Fluorinated building blocks

Munyemana, F., Frisque-Hesbain, A., Devos, A., and Ghosez, L. (1989) Tetrahedron Lett., 30, 3077-3080. 

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J.M. Bainbridge, S. Corr, M. Kanai, J.M. Percy, FIFC-134a as a fluorinated building block Short synthesis of a-fluoro enones. Tetrahedron Lett. 41 (2000) 971-974. 

Two independent screens have been developed to investigate the effects of fluorinated building blocks on the interactions of the dimeric peptide assembly. The impact of fluorine side chain substitutions on the stability of coiled coil folding has been studied using temperature-dependant CD spectroscopy. The second screen is based on the ability of a-helical peptides to self-replicate. Thus, peptide... 

Larger Fluorinated Building Blocks. Transformations of Fluorinated Motifs. . ... 

The chemistry of fluorinated building blocks involves methods for the construction of fluorine-containing target molecules from fluorine-containing starting materials by carbon-carbon bond formation to the fluorinated fragment. Ideally, the fluorinated building block should be easy to handle and relatively readily available. This could mean that the material is available commercially, or can be synthesised from such a compound via a short reaction sequence. 

Clearly, there are thousands of reactions of fluorinated building blocks mentioned in the literature this reviewer has concentrated on reactions which show generality, or solve important problems, so the review is highly selective rather than exhaustive. 

Ethyl bromodifluoroacetate is one of the fluorinated building blocks used most widely. There are scores of examples of the important Reformatsky reaction with aldehydes which occurs in THF/ether solvent mixtures, sometimes under sonication conditions (Eq. 62). 

Myers has reported on interesting fluorinated HIV protease inhibitor analogues. However, their stereoselective synthesis as relying on the respective enantiopure fluorinated building blocks derived from resolution A. G. Myers, j. K. Barbay, B. Zhong,/. Am. Chem. Soc. 

Recently, Fukumoto and coworkers used 2,4,6-trimethyl A-fluoropyridinium triflate for obtaining enantiomerically pure fluorinated building blocks. They employed a methyl menthyl malonate in order to induce a diastereomeric excess and indeed obtained a 3 1 diastereoisomeric mixture, which was separated and then either reduced or partially hydrolyzed (equation 198)342. A somewhat different approach was taken by Differding and Lang who used chiral A-fluorosultams to induce for the first time some chirality around 50% ee, when reacted with 2-carboethoxycyclopentanone enolate (equation 199)343. 

Two different approaches have been adopted here in describing fluorination reactions the production of highly fluorinated systems is discussed in this chapter on the basis of a comparison of methods, whereas selective fluorinations are described in Chapter 3 in terms of the conversion of functional groups. If we wish to produce highly fluorinated systems, then the starting materials are usually hydrocarbons, polychloro compounds or, of course, highly fluorinated building-blocks for conversion to other compounds. 

It has been demonstrated that methylsulfanyl difluoromethyl phosphonate (438) has an excellent potential as a freon-free source of phosphonodifluoro-methyl carbanion. A simple preparative procedure involving sequential treatment of the former with butyl lithium and different electrophiles allowed the preparation of a wide range of new fluorinated building blocks (439) (Figure 80). 

Enantioselective synthesis involves chemical modification via (section 9.2.1) introduction of a chiral center into achiral fluorinated building blocks, (9.2.2) chiral transposition, (9.2.3) introduction of fluorine functionality into nonfluorinated chiral building blocks, (9.2.4) modification of chiral fluorinated building blocks, and (9.2.5) enzymatic resolution of racemic fluorinated building blocks. The following sections summarize these five categories. 

Introduction of a Chiral Center into Achiral Fluorinated Building Blocks... 

Modification of Chiral Fluorinated Building Block (S)-Trifluoropropene Oxide... 

Both enzymatic esterification and hydrolysis are useful tools for resolution of racemic fluorinated building blocks. Among them, lipase-catalyzed reaction is reliable and most... 

Chiral fluorinated building blocks are in general less readily available, so that fluoro-functionalization of available chiral building blocks is one feasible approach for the asymmetric synthesis of fluorinated amino acids (see Fig. 9.2). 

Selective fluorination of prostanoids has been effected on the cyclopentane nucleus and on both side chains. A variety of techniques have been employed but may be arbitrarily divided into the fluorination reactions of intermediates and the use of fluorinated building blocks to prepare the target compounds. The chemistry and biology of fluorinated prostaglandins, prostacyclins and thromboxanes through 1981 has been reviewed (110). 

As the demand for optically active fluorinated compounds increases, the importance of the development of asymmetric synthetic methods for fluorinated building blocks grows. On the other hand, sulfur functionalities such as phenylthio and dithianyl groups have been used as useful reactive units for a variety of chemical transformations. Therefore, various trifluoromethyl ketones containing a sulfur functionality have been reduced with various microorganisms l182-185 . 

DiMagno and coworkers reported an efficient route to 58 that also employs a double elimination step, but this is performed on the readily available tetrafluor-opyrrolidine 10 (see Section 3.2.1 above) (Fig. 3.27). Optimization of conditions provided 58 in good yield in a reaction that is readily scaled up, thus providing ready access to this fluorinated building block. This has been particularly valuable for the synthesis of perfluorinated porphyrins (see the discussion below). 

FIGURE 3.57 A fluorinated building block approach to fluorinated imidazoles. 

The fluorinated building blocks have been more often used in more general approaches to ring-fluorinated pyrazoles. For example, reaction of hydrazines with 2-fluoro-1,3-diketones leads to efficient formation of 4-fluoropyrazoles (Fig. 3.66). Observed regiochemistry of products formed from unsymmetrical diketones was ascribed to initial attack of the more nucleophilic p-nitrogen of the hydrazine at the more electrophilic carbonyl group. 

In contrast, there are many reports of trifluoromethyl- and other perfluoroalkyl-substituted tetrazoles prepared from fluorinated building blocks. For example, consistent with its high reactivity, trifluoroacetonitrile reacts exothermically with sodium azide to give sodium 5-trifluoromethyltetrazole 168 (Fig. 3.98). ... 

Polyfluopyridines are versatile fluorinated building blocks. They were used as starting materials in the synthesis of fluorinated chinolonic acids, which show antibacterial activity. Examples of bactericidal mono- and difluoro-substituted 1,8-naphtiridines 140 and 141 prepared from pentfluoropyridine are shown below. ... 

Nucleophilic cyclization reactions are widely used for the synthesis fluoroalkyl heterocycles. This process relies on the use of fluorinated building block for the introduction of perfluoroalkyl group into heterocycle. For example, heating of compound 30 with urea or guanidine results in the formation of the corresponding pyrimidines 31 and 32 in moderate yield (Fig. 7.10). 

Oxazepines containing fluoroalkyl substituents are often prepared using a fluorinated building block approach. For example, a considerable number of 1,4-oxazepines 37 (an effective inhibitors of y-secretase) are synthesized through the condensation of a heterocyclic amine with fluorinated malonamides. 

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