Functional Fluorinated Amino Acids

Taking into account the modifications of steric hindrance—of pK, of pKt, and so on—introduced by the presence of fluorine atoms, it is obvious that only a fluorinated amino acid with few modifications, or with modifications that are far from the amino and acidic functions, has some chance to be incorporated by a microorganism. This explains why the only known examples are F-Phe, 3-F-Tyr, 5-F-Tryp, (5)-trifluor-omethionine, and 4-F-Pro however, trifluorovaline, trifluoroleucine, and 2-F-histidine have also been incorporated into bacterial proteins. Despite the... 

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). 

Recent advances in the syntheses of fluorinated amino acids have been summarized on the basis of the strategies for creating chiral centers in target amino acids (1) enantioselec-tive, (2) diastereoselective, and (3) racemic syntheses. Remarkable progress in fluorinating reagents and fluoro-functionalization methodologies the commercial availability of... 

Amino acids, peptides and proteins play essential roles in living systems. As chemists, we have the ability to fabricate new structures of great complexity. Yet frequently the synthesis and application of even the simplest chemical structures can contribute substantial information on living systems. This has certainly been true for the application of fluorine chemistry to the synthesis of fluorinated amino acids [1, 2], These molecules are not only interesting in their own right but may act as potent mechanism-based enzyme inhibitors that may have application in medicine or diagnostics, or they can be valuable probes that, incorporated into peptides or proteins, elucidate fundamental biological chemistry or uncover new aspects of biochemical structure and function [3-5],... 

Incorporation of fluorine into peptides and proteins is usually achieved through biosynthetic routes, chemical synthesis, or a combination of these two methods. Each method has its own advantages and shortcomings, but each requires a 19F-labeled amino acid. The most commonly used ones are commercially available analogues of aromatic amino acids, such as tryptophan, phenylalanine, tyrosine, and phenylglycine. Aliphatic 19F-labeled amino acids are not commonly available and usually have to be synthesized. The synthesis of most fluorinated amino acids is described in detail in the literature [1, 9,10], For structure analysis of peptides and proteins, it is important that (i) the fluorine label is rigidly attached to the peptide backbone, (ii) the label does not alter the structure or function of the peptide, (iii) the extent of fluorination is restricted to avoid multiple signals, and (iv)... 

The addition of perfluoroalkyl iodides to simple olefins has been quite successful under aqueous conditions to synthesize fluorinated hydrocarbons.119 In addition to carbon-based radicals, other radicals such as sulfur-based radicals, generated from RSH-type precursors (R = alkyl, acyl) with AIBN, also smoothly add to a-allylglycines protected at none, one, or both of the amino acid functions (NH2 and/or CO2H). Optimal results were obtained when both the unsaturated amino... 

Several fluorine-18-labelled reagents for coupling to peptides and proteins have been described (Fig. 8). Most of them were designed for coupling with the amino function of an amino acid residue (A/-terminal a-NH2 or internal lysine E-NH2) or... 

Nonbranched amino acids substituted by a fluoroalkyl chain on a carbon distant at least one methylene from the amino acid function have been prepared as racemates by various methods." Under nonracemic form, co-perfluoroalkyl norvaline and norleucine (Rf = C2F5 or more) have been prepared by bromination of an anion of a fluorinated chiral oxazolidinone (derived from RfCH2CH2C02H). Substitution of the bromine atom by an azide and subsequent reduction yield the desired amino acids (Figure 5.10)." ... 

While the amino acid, which has been replaced by its fluorinated analogue, is essential for the functionality of the protein, some biological consequences can occur. Thus, incorporation of 2-F-His into mammalian proteins (4-F-His cannot be incorporated), in cell culture or invivo, is accompanied by inhibition of the induction of several enzymes (e.g., inhibition of acetyltransferase activity of the pineal gland). This probably stems from the formation of defective or inactive enzymes. Indeed, histidine plays an important role in the nucleophilic and acid-base processes connected to the catalytic activity of numerous enzymes. 

Asymmetric Synthesis of Functionalized Fluorinated Cyclopropanes and its Application to Fluoromethano Amino Acids ... 

Stella et al. [132] considered the use of imines coming from commercially available fluorinated a-amino-acids and applied the following synthetic pathway. The acid function is used to anchor the substrate on a Merrifield or Wang resin and the fluorine atom is used as an analytical probe for the recording of NMR spectra. Thus, each of the chemical products linked to the resin is characterized by a... 

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