Synthesis of peptides and oligosaccharides by using a recyclable fluorous tag

A hexakis(fluorous chain)-type alcohol was used in the synthesis of oligosaccharides and peptides through connection with a linker suitable for the particular type of target compound. After the preparation of the desired compound, the fluorous alcohol was easily recovered in good yields under basic conditions. It appears that the fluorous alcohol can be recovered, recycled, and reused.     

Synthesis of the Lewis a trisaccharide based on an anomeric silyl fluorous tag

The synthesis of the trisaccharide Lewis a was performed using an anomeric fluorous silyl protective group. This methodology allowed us to fully characterize each product (NMR, MS) and monitor each synthetic step (TLC). Although the product purifications could be performed by fluorous-solid-phase extraction (F-SPE) technology, standard chromatography could be used to effect purification if necessary. Trichloroethoxy carbonyl (Troc) protection of the amino group of the glucosamine moiety was found essential to allow protecting group manipulation of the fluorous protected sugar.     

Practical heavy fluorous tag for carbohydrate synthesis with minimal chromatographic purification

A practical heavy fluorous tag 5 bound to a benzylic linker was prepared and applied to carbohydrate synthesis. The fluorous tag 5 was readily introduced to the desired hydroxyl group and carboxyl group by using various methods. Synthesis of the oligosaccharide, which included the terminal structure of class III mucin, was achieved with single-column chromatographic purification. In addition, because of the symmetrical structure of 5, each fluorous synthetic intermediate could be analyzed much easier by NMR spectroscopy than in the case of the fluorous compounds connecting our previous fluorous tags.     

p-Alkoxyphenyl-type heavy fluorous tag for the preparation of carbohydrate units

Carbohydrate glycosyl acceptor and donor moieties were synthesized efficiently by using the fluorous tag method. The p-alkoxyphenyl-type heavy fluorous tag was stable under all the reaction conditions used in the preparation of the various carbohydrate units. Each synthetic intermediate carrying the fluorous tag could be obtained in a simple straightforward manner by partition between fluorous and organic solvents.     

Synthesis and properties of a novel family of fluorous triphenylphosphine derivatives

A novel approach to the preparation of perfluorotail-functionalized triarylphosphines using a p-silyl substituent as the branching point has been developed. This approach enabled the attachment of between three and nine perfluorotails per phosphorus atom, resulting in the production of highly fluorous tris[p-(1H,1H,2H, 2H-perfluoroalkylsilyl)aryl]phosphines, P[C(6)H(4)-p-SiMe(3)(-)(n)()(CH(2)CH(2)C(x)()F(2)(x)()(+1))(n)()](3) (n = 1, 2, 3; x = 6, 8), containing between 50 and 67 wt % fluorine. (31)P NMR studies indicate that the phosphorus atoms, and consequently the sigma-donor and pi-acceptor properties of these phosphines, are not influenced by the electron-withdrawing perfluoroalkyltails. The fluorous triarylphosphines are readily soluble in fluorous solvents and display fluorous phase preference in several fluorous biphasic systems. The phase partitioning of these fluorous ligands, as well as their donor properties, is discussed in relation to their potential for fluorous biphasic catalyst separation.     

Synthesis of fluorous acetal derivatives of aldehydes and ketones

The formation of acetals (and ketals) from polyfluoroalkylated 1,3-alkanediols and aldehydes and ketones is demonstrated for the first time. Four sets of reaction conditions are examined and the degree of conversion is shown to depend upon reaction conditions and the structure of the carbonyl substrate. Excellent yields are obtained, and wherever possible, diastereomeric products are observed.     

Synthesis of a library of stereo- and regiochemically diverse aminoglycoside derivatives

A library of forty modified aminoglycosides was prepared in which the configuration and regiochemistry of two or three rings was widely varied. The library was based around three core ring systems: the 2-deoxystreptamine ring system found in the natural products, and both enantiomers of (1R*,2R*,4R*,5R*)-2,5-diamino-cyclohexane-1,4-diol and (1R*,3R*,4R*,6R*)-4,6-diaminocyclohexane-1,3-diol. In each case, the core was modified by glycosylation with one or two sugar rings. The absolute configuration of the sugar substituents (d or l), the configuration of the anomeric centres (alpha or beta), and the regiochemical arrangement of the amine(s) were varied.     

Synthesis and reactions of fluorous carbobenzyloxy (FCbz) derivatives of alpha-amino acids

Fluorous carbobenzyloxy ((F)Cbz) reagents RfCH(2)CH(2)C(6)H(4)CH(2)OC(O)OSu (where Su is succinimidoyl and Rf is C(6)F(13) and C(8)F(17)) have been used to make (F)Cbz derivatives of 18 of the 20 natural amino acids. The potential utility of this new family of reagents in both standard fluorous synthesis with spe separation and fluorous quasiracemic synthesis is illustrated with representative reactions of the (F)Cbz-Phe derivatives.     

Synthesis of 4'-aminopantetheine and derivatives to probe aminoglycoside N-6'-acetyltransferase

A convenient synthesis of 4'-aminopantetheine from commercial D-pantethine is reported. The amino group was introduced by reductive amination in order to avoid substitution at a sterically congested position. Derivatives of 4'-aminopantetheine were also prepared to evaluate the effect of O-to-N substitution on inhibitors of the resistance-causing enzyme aminoglycoside N-6'-acetyltransferase. The biological results combined with docking studies indicate that in spite of its reported unusual flexibility and ability to adopt different folds, this enzyme is highly specific for AcCoA.     

Synthesis of novel fluorous surfactants for microdroplet stabilisation in fluorous oil streams

The synthesis of a number of potential fluorous surfactants, prepared with a view to stabilising microdroplets in microfluidic systems is described. The surfactants comprised compounds with both perfluoropolyether (PFPE) and perfluoroalkyl (PFA) tails with three classes of hydrophilic head group, including crown ethers and hexaethylene glycol. Hydrophilic head groups and alkyl fluorous-based tails were coupled together via amide, ester and ether linkages to afford the fluorous surfactant candidates in good yields. The resulting molecules show promise in forming and stabilising both aqueous and non-aqueous microdroplets in fluorous oil streams within poly(dimethylsiloxane) (PDMS) devices to a greater degree than the pseudosurfactants commonly employed in microdroplet research.     

Organocatalysis with a fluorous tag: asymmetric reduction of imines with trichlorosilane catalyzed by amino acid-derived formamides

Asymmetric reduction of ketimines 1 with trichlorosilane can be catalyzed by N-methylvaline-derived Lewis-basic formamides 3a-d with high enantioselectivity (< or =95% ee) and low catalyst loading (1-5 mol %) at room temperature in toluene. Appending a fluorous tag, as in 5a-c, simplifies the isolation procedure, while preserving high enantioselectivity (< or =92% ee).     

A convenient method for the preparation of fluorous tin derivatives for the fluorous labeling strategy

A convenient method for the preparation of fluorous aryl stannanes was developed as a means of expanding the general utility of the fluorous labeling strategy (FLS). Following the synthesis of a novel fluorous distannane, a palladium-catalyzed cross-coupling reaction was used to prepare the target compounds from aryl halides. The scope of the reaction was investigated by preparing a small library of model compounds where the reaction yields were similar to those reported for the analogous procedures employing hexamethyl- or hexabutyldistannanes. The utility of the reported methodology was demonstrated through the successful synthesis of fluorous precursors to two established molecular imaging and therapy agents (FIAU, IUdR). These were radiolabeled with iodine-125 and the desired products isolated in high yield and effective specific activity.     

Synthesis and solid state structure of fluorous probe molecules for fluorous separation applications

A series of colored hydrocarbon and fluorocarbon tagged 1-fluoro-4-alkylamino-anthraquinones and 1,4-bis-alkylamino-anthraquinone probe molecules were synthesized from a (fluorinated) alkyl amine and 1,4-difluoroanthraquinone to aid in the development of fluorous separation applications. The anthraquinones displayed stacking of the anthraquinone tricycle and interdigitation of the (fluorinated) alkyl chains in the solid state. Furthermore, intramolecular N-H?O hydrogen bonds forced the hydrocarbon and fluorocarbon tags into a conformation pointing away from the anthraquinone tricycle, with the angle of the tricycle plane normal and the main (fluorinated) alkyl vector ranging from 1° to 39°. Separation of the probe molecules on fluorous silica gel showed that the degree of fluorination of the probe molecules plays only a minor role with most eluents (e.g., hexane/ethyl acetate and methyl nonafluorobutyl ethers/ethyl acetate). However, toluene as eluent caused a pronounced separation by degree of fluorination for fluorocarbon, but not hydrocarbon tagged probe molecules on both silica gel and fluorous silica gel. These studies suggest that hydrocarbon and fluorocarbon tagged anthraquinones are useful probe molecules for the development of laboratory scale fluorous separation applications.     

Synthesis of monosaccharide units using fluorous method

The efficient synthesis of monosaccharide units, glycosyl acceptor, and donor, by using the fluorous tag method was achieved. Fluorous tag 5 was stable in each reaction condition to the preparation of various monosaccharide units. Each fluorous synthetic intermediate could be obtained in a straightforward manner by a simple fluorous-organic solvent partition.     

Ytterbium perfluorooctanesulfonates catalyzed synthesis of benzimidazole derivatives in fluorous solvents

Catalytic condensation of o-phenylenediamine and aldehydes was accomplished using rare earth(III)perfluorooctane sulfonates (RE(OPf)₃), RE = Sc, Y, La ∼ Lu) as catalysts in fluorous solvents. Ytterbium perfluorooctanesulfonates (Yb(OPf)₃) catalyzes the high-efficient synthesis of benzimidazole derivatives in fluorous solvents. By simple separation, fluorous phase containing only catalyst can be reused several times.     

A novel, base-labile fluorous amine protecting group: synthesis and use as a tag in the purification of synthetic peptides

A new, base-labile fluorous tag based on the Msc amine protecting group was synthesized. Its use in the purification of synthetic peptides by fluorous HPLC or fluorous SPE was demonstrated.     

Synthesis and application of a fluorous Lawesson's reagent: convenient chromatography-free product purification

[reaction: see text] A fluorous analogue of Lawesson's reagent for thionation of carbonyl compounds has been developed and its use demonstrated on a series of amides, esters, and ketones. The separation of the Lawesson's reagent-derived byproducts can be achieved by a simple fluorous solid-phase extraction.     

Synthesis and X-ray crystal structure of fluorous imidazolium salts

Synthesis of two salts involving CH₂O spacer between the imidazole nitrogen and hexafluoroisopropyl group in the fluorous imidazolium cations is reported. Such an insertion would result in the formation of ??-ammonium ether. The two fluorous imidazolium salts involve one or two -CH₂OCH(CF₃)₂ groups attached to the imidazole nitrogen atoms. These products were synthesized from the reaction between methyimidazole and imidazole as nucleophiles and sevochlorane, ClCH₂OCH(CF₃)₂, as electrophile, in different molar ratios. The resulting products have been characterized by ¹H, ¹³C, and ¹⁹F NMR and FTIR spectroscopy. Also, the single crystal X-ray diffraction analysis for the symmetrically substituted imidazolium product is presented. The preliminary animal tests indicated no anesthetic property but the two tested salts were found to behave as calmative.