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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 17, 2014

What If Total Syntheses Had Only 25 Steps to Work In?

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Posted by Derek

Via the Baran lab's Twitter feed, here's a provocative article on whether total organic synthesis has a place in the modern world or not.

One may wonder why this situation has passed undisputed for such a long time. Currently however, wide parts of the chemical community look upon total synthesis as a waste of time, resources and talents. Behind the scene, it may even be argued that the obsession to synthesize almost any natural product irrespective of its complexity and practical importance has blocked the development of other more relevant fields. Therefore, it is high time to consider a reorientation of the entire discipline

That's a bit of a straw man in that paragraph, and I have to note it, even though I do feel odd sticking up for total synthesis (about which I've been pretty caustic myself, for many years now.). I don't think that there's been an "obsession to synthesize almost any natural product", although it's true that many new synthetic methods have used some natural product or another as demonstration pieces. But the author, Johann Mulzer, came out of the Corey group in the old days, and has spent his career doing total synthesis, so he's speaking from experience here.

He goes on to argue that the field does have a place, but that it had better shape up. Short syntheses have to take priority over "first syntheses", because (let's face it), just about anything can be made if you're willing to throw enough time, money, and postdocs at it. The paper is full of examples from Mulzer's own career (and others'), and if you read it carefully, you'll see some unfavorable contrasts drawn to some Nicolaou syntheses. He finishes up:

In conclusion, this article tries to show how various strategies may be used to streamline and to shorten otherwise long synthetic routes to complex target molecules. The reader may get the impression that it pays very well to think intensively about cascade reactions, intramolecular cycloadditions, suitable starting materials and so on, instead of plunging into a brute-force and therefore mostly inefficient sequence. After all, there is an iron maxim: if a target cannot be reached within, say, 25 steps, it is better to drop it. For what you will get is a heroic synthesis, at best, but never an efficient one.

A 25-step limit would chop an awful lot out of the synthetic literature, wouldn't it? But it's not fair to apply that retrospectively. What if we apply it from here on out, though? What would the total synthetic landscape look like then?

Comments (46) + TrackBacks (0) | Category: Chemical News | The Scientific Literature


COMMENTS

1. Anonymous on March 17, 2014 11:38 AM writes...

I agree that placing a limit/constraint on the number of steps might inspire a bit more more creativity and innovation, kind of like setting a challenge. Taking 100 steps to make a compound does not add value. Finding a creative new way to make the same compound in fewer steps does.

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2. NUChemist on March 17, 2014 11:40 AM writes...

It should be shortened to 15. What's the longest synthetic sequence you've ever seen in Org. Process Res. Dev.?

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3. Hap on March 17, 2014 11:40 AM writes...

An ironclad rule on steps to target might overcredit inefficient but short routes to a target, and might not reasonably factor the value and purpose of making a target (if a target is valuable enough, lots of steps might be OK; it also matters how much of the target you need to make).

Step economy is only one way to count how effective a synthesis is - what (I think) you want to know is how well a synthesis fits the purpose for which it is performed - to make the molecule, to be scalable, to be easily optimized, and so on. If it's a playground to train students, well, then a step limit might be good (why train people to get lost in the weeds?), but might not.

If you don't think an endeavor is worthwhile, then any number of steps to do it is too many.

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4. SP on March 17, 2014 11:52 AM writes...

It's kind of odd to use "iron maxim" and "..., say,..." in the same sentence. If it's iron shouldn't you have a good argument for a particular number of steps? Or maybe some other metric like steps per heavy atom or ring system or something. Hey, we can dig up all the LE arguments again for a new purpose!

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5. biotechtoreador on March 17, 2014 11:52 AM writes...

While I find a lot of KCN's work ridiculous, I'd hate to suffer from a disease in which the best available treatment takes 26 steps.

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6. Anonymous on March 17, 2014 11:53 AM writes...

Just as well this rule wasn't considered when Sanger was working on insulin...

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7. Anonymous on March 17, 2014 12:00 PM writes...

@5: Why would a publication limit of 25 steps limit what can be made for treatment?

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8. anon the III on March 17, 2014 12:01 PM writes...

It's a good thing nobody ever went after a molecule like Halichondrin B.

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9. MTK on March 17, 2014 12:08 PM writes...

Why do we have to put some arbitrary rule or limit?

Just use the ol' Potter Stewart line of "I can't define it, but I know it when I see it."

Those in the field have a good idea of what's a good synthesis, a bad synthesis, or a total waste of time. Not to mention that less than great syntheses can be educational also.

Zero tolerance rules with little flexibility generally dumb things down which really isn't what we try to achieve.

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10. anon on March 17, 2014 12:21 PM writes...

Putting limits on step count only leads to fancier ways of counting steps. Have you made ingenol in 14 steps from carene but the longest linear sequence is longer? And did you get there by doing some interesting telescoping tricks? Great! Make step count the title of your Science paper!

Step count is ridiculous because we can count it however we like. Focusing on it detracts from the what we're really accomplishing. We should talk about efficiency (overall, and this is often subjective) and convergency instead if we really have to compare two different syntheses.

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11. Ex Med Chem on March 17, 2014 12:34 PM writes...

I've never been impressed or inspired by total synthesis since the vast majority is of no use to the practical applications of chemistry in industry. To me its self indulgent and inefficient, while also if >25 steps of little real value when training new chemists for a successful career in industry.

Wouldn't it be interesting if synthetic journals insisted on less than 25 steps, the estimate of cost of goods in $/g of the final natural product synthesised and the list of the total reagents and solvents used in the entire process from start to finish (including solvents used for purification)?

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12. barry on March 17, 2014 12:43 PM writes...

we took pride in knocking the synthesis of Laurenene down from 38 steps (the first reported syntesis) to 13 steps. But we would have been proud to finish it first if we could.

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13. Yancey Ward on March 17, 2014 12:44 PM writes...

#8,

My former boss worked on Halichondrin B.

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14. Anonymous on March 17, 2014 12:44 PM writes...

I would like to tell these egotistical chemists that as long as they are not making their own carbon, nitrogen and oxygen atoms from hydrogen, then it's not *real* total synthesis.

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15. Anonymous on March 17, 2014 12:48 PM writes...

I should remind everybody that usually "the first total synthesis" is to confirm or correct the structure of the natural product. It would be worth more than 25 steps to know the right structure, especially for biologically important compounds.

On the other hand if it is just to make the compound using the professor's signature methodology, 25 might be too long.

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16. Anonymous on March 17, 2014 12:56 PM writes...

@Anon, you nailed it Sir!

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17. CMCguy on March 17, 2014 12:57 PM writes...

Similar to other opinions expressed I have a little difficulty with setting any arbitrary criteria on a total synthesis effort. Corey's books, plus historical perspectives, focused not only on the science required but played on theme as Artistic. A beautiful synthesis can be in the eye of the beholder as one takes in the outcome (molecule made) plus the the paint palate used (route) and comparison to others of the genre (other molecules or routes). Total syntheses lost luster because so many approaches mostly applied readily available tools rather then being platforms for novel transformations, which may have been driven by funding agencies demanding outcomes or innovation. From the public and political view it has become routine and that may be partly true however there is probably much room left for future contributions even if total synthesis types are not the Big Men on Campus that they once were.

Further I cringe when I hear academicians talks about "efficiency" as although some do have adequate definition of what that means majority do not have a clue on what is required in a real world scaled manufacturer. In this circumstance I think you can have an elegant and worthwhile synthesis route but should not generally be confused with a workable process.

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18. Jordan on March 17, 2014 1:01 PM writes...

I like where #11 Ex Med Chem is going with this. The number of synthetic steps is only part of a picture that also includes the number of purification steps, solvent waste (particularly chlorinated solvents), use of precious-metal catalysts, need for extreme low-temperature conditions, etc.

From a practical chemistry / scale-up perspective, shortening a process from 14 to 10 steps isn't such an amazing feat if eight of those steps can only be run in CHCl3 and use 10 mol% Au-based catalysts (just to take an extreme hypothetical example).

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19. John Wayne on March 17, 2014 1:31 PM writes...

The most important result of working in total synthesis is the production of chemists that have been exposed to a wide variety of chemical reactions, learned troubleshooting of difficult steps, and learned the strategy of rethinking a synthesis. Total synthesis isn't necessarily a end unto it's own (you can do things badly, or do things that don't matter), but it does have an important and diminishing role in graduate training.

Based on a resumes I've looked at in the last few years, there is a widening skill gap that isn't good for anybody.

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20. Anonymous on March 17, 2014 1:50 PM writes...

@19

Yes, total synthesis is good at training students to make stuff. But, who cares if you can synthesize some natural product in some arbitrary number of steps. Geez, this field is dying fast if that is the big idea.

Its too bad these (mostly) guys can't come up with something interesting to make. they are so good at making things, but can't think of what to make, so they come up with an arbitrary goal to keep them and their students interested...sad.

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21. Anonymous on March 17, 2014 2:21 PM writes...

I'm getting a laugh out of all the comments from folks that are presumably process chemists arguing that the metrics used in their jobs should be universally applicable to all synthetic work. Look at the targets you usually work on. Now look at the average natural product structure for which a synthesis is reported in JACS/ACIE/OL/etc. Anything look different?

In all seriousness, I agree that total synthesis is facing an existential crisis. There are a small number of structures that probably should be synthesized for practical reasons - structure elucidation, interesting function (or suspicion of one), or potentially demonstration of a new method. However, there are also lots of syntheses that don't add much to the knowledge base of humanity. Whether the syntheses that fall in the latter camp should be executed is a tough question. That said, look at the most read articles in JACS this year (12 month tab). The majority of papers are total syntheses. So why do so many chemists read these papers? If we can answer that question, we may be able to define the utility of (parts of) the field of total synthesis.

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22. molecular architect on March 17, 2014 3:27 PM writes...

Eribulin, a synthetic derivative of halichondrin B, which is a a clinically useful agent for metastatic breast cancer, is MANUFACTURED by a synthesis of more than 60 steps. Presumably, it is indeed efficient by any cost of goods measurement or other marketability metrics. This is compelling evidence that total number of steps alone is enough to judge the usefulness of a synthesis. Furthermore, this work was based on Kishi's total synthesis of halichondrin B. While I agree that many total syntheses are not worthwhile endeavors, some clearly are.

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23. totalsynforthewin on March 17, 2014 3:28 PM writes...

As someone who did a total synthesis during their PhD training, I have to say that I believe it helped me immensely as a chemist. I agree that my 27 step synthesis would never be looked at by industry, and that the target would most likely be shunned by industry as well, however, the training I received while undertaking that project was second to none. In my view a PhD program is for training and organic chemists need to be trained well. As an organic chemist, I wanted to have my hands on a large number of reactions before I went into industry. With total synthesis, I achieved that goal.

During my postdoc I met other postdocs who had methodology based PhDs. They were great at those reactions, but lacking in solving synthetic problems that take multiple steps. I am not saying they were not great chemists. I simply noticed that in terms of synthetic strategy they were not as good as their counterparts who had total synthesis experience.

Being in industry now for a short time, I realize that many of the reactions I performed will not be used by med chem programs. With that being said, if industry is coming down to Pd/Cu/Metal couplings as a sole way of making compounds, lets just write a cookbook for chemists and stop giving out synthetic organic PhDs. I believe as organic chemists we need to continue to dissect and solve difficult multistep problems because sooner or later the aldrich/alfa aesar/CRO we all order from will run out of "novel" compounds for quick screening.

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24. NR on March 17, 2014 3:29 PM writes...

@20

I don't think his point was that it would have some ridiculous purpose beyond the obvious but that total synthesis was and, in my opinion, still is, the best way to train organic chemists in the areas of problem solving and multistep synthesis.

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25. Lyle Langley on March 17, 2014 3:31 PM writes...

Agree with #21...

@11 Ex-Med Chem...
Please tell me when you as an industrial medicinal chemist every cared about those things? How many times in J. Med. Chem. do you ever see the cost of goods? The list of reagents, etc. Please, step off the high-horse and come back to your reality.

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26. Anonymous on March 17, 2014 3:40 PM writes...

I really hope the ultimate goal of academic science is NOT to train students in the trade of molecule making for pharma. If so, this should not be called 'science', it should be a trade-school. Please recall that Science is investigation of the unknown and to uncover new knowledge.

Maybe separate synthesis trade schools can be opened and paid for by big pharma. Then, let the academic science do what it should, which is answer questions, and hopefully big ones.

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27. totalsynforthewin on March 17, 2014 3:53 PM writes...

@28

molecule making during a PhD should equal solving problems and answering questions to make those molecules. I believe that most total synthesis projects are not simply "look I can make this molecule in 60 steps using known reactions." If they are I would hope that mostly postdocs are on those projects because a mentor who gives a PhD in "I can repeat my fellow coworkers 30 steps" should be condoned for wasting a bright mind.

Furthermore, do you honestly believe that all the grad schools in the USA are uncovering new knowledge in their programs?

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28. Anonymous on March 17, 2014 5:50 PM writes...

@27

can i use known reactions to make a secondary metabolite is not trying to answer a question. its largely engineering. sadly, synthetic chemistry does not seek to answer questions. most big ones have been answered. its ok, fields do mature and cease to exist.

yes, many of the best programs in physics and biology are seeking to uncover new knowledge. like, 'what happened right after the big bang?' (see headlines today), 'how does the brain work?', 'why do most tumors resist therapies?'

now, what are the big questions in natural product synthesis? can we make taxol in 15 steps?--please...

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29. totalsynforthewin on March 17, 2014 6:22 PM writes...

Your right.

Apple should have stopped making computers after the apple IIe because heck we already know how to make computers and nothing new can come of it.

Chemistry is a mature field, yet there are still many types of reactions chemists cannot do well. I believe there is still plenty to be uncovered and a taxol synthesis in 10 steps utilizing both chemistry and newer biotech techniques? Count me in.

Now excuse me, I have to play some commander keen.

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30. Anonymous on March 17, 2014 6:39 PM writes...

@29

Mature fields have things to do, just not big things-there is a difference. i don't think we are entering an era of exploding discoveries in natural product synthesis. the 1960s called, they want your scientific goals back.

the analogy to computer/microprocessor design is ignorant. did you hear of Moore's law. not sure the equivalent exists in synthesis. i have trouble differentiating the synthesis papers of 2013 from those of 1990.

keep drinking the kool-aid...

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31. jd on March 17, 2014 7:57 PM writes...

@30

Perhaps there's a point to be made with your rejection of the computer analogy. But you certainly aren't making it.

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32. PharmaHeretic on March 17, 2014 8:55 PM writes...

FYI..
---

Infomercial pitchman Kevin Trudeau gets 10-year sentence

http://www.lasvegassun.com/news/2014/mar/17/infomercial-pitchman-kevin-trudeau-gets-10-year-se/

Best-selling author Kevin Trudeau, whose name became synonymous with late-night TV pitches, was sentenced to 10 years in prison Monday for bilking consumers through ubiquitous infomercials for his book, "The Weight Loss Cure 'They' Don't Want You to Know About." As he imposed the sentence prosecutors had requested, U.S. District Judge Ronald Guzman portrayed the 50-year-old Trudeau as a habitual fraudster going back to his early adulthood. So brazen was Trudeau, the judge said, he once even used his own mother's Social Security number in a scheme.

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33. BG on March 17, 2014 9:05 PM writes...

I believe that the big questions in total synthesis today are more involved with redefining the disconnections used to make the molecule. Look at the Acc. Chem. Res. paper for Guided C-H Functionalization Logic (doi: 10.1021/ar200194b)- this is an example of a new way to think about making natural products or molecules in general that is drastically different than traditional methods. Having a fewer number of steps is usually an outcome of a new, better way of making a compound. So, the end goal of synthesis has not changed (make the compound as quickly as possible in high yield), but the means to that end is what is evolving in the field.

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34. Probocateur on March 17, 2014 11:28 PM writes...

Too much intellectual mad truncation going on.
How about we count cost and yield of the synthesis?
In a. 50 step synthesis there will be this cool one step that will reduce your 25 steps to 10.
Organic Synthesis is an intellectual and practical art.Practical is what counts after all

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35. RCM on March 17, 2014 11:39 PM writes...

It seems to me that the era of "egotistical" natural product chemists is long over. In fact I have not for some time come across any natural product paper without a distinct application for being a potential pharmaceutical.

Sure, gearing natural product work toward atom, step and cost economic means is vital and advocates like Baran and Movassaghi are leading the current endeavors. Unfortunately, to "limit" the number of steps of a synthesis is a pitfall in its own right and will limit fundamental science. Of course, a 25+ step protocol isn't practical for industry, but there is something to be said for reaction development, which goes hand in hand with natural product work.

There is no doubt that current funding will go to the groups that have practical synthetic schemes for promising agents (as it should be). We can't forget though that the pure meticulous, precise, and tremendous (even unparalleled) problem solving skills that natural product chemists gain in the lab is and should be sought after by employers in industry.

It doesn't matter what sub-discipline of chemistry you are in, a natural product chemist, with their skills, can add value to your current endeavors.

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36. Iridium on March 18, 2014 5:17 AM writes...

Everybody says: "total synthesis is good at training students"

I doubt that.

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37. simpl on March 18, 2014 5:44 AM writes...

In the '80s, when Europe's finest were chemical conglomerates, a development chemist for additives confessed that they were only allowed a maximum of three steps, to be ensure a saleable product.
That tells you more about their range of options, and about the life cycle of the additives business at that time, and less about the chemicals they made.

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38. p on March 18, 2014 8:28 AM writes...

I think there are many valid criticisms of total synthesis both in the abstract and in practice.

However, those criticisms coming from the pharmaceutical industry is kind of funny.

Dying pot saying the kettle is dying. Maybe big pharma ought to take a look at longer, more complicated syntheses. Maybe both ought to get together and figure out what the hell they should do with themselves.

(Okay, neither is dying, exactly, but it's clear in both fields that times have changed and the big players haven't exactly been nimble in response).

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39. fluorogrol on March 18, 2014 8:40 AM writes...

@10. anon on March 17, 2014 12:21 PM

"Putting limits on step count only leads to fancier ways of counting steps."

Here's a neat way around the 'rule of 25': http://syntheticremarks.com/?p=3970

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40. fluorogrol on March 18, 2014 8:46 AM writes...

In general I agree with MTK - an arbitrary numerical limit is too binding. Judgement is needed to decide if a long synthesis is mere brute force or not.

Also seen a fair few short syntheses that are unimaginative, inefficient, mechanical sequences of known reactions. 'Mercifully brief', perhaps.

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41. Ex Med Chem on March 18, 2014 8:47 AM writes...

@25 Sure happy to, I just hope I can keep this short.

I spent the vast majority of my med chem career in lead op, the stage of development where you turn a ligand into a drug.

I was personally very interested in COG, number of steps and the types/quantities of reagents used, yields, etc used since
- some point very soon after solving all the other issues my team was going to have to make 100+g in a very short space of time. Then Chem Dev would have to make a few kilos in a few months.
- COG is a key part of any ROI projection for a drug
- If you have a nasty step, reagent or solvent in there, that reduces your probability of success since it has to be (a) replaced or (b) optimized greatly or (c) managed appropriately which usually means high cost and lots of time
- All the delays to fix the issues in the synthesis eat into your patent life, reduce the ROI and extend the time it takes to get the drug to patients.
- I also tried to avoid reagents that would eiter kill me or damage my body in bad ways (e.g. 1,2 dichloroethane, osmium tetroxide, KCN, etc)

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42. Ted on March 18, 2014 11:06 AM writes...

Hi:

The biggest driver for COG is almost always labor and overhead. In many cases, the efficiency of a production process is really associated with how well matched the process is to your equipment train. Sometimes reducing the pot size by 3% can make a huge difference, and other times increasing a yield by 10% makes little. It's all about the specifics.

My first job out of school was helping to evaluate a number of 'academic' total syntheses for a PIII candidate with strong prospects. It ended up becoming a 'blockbuster.' We developed a novel approach, published as a 'practical' synthesis (this was just before OPRD, so it came out in JOC, albeit with at least one multikilo scale step in the experimental...).

Even at 17 - 20 steps (I can't remember off the top of my head...) it was an order of magnitude superior to the best existing semi-synthesis in both COG and scalability. My understanding is that this process (probably with some modifications) is being used to this day.

In the drug world, we really only worry about the number of registered steps. The five (20?) steps to set aromatic substitutions, build cores, etc... all comes from China or India. Do we count those steps? SAFC either made it or bought it from someone. We started with citrazinic acid. Do we count the step where someone condensed citric acid and ammonia?

No matter how you break it down, counting steps is a fundamentally academic exercise. Whether the product (either goods or knowledge) is worth more than the work you put into it is the real question.

-t

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43. Gilgerto on March 18, 2014 12:08 PM writes...

Eisai has commercialized Halaven which takes 62 steps to make...
https://pubs.acs.org/cen/coverstory/89/8943cover2.html

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44. LM on March 18, 2014 12:23 PM writes...

Even as a fan of total synthesis, its hard to disagree with a lot of the points made against it. But personally, perhaps due to my ignorance and lack of understanding about process chem, I just don't really find a lot of the structures and synthetic routes to medicinal compounds that exciting. Its pop vs classical for me.
I'm curious about the long term consequences if all funding was cut for TS projects. I've definitely seen chemists publishing high impact nano research who fumble with basic organic chem. I'm sure that the skills provided by TS will be required in the future once the chemical space accessed by couplings and substitution chemistry is pillaged.

Permalink to Comment

45. Anonymous on March 18, 2014 3:55 PM writes...

I would take a 62 step synthesis and optimize the potential lead such as Halochondrin B to Halaven than the combinatorial synthesis of the billion random molecules and end up with nothing to show for.

Johann Mulzer mentioned that it is time re-orient the field, and he laid the criteria for the synthesis.

Can the funding agencies come up with the list the potent molecules that they want TS chemists to develop the routes for/ invite the proposals through their RFPs i.e., mechanisms?

I think all the PIs know what they are doing and why they are doing. A best practical route would only evolve when a bunch of routes are developed and/or with the advancement of suitable methodologies.

I am sure no one would jump in to synthesis of a molecule if there is no scope for some novelty. The novelty lies in the eyes of the practitioner of this very challenging and demanding field.

We would not have been able to reach the stage we are at if not for the total synthesis. As Phil Baran says it is the engine the drives the discovery process of new reagents, new reactions and new methodologies. How many of us have experienced the joy of completing the synthesis of a natural product? Go make one, if you can and come back and comment. Me and my boss are ardent fans of this area of research though we are starving of funds. We are excited each day when we create new compounds and form new bonds that did not exist before.

Permalink to Comment

46. Anonymous on March 18, 2014 8:53 PM writes...

There is a pitfall in Mulzer's suggestion which is

"On developing a retrosynthetic analysis of a more complex target it is advisable to design several strategies which are then pursued in parallel by the individual coworkers, until, in a pseudo-Darwinian manner, the most eļ¬ƒcient route emerges"

In reality, individual PIs pursue total synthesis of same molecule until an efficient route develops by learning the strengths and draw backs of each other approaches, as exemplified by his own pltaensimycin's approach.

You simply got to appreciate "total synthesis".

The crappy funding agencies go with messy "bandwagons" such as nanaoscience, combichem, etc.

Time will prove as to how much of nanoscience is reproducible and how much would pay off for the investments.

What triumphs at the end is real ability to make the bonds in stereo, regio, chemo specific ways!

Stop blaming total synthesis!

Where are all the stalwarts of "total synthesis"? Hwy don't you all make a collective effort to re-define/ re-orient the younger chemists so that the field would thrive in future.

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