Orthogonal Fluorous Mixture Synthesis (FMS)

University of Pittsburgh Professor and Fluorous Technologies, Inc. founder, Dennis Curran, has over the last several years dedicated a good portion of his research to fluorous mixture synthesis (FMS).  In FMS, libraries or isomers of compounds can be made in a minimum number of reactions by labelling the molecules with a specific length fluorous tag in a single reaction vessel.  The molecules can then be separated in a predictable fashion by fluorous HPLC (F-HPLC) based on their fluorine content.  So those molecules tagged with a C4F9 tag can be readily separated from those with a C6F13 tag or a C8F17 tag.

One issue with FMS is the limited number of tag lengths that are practically available.  In theory any perfluorocarbon chain length should be usable from CF3 to CxF2x+1.  In practice, though, anything above C9F19 introduces solubility problems in organic solvents which defeats the purpose, since they won’t react in a similar fashion as the soluble components.  In addition, the odd numbered lengthed perfluorocarbons (C3,  C5, C7, and C9) are considerably more expensive than the even numbered chain lengths.  So now we’re down to just four lengths.  That then lowers the overall value of FMS since it limits the total number of reactions saved over parallel synthesis.

In response to that Prof. Curran has previously reported two methods to increase the number of reactions that can be conducted in a single pot and still be able to deconvolute the mixture.  One is to use fluorous tags in conjunction with oligoethylene glycol (OEG) tags of different length.  In this strategy, a two dimiensional separation strategy is used; a fluorous based separation and a RP-HPLC based separation.  Another is to use a double tagging strategy and separate the mixtures based on the cumulative fluorine count.  The synthesis of the cytostatins which we’ve covered in F-Blog before is an example.  This binary encoding works well, but is limited by additive redundancies.  In other words, the C6 and C4 tags in combination add up the same as the C2 and C8 tags in combination.  So even if you can easily separate the two by F-HPLC (not at all guarenteed), it’s impossible to predict which one is which.

A new paper from Dr. Curran’s labs in Nature Chemistry describes another double tagging FMS strategy which increases the number of molecules that can be made and overcomes the redundancy issue.  In this approach the researchers once again use two fluorous tags, but in this instance orthogonal tags rather than the same tags as in the cytostatin case.  The researchers produced a 16 member steroisomer library of macrosphelides (shown above) using a F-PMB and a F-TIPS tag as the orthogonal tags.  Each tag had four variants, C2, C4, C6, and C8, so 4 x 4 provides the 16 members.  By utilizing two tags that can be selectively removed, they were first able to partially deconvulute by FHPLC based on the cumulative fluorous content of both tags to provide 7 fractions.  These fractions were selectively deprotected of one tag and subjected to another FHPLC to completely deconvolute the mixture.  The figure below from the paper shows the redundancies and the fractions.

The macrosphelides are a series of natural product macrocycles containing five stereocenters.  The authors went on to prepare 16 of the 32 stereoisomers, leaving C3 stereochemistry fixed.  Each of the 16 stereoisomers had a distinct 1H and 13C NMR and they were able to match one of the isomers with previously characterized macrosphelide A and one with macrosphelide E (Note that the molecule they produced was enantiomeric macrosphelide E), thereby confirming the structure of each.

A problem was encountered, however, in that none of the spectra matched that of the reported structure of macrosphelide D.  After considering the possible structural isomers they hypothesized that macrosphelide D was actually a the ring contracted isomer shown below.  They then confirmed this through independent total synthesis.In conclusion the authors demonstrated that orthogonal binary fluorous tagging with double F-HPLC separation is a viable strategy for miaximizing FMS efficiency.  In the synthesis of the macrosphelides they required only six chemical reactions once the tagged intermediates were in place vs. 72 reactions if one were to do this in parallel synthesis mode.  In addition they once again demonstrated how important the synthesis of all possible isomers can be in natural products chemistry since it led to a definitive structural assignment of macrosphelide D.

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