A. Milius

Addition of perfluoroalkyl iodides to 4-pentenol and its derivatives: one-pot preparation of 2-[(F-alkyl)methyl]tetrahydrofurans

Abstract Depending on the nature of the alkaline medium, the radical addition of perfluoroalkyl iodides to 4-pentenol gives a mixture of 5-( F -alkyl)-4-pentenol and 2-[( F -alkyl)- methyl]tetrahydrofuran, or the latter alone.

The abnormal issue of the Koenigs−Knorr reaction with perfluoroalkylated alcohols

Abstract The reaction Of C 6 F 13 CH 2 CH 2 OH with the protected glucose 1a in the usual Koenigs-Knorr conditions yields the orthoester 3a as the major product (64%) instead of the expected glucoside 5a . The reaction is normal again when the hydrocarbon “screen” between the R F chain and the hydroxyl group is longer, as in 4 . Compounds 4–6 after deacetylation display strong surface activity without causing hemolysis.

Synthesis of D-glucose 3- and 6-[2-(perfluoroalkyl)ethyl] phosphates: a new type of anionic surfactant for biomedical use.

D-Glucose 3- and 6-[sodium 2-(perfluoro-hexyl or -octyl)ethyl phosphates) have been synthesized by condensation of 1,2,3,4,-tetra-O-acetyl-beta-D-glucopyranose and 1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose with 2-(perfluoroalkyl)ethylphosphoroditriazolides followed by O-deacetylation or deacetalation. The structures of the compounds were established on the basis of 1H-, 19F-, 31P-, and 13C-NMR data. These salts display strong surface activities and appear to have good biocompatibility.

Amphiphilic Sugar Phosphates with Single or Double Perfluoroalkylated Hydrophobic Chains for Use in Oxygen and Drug Delivery Systems

New anionic amphiphiles with a phosphate ester junction between the fluorophilic-lipophilic tail and the sugar-based hydrophilic head were synthesized and evaluated. The single hydrophobic chain surfactants 1 a, b and 2a allowed the preparation of stable and fine highly concentrated emulsions of perfluorodecalin or perfluoroocytl bromide, either when used alone or in conjunction with egg yolk phospholipids (EYP). Surfactants 3d, 5d, 6d and 6e, with two hydrophobic chains, one fluorinated the other not, gave liposomal structures, and displayed encapsulation properties for carboxyfluorescein. The phosphodiesters tested cause no significant inhibition of the growth and viability of Namalva cell cultures (0.1-1 g/L range). Single chain phosphodiesters manifest no detectable hemolytic activity (at 100 g/L for 1a) whereas double chain compounds do moderately (ca 20% hemolysis at 20 g/L). The maximum tolerated dose compatible with the survival of all of a series of 10 intravenously injected mice is in 130 mg/kg body weight range.

Improvement in emulsification particle size reduction and stabilization of concentrated fluorocarbon emulsions by small amounts of (d-glucosyl)[2-(perfluoroalkyl)ethyl] phosphates as surfactants

Abstract The achievement of an effective intravenously injectable oxygen carrier based on fluorocarbons requires highly concentrated, stable emulsions. Significant progress has now been achieved by using minor amounts of sodium (3- or 6- d -glucosyl)[2-(perfluoroalkyl)ethyl] phosphates as surfactants, or as co-surfactants with egg yolk phospholipids (EYP). A preliminary comparative evaluation of these water-soluble anionic surfactants in 50% (w/v) perfluorodecalin (FDC) emulsions indicates significantly better emulsifying properties than those of natural EYP, the surfactant most commonly used in intravenously injectable emulsions. The fluorinated surfactants, either alone or in conjunction with EYP, give smaller particles, both at the time of preparation and after one month at 40°C, than does EYP alone. The perfluorooctyl derivatives, independent of the location of the phosphate on the glucose moiety, are more effective than the perfluorohexyl one. The remarkable emulsifying properties of these compounds are established to be related to the presence of the anionic P(O)O connector, they are also greatly enhanced by the introduction of the perfluoroalkylated chain. These effects are even more pronounced with the more concentrated (90% (w/v)) perfluorooctyl bromide (PFOB) emulsions. Replacement of a small amount (one eighth) of the EYP by [2-(perfluorooctyl)ethyl](6- d -glucosyl) (sodium) phosphate in PFOB/EYP emulsions facilitates the emulsification process, reduces the average particle size significantly, and achieves strong stabilization of the emulsions. Increasing the fluorinated surfactant/EYP ratio resulted in no significant additional benefit. Concentrated (90% (w/v)) PFOB emulsions, markedly more stable than those containing 4% EYP, were obtained with only 1% of [2-(perfluorooctyl)ethyl](6- d -glucosyl) (sodium) phosphate as the sole surfactant.

Perfluoroalkylated sugar phosphate derivatives with single or double hydrophobic chains: synthesis and evaluation in injectable oxygen carriers

Abstract There is an increasing need for tailor-made well-defined biocompatible amphiphiles in the biochemical and biomedical fields. Our aim is to design and develop new perfluoroalkylated amphiphiles to be used in fluorocarbon-based oxygen-delivery systems and other biomedical applications, including diagnosis and drug targetting system [J.G. Riess, Vox Sanguinis, 61 (1991) 225–239]. In view of the efficiency of previously synthesized non-ionic sugar-based amphiphiles in fluorocarbon emulsion stabilization [J.G. Riess, C. Arlen, J. Greiner, M. Le Blanc, A. Manfredi, S. Pace, C. Varescon and L. Zarif, in T. M.S. Chang and R.P. Geyer (eds.), Blood Substitutes , Marcel Dekker, New York and Basel (1989) 421; J.G. Riess, Proc. 2nd World Surfactant Congress 4 (Paris) (1988) 256], a series of new perfluoroalkylated ionic amphiphiles (exemplified below) was synthesized and evaluated. The latter have a phosphodiester linkage between the hydrophilic head and the hydrophobic/fluorophilic end. This end itself consists of single or double chains of various constitutions, thus allowing a wide range of stepwise modifications of their physicochemical and biological characteristics. The strategy chosen for the preparation of these phosphodiesters had to consider the nature of the hydrophobic tail, the nature of the sugar and the position to be phosphorylated. Three approaches will be presented. The physicochemical and biological evaluation of some of these compounds was undertaken. Significantly better emulsifying and emulsion stabilizing properties for fluorocarbons were found compared to natural egg yolk phospholipids. The perfluoroalkylated phosphodiesters tested showed no detectable hemolytic effect on human red blood cells and the D-glucose 6-[2-( F -hexyl)ethyl phosphate] has an intravenous LD 50 of about 750 mg/kg body weight in mice.

Perfluoroalkylated sucrose, trehalose, maltose and glucose derivatives: surfactants for biomedical uses

Abstract New neutral F-Alkylated surfactants have been synthesized and evaluated, the objectives being to improve the stability of fluorocarbon emulsions to be used as injectable O2-carriers and gain improved control over their biologically relevant characteristics. A series of mono- and diesters of sucrose (1,2)and trehalose (3,4) was prepared using Mitsunobus condensation procedure (R1-R4 = H or CnF2n+1(CH2)mC(O)). New perfluoroalkylated glycosides were obtained using the Koenigs-Knorr reaction : 5,6 : m = 3, 9, RF = C6F13; m = 9, RF = C8F17. 7 : R5 = MeC(O), RF = C6F13, C8F17; R5 = per-O-acetyl-α-D-glucopyranosyl, RF = C6F13. 8 : RF = C6F17. 9, 10 : R6 = H, α-D-glucopyranosyl, RF = C6F13. The surface activity of the new compounds was measured (γs, γ i/F-decalin, CMC). The F-alkylated maltosides were found to be particularly efficient as cosurfactants in conjunction with a polyoxypropylene polyoxyethylene block polymer (Pluronic F-68).