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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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March 23, 2007

Naked Synthesis

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Posted by Derek

There's an unusual article in Nature that several folks have e-mailed me about. It's unusual for several reasons. For one thing, it's synthetic organic chemistry, and there's not much of that in Nature at all - it's an interesting choice of journal on the part of the authors, Phil Baran of Scripps and two of his students, Thomas Maimone and Jeremy Richter. The title also gives away the other odd feature (as a title should): "Total Synthesis of Marine Natural Products Without Using Protecting Groups".

I was talking about protecting groups here just a couple of months ago. In synthesizing complex molecules, they're often necessary, because there will often be several similarly reactive groups exposed at the same time, and you need to be able to distinguish them. Or you'll need to do something severe to another end of the molecule-in-progress, which an amine or alcohol somewhere either won't let you do or won't survive if you try.

The trouble, as any synthetic chemist can tell you, is that protecting groups introduce their own complexities. Ideally, you want to be able to put them on and remove them with no loss of material, but that's impossible. Ideally, you'd want each one to be removable under conditions that won't disturb any of the others, or anything else in your molecule, but that can be a tall order too as they start to add up. And ideally, you'd want all of them to be able to stand up to anything else you'd like to do, until it's time for them to leave, but that's not available in the real world, either. Sometimes a big part of the work (mental and physical) that goes into a total synthesis is figuring out how to manage all the protecting groups.

Baran makes the case that this has gone too far. He's made several complex molecules without protecting anything at all. There's a price to be paid, of course - some of the steps along the way have not-so-impressive yields because of the bareback conditions. But the counterargument is that the overall yield of the synthesis is often higher in spite of this, because there are so fewer steps, and the cost and complexity are cut similarly.

Of course, you can't do this by just plowing ahead with the same reactions that a protecting-group-laden synthesis would use. They're on there for a reason, and that method would send you right into the ditch. Baran tries instead to mimic the biochemical synthesis of these molecules as much as possible, since after all, cells don't use protecting group chemistry, either.

This is an idea with a long and honorable history in organic chemistry, starting with Sir Robert Robinson's startling one-pot synthesis of tropinone back in the 1917. That one is usually taken as the father of all biomimetic syntheses, although it's been pointed out (by no less an authority than Arthur Birch) that this is partly a legend. But it's a legend that has performed function of its reality, leading to a whole series of biologically-inspired syntheses. This latest paper is a call to make biomimetic synthesis the centerpiece of the field again.

I'm sympathetic to that view, but it's not going to be easy. Read closely, the paper shows that this kind of work can be very difficult indeed, even when the biogenic pathways to your target molecules have been studied (which isn't always the case). There are a lot of steps here that required careful coaxing to work in reasonable yields, or at all - no one should confuse the lack of protecting groups with a savings in time. And these difficulties also undermine the claim of reduced cost and complexity a bit, since they represent plenty of time and effort - and if they aren't synonymous with cost and complexity, I don't know what is. Academia may obscure this a bit, since we're only talking graduate student labor here, but it's a real issue.

Where I see this making an impact industrially is in process chemistry. Many times companies work out several parallel routes to an important drug substance, looking for the lowest overall cost. That's where attention to no-protecting-group methods could pay off. Process groups already try to avoid these steps anyway, for the same reasons.

But for the most part, drug substances aren't so complex that they need lots of protecting group manipulation. We could always try to get into more complicated structures through these routes, but this leads to a chicken-and-egg problem. The medicinal chemists generally don't have the time to investigate the picky conditions needed to make no-protection chemistry work, so they're not going to have access to the shorter, higher-yielding syntheses needed to do analoging work. (And there's the real problem that these analogs might need complete re-optimization of the trickier steps each time, which would be a real nightmare). The process chemists would have the time and mandate to work out the no-protection stuff, on the other hand, but if med-chem can't deliver a good drug candidate, then they have nothing to optimize.

The Nature link above is subscriber-only, but you can read the supporting information with all its synthetic details here if you like. It's a pretty big PDF file, though, so be warned. I'd be interested to hear what readers, both academic and industrial, think about this one.

Comments (28) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development | General Scientific News


COMMENTS

1. Jose on March 23, 2007 10:34 AM writes...

See also yesterday's JACS ASAP paper by Baran- it is a doozy!

I feel for John Wood- the comparisons to his fischerindole / welwitindolinone syntheses by Baran has to sting.

In the discussion section, Baran pretty much lays down that his is going to be the driving philosophy for his research program.... bold!

I feel as if it is like "atom economy." Great to keep in mind, but unlikely to shape my daily choice of reaction conditions!

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2. TNC on March 23, 2007 11:30 AM writes...

It's pretty cool, but where's the alcohols in his molecules?

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3. Al on March 23, 2007 1:51 PM writes...

I was thinking that those targets looked rather functional-group lite as well! Complex carbon skeletons sure, but I can't imagine any of the polyketide/polypropionate (aldol based) natural product groups jumping on this bandwagon any time soon.

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4. MolecModeler on March 23, 2007 2:23 PM writes...

Al, true. Baran himself conceded that this strategy is not amenable to certain target classes, and explicitly mentioned polyketides, sugars, and peptides.

What I like about his work is that there is a real core principle behind it other than "slap it together ASAP".

I think industry would generally find this kind of chemistry great (no PG's = win), but no project chemist has the time to futz with exp conditions to get it to work. On the other hand, in industry, yields don't mean as much. I just think the average synth chemist wants to make something as quickly as possible and register it, and this kind of chemistry does not fall into the "as easy/quickly as possible" category.

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5. been there on March 23, 2007 2:53 PM writes...

Perhaps 'gimmick' is too strong a word, however, given the realities presented by Derek, in the end it is what it is. Having said this, I would not be surprised if Baran's future work in this area will produce something of great value. "Hats off" to him for trying to do something other than the status quo. I would like to see some of his "risk taking" rub off on his peers etc.

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6. milkshake on March 23, 2007 4:34 PM writes...

I think Kishi was an early proponent of total synthesis done without any protection groups. But I don't know how far he got with it, when making his polyhydroxylated polycyclic spongisuckins.

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7. Wavefunction on March 23, 2007 4:41 PM writes...

It's a really cool paper...but does not really change the future of the field. Theoretically, you could have come up with a set of conditions for making some molecule without PGs long back. Practically, it's a real challenge. But it's not a practical landmark for the field...as you said, people are not going to start doing this as such.

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8. Hap on March 23, 2007 5:00 PM writes...

It seems like a neat idea (Baran does neat work), but people already knew they didn't want protecting groups - they want to make whatever they're trying to make as predictably as possible, and protecting groups are (supposed to) reduce secondary sites of reactivity and help achieve that goal. In some cases (really small fragments that are volatile), they may even be necessary to proceed.

It would probably more interesting with more highly functionalized targets - in addition, haven't terpenes/steroids been assembled previously and fairly concisely with little protection via cationic cyclizations? On the other hand, we're supposed to be paying acaademic chemistry to come up with neat ways of doing things, and this seems like one of those.

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9. one in ten thousand on March 23, 2007 8:48 PM writes...

In my own work, I usually use protecting groups from the outset, without ever knowing if one is required or not. I suspect that there are plenty of instances where the chemistry would have been selective enough without a protecting group.

Altnernatively, I have experienced instances where a protecting group actually hampers in the transformation I was trying to accomplish. For example aminolysis of an alpha-hydroxy ester is very facile when the alpha-alcohol is not protected.

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10. yepyep on March 24, 2007 4:36 AM writes...

I don't think we should label all the protecting groups equally bad. Although I like TBDPS in some cases, the fact is that it's expensive and sucks atom economically, whereas acetals, for example, are usually easy to introduce/remove, and doesn't cost that much.

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11. Chemist of Sorts on March 24, 2007 3:21 PM writes...

I am a huge fan of Baran, but I have to agree that this is just a gimmick. Put it up there with "atom economy" as a formalization of the obvious.

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12. luckss on March 24, 2007 4:02 PM writes...

no more of a gimmick than nano or chembio or organocatal or whatever. the paper is a masterpiece in my opinion

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13. buyproduct on March 24, 2007 6:02 PM writes...

I like this paper because of what it attempts to do. I am not a total synthetic chemist, I focus more on methodology. This paper is all about figuring out the chemoselectivity of your substrates. C-H insertion reactions that are very chemoselective and stereospecific. This paper actually foster development in this field. I love it for that fact alone.

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14. wtf on March 25, 2007 8:52 PM writes...

The real question is does this paper belong in Nature? No way. I give him points for pulling of the biggest sale of the century.

Of course doing a total synthesis without protecting groups is the ultimate goal and most synthetic chemists try to develop routes to minimize the use of protecting groups. So, Phil comes up with one that does not use protecting groups. Where is the novel idea? Why did it get into Nature? This is at best a JACS paper. Is this really a new concept. When I was in academics, I always planned my synthesis with minimal use of protecting groups.

I take my hat off to Phil, who is one of the best spin masters around.

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15. goraw on March 26, 2007 12:06 AM writes...

wtf: you are really jealous and are missing the point of the paper. it is chemists like you the reason that synthesis is dying. It is why we see everything BUT chemistry make it into Nature and Science. Because of people exactly like you.

if it is so obvious and easy, why did the previous syntheses of these compounds look like land-wars? Were all the referees of the paper also stupid?

if you wanna see some spin, open a issue of JACS or angewandte. C-H activation, Nano, DNA, Organocat garbage.

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16. Synchem on March 26, 2007 9:52 AM writes...

His group has published similar work prior to this. It's nice work but of little use. Because it's Not a methodology that others can use. It's mere trial and error to see what chemistry works without protecting groups.

To me this belongs to the same gimmicky catagory with the "click chemistry".

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17. annoyed on March 26, 2007 2:27 PM writes...

I agree with wtf. That paper is way oversold. It is a cool synthesis, no doubt, but not Nature-worthy. Baran is a really smart guy, and his amazing vision can be seen in the synthesis, but putting the "no protecting group spin" is showmanship (he hails from the master of showmanship himself). There really are no heteroatoms to protect, and technically they have a transient protecting group on the lone nitrogen.

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18. Liquidcarbon on March 26, 2007 2:57 PM writes...

I'm a big fan of Baran, too, but they should learn making supplementary PDFs. 38 MB in Nature and 57 MB in JACS. It's nonsense!

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19. Jose on March 26, 2007 5:25 PM writes...

Baran is an exceedingly bright cat. John Wood is no slouch, either, but just compare the syntheses! Baran is

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20. Jose on March 26, 2007 5:27 PM writes...

Arggh, comments got cut off- Baran is an exceedingly bright cat. John Wood is no slouch, either, but just compare the syntheses! Baran is 10 steps, no PGs, and they made GRAMS of material. Wood spent years (6,7 8?) to make enough for an NMR with steps and PGs up the wazoo! I think Baran is throwing down some mad spin, as well, but it is impressive all the same. Will it revolutionize synthesis? It reminds of EJ codifying retrosynthetic analysis- dimes to donuts, RB was doing it in his sleep; he just never felt the need to find a fancy name for it or write arcane programming languages to map out trees for you....

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21. Hap on March 27, 2007 12:58 PM writes...

The making grams part isn't novel, but it's been remarked previously (By Danishefsky? or Smith? I don't know) that we should be able to deliver enough material to actually test compounds and analogs at this point, particularly when that has been a justification for natural products synthesis for a long time. Maybe Baran's recommendations will be as big as retrosynthesis is for Corey, but I don't think so (just because they don't seem as well defined in application). The challenge, though, should be important - everyone knows (and perhaps should have known before) that we can do better.

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22. Skeptic on March 27, 2007 10:32 PM writes...

This Nature paper is not as impressive as Baran makes it out to be. I don’t know why reviewers don’t stop him.

Let’s just take his synthesis of ambiguine H as an example.

Here is what Baran reports: 10 steps from commercially available material

Here is what a close look at the supporting info tells you: It is actually 15 steps.

Not a big deal, right? Just a little fudging to impress the community. But here’s the thing; IT IS A BIG DEAL! He has a 50% error in his step count. So lets take a closer look at how he perpetrates this academic fraud:

He starts his synthesis with a compound that he says is “4 steps from commercially available material”, but it is actually 8 steps. He has four steps written down, but the material he starts from isn’t available (1 extra step), and his four steps have 3 extra steps hidden in them. This guy apparently considers a reaction, workup, COLUMN, and another reaction as one step!!!! What the hell is that? He does it again in step c (figure 3 of the Nature paper). How is he counting steps? If you do a sequence in one day is it one step? What if you pull a couple of all nighters and run four reactions - is that one step? And this is nothing new, or an innocent oversight. He has done this in many of the papers he has published to date.

Check it out for yourselves, this is revealed upon inspection of the supporting info (but apparently the reviewers did not take the time to thoroughly review the paper).

Also, take a moment to consider that in his “gram-scale synthesis” of welwitindolinone A, the second intermediate in his scheme (Figure 4, compound 16 in the Nature paper) he is already at 9% overall yield from carvone oxide (which is not commercially available). The next two steps (26% not brsm, 42%) bring him to a stellar 1% yield with 3 steps still to go. Not that this is bad by any means, but it is certainly not the efficient route he sells it as (0.4% overall yield of the natural product).

Anyway - I don’t understand why everyone who does chemistry isn’t furious at this guy - You should be too. He is setting a falsely high standard of success and productivity for new professors - and you are going to measured against this standard. Unless you also lie about your research you can’t possibly measure up to this guy.

I encourage everyone to dig into his supporting info for all of his syntheses. We are scientists after all, which is to say we are skeptics. Why are so many so easily swayed by hype when the truth is right there…dig into that supporting info!

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23. buyproduct on March 28, 2007 9:29 AM writes...

Skeptic funny mention that. Dr. Baran gave a talk here at univeristy a week ago. It was all about the stuff in this nature paper. When talking about ambiguine H, he showed the picture of the student who worked on it, how many days it took him to make it, how much he made and the overall yield. When he put all that information the crowed was pretty wowed. Expecting this he then said how some people find this unbeliveable including reviewers. And proceeded to show quotes from reviewers of the paper that implied that he was not telling the truth and did not make the moleucule at all. So he said he had his student make it again and it only took him five days and had him get crystal sturctures for all the intermediates. That apparently appeased the reviewer.

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24. Jose on March 28, 2007 6:41 PM writes...

So, when Phil said "five days" he really meant 120 continuous hours in lab, right? Those poor bastards- but I've heard they get cute little military campaign medals and flak helmets for pulling all nighters...

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25. wtf on March 29, 2007 9:30 PM writes...

goraw: I totally disagree with you. Nature and Science should be reserved for papers that report big advancements. Do you really think that Phil's paper is a big advancement in total synthesis.

The truth is that he tried a bunch of different strategies and got lucky and found a really good one.

The synthesis is very nice and belongs in JACS. Can you apply his total synthesis to a many natural products? Maybe 10%. Lets see if he can keep up his strategy of using no protecting groups in his syntheses.

This is just a gimmick to get funding.

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26. goraw on March 29, 2007 11:48 PM writes...

he did it again in JACS last week fool.

gimmick?

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27. Liquidcarbon on March 31, 2007 8:48 AM writes...

Tot. Syn. closed comments...

Why nobody is talking about the people who actually did that, I mean his students? They are very good, I must say. I know that it was the student who came up with the pyrone trick in Haouamine synthesis.

BTW:
Date of Birth: 10 Aug 1977
Assistant Prof: June 2003
Associate Prof: July 2006

I wish I could work for him myself. Currently he has about 30 students/postdocs, and there are no positions until late 2009!

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28. wtf on April 1, 2007 7:38 PM writes...

goraw: your blind loyalty to Phil is so sad...do you work for him? when I said lets see if he can keep it up, I mean't a couple of years.....and the JACS communication of a fucked up natural product did not impress me.

His total syntheses belong in JACS but not in nature or science....the only way he got his paper into nature was with K.C.'s help and a big gimmick.

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