineers ultimately build the highways for consistent travel.

Permalink to Comment

8. SciChick on July 20, 2009 11:07 AM writes...

Has anyone (Seeberger, perhaps?!) done any oligosaccharide synthesis in flow mode? Nature certainly takes the compartmentalization approach in making complex glycans. One would think thats something logical to try.

Permalink to Comment

9. CMCguy on July 20, 2009 11:07 AM writes...

I have been involved in several attempts at "telescoping" reactions and the experience was mixed: as might be anticipated when it works out well one wonders why its not done more often, however when its fails can lead to god-awful mess. In cases its not so much about if can do the different reactions in sequence but without an effective purification in between the impurity profiles and yields can suffer to a point of lack of utility.

per gyges comments I also like an "Explorer Analogy" where med chemists are doing the initial trail blazing, followed by trafficking paths/routes and initial roads by process people, then the engineers ultimately build the highways for consistent travel.

Permalink to Comment

10. CMCguy on July 20, 2009 11:07 AM writes...

I have been involved in several attempts at "telescoping" reactions and the experience was mixed: as might be anticipated when it works out well one wonders why its not done more often, however when its fails can lead to god-awful mess. In cases its not so much about if can do the different reactions in sequence but without an effective purification in between the impurity profiles and yields can suffer to a point of lack of utility.

per gyges comments I also like an "Explorer Analogy" where med chemists are doing the initial trail blazing, followed by trafficking paths/routes and initial roads by process people, then the engineers ultimately build the highways for consistent travel.

Permalink to Comment

11. alig on July 20, 2009 11:53 AM writes...

lots of double posts today. Even the drug spammer getting the double in.

Permalink to Comment

12. dreamonprocesshack on July 20, 2009 12:02 PM writes...

"per gyges comments I also like an "Explorer Analogy" where med chemists are doing the initial trail blazing, followed by trafficking paths/routes and initial roads by process people, then the engineers ultimately build the highways for consistent travel."

You wish guys, the simple making of a compound, that has billions of dollars in value as a drug, is worth practically nothing, the discovery is everything.

Permalink to Comment

13. processchemist on July 20, 2009 12:51 PM writes...

@14

"the discovery is anything"

Sure, as long as no big pharma will implement a total "offshoring of innovation" strategy and everyone in this field, from biologists to chemists will worth less than nothing in western world...

And how much is valued, today, a simple discovery, or better, a single discoverer?

ops, I'm probably feeding a troll...

Permalink to Comment

14. CMCguy on July 20, 2009 2:52 PM writes...

Gosh if "the discovery is everything" probably would mean we could then just rely on uni's and government for new drugs. However I have also heard similar statements "the target is everything", "the IP is everything", "the Clinical Trials are everything", "the Approval is everything" or then "the Sales are everything". What I most understand most is that in drug R&D it takes significant contributions from a wide scope of disciplines and attempting to assign universal predominance is a fool's venture.

Permalink to Comment

15. MoD on July 20, 2009 3:31 PM writes...

The "plug an play" approach to medicinal chemistry is bogus. Continuous flow chemistry will only be used for drug development and manufacturing.

Permalink to Comment

16. SteveM on July 20, 2009 3:42 PM writes...

Continuous flow chemistry is what Chemical Engineers do for a living. They spend a lot of hours tuning a process sequence to yield a target molecule of acceptable purity.

R&D chemistry is most one-off synthesis with perhaps some process step standardization when making analogues. Maybe those opportunities could be automated, but it would probably be more trouble than it's worth. (Ask the Chem Engs.)

The different synthetic goals of the engineers and scientists seem to make flow chemistry a flaccid point of discussion.

Permalink to Comment

17. Bruce Hamilton on July 20, 2009 4:58 PM writes...

From sci.chem.organic.synthesis in 2000...
Apologies for the formatting....

.......
In my oppinion, more research must be directed to the improvement of old classics that very often fail. For example Wittig fails in hindered acidic
ketones, and in base sensitive substrates. There are alternatives using titanium based reagents, but they are only able to introduce a simple
methylene. Is there somebody out there trying to broaden the scope of these reagents?

Research in Chemistry is like making discoveries in Geography. It is very interesting to discover new continents, and even to study new planets. On the other hand, it is more important to have a good plan of your own city that to study the mountains of one of Jupiter´s moons.

The lure of research on completely new fields, means that in chemistry we manage ourselves very badly driving in our own town, while most research goes to planets on which we will not drive during our generation.

We just need to take a look at the posts in this newsgroup. Most of them involve problems with well know reactions.

Best regards
Gabriel Tojo
***************
"schneider.jm" wrote:
> I can agree with you : the most interresting is > to understand wath we are doing and wath is the > best way to accomplish our goal......

Making a detailed map of New York is much more time consuming and uninteresting than discovering water in the satellite Europe. On the other hand, it is much more useful.

Best regards
Gabriel Tojo

Permalink to Comment

18. Jonadab on July 20, 2009 7:05 PM writes...

If living cells have ways of compartmentalizing everything and keeping the product flowing, perhaps eventually drugs will be made *using* living cells. Actually, come to think of it, that's already done now for products like insulin, wherein the genetic instructions for making the stuff were already written and just had to be identified and put to work. I suppose it will be a good long while before we can write custom genes for new drugs, but it seems like it would make for pretty efficient synthesis once the initial setup work was done.

As for discovery, it's not everything. It's not even the big thing. Lots of things are discovered that never turn out to be any practical use. The real trick is identification, sorting out which compounds are the worthwhile ones. Figure out a reliable way to short-circuit that long and arduous process and pour all the development money into the compounds that will end up actually paying off, and you can presumably name your salary at any pharma company you like.

Permalink to Comment

19. Lily Kim on July 20, 2009 9:06 PM writes...

Microfluidics is a great option for creating localization, both at subcellular and cellular scales. There are a bunch of ways to make things spatially localized: micropatterned local surfaces, local heating, local actuation, droplet-based systems, separate compartments, and laminar flow.

As you've noted, one of the biggest issues in microfluidics is the current absence of plug-and-play. Although there are movements toward more "programmable" devices, most chips developed today are custom-designed to solve a narrow range of specific scientific questions. New question? Build a new device (usually)...

Maybe localization could also be created in a macroscale solution using engineered microparticles? Or a combination of a microfluidic channels and microparticles?

Permalink to Comment

20. gyges on July 21, 2009 1:56 AM writes...

@Bruce Hamilton

Hi Bruce

Thanks for taking the time and trouble to post the note. The post was better than I remember it.

It also made me feel quite nostalgic.

Permalink to Comment

21. Sock Puppet of the Great Satan on July 22, 2009 11:34 AM writes...

"Continuous flow chemistry is what Chemical Engineers do for a living. They spend a lot of hours tuning a process sequence to yield a target molecule of acceptable purity."

Same reaction (pardon to pun) as I had to the post. However, part of the benefit of continuous flow in ChemE is the reduced size of equipment (and hence capital cost) compared to batch operation, as well as optimization of reaction conditions and yield. (The math for modeling and hence designing a continuous process is also more straightforward.) So you see more batch chemistry for specialty chemicals (like pharma intermediates) and agrochemicals.

Applying continuous methods in bench-scale chemistry is logical, but its not quite the same beast or driven by the same drivers as why us ChemEs (i.e. dumb jocks with big tanks) luv us our continuous processes.

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