Amino acids, fluorinated racemization

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. 

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)." ... 

Enzymic Resolution of Racemic Fluorine-Containing Amino Acids ... 

In this section, recent advances in the syntheses of racemic fluorinated amino acids and the related peptides that involve conceptually new synthetic designs are briefly summarized. 

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... 

Osipov, S. N., Artyushin, O. I., Kolomiets, A. F., et al. (2001) Synthesis of racemic cyclic amino acids Synthesis of fluorine-containing cyclic a-amino acid and a-amino phosphonate derivatives by alkene metathesis. Fur. J. Org. Chem., 3891-3897. 

A NMR study on the formation of diastereoisomeric inclusion complexes between fluorinated amino acid derivatives and a-CD in 10% D2O solution shows that the chemical shifts of the D-amino acid derivatives included by a-CD are upheld from those of their L analogues [77]. The shift difference between the diastereoisomers formed with D and L enantiomers can be used for chiral analysis and optical purity determinations. For example, the interaction of -CD with propanolol hydrochloride produces diastereomeric pairs. The protons of the antipode give NMR signals which differ in chemical shifts in D2O solution at 400 MHz. The intensity of the resonance signals for each diastereoisomer has been used for optical purity determination. By adding racemate to pure (—) isomer, this technique is able to measure optical purity of propanolol hydrochloride in water down to the level of 1%. 

NMR spectroscopy can be used to analyze mixtures of amino acids and peptides (Sievers et al, 1969). Trifluoroacetyl (TFA) derivatives are prepared and the F spectrum recorded. The F chemical shift is sensitive not only to the nature of the amino acid to which it is directly boun4 but also to the nature of the next amino acid. TFA-Gly-Leu-OMe and TFA-Gly-Ala-OMe show differences in F chemical shifts. The first difference in structure between these two peptides is nine bonds removed from the fluorine nucleus. F spectra show two peaks in a mixture of TFA-D-Val-L-Val cyclohexylester and TFA-D-Val-D-Val the technique could prove useful in detecting racemization during peptide synthesis. 

Furthermore, P-fluoro a-amino aldehydes are expected to have high proclivity toward racemization even in a very weakly basic environment, the a-proton being strongly acidic due to the presence of fluorine (32,33). 

---