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How Does it Work?

Fluorous Mixture Synthesis (FMS) is a new paradigm in solution phase chemistry.[1] FMS is the first technique that allows scientists to reap the benefits of solution phase mixture synthesis and still maintain predictable isolation of individual high purity products. The concepts of fluorous mixture synthesis are shown in Figure 1.

Members of series of substrates are tagged with a corresponding series of homologous FluoroFlash® tags. Each fluorous tag bears the same basic functionality, but the tags differ in fluorine content. The tagged substrates are mixed and then taken through a series of synthetic reactions. Intermediate and final mixtures can be analyzed and characterized via demixing (separating) by FluoroFlash® chromatography. During separation, the molecules elute in order of increasing fluorine content of the tag (Fig. 2). Compounds are predictably identifiable by simple comparison to the original tag/substrate pairings.

The tags are then removed via chemical transformation followed by fluorous SPE to yield the pure target products.

Basic Techniques and Applications

Two-Tag Synthesis and Separation of Enantiomers

In the simplest application of FMS, two substrates are tagged, mixed, and reacted together. Curran and coworkers showed that by tagging two enantiomeric starting materials, a quasiracemic mixture could be made. After several synthetic steps, the mixture was separated by fluorous HPLC to deliver both product enantiomers.[2]

Four-Tag Synthesis and Separation of Discodermolide Analogues[3]

In a more advanced application, four truncated analogues of the potential anticancer agent discodermolide were synthesized in a single synthetic sequence. An eight step synthesis was conducted on a mixture facilitated by the use of four homologous fluorous PMB-Br tags. The final mixture was demixed into four pure components by fluorous chromatography.

Advanced Techniques

Split and Parallel Synthesis

For maximum benefit, up to seven FluoroFlash® tags are used in a solution phase split scheme. In this case, substrates are tagged and mixed before the execution of additional reaction steps. The reaction mixture is split and carried down different synthetic paths. After the last synthetic step, pure products from each mixture are separated and identified by fluorous HPLC.

Advanced Applications

Mappicine Library

This value of fluorous mixture synthesis has been demonstrated by the synthesis of a mappicine library. FTI scientists prepared all members of a 560-member library of mappicine analogs on a 1 mg scale. A seven-component mixture underwent one-pot and split-parallel syntheses using two sets of building blocks to make a library of 560 compounds in four steps of mixture synthesis.[4]

The value of the mixture approach is readily illustrated by counting synthetic steps as shown below. Comparable savings accrue in separation steps.

The savings increase with the number of compounds mixed, with number of synthetic steps, and with the number of splits after mixing.

Selected References

1. Curran et al. Fluorous Mixture Synthesis: A Fluorous-Tagging Strategy for the Synthesis and Separation of Mixtures of Organic Compounds Science 2001 1766-1769. [Back to Text]
2. Curran et al. Quasiracemic Synthesis: Concept and Implementation with a Fluorous Tagging Strategy to make Both Enantiomers of Pyridovericin and Mappicine J. Am. Chem. Soc. 2002, 5774-5781. [Back to Text]
3. Curran and Furukawa Simultaneous Preparation of Four Truncated Analogues of Discodermolide by Fluorous Mixture Synthesis Organic Letters 2002 2233-2235. [Back to Text]
4. Zhang, Chen, Luo, and Curran Solution-Phase Preparation of a 560-Compound Library of Individual Pure Mappicine Analogs by Fluorous Mixture Synthesis J. Am. Chem. Soc. 2002, 124, 10443-10450. [Back to Text]