Diversity Oriented Synthesis Using Fluorous Tags

Diversity-oriented synthesis (DOS) has been discussed here often and the benefits of employing fluorous tags and purification methods to the construction of such libraries has been effectively established.  Among these are the solution phase nature of the chemistry, the general purification method across varied structures, and the high degree of chemical compatibility.  All of these are important when one is trying to target a diverse set of chemical compounds which has a little different set of demands than a library of analogs (although fluorous is good for that too).

Just published in ACS Combinatorial Science is a paper from Park et al at Seoul National University describing their work at producing a diverse set of polyheterocyclic benzopyrans.  Within this paper they use six different reaction pathways to prepare 284 compounds.  Each reaction pathway produced a different core structure.  In five of the six pathways (paths II-VI) the authors used a fluorous tag while in the other pathway (path I) a solid phase support was used.  The structures are shown below with the authors starting from four different benzopyrans 3.

This paper is actually part II and in part I, published in 2010, the authors strictly used solid phase methods to produce 434 compounds.  In reading the current paper the advantages of fluorous methods become readily apparent.  First, the authors point out that they tried to use the solid phase strategy which worked reasonably well in the previous report, but found that the reactions were sluggish.  This resulted in either incomplete reaction or in high amounts of side products for pathways II-VI.  That is when they decided to turn to a fluorous strategy and use fluorous solid phase extraction (FSPE) as a purification method.  In this instance they used a fluorous silane to tag their four starting benzopyrans.  The solution phase nature of the chemistry clearly was needed in order to have a viable route to the desired compounds.  The average purity of the compounds derived from the fluorous pathways was ~87% without final HPLC purification.  That doesn’t seem too much higher than the 85% avg. purity reported from the previous paper using solid phase, but remember that the chemistry here was more demanding and that they couldn’t even get to the compounds in reasonable purity using solid phase methods.  The scheme below shows two of the pathways.  Note the use of FSPE for the purification of intermediates.

There are also some other more subtle aspects which were interesting.  For example, for pathway II the substituted triazolinediones were not all commercially available, so were prepared in-house by the authors.  If you have to make something, you don’t want to use more than you have to in any reaction.  Solid-phase techniques usually require large excesses of reagents which is not the case for fluorous methods.  There was also the manner in which the amount of compound is on the solid phase was determined by measuring the mass increase of the resin and then confirming that  after cleavage from the resin.  Let’s compare that to a fluorous tag which can be directly weighed and analyzed to NMR, LC/MS, or any other method to not only give you an amount, but also structural and purity information.

So once again we see how fluorous methods are applied to DOS and the value they provide.


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