Thursday, August 29, 2013

Reflecting on Yield, and the Need for a Qualitative Assessment of Reactions

Here's some thoughts:

1. I categorize all reaction yields qualitatively. 
What does this mean? Generally speaking, I don't really believe in yields other than 0%, 25%, 50%, 75%, or quantitative. I also sometimes break this down as 1.) Doesn't work, 2.) Works a little, 3.) Goes halfsies, 4.) Pretty alright, 5.) The bomb diggity. Now, I might conform to the standards of society and report a 62% yield for a publication or presentation, but for the purposes of a practicing-academic-chemist-grad-student, my breakdown is good enough. I readily acknowledge that this view of looking at yields is generally flawed, but it gets the job done on a day-to-day basis.

2. I don't record yields on reactions less than 10 mg.
This isn't entirely true. If I've rigorously run a reaction, and then repeated it, I'll believe a yield on 10 mg scale. But generally speaking, there are too many ways for the yield to go wrong: trace solvent, water, silica, or dust? add 10-20%. Did any manipulation of the material? subtract 10-20%. If I do record a yield on this scale, its most likely going to be as defined in section 1, rounded to the nearest 25%. 

3. TLCs of reactions in SI
Why doesn't anyone do this? We record our TLCs in our notebooks and report Rf in the SI. But in my opinion, the TLC is the most important qualitative and rapid way to assess a reactions "goodness." If your reaction has an 75% yield, and an Rf = 0.40, but an inseparable side product at Rf = 0.37, then I hate your reaction (but I'll still use it if I need it). This is useful qualitative data! Far more useful than melting point. Believe it or not, you can optimize reactions on tiny scale by TLC alone. Its not ideal, but it definitely works when material is scarce.

4. Yield ranges on multiple scales
Reported at 95%! Awesome! Except, maybe that was the best yield you got out of 15 experiments, the reaction usually sits around 75% (and once you got a 30%). Maybe you know the reason for variabliliy (great! put it in the discussion), maybe you don't (thats ok too). Do good science: report yield ranges on multiple scales. If its not possible because its the front line of your 72-step linear synthesis, I forgive you. If its a methodology on simple starting materials, no excuses. 

5. Yield is not important.
I'm use hyperbole for effect. But honestly, my yield doesn't ever really matter, in total synthesis there are two quantities of material: enough and not enough. There is a need in the literature to deemphasize the importance of yield. Its been said before that emphasizing yield is bad. If it were me, I would do so in favor of honest reporting of pros and cons of reactions, with a discussion of more qualitative aspects: ease of running and purifying, cost of catalysts, etc.

Those are my thoughts. Have a discussion. Or not. Now if you'll excuse me, I've got some scale-up to get back to. 

Friday, August 9, 2013

Thursday, August 8, 2013

iBooks will be coming to your Mac laptop this Fall

I guess this short blog entry could also be called "The Portable Chemist's Consultant Part 3" (see Part 2 here).

First off, we have a new book update (Version 2.3), as listed in Open Flask and on the book's website.

Secondly, Apple has announced a new OS X platform, OS X Mavericks, which will allow the use of iBooks on a laptop! So for those of you who own Apple laptops but who don't want to get an iPad, you will be able to read this book sometime in the Fall.


And lastly, Angewandte's book review is out, here. Thanks Angewandte!


Thursday, August 1, 2013

Ingenol: Behind the scenes

Disappointment, frustration, excitement, setbacks, thrill, and success. It has been a roller-coaster ride, but finally the reward is here. A total synthesis of ingenol from our lab was published online today. The chemistry is all described in the paper, so I will not go into too much detail here. However, I want to highlight some of the key reactions and hurdles we had to overcome to finally being able to publish this work.
Our synthesis starts from commercially available and cheap (+)-3-carene, and in five steps we get to the substrate for the first key reaction, the Pauson-Khand. In order to get enough of the Pauson-Khand product, we needed to optimize this reaction quite a bit, but we can run it on gram-scale now as shown below.

Gram-scale Pauson-Khand reaction

1,2-Addition of MeMgBr to the carbonyl group of the P-K product gives us the so-called cyclase phase end-point.

Happy Christian with 1 gram of cyclase-phase endpoint

The oxidase phase also consists of seven steps, in which we install the four hydroxyl groups and rearrange the tigliane skeleton to give the desired ingenane skeleton.
The most troublesome, frustrating, and time-consuming problem to overcome was the pinacol shift to give the ingenane skeleton.

After 8 months of desperation, numerous shift reactions in one form or the other, a lot of disappointing results, and a ridiculous amount of NMR time to figure out what we got from all these reactions, we still couldn’t get the desired product. In fact, we actually almost abandoned the whole route because we just couldn’t get that shift to work the way we wanted. Eventually, we agreed to start designing another route to ingenol, if we could not get the shift to work by November 1st, 2012.
You may call it insane luck, but on October 24th 2012 we finally hit the sweet spot and got the reaction to work on a model substrate and about a week later on the real system. What a relief! Finally we could move on.
Comparably, the last steps of the synthesis were a much smoother ride. An allylic oxidation, a deprotection, and an elimination step later we eventually had a tiny amount of our first natural product, 20-deoxyingenol, just before Christmas of 2012. About a month later, we finally made ingenol for the first time.
However, it took us another 6 months of optimization and scale-up to get the end result, which was published online on Science Express today.
Especially, the reductive alkylation of the chloro-ketone needed some serious optimization. Initially, we tried to prepare big quantities of the methyl ketone itself which turned out to be very difficult to prepare and handle. We had some really painful weeks where we would run this reaction almost everyday and get out nearly nothing. At some point, Phil suggested to run both steps - reductive methylation and aldol reaction - in one pot (!) without isolating the methyl ketone itself. Initially we had a hard time imagining that this would work but after some optimization we finally arrived at the one-pot methylation aldol procedure.

Frustration after another failed attempt at the reductive methylation

What do you do if you almost go nuts? You do stuff like drawing your team-mates.
Here is Christian’s artistic interpretation of Steve and myself.

So what’s up next? We are currently collecting data for an upcoming full paper, which will cover the side reactions and failed approaches. Furthermore, we are focusing on making analogs of ingenol for pharmacological testing. The key intermediate, the cyclase phase end-point, which is our branch point for analog syntheses is being scaled–up in conjunction with our collaborators at LEO Pharma, developers of Picato® (an ester of ingenol).

Whoever is reading this post, if any, please feel free to comment and ask us questions about the synthesis. We will be more than happy to answer them and give you more insights.