KW - Diversity-oriented synthesis

Diversity-Oriented Synthesis (DOS) libraries bridge the gap between conventional small molecule and natural product libraries, allowing the interrogation of more diverse chemical space in efforts to identify probes of novel parasite pathways.

T1 - A Planning Strategy for Diversity-Oriented Synthesis

T1 - Convergent diversity-oriented synthesis of small-molecule hybrids

KW - Diversity-oriented synthesis

Hap,
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.

B.; Wong, C.-h., Rapid diversity-oriented synthesis in microtiter plates for in situ screening of HIV protease inhibitors.
A.; Ruijter, E., Strategies for total and diversity-oriented synthesis of natural product(-like) macrocycles.

Diversity-Oriented Synthesis ..

Pre-emptive, chemistry-driven library syntheses, no matter how sophisticated the chemistry is, have a very long shot at finding any biologically useful entity, I am afraid, since you rely completely on luck. High-content cellular assay screening could increase the chance of finding something that may do something, but then you are left with a long and arduous task of target ID. If you add up all the fuzzy things along the way, you may end up not knowing what you are doing. Hmm.. Definitely a form of art, an academic endeavor.
If you want to claim usefulness in drug discovery, you should develop chemistry with a tangible purpose in the drug discovery context. For example, start with a fragment hit for a certain target, develop DOS or whatever that can quickly and easily fill up every possible spatial vectors emanating from the fragment, and show us that this approach got you the better lead more quickly. Then I’ll buy it.

Diversity-oriented synthesis of macrocyclic …

Convergent diversity-oriented synthesis of small …

I have seen DOS performed, and I do agree there is not one tool for all problems. However, being scientific, DOS has presented some real opportunities for drug discovery where others have failed. Are the solutions simple or perfect? Well, when is discovery simple?
DOS was first formulated in academia, propagated by many groups, and is now being proved and refined in the real world. There hasn’t been one incarnation of DOS which has a perfect mix of true diversity, quality, and drug-likeness, nor will there be. I back JB’s comment that high quality has been achieved, when it was important.
How far will it go? Let’s see – data will come. But to rail as commentors against what some academics have pursued, flogging them with limits required in drug discovery, is a bit brutal. When is the same standard held to other chemistry research? Say, perhaps, natural product synthesis or catalytic methods?

A Planning Strategy for Diversity-Oriented Synthesis

Diversity-oriented synthesis of bicyclic ..

In contrast to target-oriented synthesis (TOS) and medicinal or combinatorial chemistry, which aim to access precise or dense regions of chemistry space, diversity-oriented synthesis (DOS) populates chemical space broadly with small-molecules having diverse structures. The goals of DOS include the development of pathways leading to the efficient (three- to five-step) synthesis of collections of small molecules having skeletal and stereochemical diversity with defined coordinates in chemical space. Ideally, these pathways also yield compounds having the potential to attach appendages site- and stereoselectively to a variety of attachment sites during a post-screening, maturation stage. The diverse skeletons and stereochemistries ensure that the appendages can be positioned in multiple orientations about the surface of the molecules. TOS as well as medicinal and combinatorial chemistries have been advanced by the development of retrosynthetic analysis. Although the distinct goals of DOS do not permit the application of retrosynthetic concepts and thinking, these foundations are being built on, by using parallel logic, to develop a complementary procedure known as forward-synthetic analysis. This analysis facilitates synthetic planning, communication, and teaching in this evolving discipline.