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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: Twitter: Dereklowe

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April 15, 2014

Total Synthesis in Flow

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Posted by Derek

Ley%20flow.pngSteve Ley and co-workers have published what is surely the most ambitious flow-chemistry-based total synthesis ever attempted. Natural products spirodienal A and spirangien A methyl ester are prepared with almost every step (and purification) being done in flow mode.

The scheme shown (for one of the intermediates) will give you the idea. There are some batch-mode portage steps, such as 15 to 16, mainly because of extended reaction times that weren't adaptable to flow conditions. But the ones that could be adapated were, and it seems to have helped out with the supply of intermediates (which is always a tedious job in total synthesis, because you're either bored, when things are working like they always do, or pissed off, because something's gone wrong). Aldehyde 11 could be produced from 10 at a rate of 12 mmol/hour, for example.

The later steps of the synthesis tend much more towards batch mode, as you might imagine, since they're pickier (and not run as many times, either, I'll bet, compared to the number of times the earlier sequences were). Flow is perfect for those "Make me a pile of this stuff" situations. Overall, this is impressive work, and demonstrates still more chemistry that can be adapted usefully to flow conditions. Given my attitude towards total synthesis, I don't care much about spirodienal A, but I certainly do care about new ways to make new compounds more easily, and that's what this paper is really aiming for.

Comments (13) + TrackBacks (0) | Category: Chemical News


1. Curious Wavefunction on April 15, 2014 11:42 AM writes...

"Flow is perfect for those "Make me a pile of this stuff" situations."

I know very little about flow chemistry, but considering that we are now looking at more complex, natural product-like molecules in drug discovery, does something like this herald good days for process chemistry synthesis of "beyond rule of five" drug candidates?

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2. Anchor on April 15, 2014 12:19 PM writes...

..go with the flow!

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3. anon on April 15, 2014 12:55 PM writes...

As a proof of principle, I can understand this, but look at the tremendous quantity of solvents and reagents required - and how much material is wasted during equilibration of the reactors. I can't envisage anyone actually wanting to do something like this to solve a real problem

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4. MTK on April 15, 2014 1:25 PM writes...


I partially agree with you.

Ley of course did the same thing (an entire synthesis or close to it) using only solid supported reagents. And yes as a proof of principle he's trying to show that just about any reaction can be done using flow or solid supports. But criminy, he doesn't have to repeatedly beat me over the head and shoulders with it.

There's making your point and there's liking to hear yourself talk once everyone has already agreed with you.

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5. Diogenes on April 15, 2014 1:40 PM writes...

" ways to make new compounds more easily."

Is using flow chemistry (with all of the requisite on-line monitors and hydrodynamic infrastructure) *really* easier than using a series of round bottom flasks for a molecule like this? Really?

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6. CMCguy on April 15, 2014 1:44 PM writes...

I do not have access to the paper but would be interested to know if the paper discussed the whys and why nots for flow-chem application at various stages especially if they included any direct comparison examples for the quality, yield and time elements involved. Regardless it would appear to be a good demonstrative effort on using flow-chemistry which is definitely unconventional for most Syn Chemists. In process ChemEs are generally the drivers behind such technology because they are taught to think this way whereas the chemists default is batch mode. This type of operation is well-established in petro- and bulk chemical industry but has been far less common in pharma (therefore #3 many real problems are solved this way), probably due to lack on as strong costs control. It is not always the best choice for doing reaction but if it works continuous processing typically are much cheaper to set up and operate. Perhaps as such exposure increase more chemists will consider how flow-chem might be of value and if there are any process jobs left in the future they will have better tool sets.

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7. malcolm on April 15, 2014 1:50 PM writes...

There's a company in the UK, Cyclofluidics, that claims it can synthesize, purify and assay a compound in 90 minutes using flow chemistry. Then a computer plugs the structure and IC50 data into an alogorithm and chooses the next compound to synthesize, and the process repeats over and over. It's plug and play SAR; all the chemist needs to do is keep the solvent reservoirs full and the waste barrels empty.

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8. Other great flow on April 15, 2014 2:28 PM writes...

I haven't had a chance to look deeply at this work, so I'll reserve comment. In terms of what is possible at the limits of flow chemistry, I'd encourage everyone to look at what just came out of Brad Pentelute's lab at MIT (disclosure: MIT affiliated, though not directly with that lab). This is just the propaganda link: , but there are a couple manuscripts that just came out that might be linked through there. The nuts and bolts of it: peptide synthesis in flow can be much, much faster than solid supported.

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9. A Nonny Mouse on April 16, 2014 3:07 AM writes...


A company which Victor (S V Ley) is heavily involved with (probably as he will be retiring soon). They have also just received a government grant of over £1m to do further development work.

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10. Pedantic Speaker on April 16, 2014 9:53 AM writes...

"Is using flow chemistry (with all of the requisite on-line monitors and hydrodynamic infrastructure) *really* easier than using a series of round bottom flasks for a molecule like this? Really?"
The simpler method may be easier at laboratory scale and for simple syntheses with only a few steps, but at larger and larger scales it becomes easier to do reactions in flow rather than in batch mode. And as has been pointed out before, in many complex syntheses, you need almost an industrial process for the first few steps in order to get enough of the later intermediates ( "Long linear sequences are a slog. You have to start them in the largest buckets you can find...."). In fact, Derek notes explicitly that "[t]he later steps of the synthesis tend much more towards batch mode".

PS: I was going to list a few reasons why industrial chemistry relies on flow chemistry before I realised it would be superfluous, but I spent so much time writing them that it feels wrong to waste it:
First, at industrial scales, it is necessary or perhaps even mandatory, for completely justified safety reasons, to have some or all of that equipment anyway. That round-bottom flask, when you stopper it and put it in the fridge overnight? The industrial-scale equivalent is called a pressure vessel and is heavily regulated because they can burst like the flask did in that early installment of How Not to Do It (
Second, as you get to larger and larger scales, batch-mode reactions become harder and harder to manage (because, for example, of the square-cube law) and have more and more catastrophic consequences if something goes wrong. Remember T2 Labs? Flow-mode reactions probably suffer from the same problems, but the operator has more control over the process and less material at a time is in the reactor.
Third, batch-mode reactors take up more room and require more material than flow-mode reactors (in fact, I think Derek had a post once about how the reaction chambers of laboratory flow chemistry units needed to be larger so they could be more easily cleaned). And at large scales, it almost certainly makes more economic sense to buy more monitors and valves than things than to buy hundreds of tonnes more steel to build a bigger reactor that can handle the same overall reaction rate in batch mode. In fact some of the largest chemical reactors are blast furnaces and they all work continuously.
Fourth, at least in my experience (some chemistry courses in high school and university), there are many steps to a reaction that we do not think to count as steps, or consider their cost in time and money. For instance, I did not think to consider the cost of scraping crystals out of the reaction flask onto the filter in the vacuum funnel, but obviously another stage has to be tacked on to a batch-mode reaction to remove the product when it automatically takes place in flow mode. And another step has to be tacked on to start the process. And starting a process is apparently the most dangerous part of many industrial processes (source, the Seconds From Disaster episode about the 2005 BP refinery explosion, numerous Chemical Safety Board reports). So industry likes reactors that work continuously for years at a time.

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11. Nick K on April 17, 2014 12:37 AM writes...

Everyone who has done synthetic work knows that some reactions simply can't be scaled up. This is especially true of low-temperature anionic chemistry. Could flow chemistry be applied to such cases?

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12. MintB3rryCrunch on April 19, 2014 8:54 PM writes...

@ 11 yes, See Tim Jamison's work! Particularly there flow solution to the ever-frustrating DIBAL reduction of esters to aldehydes.

@ Other comments, Jamison and engineering co-workers have actually designed and built a drug manufacturing system based upon continous flow chemistry and purification.

Alright, I will now disembark from the Jamison train...

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13. Nick K on April 20, 2014 8:54 PM writes...

#12: Many thanks for this. I'll look up Jamison's work.

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