Shattered Dreams

Another fine and glorious week in the world of research… by that I mean long hours, troublesome analysis and nothing interesting… the usual.
I guess this week it’s best to start at the start which was a full day conference at Sheffield uni, stereochemistry 2017. A fine conference that’s been hosted every year for 50 years now.
Kicking off the show was Emeritus Prof. Charles J.M. Stirling. More of a welcome to the 50th event than science but I must admit I warmed to the old chemist. A very friendly, funny and relaxed person. I would like to think that my grandfathers would have had these qualities should they have lived long enough for me to meet them. I digress.
Following this intro, a weird looking creepy guy from industry stood up. Looked like the type of individual who might have pictures of Princess Leia as his desktop background. Dr. Al Dossetter of MedChemica. He presented some interesting findings on computer aided synthesis and its money saving capabilities. It “focussed” around the idea of big data, big pharma and computational chemistry. In essence it felt more like a sales pitch to me. He highlighted his company’s involvement with the synthesis of Cathespin. K inhibitors for treatment of certain cancers. As is often the way with industrial talks (and rightly so I suppose) compounds are shown but the synthetic steps kept secret and hidden under lock and key. Also, it turns out that Merk have a molecule already in Phase III trials similar to theirs and published long before this one. In my opinion Merk probably made the molecule long before MedChemica but didn’t bother developing it further as their  candidate molecule (Odanacatib) out performed it in trials. 45

In order, MedChemica compound (above)  and Odanacatib (below) .

When he said that the enantiomers do indeed possess the same physical qualities such as MP and BP I started to switch off, amazed that they’d wasted time and money on these experiments. Thankfully I was awoken by a fire alarm so I had to evacuate the building and stand about in the cold for 10 minutes or so.
Next up was the guy I was looking forward to the most, Prof Lutz Ackermann. He did not disappoint. A powerhouse chemist presenting a CH activation tour de force. His work highlighted the true capabilities of what Ruthenium(II) catalysis can of achieve. He is certainly re-writing the rule book on arylation chemistry!
As he moved from slide to slide I started to notice something familiar… Shit. These were amino acids.
And there it was.
CH activation on a peptide utilising [Ru(p-cymene)Cl2]2 as catalyst. The exact same reaction I had tried myself (unsuccessfully) 6 days previously. My dream of being the first to report this shattered.  I still listened diligently to the remainder of his talk on aniline CH activation and subsequent alkylation, copper and cobalt catalysis and C=O forming elimination reactions. He concluded on his current efforts to achieve CH activation on aldehydes, without oxidation occurring, something rather challenging due to the natural reactivity of aldehydes. Currently I believe it can only be achieved with the use of directing groups or transient directing groups suffering from modest yields.
After his talk it was lunch time. I went to the pub and sulked over a couple of pints. I tried to find his article in press but it wasn’t even on the webpage yet. I’d just have to wait and suffer. As one colleague told me “ It’s almost like he’s an established Prof with a 50 man research group and you’re a first year PhD”.
I couldn’t properly enjoy the next talk by Tobias Ritter (who has a chair at Harvard AND the Max Planck institute) on late stage fluorination. A relatively boring topic that he made somewhat interesting. A very charismatic and intelligent chemist.
Following this was Prof Marcey Waters and her work on unnatural amino acid mutagenesis for the study of cation-π protein interactions. It was stereochemistry I guess but it didn’t get me going quite the way Lutz’s work did.
This was followed by a coffee break whereby I said to myself “Fuck this lets just go and talk with the guy and if he laughs at me or tells me to fuck off then at least I tried”. So I nimbly walked down the steps to where Lutz was at the front and patiently waited for him to finish what he was up to so I could have a chat.
Petrified, I introduced myself to him and tried to be as honest as I could with him about his work. I was a little shaky and determined not to embarrass myself. His work is some truly awesome stuff, but I wanted the info on his Peptide CH activation. I simply couldn’t wait. We spoke for a while and he gave me far more time then I could have asked for. He was very open and friendly, happy to discuss his research with me. He even gave me a follow on Twitter and asked me to get in touch with any questions about his work when it made it to print (I have since and his reply was immediate).
I warmed to him most when he (inadvertently or knowingly) openly slagged off a Prof at Oxford. I agreed with his comments on this particular Prof’s work. His work on peptide CH activation is not truly bioorthogonal and thankfully there is some space not covered where I may be able to carve myself a niche. Unless he figures that out and scoops me there too.
He also made a comment that really resonated with me and summed up eloquently my issues with this chemistry. Something that had been bugging me but I couldn’t figure out what or why.
“This peptide project is the most time consuming, everything is longer.” This is my issue. You have to make the peptides which isn’t a short process before you can start to abuse them. Then are the calculations which is longer as its working in concentrations and not equivalences. Then comes the inevitable solubility screening and making sure the solvent systems are compatible. A right faff. You can spend 2 hours preparing (after the 3-day peptide synthesis) and still not have put on a single reaction. 
In short a nice guy, friendly academic (a rare thing) and a superb chemist. I was very proud of myself, partly for holding my own in my conversation with him and mostly because it meant my research ideas are not pointless or without sense. If a top Prof has been having similar ideas to myself then I guess, I can’t complain.
The final talk of the day was by Prof Chris Hunter of Cambridge. His work seemed to focus on molecular systems that communicate with each other. He explained the concept and theory extremely well (something I’ll come back to later) but I did not fully understand the applications of his work (Will also come back to this later). He had basically made a molecular based pH meter as far as I could tell. A pH meter that has the life span of a few hours? What was evident was that, although I understood the how but not the why, the idea was novel and the academic very intelligent to craft this concept.
Despite being snubbed in the race of CH-activation on peptides, the only thing that upset me about my day at the stereochem conference was the fact that I did not see a single asymmetric synthesis described… Very odd.
Returning from Sheffield I got back to York around half 7 and immediately hit the lab. I placed on a few more reactions and read some literature. It was gone 11 by the time I left.
The following day we had a visitor at York. A visitor in the form of Prof Clayden, a great chemist whom I wrote to about a PhD and even got a reply from. I mused with the idea of taking my Organic Chemistry book for him to sign but opted against it in the end. An organolithium maestro. His talk was titled “Exploring and exploiting dynamic molecular conformation: New reactivity and artificial receptors”. The start of the lecture was chemistry I understood, challenging molecules that he was able to achieve lithiation on and the end was similar to Prof Chris Hunter’s talk the day previous. The story didn’t flow well for me and I only understood the concept and theory thanks to Hunter’s talk the day before on it. What Clayden did cover succinctly was the applications of it. I now understand why this work might want to be carried out, far surpassing pH probes with a limited lifespan. Having both talks within 24 hours allowed me to build a more complete picture on what molecular communication actually means and what it is capable of achieving. My colleagues who did not attend Sheffield stereochem were left a little puzzled and I knew why. They only had half the picture. Between them I felt like Hunter’s work was described better but Clayden’s more impactful.
The latter half of my week was spent in the lab furiously setting up more reactions and 3 consecutive nights where it was gone midnight by the time I left. Friday saw me put on 40 reactions and Saturday I set up another 36. I look forward to analysing 76 reactions all showing starting material later today. Welcome to research I guess…
This week’s #ReactionRecap we will focus on getting back to basics with the Mannich reaction. Named after German chemist Carl Mannich this reaction is an amino alkylation of an acidic proton that is adjacent to a carbonyl moiety by formaldehyde and an amine or ammonia.
The reaction requires an enolizable aldehyde or ketone (here cyclohexanone), a secondary amine (here dimethylamine), formaldehyde as it’s aqueous solution, and catalytic hydrochloric acid.
The product is an amino-ketone from the addition of one molecule of formaldehyde and the amine to the ketone.
The mechanism involves the preliminary formation of an imine salt from the amine and formaldehyde. The amine is nucleophilic and attacks the more electrophilic of the two carbonyl compounds available. This is the formaldehyde. No acid is needed for this addition step, but acid-catalysed dehydration of the addition product gives the imine salt.
2In the normal Mannich reaction, this is just an intermediate but it is quite stable and the corresponding iodide is sold as ‘Eschenmoser’s salt’ for use in Mannich reactions. The electrophilic salt can now add to the enol (we are in acid solution) of the ketone to give the product of the reaction, an amine sometimes called a Mannich base.

This is can then be easily converted from the Mannich base to the enone via alkylation with MeI.




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