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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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November 13, 2008

The Yield Monster - And Its Friend, The Model Monster

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Posted by Derek

Organic chemisty can be a real high-wire act. If you’re taking a compound along over a multistep sequence, everything has to work, at least to some extent: a twelve-step route to a compound whose last step can’t be made to work isn’t a route to the compound at all. To get the overall yield you multiply all the individual ones, and a zero will naturally take care of everything that came before it.

Even very respectable yields will creep up on you if you have the misfortune to be doing a long enough synthesis. It’s just math – if you have an average 90% yield, which shouldn’t usually be cause for distress, that means that you’re only going to get about 35% of what you theoretically could have after ten steps (0.9 to the tenth). An average 95% yield will run that up to 60% over the same sequence, and there you have one of the biggest reason for the importance of process chemistry groups. Their whole reason to live is to change those numbers, to make sure that they stay that way every time, and without having to do anything crazier than necessary along the way.

When you’re involved in something like this and you know you’re going to be approaching a tricky step, the natural temptation is to try it out on something else first. Model systems, though, can be the road to heartbreak. In the end, there are no perfect models, of anything. If you’re lucky, the conditions you’ve worked out by using your more-easily-available model compound will translate to your precious one. But as was explained to me years ago in grad school, the problem is that if you run your model and it works, you go on to the real system. And if you run your model and it doesn’t work, well. . .you might just go on to the real system anyway, because you’re not sure if your model is a fair one or not. So what’s the point?

This gets to be a real problem in some labs. While ten steps is medium to long for a commercial drug synthesis, it’s just the warmup for a lot of academic ones. Making natural products by total synthesis can take you on up into the twenty- and thirty-step levels, and some go beyond that, most horribly for everyone concerned. In such cases, you’d much rather have several segments of the big honking molecule built separately and then hooked together, rather than run everything in a row.

But what if you spend all that time on the segments, but you can’t put the things together? The most famous example of that I know happened in Nicolaou’s synthesis of Brevetoxin B. The initial disconnection of this terrible molecule into two nearly-as-awful pieces turned out to have been a mistake. Despite repeated attempts, no way could be found to couple the two laboriously prepared pieces to make the whole molecule, and untold man-hours of grad-student and post-doc slave labor had to be ditched for a new approach. If you want to see the approach that worked, here’s a PDF of a talk about it.

But if you go linear, you’re taking the same risk, and the math will absolutely eat you alive. A 90% average yield will ensure that you throw away 95% of your material if you keep going for 28 steps. And keeping a 90% average over twenty-eight steps is just not possible with real-world chemistry, either – and yes, I’ve seen those papers where they do, but I don’t believe them. Do you? Make it 25 steps of average 90%, and three 60% losers, and now you’re down between one and two percent of your material left. Which is no way to live.

I note that the above summary of the Brevetoxin synthesis counts 123 synthetic steps. It calculates an average yield of 91%. A 2004 synthesis from Japan comes to 90 steps with an average yield of 93%.

Comments (17) + TrackBacks (0) | Category: Life in the Drug Labs


1. Mike on November 13, 2008 9:40 AM writes...

Great post! The URL for the PDF file is mangled though. :(


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2. processchemist on November 13, 2008 10:00 AM writes...

Simple "yelds" have no particular meaning in process chemistry. I'd like to have a cent for every 95-99% yeld in oil/foam/slug/unprocessable messy thing I found in transmitted syntheses. And, talking about IND or API products, 99% yeld in the final step with 97% HPLC grade and 0.9 % of ashes is, again, of no use in most of the cases..

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3. Jose on November 13, 2008 10:09 AM writes...

What's the Woodward quote? Something like "The only real model system is a molecule's enantiomer."

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4. cookingwithsolvents on November 13, 2008 11:39 AM writes...

Every time I see the full structure of Brevetoxin B I shudder.

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5. Curious Wavefunction on November 13, 2008 11:53 AM writes...

Woodward: The only real model system for a molecule is the molecule

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6. EJ on November 13, 2008 12:27 PM writes...

What, you don't believe that every reaction out of my laboratory does not yield over 90%?

I suppose folks will start to think that the Woodward-Hoffmann rules were actually developed by those whippersnappers! Geez........

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7. Russ on November 13, 2008 12:30 PM writes...

I know a guy who worked with K.C. Nicolaou. He says that K.C. used to refer to model studies as "molecular masturbation"

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8. Petros on November 13, 2008 2:44 PM writes...

"What, you don't believe that every reaction out of my laboratory does not yield over 90%?"

What EJ could you be thinking of?

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9. Sili on November 13, 2008 3:36 PM writes...

Didn't they have the same problem with vitamin B12 back in the day? Though that's not even that big ...

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10. Jose on November 13, 2008 4:21 PM writes...

I'd love to see someone just do 50 aq workups and columns in a row (no chemistry) and get 93% recovery. 90 steps? 123 steps? Ah, the strange twin vortexes in La Jolla and Cambridge....

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11. poiano on November 13, 2008 4:31 PM writes...

Dude, you may want to go to the Brevetoxin slide deck and check the yields--no way they average to 91%. I think the grad student who put it together blew it.

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12. Harry on November 13, 2008 7:26 PM writes...

LOL "EJ"! Funny, thats EXACTLY the name that first popped into my head upon reading this.

I think it was actually in a comment here that I first heard of the famous Corey 1-2 inversion. If your yield is 19%; simply apply the Corey 1-2 inversion and presto! the yield becomes 91%.

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13. Eraser on November 13, 2008 8:47 PM writes...

For (very long) total syntheses it is important to distinguish between the longest linear sequence and total number of steps. Yes they are all steps you have to do, but the length of your longest sequence along with the yields determine how much starting material you need. just a few 50-60% yields in a long synthesis and you have to start from +mol quantities to make a miligram or two of your final product.
This is why in long total syntheses, success is not only a function of lab skills, but also includes an important planning component (how many times do you want to bring material through the entire sequence. This has to be balanced against the risk of bringing a lot of material up and then having to change strategy. This is also why a certain amount of slave labor (postdocs and grad students) are needed to succeed. Rarely do you see a +25 step with just one lab chemist on the paper. It is however not much fun being the "bring up material" lab slave.

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14. UK Chemist on November 14, 2008 5:44 AM writes...

Model reactions are the same as probe candidate drugs.They are a waste of time.

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15. infMP on November 14, 2008 9:02 AM writes...

"I'd love to see someone just do 50 aq workups and columns in a row (no chemistry) and get 93% recovery. 90 steps? 123 steps?"

This is the best point ive heard in a while

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16. Anonymous on November 14, 2008 11:03 AM writes...

Almost as good as not being able to get the convergence steps to work is the dreaded protecting group removal. I heard Masamune give a talk about (I think, circa 1990) bryostatin, where the last step was removing a MOM group, which didn't budge, and his mirth when he said "So the grad students had to go back to the beginning!" All of us synthetic jocks got a good chuckle out of that ...

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17. NH_chem on November 15, 2008 4:18 PM writes...

I gave up on believing yields back in grad school. Most publications are full of s@#t when it comes to yields. The one listed is either (a) the one that your professor wanted to see because he told you (i.e. Corey, so I am told) or (b) the best one you did regardless of all the others averaging 20-50% less!

The most comical one I recall was the statement in a paper of the "crude yield" being 90%. Then a short sentence stating analytical samples gave the following data.... Turns out the actual yield was on the order of 30-40$ pure. What a joke!

My advice, don't rely on yields until you do the experiment yourself!

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