Total synthesis of cucurbitoside A using a novel fluorous protecting group

The first total synthesis of cucurbitoside A was achieved using a new fluorous N-phenylcarbamoyl (^FCar) protecting group. The ^FCar group was introduced into carbohydrates in high yield and was selectively removed with Bu₄NNO₂ without damaging other acyl protecting groups. The synthetic intermediates were easily isolated by fluorous solid-phase extraction.     

A practical fluorous benzylidene acetal protecting group for a quick synthesis of disaccharides

A new fluorous benzylidene acetal protecting group was regioselectively introduced into carbohydrates, deprotected under acidic conditions, and reused. Oligosaccharides were synthesized via regioselective conversion of the fluorous acetal group to the benzyl group by traditional reaction conditions. The fluorous compounds were easily separated from non-fluorous by-products by fluorous solid phase extraction.     

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.     

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.     

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.     

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.     

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.     

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.     

Fluorous synthesis of sclerotigenin-type benzodiazepine-quinazolinones

A new synthetic protocol for sclerotigenin-type benzodiazepine-quinazolinone library scaffold is introduced. A fluorous benzyl protecting group is used for the synthesis of 4-benzodiazepine-2,5-dione intermediate and also as a phase tag for fluorous solid-phase extraction (F-SPE).     

Methylsulfonylethoxycarbonyl (Msc) and fluorous propylsulfonylethoxycarbonyl (FPsc) as hydroxy-protecting groups in carbohydrate chemistry

The methylsulfonylethoxycarbonyl (Msc) group is presented as a non-lipophilic, base-labile, participating protecting group for carbohydrate alcohols. It can be introduced using Msc-Cl and pyridine and is readily cleaved via β-elimination under mild basic conditions. Its fluorous counterpart, the perfluorooctyl propylsulfonylethoxycarbonyl (FPsc) group, is used in a ‘light fluorous’ trisaccharide synthesis sequence.     

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 linker facilitated synthesis of teichoic acid fragments

The use of perfluorooctylpropylsulfonylethanol as a new phosphate protecting group and fluorous linker is evaluated in the stepwise solution phase synthesis of a number of biologically relevant (carbohydrate substituted) glycerol teichoic acid fragments. Teichoic acid fragments, up to the dodecamer level, were assembled by means of phosphoramidite chemistry, using a relatively small excess of the building blocks and a repetitive efficient purification procedure of the protected intermediates by fluorous solid phase extraction (F-SPE).     

Fluorous mixture synthesis of (-)-dictyostatin and three stereoisomers

[reaction: see text] A mixture of four stereoisomers whose configurations are encoded by fluorous silyl protecting groups has been prepared and converted over 22 steps to a mixture of protected dictyostatins. Demixing by fluorous HPLC followed by removal of the fluorous protecting groups (detagging) provides dictyostatin and three C6,C7 stereoisomers. Biological evaluation showed that the monoepimers of the natural product retained highly potent activity.     

A fluorous-tagged, acid-labile protecting group for the synthesis of carboxamides and sulfonamides

A new acid-labile, fluorous-tagged protecting group that facilitates the preparation of carboxamides and sulfonamides by parallel solution-phase synthesis is introduced. Its use is exemplified by the preparation of a 27-member library of biaryl sulfonamides and an 18-member library of biaryl carboxamides. Intermediates were purified by solid-phase extraction over reversed-phase fluorous silica gel to afford library members in high yields and purities (>95%) without the need for column chromatographic purification.     

Rapid oligosaccharide synthesis using a fluorous protective group

The Bfp-OH, a novel fluorous protecting reagent, was able to be easily prepared. The Bfp group was readily introduced to a carbohydrate, removed in high yield, and recyclable after cleavage. The use of the Bfp group made it possible to synthesize a pentasaccharide by minimal column chromatography purification. Each synthetic intermediate was able to be easily purified only by simple fluorous-organic solvent extraction and monitored by TLC, NMR, and MS.     

Fluorous-tagged indolylboron for the diversity-oriented synthesis of biologically-attractive bisindole derivatives

The diversity-oriented synthesis of bisindole derivatives to construct concise libraries using consecutive cross-coupling reactions and prepare new sulfonamide type fluorous protecting groups is presented.     

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.     

Size‐Tunable Micron‐Bubbles Based on Fluorous–Fluorous Interactions of Perfluorinated Dendritic Polyglycerols

This paper describes the behavior of various generations of polyglycerol dendrimers that contain a perfluorinated shell. The aggregation in organic solvents is based on supramolecular fluorous–fluorous interactions, which can be described by means of ¹⁹F NMR spectroscopy. In order to study the interaction and aggregation phenomena of dendrimers with perfluorinated shell and perfluoro‐tagged guest molecules we investigated [G3.5]‐dendrimer with a perfluorinated shell in the presence of perfluoro‐tagged disperse red. Noteworthy, the interaction intensities varied in an unexpected manner depending on the equivalents of perfluoro‐tagged guest molecules added to the dendrimers in solution which then formed supramolecular complexes based on fluorous–fluorous interactions. We found that these complexes aggregated around residual air in the solvent to form stable micron‐sized bubbles. Their sizes correlated with the interaction intensities measured for certain dendrimer–guest molecule ratios. Degassing of the solutions led to a quasi phase separation between organic and fluorous phase, whereby the dendrimers formed the fluorous phases. Regassing the sample with air afforded bubbles of the initial size again.     

Fluorous synthesis of mono-dispersed poly(ethylene glycols)

Mono-dispersed poly(ethylene glycols) (PEGs) are of great value in the development of biopharmaceuticals. However, tedious synthesis limits the availability of mono-dispersed PEGs. To address this issue, a fluorous synthesis of mono-dispersed PEGs, discretely PEGylated surfactants and ¹⁹F magnetic resonance imaging (MRI) agents has been developed. During the synthesis, both fluorous and normal phase silica gel-based solid-phase extractions were successfully employed to simplify the purifications. This synthesis provided an easy access to valuable mono-dispersed PEGs and related molecules for biomedical application on multi-gram scales.