Fluorous Tetrahydropyranyl Ether (THP, 2-Benzenesulfinyl-3-heptadecafluorooctyltetrahydropyran)
· (MW 628.34)
(reagent used to protect hydroxyl groups; protected substrates are rendered fluorous soluble and can be purified by fluorous liquid-liquid or solid-phase extraction techniques; after cleavage fluorous label can be recycled)
Physical Data: mp 66-69 °C.
Solubility: soluble in tetrahydrofuran, dichloromethane, acetonitrile; insoluble in H2O.
Analysis of Reagent Purity: 1H and 13C NMR, IR, elemental analysis.
Preparative Methods: the fluorous THP is prepared by a three-step sequence (1)1 initially involving treatment of a methanolic solution of perfluoro-n-octyl iodide, triethylamine, and [CpFe(CO)2]2 with 3,4-dihydro-2H-pyran to give a methoxy-substituted fluorous THP group. This methyl acetal is then exchanged with thiophenol to give a phenylthioacetal, which is subsequently oxidized with meta-chloroperbenzoic acid to give the desired sulfoxide. The minor, less reactive trans-diastereomer is removed at this stage by flash column chromatography on silica. The diastereomers may also be separated prior to oxidation to the sulfoxides, although with more difficulty since the RF difference is much smaller between the diastereomeric thioacetals.
Handling, Storage, and Precautions: reagent is best stored under a nitrogen atmosphere in a dry environment.
Fluorous Tetrahydropyranylation of Alcohols
Protection of alcohol functionalities with the fluorous THP group serves not only to protect the alcohol but also allows the techniques of fluorous liquid-liquid2 and solid-phase3 extraction to be used in subsequent reactions on the substrate. The tetrahydropyranylation reaction is performed by treating a mixture of alcohol, zirconocene dichloride and silver perchlorate in dichloromethane with 1.5-2.5 equiv of sulfoxide (2-4).1
The protected alcohol is usually obtained as a 8-12:1 cis/trans mixture of diastereomers. Yields vary generally between 74-92% for primary alcohols (2) and 67-75% for secondary alcohols (3). Tertiary alcohols give low yields of fluorous THP acetals (4).
Fluorous Phase Purification
Purification of fluorous THP ethers is accomplished by dissolving the crude reaction product in acetonitrile and extracting with FC-72 (perfluorohexane) 3-5 times. (FC-72 is a commercially available (3M) fluorocarbon solvent which consists of perfluorohexane (C6H14) isomers, bp 56 °C.) Concentration of the fluorous extracts yields the fluorous THP-labeled product contaminated only by traces of starting sulfoxide. This fluorous liquid-liquid extraction purification method works well for small molecules, but larger or more polar molecules require fluorous solid phase extraction4 using fluorous reverse phase silica gel5 (FRP SiO2). Loading of crude fluorous THP-protected cholesterol (3) onto a short FRP SiO2 column, washing first with acetonitrile to elute organic components, then with FC-72 to elute the fluorous-labeled compound allowed efficient purification of this relatively large substrate. The fluorous THP-labeled substrates may be carried through subsequent reactions using these fluorous extractive techniques for purification. The fluorous THP is stable to basic, nucleophilic, and even mildly acidic reaction conditions. This fluorous protecting group is more stable to basic and acidic reaction conditions than the fluorous AE6 and BPFOS,7 as well as the various tris(perfluoroalkyl)silyl ethers.2,8
Removal of the Fluorous THP Group
The organic substrate alcohol can be freed from the fluorous THP via acid catalyzed transacetalization with methanol (5). Fluorous liquid-liquid extraction of the crude reaction product mixture using acetonitrile/FC-72 allows complete separation of the desired alcohol (acetonitrile layer) and the fluorous methyl acetal (FC-72 extracts), both in good yields.
Rather harsh conditions are necessary for the deprotection reaction due to the powerful electron-withdrawing ability of the perfluorooctyl group. Accordingly, this protective group is limited to substrates with no acid-sensitive functionality. The conditions of deprotection for this fluorous protective group are considerably harsher than those required for fluorous AE,6 BPFOS,7 and the tris(perfluoroalkyl)silyl ethers.2,8 Once deprotected, the fluorous methyl acetal can be recycled (1) to the sulfoxide. The fluorous THP and the fluorous AE are the only readily recyclable fluorous protecting groups.9
- 1. Wipf, P.; Reeves, J. T., Tetrahedron Lett. 1999, 40, 4649.
- 2. (a) Horváth, I. T., Acc. Chem. Res. 1998, 31, 641. (b) Curran, D. P., Angew. Chem., Int. Ed. 1998, 37, 1175. (c) Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P., J. Org. Chem. 1997, 62, 2917. (d) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S. Y.; Jeger, P.; Wipf, P.; Curran, D. P., Science 1997, 275, 823.
- 3. (a) Kainz, S.; Luo, Z.; Curran, D. P.; Leitner, W., Synthesis 1998, 1425. (b) Billiet, H. A. H.; Schoenmakers, P. J.; De Galan, L., J. Chromatography 1981, 218, 443.
- 4. Curran, D. P.; Luo, Z. Y., J. Am. Chem. Soc. 1999, 121, 9069.
- 5. Curran, D. P.; Hadida, S.; He, M., J. Org. Chem. 1997, 62, 6714.
- 6. Wipf, P.; Reeves, J. T., Tetrahedron Lett. 1999, 40, 5139.
- 7. Röver, S.; Wipf, P., Tetrahedron Lett. 1999, 40, 5667.
- 8. Boutevin, B.; Guida-Pietrasanta, F.; Ratsimihety, A.; Caporiccio, G.; Gornowicz, G. J., J. Fluorine Chem. 1993, 60, 211.
- 9. Jarowicki, K.; Kocienski, P., J. Chem. Soc., Perkin Trans 1 2000, 2495.
Jonathan T. Reeves
University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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