Liquid-liquid extractions following "heavy" fluorous scavenging

The first fluorous scavengers introduced by Curran in 1996, were considered "heavy fluorous" scavengers.  These compounds contain >60% of fluorine by molecular weight, and they rely on liquid-liquid extraction methods with fluorous solvents to accomplish separations.

While light fluorous scavengers and F-SPE cartridges are the preferred scavenging method, use of heavy fluorous scavengers is still relevant, particularly in large scale industrial applications.  Heavy fluorous scavengers can also be used in 'green' processes.   To date, three specific applications of heavy fluorous scavenging have been reported.  Examples of heavy fluorous scavengers are given in Figure 1.

The Curran group first developed fluorous amine as a nucleophilic scavenger to remove excess isocyanate in parallel synthesis of aryl ureas.  The quenched reaction mixture was separated by a liquid/liquid extraction to afford pure product in the organic phase and fluorous species in the FC-72 layer (Figure 2).

The Curran group also introduced fluorous trialkyltin hydride in Giese reactions.  A catalytic amount of reagent was first used to promote the addition of alkyl radicals to alkenes.  Then, the fluorous compound was used to scavenge excess alkenes (Figure3).

The reaction mixture was separated by an aqueous/organic/fluorous triphasic extraction.  The product was collected in the organic layer.  The utility of trialkyltin hydride has been further extended for scavenging of alkenes in nitrile oxide cycloadditions and alkynes in Diels-Alder reactions (Figure 4).

The Wipf group utilized fluorous vinyl ether to isolate a key intermediate from a reaction mixture in the synthesis of analogs of marine natural product curacin A (Figure 5).  The function of this fluorous compound is different from those of conventional scavengers.  Instead of scavenging the undesired component, the scavenger was used to isolate the desired alcohols from the reaction mixtures using a "catch and release" strategy.

Fluorous quenching of crude alcohol with excess vinyl ether ("catch") was followed by a triphasic liquid extraction with FC-72 and MeCN/H20 to separate the partially fluorinated acetals.  Methanolysis of the fluorous extraction provided "release", followed by another triphasic liquid extraction, which finally afforded pure alcohol in the organic phase.  Following this "catch and release" scavenging protocol, six mixture libraries of analogs were prepared and screened.  Despite their simplified structures, this approach identified, in short order, the most potent curacin A analogs identified to date.

It is important to note that these capture experiments predate the widespread application of fluorous silica, which is now probably the preferred separation medium for this type of experiment.

Selected References

1. Lindsley, Craig W.; Leister, William H. Fluorous Scavengers Submitted to Handbook of Fluorous Chemistry. [PDF Article]
2. Wipf, P., et al. Synthesis and biological evaluation of a focused mixture library of analogues of the antimitotic marine natural product curacin A J. Am. Chem. Soc. 2000 , 122, 9391-9395. [PDF Article]
3. Zhang, Wei, Fluorous Scavengers for Solution-Phase Synthesis The World Pharma Chem Directory 2003, 18-20.
4. Curran, Dennis P. Fluorous Techniques for Combinatorial and Parallel Synthesis Pharmaceutical News, submitted.
5. Linclau, Bruno; Sing, Ashvani K.; Curran, Dennis P. Organic-Fluorous Phase Switches: A Fluorous Amine Scavenger for Purification in Solution Phase Parallel Synthesis J. Org. Chem. 1999 , 64, 2835-2842 [PDF Article]
6. Curran, Dennis P.; Hadida, Sabine; Kim, Sun-Young; Luo, Zhiyong Flurous Tin Hydrides: A New Family of Reagents for Use and Reuse in Radical Reactions J. Am. Chem. Soc. 1999 , 121, 6607-6615 [PDF Article]