Amino acids, fluorinated synthesis

Fluorine-Gontaining Amino Acid.s Synthesis and Propertie.s, Kukhar, V. P. Soloshonok, V. A. Eds. Wiley Chichester, 1994. 

C Kaduk, H Wenschuh, M Beyermann, K Fomer, LA Carpino, M Bienert. Synthesis of Fmoc-amino acid fluorides via DAST, an alternative fluorinating agent. Lett Pept Sci 2, 285, 1995. 

Dynamic Kinetic Resolution Synthesis of a Fluorinated Amino Acid Ester Amide by a Continuous Process Lipase-mediated Ethanolysis of an Azalactone... 

The successful use of [ F]FDG in oncology PET imaging has prompted the design of several other radiopharmaceuticals, such as [ F]FLT ([ F]fluorothymi-dine, used as cellular proliferation marker. Scheme 36) [152-154], F-MISO ([ F] fluoromisonidazole, used to assess tissue hypoxia. Scheme 37) [155], c/s-4-[ F] fluoro-L-proline (used as abnormal collagen synthesis marker. Scheme 38) [156] and 0-(2-[ F]fluoroethyl)-L-tyrosine (used as amino acid transport and/or protein synthesis marker. Scheme 39) [157]. All these fluorine-18-labelled molecules have been prepared by aliphatic nucleophilic fluorination followed by a deprotection reaction. 

In fluorine-18 chemistry some enzymatic transformations of compounds already labelled with fluorine-18 have been reported the synthesis of 6-[ F] fluoro-L-DOPA from 4-[ F]catechol by jS-tyrosinase [241], the separation of racemic mixtures of p F]fluoroaromatic amino acids by L-amino acylase [242] and the preparation of the coenzyme uridine diphospho-2-deoxy-2-p F]fluoro-a-o-glucose from [ F]FDG-1-phosphate by UDP-glucose pyrophosphorylase [243]. In living nature compounds exhibiting a carbon-fluorine bond are very rare. 

P. Damhaut, C. Lemaire, A. Plevenaux, C. Brihaye, L. Christiaans, D. Comar, No-carrier-added asymmetric synthesis of alpha-methyl-alpha-amino acids labeled with fluorine-18, Tetrahedron 53 (1997) 5785-5796. 

D.M. Shendage, R. Froehlich, K. Bergander, G. Haufe, Asymmetric synthesis of y-fluorinated a-amino acid derivatives, Eur. J. Org. Chem. (2005) 719-727. 

The numerous applications of fluorinated amino acids in medicinal chemistry and in enzymology have induced a large number of studies dedicated to their synthesis. Synthetic chemists have provided protein biologists and chemists with an incredible range of fluorinated amino acids. Since this work has been covered in the literamre, we only review some representative examples of proteogenic fluorinated amino acid analogues, with special focus on the synthetic aspects proper to fluorine chemistry. The numerous fluorinated peptidomimetic units (e.g., amino alcohols) are not included in this chapter. 

These compounds can be prepared by using either classical processes for synthesis of amino acids (starting from the ad hoc precursor bearing fluorine on the aromatic moiety) or electrophilic fluorination of the arene moiety (e.g., elemental fluorine, xenon fluoride, acetyl hypofluorite). Although these methods are often poorly regioselective, they are useful for the preparation of F labeled molecules used in PET, for example, F tyrosine and dihydrophenylalanine (L-Dopa). ... 

The methods of peptidic synthesis, in the liquid phase as well as in the solid phase, have led to the preparation of numerous polypeptides that contain a fluorinated amino acid. Most of the examples concern peptidic hormones and neuropeptides, with replacement of either (1) a phenylalanine (or of a tyrosine) by an analogue containing a... 

The possibility of studying the structure and dynamic properties of proteins by F NMR requires the use of labeled proteins with fluorine. Various approaches can be envisioned trifluoroacetylation or derivatization of side chains by direct fluorination or trifluoromethylation or with small fluorinated molecules. It is also possible to incorporate a fluorinated amino acid into a protein, by using either a classical chemical synthesis or a biosynthetic approach. It is obvious that the chemical synthetic... 

Inhibition of Chorismate Synthase Shikimic and quinic acids are used by microorganisms, fungi, and superior plants for the synthesis of essential aromatic amino acids from acyclic sugars. Fluorinated analogues of substrates and reaction intermediates have been synthesized in order to inhibit enzymes involved in... 

Antipyrine (18) a lipophilic compound that has been shown to have a high uptake by the brain is also fluorinated and consequently dehydrofluorinated.75 The cxv-addition mode is exploited for the preparation of the adducts 19 and 20 of 7-oxabicyclo[2.2.1]hept-5-ene and 2-azabicyclo[2.2.1]hept-5-en-3-ones with fluorine which arc used in the preparation of di-fluorodeoxyhexofuranosides and fluoronucleosides.76 Fluorine also undergoes addition to oxazolones 21 for the eventual synthesis of /i-fluorinated a-amino acids.77... 

Our approach was based on the observation that it is possible to perform SwAr reactions on solid support with amino acids using a solvent system comprised, in equal parts, of acetone and an aqueous 0.5 M NaHC03 solution at temperatures around 70-75°C. Application of this solvent system to the synthesis of quinoxalin-2-ones 6 from la and a-amino acids is described in Section 3.3.2. With respect to the synthesis of 1,5-ben-zodiazepin-2-ones 4, more than 40 examples of aliphatic and aromatic P-amino acids 35 were found to furnish the desired o-nitro anilines 36, about 80% of which were successfully carried on to eventually afford the ben-zodiazepinone products 4 (Scheme 6). In general, the anthranilic acids required slightly harsher conditions to drive the fluorine displacement to completion (75-80°C, 72 h vs. 70-75°C, 24 h for aliphatic P-amino acids). 

Enzymic Synthesis of Fluorine-Containing Amino Acids ... 

Kuhkar, V. P Soloshonok, V. A. Fluorine-Containing Amino Acids Synthesis and Properties Wiley Chichester, U.K., 1995. 

A multistep solid phase synthesis of (3-lactams with imines of benzaldehyde coming out from commercially available fluorinated a-amino acids has been reported in 2003 [77]. Using the Merrifield resin-bound imine [78, 79] in dichlor-omethane, the cycloaddition was carried out between -78°C and rt by addition of benzyloxyacetyl chloride in the presence of triethylamine. The resin cleavage using sodium methylate resulted in the two cis p-lactam derivatives (Scheme 20). 

The very short reaction times required for the alkylation of substrate 11a with benzylic bromides using Nobin as an asymmetric phase-transfer catalyst are important for the synthesis of 18F-fluorinated amino adds for use in positron-emission tomography (PET)-imaging studies. Thus, Krasikova and Belokon have developed a synthesis of 2-[18F]fluoro-L-tyrosine and 6-[18F]fluoro-L-Dopa employing a (S)-Nobin-catalyzed asymmetric alkylation of glycine derivative 11a as the key step, as shown in Scheme 8.14 [29]. The entire synthesis (induding semi-preparative HPLC purification) could be completed in 110 to 120 min, which corresponds to one half-life of18 F. Both the chemical and enantiomeric purity of the final amino acids were found to be suitable for clinical use. 

Katagiri, T. Uneyama, K. Stereospecific substitution at a-carbon to trifluoromethyl group application to optically active fluorinated amino acid synthesis. Chirality 2003, 35, 4-9. 

Scheme 3. Synthesis of fluorinated amino acids via enantioselective fluorination. The absolute configuration of the product is unknown.

Other compound classes in the synthesis of which chiral 3-carbon synthons were used include sphingosine chains (32), 3-amino-2-azetidinones (33), (3,y-unsaturated-a-amino acids 34), fluorinated macrocyclic bis(indolyl) maleimides35, fluorocyclopropyl alcohols (36), l-O-phosphocholine-2-O-acyl-octadecanes and l-Ophosphocholine-2-N-acyl-octadecane (37) diacyl glycerols 38-42) and analogs of fragments of leukotriene-B4 43). 

Heterocycles as intermediates in synthesis of fluorine-containing aliphatic amino acids 91UK1680. 

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