A fluorous phosphate protecting group with applications to carbohydrate synthesis

The first fluorous protecting group for phosphate is reported. This group can be used as a facile tag for purification and be removed under mild reducing conditions using zinc and ammonium formate. Synthesis of a disaccharide from Leishmania using this fluorous protecting group demonstrated the group's stability to the acidic conditions necessary for glycosylation as well as its orthogonality to several other common protecting groups.     

An expeditious synthesis of bistratamide H using a new fluorous protecting group

A total synthesis of bistratamide H has been achieved using a new ‘highly’ fluorous amino protecting group, tris(perfluorodecyl)silylethoxylcarbonyl (^FTeoc) group. The synthetic intermediates were easily isolated by liquid-liquid extraction with fluorous solvent. The fluorous protecting group was demonstrated to be recycled.     

Fluorous Boc ((F)Boc) carbamates: new amine protecting groups for use in fluorous synthesis

The first fluorous variants of the Boc (tert-butyloxycarbonyl) group have been prepared and tested for their suitability as nitrogen protecting groups. A group with two fluorous chains and an ethylene spacer, (RfCH2CH2)2(CH3)COC(O)-, was readily attached to a representative amine but was difficult to cleave. In contrast, groups with two fluorous chains and a propylene spacer, (RfCH2CH2CH2)2(CH3)COC(O)-, or one fluorous chain and an ethylene spacer, (RfCH2CH2)(CH3)2COC(O)-, were readily formed and cleaved. The fluorous alcohol component of the (F)Boc group can be removed by evaporation and can be recovered and reused. The utility of the new (F)Boc group (C8F17CH2CH2)(CH3)2COC(O)- was demonstrated in 16 and 96 compound library synthesis exercises. Separations can be achieved either by manual, parallel fluorous solid-phase extraction, or automated, serial fluorous chromatography. The results provide additional confirmation of the value of "light" fluorous synthesis techniques, and the new fluorous Boc groups expand the applicability of fluorous synthesis techniques to many classes of nitrogen-containing organic compounds.     

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.     

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.     

Efficient condensation of carboxylic acids with alcohols catalyzed by fluorous ammonium triflates

The use of fluorous ammonium salts as metal-free catalysts for the direct condensation of equimolar amounts of carboxylic acids and aliphatic alcohols has been investigated. Esterification reactions were thus conveniently carried out under mild fluorous biphasic conditions, in the presence of 1 mol % of fluorous ammonium triflate and without recourse to any additional water removal technique. Good to excellent ester yields were obtained in the case of primary and secondary aliphatic alcohols. The fluorous salt was easily recovered by simple phase separation and reused at least three times without considerable loss of activity.     

Fluorous thiols in oligosaccharide synthesis

A new, almost odorless fluorous thiol is synthesized, which is utilized to prepare highly fluorinated thioglycosyl donors. These thioglycosides showed excellent reactivities in glycosylation reactions. The fluorous chain, stable under esterification, etherification, deacetylation, and glycosylation conditions, allowed facile purification of the thioglycosides by solid-phase extraction through fluorous silica gel. The fluorous thiol was readily recycled.     

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.     

Froc: a new fluorous protective group for peptide and oligosaccharide synthesis

[STRUCTURE: SEE TEXT] The synthesis of a new fluorous protecting group, Froc, is described. This new fluorous tag has been used in peptide and carbohydrate synthesis by our group and readily allows us to fully characterize each product (NMR, MS) and monitor each synthetic step by TLC. Purification of the products is generally performed by standard fluorous solid-phase extraction techniques (e.g., F-SPE), but standard chromatographic purifications are also possible if required.     

Just add water: a new fluorous capping reagent for facile purification of peptides synthesized on the solid phase

A novel fluorous capping reagent is introduced to facilitate purification during solid-phase peptide synthesis (SPPS). Reagent 1 is a trivalent iodonium salt that reacts vigorously with free amines to deliver a long-chain fluoroalkyl group. It has been used to tag all unreacted amines following the peptide coupling step in SPPS. The resulting fluoroalkylated amine is no longer able to couple in further peptide coupling steps and is also stable to standard peptide synthesis conditions. Deletion products are removed using flash fluorous chromatography to yield the pure, full-length peptide.     

Amide bond formation with a new fluorous carbodiimide: separation by reverse fluorous solid-phase extraction

A new fluorous carbodiimide is introduced along with a convenient procedure for amide coupling reactions. Reactions of acids and amines under standard conditions for carbodiimide couplings, followed by simple reverse fluorous solid-phase extraction (FSPE) over standard silica gel, provide the target amide products in good yields and purities. The use of HFE-7100 as a fluorous solvent is crucial for the success of the reverse FSPE.     

Development of fluorinated,monolithic columns for improved chromatographic separations of fluorous-tagged analytes

With applications that take advantage of highly selective fluorine–fluorine interactions appearing with greater frequency in the literature, the development of porous polymer monoliths from fluorous components is reported here for the purpose of chromatography of tagged analytes. With potential uses in fields as diverse as separation science and proteomics, facile fabrication of materials with fluorous specificity that can be applied in a high-throughput manner is greatly desirable. To this end, we have developed porous polymer capillary columns with varied fluorous content using a simple UV-initiated radical polymerization process and characterized them using flow-induced backpressure and scanning electron microscopy (SEM). With structural similarities assured (visually, and by backpressure variations of less than 42%), the monoliths were tested as chromatographic columns for the separation of a series of fluorous-tagged analytes under gradient conditions. It was found that columns made with fluorinated components exhibited greater selectivity for fluorous analytes than did equivalent, non-fluorinated monoliths, retaining analytes with either one or two fluorous tags for approximately 6% and 13% longer, respectively. This supports the idea of differences existing between fluorous and reverse-phase separation mechanisms, and encourages a broader range of potential applications for fluorous monoliths of this type.     

Synthesis of polyoxiranes and polythiiranes bearing a potential aldehyde group in the side chain

Polyoxiranes and polythiiranes with acetal group in the side chain are prepared by polymerization of 1,1-diethoxy-2,3-epoxy-propane (DEO) and of the corresponding thiirane (DET) using different chiral and achiral initiators. In the case of poly(DET) acetal groups can be removed leading to a polymer with an aldehyde content up to 64 %. In similar experimental conditions the extent of acetal hydrolysis does not exceed 23 % for poly(DEO).     

An efficient, recoverable fluorous organocatalyst for direct reductive amination of aldehydes

A commercially available perfluorooctyl aniline and phenyl isothiocyanate were reacted under mild conditions to give 1-[4-(perfluorooctyl)phenyl]-3-phenylthiourea as an analogue of thiourea-based organocatalyst. This fluorous organocatalyst was successfully employed to direct reductive amination of aldehydes. It could be readily separated from reaction product by fluorous solid phase extraction for direct use.     

Rapid synthesis of oligosaccharides using an anomeric fluorous silyl protecting group

A fluorous silyl ether tag as protecting group at the anomeric position of sugar acceptors allows rapid synthesis of oligosaccharides by reducing the purification procedures to a simple and fast fluorous solid-phase extraction.     

Fluorous biphasic catalysis with dirhodium(II) perfluorocarboxylates: selective silylation of alcohols under fluorous biphasic conditions

Dirhodium(II) perfluorocarboxylates bearing C7–C13 perfluoroalkyl chains have been prepared and used as catalysts under fluorous biphasic conditions. They were found to be active and recyclable catalysts for the silylation of alcohols with triethylsilane. Hydrophobic, primary alcohols are preferentially silylated by the fluorous biphasic catalytic system in comparison with hydrophilic or secondary ones. This opens the way to the development of selective silylation protocols.     

Preparation of a fluorous protecting group and its application to the chemoenzymatic synthesis of sialidase inhibitor

2-(Perfluorohexyl)ethoxymethyl chloride was prepared as a novel fluorous protecting reagent. Neu5Ac aldolase-catalyzed chemoenzymatic transformation of N-acetyl-D-mannosamine to Neu5Ac derivatives was achieved successfully by using the fluorous reagent not only for hydroxy group protection but also for fluorous tagging. This chemoenzymatic method was applied to the synthesis of 2-deoxy-2,3-didehydrosialic acid 1 known as a potent sialidase inhibitor.     

Mono- vs. di-fluorous-tagged glucosamines for iterative oligosaccharide synthesis

Fluorous-tagged protecting groups are attractive tools for elongating carbohydrate chains in oligosaccharide synthesis. To eliminate the accumulation of failed sequences during automated oligosaccharide synthesis conditions, an additional C₈F₁₇ ester derived protecting group was attached to the glycosyl donor to better retain the desired doubly tagged glycosylation product on fluorous solid-phase extraction (FSPE) cartridges. Initial studies show that the double-fluorous-tagging strategy offers a robust enough separation using a commercial FSPE cartridge using simple gravity filtration to separate the desired product from the singly fluorous-tagged starting materials and their decomposition products. In addition, removal of the fluorous acetate and its by-products after sodium methoxide treatment and neutralization required only dissolution of the desired sugar in toluene and subsequent removal of the toluene layer from the denser fluorous by-products.     

Rapid synthesis of oligosaccharide moieties of globotriaosylceramide using fluorous protective group

The use of the Bfp (bisfluorous chain type propanoyl) group as a fluorous protective group made it possible to rapidly synthesize galabiose and the Gb3 oligosaccharide derivatives by a simple fluorous-organic extraction purification. The fluorous oligosaccharide synthesis using the Bfp group is an excellent strategic alternative to solid phase oligosaccharide synthesis, and removes some of the disadvantages of the solid phase method.     

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.