Perfluoroalkylated amino acids

Soloshonok and co-workers have demonstrated that the racemic /(-(perfluoroalkyl)-/ -amino acids obtained from the 1,3-proton shift reaction can be resolved biocatalytically as the 7V-(phenylacetyl)-substituted derivatives using penicillin acylase.20 -22 An attempt has also been made to carry out an asymmetric 1,3-proton shift reaction to synthesize chiral / -(per-fluoroalkyl)-/ -amino acids directly.23 24 The isomerization has been carried out on enamines 29a-c, e, and f using ( —)-cinchonidinc as chiral base, giving the corresponding ben-zylideneamines 31 a-c, e, and f in 67-89 % yield. The /5-(perfluoroalkyl)-/,y-aniino acids 32a-c, e, and f are obtained in 88 — 93 % yield, but in only 16-36%ee of the /Cisomer.23 24... 

A synthesis of a-hydroxy-/f-(perfluoroalkyl)-/)-amino acids has been reported via s-hydroxy-/ -imino esters 18. Tmidoyl esters 17 are readily obtained from imidoy] chlorides 16 and undergo a 1.2-shift from oxygen to carbon under basic conditions.1 The authors propose an a,/f-epoxy ester intermediate. 

Many compounds containing a perfluorinated or hydrogenated hydrophobic chain and an amino acid as either polar head or junction modulus have been synthesized. Among the different structures that have been prepared, a variety of amino acids are encountered, but a-amino acids are the most common however, P-alanine or its derivatives play an important role, too. Moreover, molecules based on perfluoroalkyl-amino acids, prepared from different functionalized perfluoroalkyl starting compounds, have been synthesized. It should be stressed that the different types of surfactants based on amino acids encountered in this family of products may be classified as ionic, nonionic, or zwitter-ionic. In all the structures obtained, the concept of modularity is important, since the amino acid—with or without prior chemical transformation—represents either the polar head group or a pivot modulus linking one or more lipophilic chains to different polar heads. 

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... 

To improve DPP-4 activity as well as pharmacokinetic properties, the effects of substituents on triazolopiperazine moieties were examined (Table 17.7) [48], Aryl and heteroaryl substituents were found to be as effective as alkyl substituents at improving DPP-4 activity. Unlike most ofthe previous (1-amino acid amide analogues in this series, these analogues (e.g. 43 and 44) exhibited unacceptable DPP-8 and hERG activities (IC50 S — 1-4 pM). The effects of perfluoroalkyl substituents were... 

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)." ... 

Perfluoroalkyl lithium reagents reacted with imines in the presence of boron trifluoride to give the corresponding adducts in good yields [15], and this methodology has been applied to the synthesis of perfluoroalkyl-containing amino acids [16] (Scheme 7). 

Soloshonok and co-workers have developed a method for the synthesis of a-(perfluoro-alkyl)amines from perfluoroalkyl carbonyl compounds by a transamination involving an azomethine a/omethine (Schiffbase) isomerization. They call this method a biomimetic, base-catalyzed 1,3-proton shift reaction, and have applied it to perfluoroaldehydes,12-15 perfluoroalkyl ketones,12 18 / -(perfluoroalkyl)-/l-oxo esters,15 16 19 24 and - -( perfluoroalkyl)-a-oxo es-ters2 " -26 to synthesize the corresponding a-(perfluoroalkyl)amincs, / -(perfluoroalkyl )-/i-amino acids, and 3 -(perfluoroalkyl)- x-amino acids. 

Table 6. 1,3-Proton Shift Reaction of x,/ -Unsaturated / -(Perfluoroalkyl)-/ -bcnzylamino Esters 29 To Form /l-(Bcnzylideneamino) Esters 31 and /1-Amino Acids 32...

The 1,3-proton shift reaction has also been applied to the synthesis of a-(perfluoroalkyl)-a-amino acids, specifically 3.3,3-trifluoroalanine.2 -26 Attempts to prepare the A-benzylimine of ethyl 3,3.3-trifluoro-2-oxopropanoate by direct condensation with benzylamine were very difficult due to the exceptionally high stability of the intermediate a-amino alcohol, which fails to dehydrate. By contrast, 1-phenylethanamine reacted with ethyl 3,3,3-trifluoro-2-oxo-propanoate to form ketimine 33 in 83 % yield.26 The 1,3-proton shift reaction of 33 is much faster than those of ketimines derived from perfluoroalkyl ketones or perfluoroaldehydes (see Table 5). Complete conversion in triethylamine required 6 hours at room temperature and afforded the isomeric Shiff base 34 in 92 % yield. Mild hydrolysis of Shifif base 34 gives a-amino ester 35, which in turn hydrolyzes to 3,3,3-trjfluoroalanine hydrochloride (36). 

Oppolzer s camphor sultam, a well known chiral auxiliary, has been applied to the asymmetric synthesis of chial fluorine-containing amino acids <07OL2513>. Photoinduced addition of perfluoroalkyl iodides 189 to /V-acyloylcamphorsultam 188 in the presence of an aqueous solution of sodium sulfite provides alkyl iodides 190 with moderate to good stereoselectivities. Azide displacement with the major diastereomer of 190 proceeds with inversion of configuration. Subsequent removal of the sultam auxiliary and hydrogenation of the azide afford the chiral fluorine-containing amino acid 192. 

The radical perfluoroalkyl-iodination reaction of a,P-unsaturated lactam 154 proceeds diastereoselectively. The stereospecific azide formation and subsequent chemical transformation of the (R)-isomer result in the synthesis of a series of perfluoroalkylated a-amino acids 156 (see Scheme 9.34) [60]. 

Yajima, T. and Nagano, H. (2007) Photoinduced diastereoselective addition of perfluoroalkyl iodides to acrylic acid derivatives for the synthesis of fluorinated amino acids. Org. Lett., 9, 2513-2515. 

Scheme 2.152 Example of the synthesis of an aryl 1 H,lH-perfluoroalkyl iodonium triflimide (11) which is sufficiently hydrolytically stable to electrophilically trifluoroethylate amino acids in an aqueous medium [26]. The N-trifluoroethyl substructure element has recently gained importance in medicinal chemistry as a means of blocking the oxidative metabolism of pharmaceuticals via the nitrogen site.

Some synthetic applications are shown in Schemes 2.39-2.41. 1,1-Addition of perfluoroalkyl iodides to isonitriles (26) provides perfluoroalkyl imidoyl iodides (27) [24], which have been employed as useful reactive intermediates for trifluoromethylated amino acids and heterocycles [25].Stereo-controlledperfluoroalkylation [26] andbromodifluoromethy-lation [27] of the enolates (28) and (30) give diastereomerically enriched fluoro-building blocks (29) and (31). 

Perfluoroalkyl pseudoxazolones,103 104 e.g., 36, are useful intermediates for separation of enantiomers of the parent amino acids. 

The mass spectrum shows an abundant molecular ion and the derivatization procedure is a simple one-step reaction with trifluoroacetic anhydride/trifluoroacetic acid (1 1). The 2-perfluoroalkyl-3-oxazolin-5-one (FOx) derivatives appear to have significant potential for the low level definitive determination of difficult amino acids and labelled amino acids, as seen in the recent application to plasma arginine [175]. 

SCHEME 2 Perfluoroalkyl-acyl-amino acids of type 1. 

SCHEME 7 Perfluoroalkyl-esters of amino acids of types 7 and 8. 

Carnitine is at the origin of two types of fluorinated surfactants. The perfluoroalkyl-acylcarnitines (28) (Scheme 24), obtained with satisfactory yields (44-80%), show good surfactant characteristics [60], The synthesis of Ai-perfluoroalkyl carnitine (29) (Scheme 25) is less efficient, and its physicochemical properties have not been evaluated [61]. The betaines of perfluoro-alkyl a,co-amino acids (30) (Scheme 26) are accessible in a similar manner [62]. They are good surface agents [63]. 

Among the numerous approaches described to graft a perfluoroalkyl chain on an aminoacid skeleton, the methods allowing one to create a C-C bond between the fluorinated part and the amino acid are of special interest. The access to this less frequently encountered type of compound uses classical methods of synthesis, such as that leading to the perfluoroalkyl-glycine 31 (Scheme 27). The compounds 31 are barely soluble, except for the betaine derivatives 32, which are obtained with very poor yields, however [64], The perfluoroalkyl-glycines have been condensed on cholic acid (Scheme 28) to give products 33, also with unsatisfactory yields [37]. 

Yajima T, Tonoi T, Nagano H, Tomita Y, Mikami K. Direct racemic mixture synthesis of fiuorinated amino acids by perfluoroalkyl radical addition to dehydroamino acids terminated by asymmetric protonation. Eur. J. Org. Chem. 2010 2461-2464. 

Amino-acid-based amphoteric surfactants containing a hydroxyl group have been obtained by reacting an amino acid with a perfluoroalkylated epoxide [197] ... 

---