How does Fluorous Mixture Synthesis Work ?

Fluorous Technology Primer - Part VII

Introduction

The synthesis of compound mixtures economizes time, effort and money since many fewer operations are required compared to standard serial or parallel synthesis. However, solution mixture synthesis is not used because it is not possible to ensure that the final mixture can be resolved into its individual pure components. Fluorous mixture synthesis is the first technique that captures the economy inherent in solution phase synthesis of mixtures yet still allows the predictable isolation of individual pure products at the end of the exercise.

Concepts

The concepts of fluorous mixture synthesis are shown in the cartoon on the right. Members of series of substrates are tagged with a corresponding series of fluorous tags. Each fluorous tag bears the same basic functionality, but the tags differ in fluorine content. This crucial difference controls the final separation. The tagged substrates are mixed and then taken through a series of synthetic reactions where the economy of the mixture techniques is harvested (the number of operations required at each stage is divided by the number of tags). Just prior to detagging, the final products are "demixed" (separated) by fluorous chromatography. This separates the molecules, which elute in order of increasing fluorine content of the tag. The compounds are simultaneously identified in the demixing simply by comparison to the original tag/substrate pairings.

Example

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

Each final mixture was then demixed by fluorous chromatography to give the seven individual components in order of increasing fluorine content from the C₃F₇-tag up to the C₁₀F₂₁-tag (the C₅F₁₁-tag was missing from the exercise). A representative HPLC trace of the demixing is shown on the left (the absence of the C₅F₁₁-tag is readily seen by the gap between the second and third peaks in each of the 80 chromatograms). A steep solvent gradient is needed to elute all the compounds within 35 min. All 560 tagged mappicines were identified by LCMS analysis and were isolated from serial preparative runs. Finally, the tags were removed with HF followed by a simple spe to remove the residual tag from the final mappicine analogs.

Features

Fluorous mixture synthesis techniques are ideal for leveraging either serial or parallel synthesis discovery efforts since more compounds are produced without a proportional increase in effect. The analytical power of the fluorous silica gel allows one to follow reactions and identify products in mixtures almost as easily as with individual pure compounds. This technique is especially useful for making analog libraries or for making multiple stereoisomers in a single synthetic sequence.

Our Technology Primer - Table of Contents

• Liquid-Liquid Extractions
• Solid-Liquid Extractions
• Fluorous Chromatography

• Advantages at a Glance
• For Further Reading