Binary fluorous tagging enables the synthesis and separation of a sixteen-stereoisomer library of macrosphelides

Fluorous mixture synthesis minimizes the effort to synthesize small molecule libraries by labeling the molecules rather than the reaction vessels. Reactants are labeled with fluorinated tags and products can later be demixed based on fluorine content. A limit in the number of available tags can be overcome by using binary encoding so that a total of four tags can be used to uniquely label a library of sixteen compounds. This strategy, however, means that separation based on fluorine content alone is no longer possible. Here, we solve this problem by selectively removing one tag after an initial demixing step; a second demixing provides each individual compound. The usefulness of this strategy is demonstrated by synthesizing a library containing all sixteen diastereomers of the natural products macrosphelides A and E. Macrosphelide D was not in this library, and so its assigned structure is incorrect. We determined its constitution by using NMR spectroscopy and its configuration by synthesizing four candidate stereoisomers.