Enantiopure fluorinated amino acids

Fluorinated amino acids are very interesting targets since they confer new physical and biological properties to the molecules in which they are incorporated. However, their preparation in enantiopure form remains a challenge, which explains their low use to date. Our laboratory has developed several access routes for the preparation of amino acids in enantiopure form, all based on the use of a common intermediate: chiral fluoromethylated oxazolidines (FOX). These particularly stable compounds are obtained from fluorinated derivatives and various commercial chiral amino alcohols (in general, (R)-phenylglycinol).

The first synthetic route is based on the implementation of a Strecker reaction. A methodological study was carried out using chiral trifluoromethylated imines or oxazolidines, by varying the nature of the Lewis acid and the chiral copula. Although the diastereoselectivity of the reaction is modest, the separation of the two diastereoisomers is simple. This strategy allowed the synthesis of (R)-(+)-trifluoroalanine as well as that of the two enantiomers of α-Tfm-alanine, α-Tfm-aspartic acid and α-Tfm-serine.

A Mannich-type reaction via the addition of a silylated ketene acetal in the presence of Lewis acid gives access, after separation of the diastereoisomers, to the corresponding (R)-β-trifluoromethyl-β-amino acid in enantiopure form. The use of Reformatsky's reagent provides α-Tfm-β-lactam, precursor of β-trifluoromethyl-β-amino acid.

We have developed a second route for the synthesis of original α-Tfm AAs based on the use of an α-trifluoromethylated allylmorpholinone. Several grams of this key intermediate can be obtained in two steps from the imine or oxazolidine derived from ethyl trifluoropyruvate via an allylation reaction. After separation of the two diastereoisomers, (S)-α-Tfm-α-allylglycine and (S)-α-Tfm-norvaline were obtained enantiopurely. The incorporation of the allylic chain also allowed the synthesis of various pyrrolidine motif α-Tfm AAs. A hydroboration-aminocyclization sequence allowed the synthesis of each enantiomer of α-Tfm-proline. The implementation of a hydroboration-oxidation-aminocyclization sequence leads to each enantiomer of α-Tfm-pyroglutamic. We have also described an iodocyclization reaction from allylmorpholinone which also leads to the two enantiomers of α-Tfm-proline. Intermediate iodine derivatives can be engaged in an elimination-dihydroxylation sequence to lead in a completely diastereoselective manner to enantiopure dihydroxylated α-Tfm-prolines.

In collaboration with the team of Professor Charles Portella (University of Reims Champagne Ardenne, UMR 6519), the reactivity of chiral difluorinated oxazolidines was studied to access α-Dfm-amino acids via the Strecker reaction. After separation of the diastereoisomers, (S)-α-Dfm-alanine and (R)-α-Dfm-alanine are obtained in enantiopure form.