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Fluorous Protecting Groups1

Chemfiles Volume 7 Article 3

Fluorous protecting groups are able to serve multiple purposes at the same time. While acting as a regular protecting group for a specific functional group they also offer an ideal opportunity to introduce a temporary fluorous tag into a molecule. This tag can be carried through a multi-step synthesis procedure, and can facilitate product workup and purification after every synthetic step.

As a general guideline, fluorous-tagged products with high fluorine content (heavy fluorous products) are recommended for natural products or medicinal chemistry synthesis in combination with either liquid-liquid or fluorous solid-phase extraction (F-SPE). Homologous fluorous-tagged products with lower fluorine content (light fluorous compounds) are useful in either fluorous chromatography or fluorous mixture synthesis.2,3 Products with smaller fluorous tags show increased solubility in organic solvents; therefore, fluorous solvents are not necessary during the reaction, and the fluorous phase (either solid or liquid) can be used only in the separation step. At the final stage of the synthesis the desired target molecule is deprotected by the same methods as the non-fluorous analogue.

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F-Boc-ON

F-Boc-ON is the fluorous equivalent of 2-(tert-butoxycarbonyloxyimino)- 2-phenylacetonitrile (Boc-ON) used in protecting amino groups in peptide synthesis or other functionalities in multi-step organic synthesis. Protection of the amino group with F-Boc-ON and deprotection are achieved under traditional reaction conditions, with the advantage that products containing the F-Boc group can easily be separated from organic reagents, reactants, or products by performing a quick fluorous solid-phase extraction over FluoroFlash® Silica Gel.4

In a recent example, F-Boc-ON was used for the preparation and isolation of DNA minor groove binding polyamides containing Nmethylpyrrole. The authors found that the isolation of the fluorous intermediates in the synthetic scheme was advantageous when compared to conventional purification methods (Scheme 1).5

Scheme 1

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F-PMB-OH

F-PMB-OH is the fluorous equivalent of p-methoxybenzyl alcohol (PMBOH) used in protecting alcohols in multi-step organic synthesis. F-PMB can be deprotected either under typical acid or oxidizing conditions. The reactivity of F-PMB and conventional PMB are so similar that a 3,4- dimethoxybenzyl (DMB) protecting group has been selectively cleaved in the presence of both F-PMB and PMB (Scheme 2).6

Scheme 2

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F-Trityl Alcohol and Chlorides

Several fluorous versions of trityl protecting groups are available from Sigma-Aldrich for the protection of alcohols, amines and carboxylates. These include F-Trt, F-MMT, and F-DMT that are analogous to the conventional trityl, monomethoxy trityl, and dimethoxy trityl groups and react analogously to their non-fluorous counterpart. Each of these groups is acid labile with the relative rate of deprotection being F-Trt < F-MMT < F-DMT. The F-DMT group has recently been used in oligonucleotide synthesis followed by purification through F-SPE.7

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F-Silanes

F-Silanes are the fluorous equivalent to a TIPS group. They exhibit properties similar to most silicon protecting groups and have been used in both parallel and fluorous mixture synthesis.8,9 Tagging of an alcohol is accomplished by in situ activation of the F-silane to either the bromide or triflate followed by addition of the alcohol. Detagging of the F-silane is accomplished either by treatment with fluoride or acid.

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F-Benzyl Alcohol, F-Fmoc-Cl, F-Z-OSu

These reagents are the fluorous equivalents of their parent protecting groups and are fully compatible with the corresponding protection and deprotection methods conventionally associated with that group.

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References

  1. The fluorous products featured here are manufactured by Fluorous Technologies, Inc. U.S. patents 6,156,896; 5,859,247; 5,777,121 and 6,673,539 may protect use of these compounds.
  2. Zhang, Q. et al. J. Am. Chem. Soc. 2004, 126, 36.
  3. Curran, D. P.; Oderaotoshi, Y. Tetrahedron 2001, 57, 5243.
  4. Curran, D. P. Synlett 2001, 1488.
  5. Mamidyala, S. K.; Firestine, S. M. Tet. Lett. 2006, 47, 7431.
  6. Curran, D. P.; Furukawa, T. Org. Lett. 2002, 4, 2233.
  7. Pearson, W. H. et al. J. Org. Chem. 2005, 70, 7114.
  8. Palmacci, E. R. et al. Angew. Chem. Int. Ed. 2001, 40, 4433.
  9. Zhang, W. et al. J. Am. Chem. Soc. 2002, 124, 10443.

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