Monday, December 19, 2016

11-Step Synthesis of (–)-Thapsigargin

Our synthesis of thapsigargin is out today in ACS Central Sci. Since we’ve prepared a detailed supporting information, we will forego discussion of the failed approaches & optimizations in this blog post (feel free to email us or comment if you’ve got any questions though). We will instead use this post as a means to openly discuss a defining aspect of not only this synthesis, but also of all of our 2016 syntheses: step-count.  Thus, this blog is intended to stimulate an alternative type of peer reviewing–we present our reasoning behind a simple definition of a step and seek opinions from all readers.


Similar to other recent total syntheses (pallambins, maoecrystal V, and araiosamines) emerging this year from our lab, our manuscript was originally titled “11-Step Synthesis of (–)-Thapsigargin” (kinda gave away the punchline to the tweet here). In doing so, we abstained from using subjective and assertive descriptors such as “concise” and “short”. Here is the direct feedback we got from peer review:

"Their claim of 11 steps in a title is unhelpful, I would accept a “Short synthesis of…”, but not a step count. This sets a bad precedence in that we no longer claim “a first synthesis” as being valid. The same is true of step count since as the authors are well aware, step counting is just one of many criteria to judge a synthesis. If we allow a step count number to become normal practice, all total natural product synthesis will have to begin with this count of the synthesis steps. As we know this says nothing about efficiencies or the elegance or costs of an approach."

And:

"The work includes the step count as primary consideration, something that has become a trademark of the author, as noted in the title. There are serious problems with this metric as practiced by the author: (1) the count is conducted in a manner not entirely transparent or logical, as such it does a disservice to the community and pioneering efforts of others that have previously worked on the targets; (2) it leads to erroneous conclusions. The principal investigator has repeatedly been engaged in such miscalculations; and prior ways of counting should not justify continued obfuscation."




This is really valuable feedback as it is likely that if these referees believe this then certain members of the community must also feel the same way. Although we are perplexed by the reviewer’s assertion that somehow the exact step-count included a title makes the first synthesis invalid, the other points raised by the referees deserve comment. To us, inclusion of the step-count in the title solely provides an immediate, objective, and unopinionated depiction of the synthesis – it informs the readers that the synthetic sequence disclosed comprises 11 steps.  And we're certainly not alone as there have been dozens of high-profile total syntheses by other groups published with step counts in the title. By no means is this a Baran lab "trademark".  

The more serious accusation, however, is that our definition of step-count is somehow not logical or transparent. Or even worse that we are engaging in outright deception. Open-Flask was started years ago specifically to bring more transparency to our research. We feel that the most transparent and fair way to discuss this is out in the open rather than in the comfortable anonymous basement of peer-review.


IUPAC defines a step as a process that "proceeds through a single transition state" which largely pertains to physical chemistry phenomena. When organic chemists refer to a step of a synthesis they are usually referring to what goes on in a flask (reagent additions, etc.) followed by some sort of work-up or purification (which signifies the end of a step).  On several occasions we’ve explicitly defined that a single reaction step is one in which a substrate is converted to a product in a single reaction flask (irrespective of the number of transformations) without intermediate workup or purification. This definition seems to be the most pragmatic and encompasses what most organic chemists think of when speaking of a step (things go into a flask followed by a work-up which signifies the end of a step).

Although we can't rule out hacking from an outside group, or other sorts of rigging, the Twitter community seems to mostly agree as well based on this super-scientific poll we did the other day:
Yes, some people will argue that amide-bond formation should be counted as 2 steps...
Some of the discussion on Twitter is really revealing. Many people have different opinions as to what constitutes a step or not with some arguing that the whole concept of a step is outdated and should instead be replaced with other metrics, such as number of operations or even person-hours. 

In our most recent syntheses as well as this one, we have strictly conducted our step-count according to the definition outlined above. While not perfect, it is a simple definition that accounts for many types of reactions. For example, a number of classic transformations (e.g. Swern, Ugi, Passerini, Strecker) involving multiple distinct intermediates (the last 3 isolable) and all fit into this definition. So do cascade or tandem-reactions. How many steps is Corey's legendary aspidophytine total synthesis if we break up the key step into individual components (multiple reagent additions and at least eight elementary intermediates, some of which are isolable)? How about Noyori's classic prostaglandin synthesis that introduced the world to vicinal difunctionalization (multiple reagents added and 2 new C–C bonds generated)?  Let's take the Swern oxidation as a glaring example of this discontinuity in step count – this venerable reaction comprises three distinct transformations as shown here. 
How many steps is this step?
However, since all of them take place in a single flask, it has always been considered as one step. So, three different transformations actually happen, but the net result is that an alcohol is oxidized to a ketone.  Finally, what about the most used reaction in all of organic chemistry: Amide bond formation. There, one adds an activating agent like DCC to form an activated ester (sometimes isolable) followed by addition of an amine. Is that two-steps or one (a few people apparently think 2, see above poll)?   By now you might be rolling your eyes and thats the point. This is common sense. Most people will agree that the sequential addition of reagents or solvents to the same flask does not constitute a new step.  Filtering over silica or Celite, workup of any kind, adding scavenger resins – all of those things signal the end of a step with further operations on crude or semi-crude material representing a "telescope". For example, in Wender's synthesis of Phorbol (summarized graphically here), the following procedure is characterized as a single step in the overall step count (reported as 36 total) as presented the manuscript but I think most people would agree that the SI clearly describes a two step process (ketone to enol ether to alpha-bromoketone):
Flash Chromatography, rapid or slow, signifies the end of a step.
Now lets take a look at one of the steps in our synthesis that triggered the referee comments above. It accomplishes two transformations in a single flask (TBS installation and allylic oxidation).  By the logic outlined above, this should also be counted as one step. There is no deception here.  We are uncertain how alternative definitions of a step can be rewritten – after all, each single transformation within the “step” can be further divided into combinations of elementary steps.  
How many steps here?

Here's the procedure. Still looks like one step to us.
We've had this discussion in the lab and in group meeting to try to derive the contrary view. And it basically boils down to this:  If folks can get away with this then why not just take 40-step syntheses and turn them into 5 step syntheses by doing everything in one pot? But this is a vast oversimplification of how synthesis works and the strategic thinking that underpins the design of a multi-step synthesis in which orthogonal transformations can be incorporated into a single reaction vessel. Simply stated, not all transformations can get along together in the same flask. 
Indeed, one-pot multi-transformation steps are embedded into the strategy of a synthesis, meaning that when steps in which one pot reactions can be engineered (e.g. without sacrificing yields significantly & saving solvents, purifications, and manual labor), we went ahead and performed them. As a result, there’s a very clear logic behind conducting these one pot sequences. Although orchestrating such one-pot sequences can conceivably improve the overall efficiency of a concise synthesis, the improvements will be proportionally less substantial for longer syntheses. In other words, attempting to shorten a 40-step synthesis with just this tactic alone will be fruitless just like speeding up a conveyor belt does not always lead to a higher production rate.
Image result for lucy chocolate factory gif
Thus, we believe the discussion on step count is entirely perched on the overall strategy of the synthesis. 

Although step-count is an important metric for measuring the efficiency of a synthesis, we are not claiming that as long as it’s short, one can go ahead and ignore all the other criteria for a good synthesis. The best example we can think of where a longer synthesis can be better is in the commercial synthesis of Halavan where the heroic Eisai team, led by process legend Frank Fang, favored a longer route due to the identification of crystalline intermediates that facilitated purification. In the case of thapsigargin, we actually report an alternative longer sequence (14-steps) that offers a distinct advantage for the production of certain analogs (in this case a higher yielding photo-rearrangement and the ability to incorporate different esters via simple acylations) over the shorter sequence. Details of this other route are included in the manuscript & the SI.

Some might argue that a better way to present step-count in synthesis would be to report actual isolated intermediates instead of actual steps. At the end of the day, someone (referees, students in a group meeting somewhere, readers, your parents?) will be counting the actual steps (which begin and end with isolated intermediates) so we're not sure it makes any difference. Also, we are still on the fence regarding the removal of a solvent as representing a new step (there was some fruitful debate on Twitter about this - the classic Arndt-Eistert reaction for example usually involves a solvent swap but no workup) and lean towards a definition where PURIFICATION of any type signifies the end of a step as the evaporation of a solvent is no different than refluxing a solution (without the cap).


In any event, the short or concise or 11-step or 14-step (your preference) scalable synthesis reported here facilitated LEO Pharma's interest in a medicinal chemistry campaign based on this chemotype. They filed a provisional patent on the route, have successfully outsourced it on 100-gram scale, and we are currently working on interesting analogs with them using advanced intermediates they have provided. 
However one counts it, the synthesis of Thapsigargin is now scalable.
One of the most interesting publications on the topic of trying to design syntheses that incorporate multiple transformations in a single step (cascades) was written by Tom Kieboom, a process chemist at DSM and adjunct professor at Leiden University. In that insightful review, the challenge of mimicking Nature's ability to conduct multiple orthogonal reactions without intermediate work-up or purification is discussed. As someone mentioned on Twitter, by the current definition, Nature makes most of it's products in one "step".  One thing that is clear is that if chemists could make natural products the same way, it would be a cause for celebration rather than a moment to debate step count. 

For some other recent reviews on the topic of efficiency that incorporate step count into the equation, see these from process grandmasters Martin Eastgate and Chris Senanayake. In addition, the Krische lab's impressive perspective published earlier this year in JACS defines a step in a similar fashion (see SI - "a step is defined as an operation that does not involve any intervening purification/separation, including removal of solvent, commencing with compounds that are over $50/gram.").

We welcome any critique and feedback and look forward to an open dialogue of step-count here at Open Flask or on Twitter.  We realize and respect the fact that not everyone will agree with this simple definition of a step and thus, as the referee above stated, it is important to evaluate syntheses based on more than a single variable

Yours truly,

Thapsigargin team 
(thanks to Phil and other Baran Lab members for help with this post)

41 comments:

  1. I actually admired your lab's way of titling the syntheses since phorbol.
    That first reviewer's line "this says nothing about efficiencies or the elegance or costs of an approach" is laughable. As if someone still buys those "elegant", "efficient" or "concise" adjectives in the titles. And nobody holds one from naming the paper something like "The first, n-step, synthesis of whatever" if they really want to.
    And, anyway, de gustibus non est disputandum. Looks like peer-reviews need some sanity checkups, to keep the discussion on what really matters.

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  4. Phil and the group have undeniably changed the climate in the area of total synthesis. They've really pushed the envelope and come up with a lot of strategic mastery and redefined what a "great synthesis" is and what it should be.

    What I think is that the reviewer is echoing sentiments across the field to what might be an overemphasis on step count that detracts from the importance of his prior work. This newest paper is awesome, strategically it's important and a huge leap over prior syntheses. But it understandably irks the older generation to have different definitions of step count because their work is set. The fact is, in the 90's, there wasn't any emphasis on step count. Nobody cared! It wasn't in their scope! So now you're telling a whole bunch of older professors that their syntheses are shitty and inefficient because of something that wasn't their focus.

    It's a really hard standard. If in 20 years the entire field decides that solvent concentrations more dilute than 0.5 M are totally useless, should we say that all of the Baran group's syntheses are horrible because they use higher solvent concentrations? Fields evolve, they change, and comparisons across generations are never going to hold up well to comparisons.

    The last synthesis of Maoecrystal V, in particular, seemed to really stretch definitions. If we consider it from a strategic point of view, the syntheses was not quite as short as the step count would indicate.

    Although I think there are a lot of jealous haters in the field that criticize harshly, I don't that their criticisms aren't founded in some element of truth.

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    1. Thanks for the kind comments but especially for the critique. We see your point here but step count is not a new thing. We've been hearing about counting steps for atleast 20 years now. Hudlicky's book on synthesis uses step count extensively as an important metric. It's not the only metric but it is a simple one and almost always indicative of synthesis simplicity. Step count is not going away any time soon.

      We fully expect that in 20 years people will view the synthesis of today as outdated. Theres nothing wrong with that. That's the nature of advancement.

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  5. ACIE, 2012, 7507: "The concise synthesis of the proposed structure of A (5) further demonstrates the power of C-H functionalization logic in synthesis to provide substantial amounts of complex cyclobutanes (7 steps, 5 chromatographic purifications, 5 % overall yield, > 100 mg prepared).

    According to the Baran group definition of a step as stated above: "On several occasions we’ve explicitly defined that a single reaction step is one in which a substrate is converted to a product in a single reaction flask (irrespective of the number of transformations) without intermediate workup or purification" this fine synthesis should really be summarised as an 8 step synthesis.

    The first step involves a reaction in a photoreactor, then a change in reaction vessel, followed by partial concentration..
    SI:
    S1(12): Methyl coumarate 1 (1.00 g, 6.49 mmol) was dissolved in dry DCM(1.0 L), transferred to a photoreactor [ACE glass, 1 L jacketed reaction vessel (#7841) with quartz immersion well (#7854)] and purged with argon for 30 minutes. The vessel was irradiated using a 450W mercury Hanovia lamp through a pyrex filter at 15 °C for 96 h. The solution was then poured into a roundbottom flask and concentrated to ca. 100 mL. 50 mg of 10% Pt/C was added and hydrogen gas was bubbled through the reaction mixture for 4 hours. The reaction mixture was then purged with nitrogen, 8-aminoquinoline (1.12 g, 7.79 mmol, 1.2 eq) was added
    and the flask was cooled to 0 °C in an ice bath. EDC (1.49 g, 7.77 mmol, 1.2 eq) was added in a single
    portion and the reaction mixture was warmed to room temperature and stirred for an additional 3 h. After
    filtering the reaction mixture through a pad of celite, it was washed with saturated aqueous NaHCO3 (50
    mL), brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The resulting dark red oil was
    purified by column chromatography (25% to 50% Et2O in hexanes) to give S1 (995 mg, 3.50 mmol, 54%
    yield) as an orange oil.

    I can understand the referees potential frustration with the way in which step count has been reported over the years. Why not let the science speak for itself? It is already a great synthesis, why not err on the side of caution and keep the tally at 8 and not 7?
    I think that is the problem a lot of the synthetic community have - there isn't a unified way in which we all report step count, and when we contradict the metrics we define, then it just muddies the water further and makes it harder to compare step count in a fair manner across the generations.

    Great paper though

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    1. Thanks but still stand by this as being one step. There's no purification till the end and if we wanted to we could do the next transform in the photovessel. No purification here.

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    2. That maybe true, but as written in the scientific literature, the procedure uses two reaction vessels and partially removes solvent. Perhaps a more accurate definition of step count would be: "a single reaction step is one in which a substrate is converted to a product in a single reaction flask, or if convenient, in a different flask, and reaction concentration can be fine tuned through use of a rotorvap (irrespective of the number of transformations)" I am not trying to be critical, I think the synthetic community would generally agree that it is important to be consistent with how we present our research, and maybe if there was a twitter poll for this particular example, then the findings would be different to the twitter poll presented in the post. Like I said, the science is great, why not err on the side of caution and round the step count up one instead of down, and perhaps the lab won't receive anymore reviewer comments like the one posted above.

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  6. As you say the literature is not entirely consistent, but I think the convention overwhelmingly is to count a TBS protection as a step even though in 95% of cases it could be easily added to another transformation with minimal effort. More generally, the common practice is to isolate, purify and characterize all intermediates that are stable to standard work up and purifications (although not 100% consistently, as you note). Comparing then a "11-step" synthesis where every possible step has been telescoped to the synthetic literature at large then becomes an apples to oranges comparison. The entire synthetic community could in principle switch to the Baran paradigm, but I envision countless graduate student years being spent optimizing reaction cascades to minimize step count that would be better served doing other things. A better solution might be to report a 14 step,11 pot synthesis (or similar language)

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    1. Appreciate this critique. As mentioned above, it's conceivable that the conditions for installing a TBS are mild enough to withstand some ensuing steps but again, the example above is not a telescope. We present both syntheses (14 and 11) here. We argue that the act of combining transformations is not as easy as you imply and actually requires thought and strategy design. And even if you succeed you won't be able to shorten a 40-stepper more than 10%.

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  7. I hope this is not too harsh - but it feels as if your group, and particularly the attitude of this post and some of the replies, detracts from what I think is the most significant message out of the Baran group. As you said above: "the act of combining transformations is not as easy as you imply and actually requires thought and strategy design."

    I think this is really the KEY here. I think that is what underscores amazing synthesis, in sequences and so on, and really needs to be emphasized to the next generation of chemists. HOWEVER, I think that overemphasizing "getting multiple things that we used to do in two steps to go in one pot at two stages with a solvent swap" is a massive distraction from the primary message.

    For an online message board I think these are reasonable debates to have, and I appreciate the process-oriented view of reaction economy, but if you were to go out onto the job market, and try to have the same semantics argument about what constitutes a single step during job interview, you would absolutely get hammered. People aren't looking at who can argue about how to make one step or one pot better, they are going to be more interested in how you approached the molecule as a problem that needs to be solved, at how you made it scalable and efficient (which you did excellently!), but you'll really turn people off by overselling a detail that many people will fundamentally disagree on.

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    1. Good point and thanks for your kind comments. As you mentioned, this is why we are discussing this on a blog where people can tune out and pay no attention to us. There's nothing "in your face" about publishing in a blog. This is an issue that people DO talk about. We agree that this IS A MASSIVE WASTE of time and distraction to obsess about BUT it keeps coming up. We have devoted all of our blog posts to the underlying strategies and big picture but this time we wanted to talk about something that keeps coming up so that we never need to address it again (including when we interview for a job).

      Thanks for your feedback!

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  8. You emphasize it's important to avoid evaluating a synthesis using a single variable, but so much in this paper points to using step-counts as a metric to evaluate and compare syntheses. You wanted the title to have the step-count. The abstract, graphical abstract, introductory paragraph, and introductory scheme all point out the step-counts for previous syntheses of these molecules. If you take these together of course it is begging for single-variable comparisons even if you aren't explicit about it. This emphasis is where you get people uncomfortable, because, like you imply in this blog post, it is only marginally useful to compare step-counts for two syntheses of the same molecule and it detracts from the important parts of the science.

    I disagree when you say that not every synthesis can benefit from telescoping techniques and that a standard 40-step synthesis could only be reduced by 4 steps because it lacks the strategy and thought necessary for combining steps. I'd love to have the grad student who worked on this try to maintain a straight face while telling me that combining a TBS protection and a SeO2 oxidation required strategy. I'm not saying it's easy (it takes thought and effort for sure), but it hardly adds to the science of synthesis. Perhaps we can agree to disagree on this point, but I think that's the crux of why people are uncomfortable with your overwhelming emphasis on step-count. It looks like you're taking the field two steps forward when you drastically simplify a synthesis to a natural product, but one of those steps feels fake because it's based on reducing steps using telescoping techniques. Scientists really don't like moving a field forward if it feels fake, so pushback is inevitable.

    My unsolicited and untrained advice is to go easy on emphasizing step-counts. I think good form is to only mention your overall step-count in comparison to that of previous syntheses in the concluding paragraphs. You can emphasize in the introduction that your goal was to shorten the synthesis because you wanted lots of material, but announcing your overall step-count before anyone has read anything doesn't serve any purpose except to draw untoward single-variable comparisons. And if you mention how you used previous labs' routes as inspiration long before you numerically describe how your synthesis is vastly superior it will show traditional deference to precedent, another thing that makes scientists comfortable. It's not your science or how you define steps that upsets people, it's how you write your papers. Sure, you gotta do what you gotta do to get your high-level publications, but it seems to me people are pushing back so you might have to find another schtick. :-)

    Good luck in the future! Very cool science!

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    1. Very good points and we appreciate the feedback! We will take these to heart moving forward.

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  9. The overreaction possibly has to do with a long-going trend in the total synthesis community, of ever increasing salesmanship and inflated yields. Referees follow their own (intuitive) understanding what is one-step synthetic transformation, and of course when you put "eleven step synthesis" in the title of your article that accomplishes several non-obvious transformations in one pot, you invite irritated responses "how dare you call this one step?!"

    I think it is legit to call a procedure one-step if you just keep adding to the flask, without removing any material in between (does Dien-Stark dehydratation count?) and there is just one traditional workup at the end, and the whole multi-operation sequence is finished within a tolerable reaction time - i.e. brought to workup in less than 4 days. But there is no precise agreed one-step definition; the more you streamline your synthetic sequences the more you may find yourself arguing these points repeatedly.


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    1. Thanks Milkshake. Great points. Agreed. We are devout followers of Hudlicky's great review on yields (https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0030-1259018) and that's another reason we like to do things on gram-scale. It requires lots of optimization and the processes are more robust and the yields are more accurate.

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    2. gram-scale final steps on targets of this complexity is really impressive. How do you go about process development and scaleup over 3L flask size - do you have kilo-lab equipment for this at Scripps, or do you have industry collaborations with process groups, to take your synthesis and re-optimize it?

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    3. Yes. LEO is really great regarding this. They contract a CRO to do the mega scale for us. Feedback is that if we can do gram in our little lab then 100-1000g is not a huge leap forward for them.

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    4. If you ever did want to try scaling up yourselves and didn't mind/had enough money in the grant for a trip to England we have a large scale lab facility in iPRD at the University of Leeds that is set-up for PhDs and postdocs to get training in and run their own reactions.

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    5. Wow that sounds like a great resource!

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  10. Step count, always a bone of contention.
    In the SeO2 example you gave above I would count that as 2 steps. Why didn't you isolate the silyl ether? Why is the yield only 52%, what is the rest of the material? Would the yield have been higher using pure silyl ether? Would using pure silyl ether reduce the amount of SeO2 from 10 equivalents to, say,5? What is the effect of having a 95% yield of silyl ether, or don't you care because of the 10 equivalents of SeO2?
    To be able to telescope a sequence you really need to demonstrate that it can be done without detriment to the final product you isolate. By detriment I mean the quality and the yield. Now this is moving into the realm of process chemistry, however, such information is of interest to everyone.
    I don't like the use of the word scalable. This synthesis, while being an excellent achievement, no denying that, is not scalable. All you can do is make larger quantities of material. This can be done in a good kilo-lab on a reasonably safe basis.
    What would you do if I said I need 50 Kg of final product?
    In spite of my comments I enjoy reading about the work emerging from your lab. It is exciting and refreshing to see a different approach to total synthesis.

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  11. Thanks Quintus. All good points. Please see our SI as some of this is addressed with the longer route. We say scalable because in the Lab's experience so far if we can handle a gram here then it can be scaled to much larger amounts (see above). It's all relative. If we did 1 kg scale someone could say "it's not scalable till you do it on metric ton". So I suppose one could have a discussion about what constitutes "scalable" as well.

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  12. I agree that, in terms of transparency, the Baran lab is leading the way with its excellent Supporting Information files (as you pointed out, the point of this blog). But there are still other practices are appear deliberately non-transparent: for instance, "A 14-Step Synthesis of Ingenol from 3-Carene" appears to be true, by shying from convention, we typically count longest-linear sequence. Given that the chiral allenyl aldehyde in that synthesis seems to go through a longer step sequence, it almost seems like there is a clear lack of transparency in that case! Of course, nothing about the title is false, but I hope you can see how that might be perceived as slightly misleading.

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    1. Good point Alan. We followed that paper up with a full account and a blog post but can still see how one could view the simple allenyl aldehyde as a problem.

      What the Twitter discussion and this blog have taught us are that there are areas we can and will improve upon.

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    2. Yes, but following up with a full paper in detail "transparently" also contributes to the the feeling of non-transparency. It's easy to be transparent after the first paper has already been published in Science, isn't it? Much like it's easier for car dealerships to be transparent about the terms of contract if the customer has already signed the forms.

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    3. Well we don't agree there. There is nothing wrong or dishonest about the 14 step title because it says from Carene.

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    4. It's not dishonest per se, but I fail to understand how you can be so surprised that people don't like this kind of practice. Everybody counts steps from something commercially available or known. In any case, convention is to count the longest linear sequence. Your way way is not dishonest, but seriously misleading as people will assume you counted the LLS.

      This is part of a bigger issue with how the Baran lab counts steps. One one hand, you stress the step count much more than usual. Nothing wrong with that. But on the other hand, some of the step counts just really derive from common practice. Look at the Maoecrystal synthesis. On multiple occasions, the reaction mixture was azeotroped multiple times with toluene before the next step. How is that not some kind of purification?
      I guess what I am trying to say is the following: The science from the Baran lab is great, no doubt about that. But I think don't appreciate the hyping that comes with it. Reporting a Maoecrystal synthesis with 14 instead of 12 steps would still have been a fine job. But in order to seemingly have a greater conceptual edge over the competition, this whole step-meddling just looks misleading and like "creative accounting".
      So why not stop this whole stressing of the step count and just do great science?

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    5. I guess we'll just have to agree to disagree on this. Regarding ingenol we clearly state that the step count is from carene and one could argue that it's not even a total synthesis but rather a semi-synthesis since we start from carene (we have a blog post on that topic too). Regarding maoecrystal, we don't think azeotroping counts as another step because operationally it's just letting solvent boil off and adding more solvent. I guess we just have a more pragmatic approach to thinking about this.

      So perhaps the way to keep people happy will be to mix it up and sometimes just put "Short" or "Concise" instead of step count in the title... We are definitely happy to have these issues aired out here on this blog.

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  13. The review comments strike me as somewhat harsh; a step count is valid - it is what it is - but I'm not sure that it's particularly informative. The subjective nature of a step could be simply addressed by discussing the number of isolations, as that reflects exactly what you are doing, but as a measure of how quick or efficient the synthesis is I think there are better metrics.

    Atom efficiency or process mass intensity are good measures of how much input material you need per output unit, carbon footprint would allow energy demands (eg: lengthy distillations/solvent swaps) to be considered, cumulative reaction and work-up time gives an idea of how much time or lab resource would be needed.

    On the linear/convergent point I do think you have to talk about how many total chemical steps/isolations are required to go from commercially available starting materials to product. In reality that's what relevant to the amount of time and effort will be required to make the target compound. Fully accept that defining the number of steps from compound x is neither wrong nor dishonest, but it's not the whole picture either.

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  14. The problem is merely one of accepted terminology. I would be happier as another contributor has said with a 14 step 8 pot description or similar. To me a step is something that produces a new molecule that could in principle be isolated by say chromatography or distillation. So activating a molecule with DCC doesnt count as one never isolates the intermediate in practice, and the intermediate reacts in situ with the nucleophile, often before all the substrate is consumed. Producing an acid chloride though is a step, as usually the solvent and XS reagent is removed before the next reaction, and the acid chloride is sometimes purified say by distillation or crystallisation and even characterised.

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    1. We get your point. It makes sense. The problem is that in practice you'll need a "step council" like a referee system to determine what's isolable and what's "a new molecule that in principle could be isolated". We could cite 50 examples that violate the logic outlined below. And then what would you propose? A handbook organized by IUPAC to let people know when they can claim a step or not? Why does it have to be so darn complicated?

      The bottom line is that we think the field will progress if the community simply agrees to a definition even if it's not perfect. At the end of the day, if one can make taxol in 5 steps but in that hypothetical synthesis one could find intermediates that "in principle could be isolated" it's missing the larger point of the advances in efficiency that are taking place.

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  15. Hello guys, I am a Hudlicky group member. Congrats for yet another wonderful synthesis. I saw Dr. Hudlicky's book/review was mentioned in the comments. We (Prof. Hudlicky and group) have had discussions in the past about your syntheses and their titles in our literature presentation meetings.
    He himself calls these 'steps' as operations; and I quite agree with it. The IUPAC terminologys were set years ago, when cascade reactions were not so much in fashion. Today, we all look forward to make processes easy, and industry-friendly. I believe this is the time to redefine the terminology.
    Happy that you guys are addressing this issue gracefully.
    All the best for your future endeavors!

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    1. Hi Mukund, thanks for your comment. He's probably right but step is just simpler than operation. Will be a struggle to convert the whole community to that system. Please send our best to Prof. Hudlicky. We are fans of his book and his science.

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  17. Further discussion of your article at the Reddit chemistry community: https://www.reddit.com/r/chemistry/comments/5qixwg/debate_over_what_counts_as_a_step_during_chemical/

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  18. Putting all the discussion about step count aside: Having read the paper, I am, frankly, a bit surprised by the terminology used in the paper.
    How can one claim to quote "invent" a route that is in essence a variation of Massanet's route as detailed in the two papers you cite? Your wording makes it seem as if you only used the key rearrangement from them.
    Fair enough, you add the missing hydroxylation via allylic oxidation, but the majority of steps seems to have a good amount of precedence. Looking at the Massanet paper of 2014, their final compound is thapsigargin minus the butyryl moiety.
    On an unrelated note, I fail to understand how 500 mg are gram scale.

    Overall, the sensationalist salesmanship approach, in my opinion, overshadows what is actually a very neat and well-executed synthesis.

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    1. Appreciate your criticism here and thanks for giving us the opportunity to respond to it. We give ample credit to Massanet however there was a ca. 10 year elapse from that work and this paper. If it were obvious someone would have done it. It turns out it was not simple to adapt the precedent to the actual natural product as extensively outlined in the SI. Thus we believe this constitutes an invention based on the Webster definition of invention. With respect, we don't see how that being sensationalist.

      All steps were carried out on gram scale and well over a gram of the next to final product (due to extreme toxicity) has been made and most of the route outsourced at this point.

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