Tuesday, June 26, 2018

The Disconnection Approach - Automated!

In my time as a synthetic organic chemist the most important advance in the field was definitely the introduction of searchable databases such as SciFinder and Reaxys. Life before these involved spending days on end in the library flipping though dusty tomes of chemical abstracts and Beilstein. And at the end you weren't even sure if you missed something of critical importance. The introduction of open access LC-MS and high field NMR has also had a big impact for me by speeding things up considerably. However, besides these milestones I think that I have pretty much been doing chemistry the same way >25 years. Anyway, what I am getting at is "what will the next BIG thing be?" It's been a considerable time since we had a major technical breakthrough for the synthetic organic chemist. My colleagues and I have been discussing this for more than a decade and now I think I am spotting the next big thing - Chematica! Chematica was developed by Polish scientist Grzybowski and has been around for quite a while. Basically it is a computer programme that disconnects your molecule and suggests ways for you to synthesise it. What's changed since I first heard mention of Chematica ~5 years ago is that apparently now it works the way you would like it to. Recently Grzybowski and co-workers published an impressive paper where they synthesise 8 very different and rather challenging molecules. The abstract from the paper nicely summarises the achievement:

"Multistep synthetic routes to eight structurally diverse and medicinally relevant targets were planned autonomously by the Chematica computer program, which combines expert chemical knowledge with network-search and artificial intelligence algorithms. All of the proposed syntheses were successfully executed in the laboratory and offer substantial yield improvements and cost savings over previous approaches or provide the first documented route to a given target. These results provide the long-awaited validation of a computer program in practically relevant synthetic design."

You really should read this paper. These are not simple syntheses and would have taken quite some time to come up with if at all. Now it is still early days and Chematica is only for those with deep pockets. I am personally waiting for a quote right now and am very curious to see exactly how deep my pockets need to be. BUT it has started and I believe that now it's just a question of time (I'm guessing  less than 10 years) before you simply hit the disconnect button in ChemDraw, look through the suggestions that appear on your screen and pick the one that you like best.
And there is more. Another game changer is already here and everyone with a PC can do this: Machine Learning. My next post will be on this topic that we are already using to great effect at my work place. D!


M.R. Maciejczyk said...

I feel exactly the same about Scifinder and Reaxys. Especially, that I started my adventure with science without having these tools. Additionally, my recent project are less synthetic more conceptual so I have to master goggling synonymous and there is always a paper that I have missed as the idea was targeted at a bit different angle.
I was impressed with Chematica when I learned about it for the first time. It will definitely make projects planning much easier. But in my opinion the breakthrough in organic synthesis is more associate with combination of software and hardware. And the only hardware that is capable of such thing is the flow chemistry. With its potential to do faster reaction due to ease of applying high pressures, increase safety, ease of scale up and integrated work-up and analysis systems makes sets a new paradigm for organic but not only organic synthesis. Moreover, as you mention machine learning; flow chemistry is the approach that allows to implement it in very easy way, check this paper: https://www.nature.com/articles/s41586-018-0307-8 Controlling an organic synthesis robot with machine learning to search for new reactivity.
I have not work on the flow yet but really looking forward. Especially that it allows to use, with high efficiency, light and electrons, which are not that easy to handle in traditional way. Check the Syrris company, they make free workshops from time to time. There are also other companies making such a equipment. Or you can follow the way as this paper "A gentle introduction to the noble art of flow chemistry" say:
'Flow chemistry isn’t hard. Don't fall for the slick marketing campaigns and glossy brochures of the corporate vendors. Steer clear of their pricey equipment and exorbitant service contracts. If you do it yourself, you can get better results at a fraction of the cost. So put away your cheque book, roll up your sleeves, and give it a go.
A nice review about flow chemistry: The Hitchhiker’s Guide to Flow Chemistry.
BTW I have remembered your blog because I was writing a paper where I have used the DCVC for the first time and needed to cite your paper, it saved me a lot time to do this columns. Thanks a lot for that and for the interesting posts.

Unknown said...

How about cryoMD micro ED? I think that should change the way we analyze a reaction mixture when it becomes available in a day to day type of set-up. what do you think CA?