Fluorous intermediates synthesis

In addition, a novel fluorous support has been developed recently as an alternative to traditional polymer supports and applied successfully to oligosaccharide synthesis in combination with the trichloroacetimidate method [541]. Each intermediate in the fluorous oligosaccharide synthesis [542,543] could be obtained by simple fluorous-organic solvent extraction, and the reactions could be monitored by TLC, NMR and MS, in contrast to solid-phase reactions. Moreover, the new liquid-phase technique is anticipated to be easily applicable to the large-scale synthesis. 

Use as Tag for Substituted Heterocycles. The fluorous thiol has been used as a phase tag to facilitate purification in the synthesis of disubstituted pyrimidines (eq 3). Using a catch and release strategy, the fluorous thiol is first attached to 2,4-dichloro-6-methylpyrimidine. Tagged pyrimidine 3 is then reacted with 3-trifluoromethylpyrazole to give 4. After the fluorous tag is activated by oxidation with Oxone, it is displaced by nucleophiles such as amines and thiols to give a variety of disubstituted pyrimidines. In this multi-step synthesis, the intermediates and the final product are purified by F-SPE. The fluorous intermediates are collected in the second fraction eluted with MeOH, while the final product is collected in the first fraction eluted with 80 20 Me0H H20. 

Scheme 7.6 Synthesis of intermediates for fluorous mixture synthesis.

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. 

Scheme 17 illustrates another fluorous sulfonate-based synthesis of library scaffolds. The tagged substrates were taken through aldol condensation and cycloaddition reactions to form the pyrimidine ring 18. The intermediates were then reacted with boronic acids for Suzuki reactions to form biaryl compounds 19 [31], reacted with HCO2H to give traceless detagged products 20 [34], or reacted with amine to form products 21 [33]. 

In the synthesis of a compound library of allosteric Akt kinase inhibitors 39, Lindsley and coworkers employed different HTS techniques (Scheme 24) [54]. A polymer-supported base and a fluorous thiol scavenger were used in the alkylation reaction of 40. F-SPE purified intermediate was then used for microwave-assisted cycloaddition of 41. Similar intermediates have been used for generation of an unnatural canthine alkaloid library 42 by performing cycloaddition reactions with an indo-tethered acyl hy-drazide [55]. 

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. 

The synthesis of small arrays of organic compounds derived from multicomponent condensations was recently reported by Studer et al. (119). A 10-member amino acid amide library L7 (Fig. 8.21) was prepared using the fluorous Ugi ( Flugi ) condensation, and another 10-member dihydropyrimidine library L8 (Fig. 8.21) was prepared using the Biginelli ( Fluginelli ) condensation adapted to the fluorous phase. The key intermediates for library preparation were the silyl bromide 8.36, prepared from a fluorous iodide (120), and the acyl bromide 8.37 and the acid 8.38, prepared from an orthothiobenzoate (121), as shown in Fig 8.21. The structure of the fluorous tag was... 

Figure 8.21 Fluorous-tagged Flugi (L7) and Fluginelli (L8) libraries synthesis of tagged intermediates 8.36-8.38.

Synthesis of the array L8 is reported in Eig. 8.23. Bromide 8.37 was esterified with a urea alcohol (step a, Eig. 8.23) and purified by triphasic extraction (step b), giving pure 8.40 in the fluorous phase. Compound 8.40 was reacted with Mi ( 3-keto esters, four examples) and with Mi (aldehydes, three examples), as shown in step c, and then intermediates 8.41 were purified by two-phase fluorous/organic extraction (step d). 

A promising technique for the tagged oligosaccharide synthesis that makes use of an ionic-liquid support has recently emerged.259 As with the polymer-supported and fluorous tag-supported syntheses, ionic liquid-supported assembly expedites oligosaccharide synthesis by eliminating the need for chromatographic purification of the intermediates. 

Figure 3. Synthesis ofpolymannose using a single CgF 17-tag for fluorous solid-phase extraction of intermediates.

A related strategy was used for synthesis of a more complex carbohydrate, the trisaccharide moiety of globotriaosyl ceramide (Gb3) [10b] (Scheme 3.19). In this reaction an acyl-based fluorous protecting group was used to facilitate the intermediate purification steps in a similar way as can be achieved by solid phase carbohydrate chemistry [12]. 

Scheme 3.22 Fluorous synthesis of a library of substituted quinazoline-2,4-diones (46) [22]. The key to this approach is a fluorous benzyloxycarbonyl group on which the target molecules are stepwise constructed and which keeps the different synthetic intermediates bound to fluorous reversed-phase silica gel (FRPSG) during the purification cycles. The structural diversity of the target compound library (46) is introduced by the different anthranilic acid derivatives and primary amines in boxes) (TBTU = 0-(benzotriazol-1-yl)-N,/ /,N, N -tetramethyluronium tetrafluoroborate).

An improvement employed the H202/MTO/fluorous alcohol system (described earlier) in a one-pot procedure for synthesis of mixed tetroxanes, which did not require isolation of the unstable and potentially explosive gem-dihydroperoxide intermediate 240. The more reactive carbonyl compound was first oxidized to the gi OT-dihydroper-oxide 240, followed by the addition of the less reactive carbonyl compound in the presence of 1 equiv of HBF4. This procedure afforded unsymmetrical tetroxanes 238 in good yields (method B, Scheme 45 Table 4) <2003TL6309>. 

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