A single failed reaction is a setback. 10 000 failed reactions is a library.
After two combichem industry jobs, these are the things I learned:
Testing cruds = We are sloppy
Testing mixtures of compounds = … but very optimistic
‘Libraries from libraries’ = Our slop got squared
On-resin-screening = I wished for this to work
One bead-one compound = …but it did not
Million-compound library = …so we pushed harder
What I ended up doing most of my time in combichem was making the precursors and building blocks, attaching them to the resin, deprotecting, loading the resin-bond compounds to the synthesizer or plates or syringes, then running one, maximum two combinatorial steps, then the cleavage, workup, purification. Lots of washing at every step. The preparatory and workup steps took more work then the actual combichem. (The purification was definitely the most tedious step, even with preparative HPLC.) It was an experience that made me increasingly fond of the traditional medicinal chemistry.
One needs to be pretty cautious, about doing a medchem research in the combinatorial fashion. Even if most reactions could be adapted to combichem in principle, this usually means lots of development time. It is worth doing in limited number cases when:
1. The reactions are very clean
2. Lots of building blocks are available, preferably in a suitably-protected form
3. The set-up does not require a low temperature or strictly oxygen-free conditions
4. The chemistry is insensitive to reagent excess, goes to completion and won’t “over-react”when pushed hard (= turn into mess because the optimum reacton time at given temperature was grossly exceeded).
So the best type of reactions for combichem is the robust kind “that a zombie can do”. For example using a reaction that is highly moisture-sensitive or prone to overheating-induced decomposition (i.e. Mitsunobu) adds significant difficulties. Titrating the stoechiometry to 1.05 equivs of the reagent is not possible, just as optimizing the reaction conditions for every single building block. Adapting chemistry to combichem format grows exponentially harder if one is trying to synthesize a very large library at once. (Just preparing the reagent stocks for a large library is a chore. There are handling delays, etc).
The other problem with combichem is that it encourages wishful thinking. One needs to be concerned about the building block combinations that do not work well. Failure is frequent if one tries to employ a wide-diversity set of building blocks - even straightforward reactions like acylation and alkylation (with the excess of nucleophile) don’t progress or they produce mixtures unexpectedly in a substantial number of cases. To avoid bad surprises, one needs to experiment on smaller pilot libraries first – to test the suitability of the blocks, test the best solid-phase attachment, solvents, reaction conditions, cleaving method, purification sequence, etc.
Also one should not fool himself that an automated synthesizer will be a great time-saver - these systems are very impressive in showroom, pumping blue-colored water- but keeping them up and running is a full time job, the gaskets can leak, the pipetting needle and the outlet channels get clogged, viscous solutions or stocks in highly-volatile solvents won’t get transferred in the correct amounts, the heating/cooling or nitrogen gas flow is uneven, and adjactent wells get cross-contaminated, moisture can condense in, etc. Turning on a big synthesizer can be unwieldy for a small-scale exploratory work, and it can take struggle to adapt the automated system to sensitive reactions that need lots of care and attention. Manual combichem experiments can be faster and easier to control. More than few times I saw a big $ 200k all-teflon automatic synthesizer system gathering dust in the corner – because the chemists got tired of the hassle.
Over the years, combichem gradually evolved into parallel synthesis of small sets (tens or hundreds) of individual compounds. Nowadays the parallel-synthesis-produced compounds are purified – so there is no actuall difference from traditional medchem. The main impact that combichem had was popularizing the high-throughput solid-phase methods in the synthetic chemistry.
The first combichem company that I joined (14 years ago) is still in business - they underwent a number of mergers and are now a part of Sanofi. Their new owners like them because they got good hits from their libraries with a reasonable frequency. (The chemists there have a pretty decent system for cranking out the compounds - too bad that they are discouraged from publishing their results.) It has always been a fairly small operation throughout – but unlike many other combichem companies it survived until today.
I think the future is in outsourcing. We have recently screened some commercially-available collections that were produced by a traditional chemistry abroad: 90%+ purified and bottled. I was very surprised by the number and high quality of the resulting screening hits. A set of 1000 dissimilar compounds that were made individually, pure, is in my opinion more usefull than 10 combichem general libraries with 1000 compounds each.
[This post was inspired by Derek Lowe’s In the Pipeline]