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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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June 29, 2010

The Ideal Synthesis

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Posted by Derek

Phil Baran of Scripps has a paper out on the "ideal synthesis" of complex molecules. It's mostly a review of a number of his group's own syntheses, but it's done in light of his definition of "ideal": all bond-forming steps, with no protecting group manipulations or oxidation-state maneuvering.

That's a tough standard, but many biosynthetic routes reach 100% against it. I think that the highest figure from one of the Baran group's own syntheses is 84%, but he emphasizes that comparing these figures across the synthesis of different molecules isn't too meaningful, since they each carry their own issues. Comparing different routes to the same molecule is what he has in mind; it's a pity that no one else is ever going to make maitotoxin.

He also emphasizes that "ideality" isn't the only consideration in a synthesis. It gets at some key issues, but others (availability of reagents, ease of experimental procedures or purifications) can trump ideality out in the real world. You certainly see that in process chemistry in the drug industry. A reliable procedure that always gives the same (but lower) purity will win out over a temperamental one that sometimes gives wonderful material but sometimes craps out. And an elegant-looking route that gives a small amount of an intractable impurity isn't so elegant, compared to a slightly longer one that delivers material that's easily cleaned up.

The same goes for reagents. Ideally, you'd want to be able to buy all of them, and cheaply, too. But that's where the comparison with those 100% ideal biosynthetic routes breaks down. The enzymes that accomplish them are nothing if not bespoke reagents, doing one thing only but nearly perfectly. And there's that matter of a billion years of evolutionary overhead to factor in to the development costs. Of course, the other great thing about enzymes is that they're catalytic, and can just keep turning over reactions constantly. If they were one-time-use, like many of our reagents from the catalogs, it wouldn't matter how incredibly high-yielding and specific they were; the horrendous waste of time and material required to produce them for just one transformation would rule them out. Average those expenses out over the turnover numbers of a typical enzyme, though, and things look very good indeed.

I think that Baran's criteria are well worth keeping in mind, although I also think that most synthetic chemists already think this way, to one degree or another. I always gritted my teeth when I put on a protecting group during my total synthesis days, because I knew that I was adding another step (and more potential trouble) down the line when it had to come off again. Mind you, I was putting the thing on to avoid what I saw as even more immediate trouble, but I guess that's one of the things that Baran is saying, that it's time to try to stop making such deals if we can.

Comments (38) + TrackBacks (0) | Category: Chemical News


1. MLBpitcher_and_MedicinalChemist on June 29, 2010 7:28 AM writes...

I do not know what is an "ideal" synthesis, the discussion seems so nuanced to me.

Don't worry about putting protecting groups on anything, Derek, just worry about not giving up too many earned runs to the Nationals today during your start. Hope you get lots of Ks tonight!!

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2. zDNA on June 29, 2010 8:03 AM writes...

I haven't read the paper yet, but from Derek's writeup, it sounds like an economics paper more than anything else. The technical term here I believe is an "isoquant", any combination of land, labor, & capital that will produce the same end result. Which is "better" than the others is not always obvious, and is very context dependent, as Derek alluded to. Papers like this are useful so long as one keeps this in mind. The "ideal" synthesis is a direction in which we should strive, but not necessarily a goal that can (or should) be reached.

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3. anon the II on June 29, 2010 8:47 AM writes...

These philosophical campaigns, about essentially the same thing, show up every 15 years or so. Wender used start off talks, about 30 years ago, showing B-12 and saying the goal is to make it in one step. Older guys remember Trost's "atom economy" stuff. These papers don't get referenced after a few years because they don't tell you how to make something. So it's necessary for the new superstar on the block to repeat it all again and point how how he's not there yet, but closer than anybody else.

Organic chemists seem to like these kinds of papers though the main message is pretty obvious to anyone working in the field. They get discussed a lot for a while and then forgotten.

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4. Jos Pros on June 29, 2010 9:03 AM writes...

He does cite the notable D. Lowe, over at the RSC blogs...

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5. Stalker on June 29, 2010 9:10 AM writes...

Ummmm. Baran references all of those papers from wender and trost here and in all his economy reviews... He isn't claiming anything new and makes that clear.

Calm the f--- down.

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6. Wow on June 29, 2010 9:13 AM writes...

This paper is the opposite of self promotion. It's self deprecation.

Kudos to baran, others in synthesis should be so honest and modest.

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7. Derek Lowe on June 29, 2010 9:13 AM writes...

You know, I hadn't even noticed that cite to one of my Chemistry World columns. . .I read that part in the article and said "Yep, I've said that, too. . .", but didn't bother to follow the reference.

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8. BIP on June 29, 2010 9:20 AM writes...

I think this 'ideality' talk is garbage. It's romanticizing (and legitimizing) a field that doesn't offer a whole lot to the world outside of training up-and-coming synthetic chemists. There is no one true 'ideal' synthesis, but rather it depends on what outcome you wish to attain with your synthesis. The best judge of what is ideal, as I see it, is to break down the dollar cost of said synthesis - and again there is no ideal synthesis as values of time and sometimes reagents are firm/group/chemist specific. If one breaks down to the 'ideal cost synthesis' all Baran is really saying is 'Avoiding protecting groups saves time, and therefore saves money', etc. which isn't adding much to the discussion. When an academic group buys some pricey advanced intermediate or chucks in stoichiometric metal catalyst to cut down on steps I think it's all bull.

Maybe a little 'profit = revenue - cost' analysis would better serve the synthetic community. Ask yourself what you're getting out and what were your costs (reagents, time, equipment, etc.) If you assign dollar values to each of the costs (and more challengingly, the synthesis target 'revenue') you might actually be able to put a quantitative number on how 'ideal' your synthesis really is.

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9. Eraser on June 29, 2010 9:25 AM writes...

Baran Modest :-)

The guy is brilliant, but modest he aint.

Went to one of his talks a few months ago. The arrogance was almost as amazing as the chemistry. However, the latter excused the former

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10. BIP on June 29, 2010 9:32 AM writes...

"Although the pursuit of an ideal synthesis may naturally lead to a better route in many instances, certain situations (ease of purifications, inexpensive reagents, higher atom economy, higher overall yield, etc.) might dictate choosing a path with lower ideality."

Haha. In other words, some syntheses may be more ideal than a 'more ideal' synthesis. Doesn't this devalue Baran's definition of 'ideality'.

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11. Gawker on June 29, 2010 9:38 AM writes...

This is great! If chemists do 50 step syntheses of molecules then everyone bitches. If they try to do short ones and lay out a framework for achieving them then people bitch.

This is why chemistry will become an applied science with some fundamental studies happening in Europe and Asia. Ha! Keep killing the field.

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12. Tc King on June 29, 2010 9:44 AM writes...

Give Baran a break, as anyone who works in the synthetic field should be given a medal. You all should look at the work of Myers, who, of course has PB on his SAB for a company that synthesizes tetracyclines. Really amazing synthesis of a molecule that scares the average organic master to death.

Their goal is to make new and better molecules where nature gave up and I applaud them!

But I would laugh at someone who wanted to synthesize chlorophyll.

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13. License on June 29, 2010 9:52 AM writes...

I'm willing to listen to advice on synthesis from anyone that can actually finish palauamine......

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14. Will on June 29, 2010 10:04 AM writes...

The differences in labor cost & overhead between an academic lab and an industrial group are so vast that what constitutes the most economical (cheapest) synthesis in an academic lab is likely to be much different than an industrial group. Perhaps Baran, Myers, Shair et al can convince their students and postdocs to work 70+ hours for ~$35,000 and no benefits, but I doubt Merck or Vertex would be so lucky

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15. CMCguy on June 29, 2010 10:14 AM writes...

To me this post illustrates the common separation that often exists between academia and industry and maybe even med vs. process chemistry. Academic researchers and medchemists are typically highly focused on a target or analogs thereof and employ whatever means to get them made. Process chemists are, or should be, aiming towards more "ideal" construction of molecules which does tend toward minimization of steps/costs and reproducibility. While it can seem more restrictive in process if one is lucky to be in proper circumstance they can do the work necessary to transform a "temperamental procedure" or "elegant route" to hit the reliable, efficient and quality standards.

#3 anon the II states "Organic chemists seem to like these kinds of papers though the main message is pretty obvious to anyone working in the field. They get discussed a lot for a while and then forgotten." Because these papers/philosophy are forgotten is why such a message needs to be repeated on occasion and I am not convinced that is so obvious to everyone since observed that most fresh PhDs have to be educated to think this way.

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16. MedChem on June 29, 2010 10:21 AM writes...

I think it all comes down to intelligent choice of targets to work on, and that in turn allows one to make really nice stories out of the eventual syntheses. Baran certian is very smart in that regard. Another person comes to mind is Matt Shair. They both pick targets that can be put together by some kind of dimerization/cyclization process (a que taken from a proposed biosynthesis) from relatively easily accessible intermediates, as opposed long linear syntheses (e.g. polyketide syntheses).

Still brilliant, albeit brilliance enabled by a narrowly defined scope of research.

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17. Caller on June 29, 2010 10:29 AM writes...

Well looking at figure 1 he sure has a lot
of different types of targets!!

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18. MedChem on June 29, 2010 10:52 AM writes...


I didn't imply a lack of structural diversity. I was speaking to the underlying strategy/philosophy he uses to put them together. Go through his syntheses, can you see a common thread? Again like I said, this only speaks to his brilliance and doesn't detract from it.

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19. J-bone on June 29, 2010 10:59 AM writes...

Academic researchers and medchemists are typically highly focused on a target or analogs thereof and employ whatever means to get them made. Process chemists are, or should be, aiming towards more "ideal" construction of molecules which does tend toward minimization of steps/costs and reproducibility.

Dave MacMillan said something similar to this in a Synlett article. An academic synthesis may span 7 orders of magnitude from start to finish (kg SM to get mg of product), but an industrial synthesis aims for about 3.

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20. barry on June 29, 2010 11:50 AM writes...

as far as I know, this philosophical thread started with Steve Bertz thirty years ago:
It's something to keep in mind, but it doesn't drive our day-to-day practice

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21. John on June 29, 2010 12:17 PM writes...

He's actually quite modest in person in a one-on-one conversation...arrogance/pride comes out during his talks, but seriously, if anyone has the right to have pride in his synthetic ability, it's him. Ideal synthesis has a beauty to it in addition to any economic considerations, and that is always worth something.

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22. Hap on June 29, 2010 12:47 PM writes...

If you ask what synthesis I'd rather have than Nicolaou and MTX, it would probably be Baran's work - he does neat things, some of which couldn't be done at all before, fairly briefly. The yields of his group's synthesis generally suck, but for doing something novel, that's an OK price to pay. He also seems (at least in writing) to recognize the constraints of what he does - he doesn't promise that his syntheses will improve natural product availability, for example, if they won't, and he recognizes what they don't do, and perhaps should.

I don't know what in the long run will make this approach possible - better reactions would help, but it isn't like people haven't been trying. Bioengineering is a possibility, but it seems to involve a skill set and infrastructure (for designing and modifying proteins) that not all that many chemists have. In addition, for most people, "good enough" is OK - they don't have the time or money or skill to do better and don't need it. If methodological breakthroughs are going to come to change how people do synthesis, it will probably have to come from people (such as Baran, perhaps) who have that as their goal and have relatively few competing goals.

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23. anonymus on June 29, 2010 2:16 PM writes...

This is a funny paper!

Speaking of the ideal synthesis, anyone noticed Cortistatin A (lower left, Figure 1).

In this tour-de-force synthesis, the Baran group uses a prednisone derivative (containing 19 carbons), 19 steps later, they got to "(+)-cortistatinone" containing also 19 carbons "cough cough". 4 more steps furnished cortistatin A.

I guess it's easier to achieve an ideal synthesis when you carefully select a natural product that no one cares about, when it's an high-fly target and a race is on between various groups, things are getting obviously more complicated, even for Baran.

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24. guppy on June 29, 2010 2:44 PM writes...

he gave a talk where he used wrinkler's synthesis of ingenol as an example of elegant but less than ideal synthesis (over 30 linear steps after the key sequence to form the core). i thought he would show us a better way to introduce that ridiculous inward pointing bridge hydrogen of ingenol's core, but alas he never did.

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25. anon the II on June 29, 2010 2:52 PM writes...

Hi Barry,

I remember the Bertz paper well. However, I think it came after and maybe was a response to all of Wender's talk about synthetic efficiency. It even included one of Wender's synthesis, if I remember. Wender had put the molecule together with one of those aryl-allyl photo-reactions that sets a zillion stereocenters in one step. If I remember the Bertz paper correctly, it showed that Wender overshot the final product in the molecular complexity of an intermediate. Very inefficient.

Maybe I should go look at the paper before I say anymore.

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26. Barry on June 29, 2010 6:00 PM writes...


I worked with Wender and remember the glee with which he greeted the Bertz paper. Just as you remember, Bertz does point to Wender's use of the arene-olefin metaphotocycloaddition as a step in which the increase of molecular complexity is vastly increased--beyond the level of complexity of the final natural product. Bertz introduced the language of molecular complexity that we've been using, but of course synthetic chemists had been making more complex structures out of less complex fragments long before that.

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27. process research guy on June 29, 2010 6:12 PM writes...

If science has to go in a forward direction, it will be through brilliant scientists like Baran - not through people who constantly look down on academicians like him because they can never be as imaginative. Besides he is one of the nicest professors around - a genuinely nice guy.

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28. EnuffisEnuff on June 29, 2010 7:26 PM writes...

I vote for a bake-off between Barry and Phil. Wender picks the molecule and the Trost and Baran group have a year to come up with the "best" synthesis. The work will be submitted to Science and the reviewers will pick the most "atom economical" approach.

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29. Quintus on June 30, 2010 6:24 AM writes...

I read this opus from Baran, interesting concept but he spoils it by making the following statement:

"Finally, scalable syntheses of complex natural products help debunk the myth that such compounds are not economically viable targets in the pharmaceutical industry".

This tells me he has absolutely no idea what the development of a compound means.

Perhaps he needs a job in industry, maybe even China

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30. processchemist on June 30, 2010 6:58 AM writes...

"Finally, scalable syntheses of complex natural products help debunk the myth that such compounds are not economically viable targets in the pharmaceutical industry"

Scalable... I'm usually skeptic about "high yelds" and "scalability" coming from academia. As far as I know the only complex total synthesis that hit the pages of OPRD was the one of discodermolide, labeled as "large scale synthesis" (not "scalable").

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31. Tok on June 30, 2010 7:27 AM writes...

So with his formula, a synthesis that's 3 steps long, creates 20 C-C bonds in the last step, but has two redox reactions is "less ideal" than an approach to the same target that makes those 20 C-C bonds one reaction at at time with no redox reactions.
This is an interesting new spin on trying to quantify the quality of a synthesis, but as with every quantitative measurement of quality there are some important aspects that are ignored.
I have to give him credit though as he says as much in his conclusion paragraph: "It (ideality) is a useful tool for the purposes of self-reflection and evaluation but NOT an ultimate measure of a synthesis."
Maybe the use of the word "ideal" was a poor choice for a quantitative measurement. For example, "atom economy" was not a qualitative idea before it was applied to synthesis, whereas "ideal" certainly was.

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32. Quintus on June 30, 2010 8:31 AM writes...

Process chemist: I agree with you completely.
The disco synthesis was scalable but up to a point, around 2kg, but the effort to get the 2kg would have been immense, after that ……..!

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33. HB on June 30, 2010 12:19 PM writes...

@Quintus - it isn't that he [Baran] has no idea how Pharma APIs are developed. These "philosophical" papers he puts out every once in awhile are, unfortunately, not very edifying. And, I am not sure that they are genuinely intended to be as such.

He is helping out his students by getting their names on these papers. It's good to pad out their CVs because, let's face it: many people are impressed by someone whose name is on a lot of publications. This is because it's often just the easiest metric to gauge. Not to discredit his students, who I am sure are quite sharp, but that's "the game." Organic chemists need to give themselves every advantage they can get.

It also helps out his research group because I'm imagining that *someone* who's approving high-profile grants doesn't fully see through his smoke screen (I profess little knowledge of this process). Or possibly, they do see and simply just don't care because they already know that Baran's group is very high-profile and tends to publish good work.

I seriously doubt that anyone believes he is going to start doing SAR on palauamine. Total Synthesis has its place - (let's go over this ONE MORE TIME) it has an excellent track record in producing first-rate medicinal and process chemists.

So, while papers like these come off as somewhat disingenuous to chemists in the know, I'd imagine Baran's inner dialog is something to the effect of "don't hate the player, hate the game."

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34. newnickname on July 1, 2010 10:45 AM writes...

Baran has some closely related reviews (e.g., Economies of Synth, Chem Soc Rev, 2009, 3010; Protecting Group Free Synth, Nature Chem, 2009, 193). In the Protection Free review, he mentions Danishefsky's patchouli alcohol (1968) as an example but I think Danishefsky's coriolin is far more spectacular. As I recall, there is only one "protection" in the form of a carbonyl to alcohol reduction before being restored to carbonyl.

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35. newnickname on July 1, 2010 12:11 PM writes...

Re: Bertz's stuff. As I recall, Bertz has said he started thinking more rigorously about the meaning of complexity while taking Corey's synth course at Harvard. Molecules (targets) such as strychnine are described as "complex" or "most complex" without recourse to any rigorous measure. So he came up with one. While at Bell Labs, he drew upon Shannon's (also of Bell Labs fame) formula for information content.

When you see the "complexity" of compounds listed at PubChem, it's the Bertz complexity index.

"Excess complexity" (Wender's arene-olefins), "reflexivity" and other Bertzian concepts are meant to guide us to plan better syntheses with mathematical rigor.

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36. The Blue Maharaja on July 1, 2010 3:38 PM writes...

Love the Comments above
...but time after time I'm left frustrated by following links that end with "Your current credentials do not allow retrieval of the full text."
Surely it's incredible that the ACS can charge $30.00 for 48 hours of access... to a 3-page article from 30 years ago?
No wonder chemistry is on its knees when Feudal mindsets like this still hold sway.
How about an annual Amnesty for all publications reaching > 5 years old?

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38. ninja on August 2, 2013 6:37 PM writes...

hey guppy... better late than never??

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