Protecting fluorous

A highly fluorous alkoxy ethyl ether was synthesized and used as a protective group of alcohols. Treatment of an ether solution of 1 equivalent of a primary alcohol and 3 equivalents of the fluorous vinyl ether 29 with 5 mol% of camphorsulfonic acid (CS A) for 3 h at room temperature provided the desired protected alcohols 30 in 84-93% yields (Scheme 33). The products and the excess fluorous vinyl ether were extracted with FC-72 and then separated by column chromatography. Secondary and even tertiary alcohols were similarly protected in good yields in THF at 65°C for 30 5 min. The protected fluorous acetals were treated in a 1 1 solution of ether and methanol with 5 mol% of CSA for 1 h for deprotection. After completion of the reaction, the products were isolated in pure form by simple three-phase extraction (reaction mixture/saturated aqueous NaHC03/FC-72). 

The use of diamine 27, bearing a fluorous-Boc protecting group, has been used with microwave irradiation in an Ugi/de-Boc/cyclization strategy for the synthesis of benzimidazoles 28 and quinoxalinones 29 [64]. Compared to the original procedures, which take 1-2 days, this approach avoids the use of... 

Scheme 7.83 Suzuki reactions utilizing fluorous-tagged acid-labile protecting groups.

Furthermore, multicomponent reactions can also be performed under fluorous-phase conditions, as shown for the Ugi four-component reaction [96], To improve the efficiency of a recently reported Ugi/de-Boc/cyclization strategy, Zhang and Tempest introduced a fluorous Boc group for amine protection and carried out the Ugi multicomponent condensation under microwave irradiation (Scheme 7.84). The desired fluorous condensation products were easily separated by fluorous solid-phase extraction (F-SPE) and deprotected by treatment with trifluoroacetic acid/tet-rahydrofuran under microwave irradiation. The resulting quinoxalinones were purified by a second F-SPE to furnish the products in excellent purity. This methodology was also applied in a benzimidazole synthesis, employing benzoic acid as a substrate. 

For this purpose, perfluorooctanesulfonyl-tagged benzaldehydes were reacted with 1.1 equivalents of a 2-aminopyridine (or 2-aminopyrazine), 1.2 equivalents of an isonitrile, and a catalytic amount of scandium(III) triflate [Sc(OTf)3] under micro-wave irradiation in a mixture of dichloromethane and methanol (Scheme 7.85). A ramp time of 2 min was employed to achieve the pre-set temperature, and then the reaction mixture was maintained at the final temperature for a further 10 min. The fluorous tag constitutes a multifunctional tool in this reaction, protecting the phenol in the condensation step, being the phase tag for purification, and serving as an acti-... 

The assembly of tetrapeptide 19 that contains all possible 0-dipeptide bonds, (03-03)-, (03-02)-, and (02-03), and also a turn inducing 03-(R)-Ala-02-(R)-Val element was achieved employing a Boc-strategy (Scheme 5). A fluorous benzyl group was incorporated in the first amino acid to streamline the purification procedure by fluorous solid phase extraction (LSPE) (Lilippov et al. 2002 de Visser et al. 2003). Thus, the assembly of the fully protected tetrapeptide commenced with the construction of the first 03-03-peptide bond by applying the previously established conditions. A residence time of 3 min at 90°C provided the Boc-protected dipeptide 15 in 91% isolated yield after LSPE. Notably, the product precipitated in the collection flask, which was kept at ambient temperature, indicating the poor solubility of this class of compounds (Hessel et al. 2005). 

De Visser PC, van Helden M, Filippov DV, van der Marel GA, Drijfhout JW, van Boom JH, Noort D, Overkleeft HS (2003) A novel, Base-Labile Fluorous Amine Protecting Group Synthesis and Use as a Tag in the Purification of Synthetic Peptides. Tetrahedron Lett 44 9013-9016... 

D. P. Curran, R. Ferritto, Y. Hua, Preparation of a Eluor-ous Benzyl Protecting Group and its Use in a Fluorous Synthesis Approach to a Disaccharide , Tetmzhedron Lett. 1998, 39, 4937. 

Fig. 4. Fluorous protecting group (Bnf) simultaneous function as protecting group and as fluorous tag.

The synthesis of proline-fused heterocyclic systems by 1,3-dipolar cycloaddition has been well-established in solution-phase synthesis (Scheme 14) [42]. It is usually performed as a one-pot, three-component reaction of a dipo-larophile with an in situ prepared azomethine ylide. Perfluoroalkanesulfonyl protected hydroxybenzaldehydes [43] or fluorous alcohol protected amino esters [44] have been developed as two different fluorous components for the synthesis of proline derivatives 11 and 12. 

Perfluorosulfonates have been demonstrated as a valuable fluorous syn-thon. In multistep synthesis, the perfluorooctanesulfonyl tag plays three roles 1) as a protecting agent for the hydroxyl group 2) as a fluorous tag to facilitate intermediate purification and 3) as an activating group to promote the coupling reaction. 

Ladlow and coworkers recently developed an acid-labile fluorous benz-aldehyde protecting group 43 to facilitate the parallel synthesis of sulfonamides 44 (Scheme 25) [56]. The Suzuki coupling reaction was conducted under microwave irradiation. All the intermediates and the final products were purified by F-SPE. 

Zhang, W. 2004. Fluorous protecting groups and tags. Handbook of Fluorous Chemistry. In J.A. Gladysz, D.P. Curran, and I.T. Horvath, eds., pp. 222-36. Whey-VCH Germany. 

Fluorous reverse phase silica gel (FRPSG) has been used in the purification of synthetic DNA fragments.In solid phase DNA synthesis, truncated sequences are often separated from the desired product after deprotection using HPLC or electrophoresis. In order to perform, parallel syntheses and separations of nucleotides the trityl-on purification procedure was developed, in which a lipophilic support material is used to separate the desired and undesired product, followed by deprotection. If the protecting group is labelled with a fluorous group, fiuorous-fiuorous interactions between the FRPSG and the protected nucleotide can be used to aid separation of the aqueous mixture. 

Oligosaccharide syntheses have also been performed in parallel using a fluorous support.A benzyl-type protecting group (HfBn) used in some of these procedures is shown in Figure 7.26. The novel approach here is that the fluorous group or tag is recycled and this can be achieved fairly easily... 

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