T1 - A Planning Strategy for Diversity-Oriented Synthesis
KW - Diversity-oriented synthesis
I work for Fluorous Technologies, Inc. and think that I can answer your questions.
First let me say that I am a regular reader of In The Pipeline and I was going to wait to answer your questions, since Derek said that fluorous would be the subject of a future post. Since you brought it up, however, I might as well chime in now.
The IP is not an issue if you buy the reagents from us or one of our distributors, such as Aldrich, and as long as you use the reagents and separation media for internal research purposes. There is an implied limited license granted upon purchase. If you were using the technology to make libraries to sell to third parties, however, that would require a explicit license from us. We certainly are not looking for any reach-through on compounds or drugs found using our products.
The cost of the reagents and separation media is considered high by many, but we like to think in terms of value. By supplying tools which facilitate a fast, simple, and general (key to the DOS libraries) purification method, we believe the technology saves money and time in the long term.
One piece of evidence to support this is some of the comments we received when applying a NIH Pilot Scale Library grant. We were awarded the grant, but the summary review included a statement that the study group believed we were being overly optimistic about how many compounds we could deliver given the budget and resources that we proposed. By the end of Year 1, however, we had met those targets in terms of number and type of compounds and actually came in slightly under budget.
Could we have done just as well not using fluorous techniques and using lots of automated chromatography equipment instead? We don’t know. The grant funds us to make compounds, not compare methods so direct comparisons have not been done.
One group that has published a direct comparison in a library synthesis is the Fustero group from Valencia. They preferred the fluorous approach over others. Of course, that’s just one example. In the end whether or not the value of a fluorous approach is worth the cost probably depends on a multitude of factors.
This is getting long, so I’ll just wrap it up by saying that we do have a very dedicated group of repeat customers who clearly believe the value is there.
KW - Diversity-oriented synthesis
The 75% number is just what JB(comment #14) said was necessary for submission at the Broad Institute and did not reflect what was done in the paper. I don’t know if 75% is still the case there, because that sounds awfully low by today’s standards. For example, for submission to NIH the requirement is now 90% purity as determined by LC at 230 nm.
I checked the supplemental data for the Nelson paper, they did not report the purity for all of the compounds made and the ones they did were determined by 500 MHz 1H NMR. As far as I can tell they did not conduct a final HPLC to purify these (I could have missed it though, since there are 537 pages in supp. info), so the purities are not that high, ranging from 50-90%.
From a practical standpoint that’s not so bad actually. You generally do mass-directed LC on everything and if you go in with things that pure, you should have no problem meeting the 90% threshold.