Not too long ago F-Blog published a post describing some of the work of Prof. Adam Nelson’s group at the University of Leeds using fluorous tags in cascade olefin metathesis reactions. The reactions described in that report built a number of polyene substrates which were set up to undergo a series of tandem olefin metathesis reactions which eventually resulted in the creation of new cyclic compounds with concomitant loss of the fluorous tag. By using a fluorous tag approach they were able to quickly construct the metathesis substrates and isolate them with little need for chromatography. They concluded their initial report in J. Org. Chem. by stating “the application of a fluorous-tagged linker in the diversity-oriented synthesis of more complex, natural product-like molecules will be described in due course.” Well, it didn’t take them long.
A very recently available publication in Angewandte Chemie Intl. Ed. by Nelson et al describes the preparation of a 96-member diversity oriented synthesis library using the cascade olefin metathesis methodology described in the JOC paper. The authors claim that within the products that 80 distinct molecular scaffold are represented. A remarkable amount of molecular diversity packed within a relatively small library. In addition, around 65% of the molecular scaffolds were previously unreported. The methodology they used was to strip away side chains to provide base ring systems, which were deemed “daughter” scaffolds, then to further strip off appendant rings to provide a core ring system which was deemed a “parental” scaffold. The parental scaffolds fit into three classes carbacycles, azacycles, and carbacycles. The tree below depicts this library through its 3 classes, 25 parental scaffolds, 54 daughter scaffolds and 84 molecular scaffolds. These molecular scaffolds run from 5 to 15 member ring and are a true testament to the power of RCM reactions. We’ll leave it up to you to view the paper for all the scaffolds and their structures.
While the key to achieving the high level of diversity reported may have been RCM, the fluorous tag played a critical role also. The fluorous tag allowed a wide variety of substrates to be quickly assembled without the need for column chromatography and it also ensured that only cyclized products were isolated, since the complete cyclization reaction occurs with detagging. So if cyclization did not occur the fluorous tag remained intact. Fluorous solid phase extraction (FSPE) was used to separate the desired non-fluorous product quickly and easily from any fluorous containing compounds, such as unreacted substrate, remnants of the fluorous tag after detagging, partial reaction products, etc. So while yields varied greatly across the library, which isn’t surprising given it diversity, FSPE provided a method for facile isolation prior to final HPLC purification.
The level of diversity obtained within this library earned this publication VIP (Very Important Paper) status from editors of Angewandte Chemie which is reserved for those papers where two referees recommend VIP designation. This is the second paper using fluorous techniques within the last year or so to be so honored and we’re happy to have played a small role in that. (The first was one from Vegas et al describing fluorous small molecule microarrays.)
Another very nice example of how fluorous techniques can be used in library synthesis.