Plate-to-plate fluorous solid-phase extraction for solution-phase parallel synthesis

A commercially available Argonaut VacMaster-96 plate-to-plate solid-phase extraction (SPE) station equipped with 24 FluoroFlash cartridges is employed for parallel purification of fluorous reaction mixtures. Each cartridge charged with 3 g of fluorous silica gel has the capability to produce up to 100 mg of purified small molecules. The 24-well receiving plate has a standard footprint that can be directly concentrated in a Genevac vacuum centrifuge. Important issues such as sample loading, product cross-contamination, cartridge reuse, and reproducibility are investigated. The SPE system has been demonstrated in the purification of three small libraries that were produced involving amine scavenging reactions with fluorous isatoic anhydride, amide coupling reactions with 2-chloro-4,6-bis[(perfluorohexyl)propyloxy]-1,3,5-triazine (fluorous CDMT), and amide coupling reactions with a newly developed fluorous Mukaiyama condensation reagent.     

Multistep Parallel Synthesis of Quinazoline‐2,4‐diones by a Fluorous Biphasic Concept without Perfluorinated Solvents

Based on perfluoro‐tagged benzyl alcohol adsorbed via fluorous–fluorous interactions on fluorous reversed‐phase silica gel (FRPSG), we have performed a multistep synthesis leading finally to a small library of quinazoline‐2,4‐diones. The whole reaction sequence runs without isolation of intermediates and most importantly, without the need of perfluorinated solvents.     

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.     

Automation of fluorous solid-phase extraction for parallel synthesis

An automatic fluorous solid-phase extraction (F-SPE) technique is developed by using FluoroFlash SPE cartridges on the RapidTrace workstation. A 10-module workstation has the capability to complete a maximum of 100 SPEs each round in 1-2 h. Another important feature of the RapidTrace system is that it has the capability to load slurry samples onto the F-SPE cartridges. The F-SPE cartridge charged with 2 g of fluorous silica gel is used to purify up to 200 mg of crude sample. Sample loading, elution solvent, cartridge reuse, and SPE reproducibility are evaluated. The automatic SPE system is used for purification of a small urea library generated from amine-scavenging reactions using fluorous dichlorotriazine, a 96-membered amide library generated using 2-chloro-4,6-bis[(perfluorohexyl)propyloxy]-1,3,5-triazine as the coupling agent, and another 96-membered library generated from fluorous Mitsunobu reactions. Approximately 90% of the products have > 90% purity after F-SPE.     

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).     

A new strategy for preparing molecular imaging and therapy agents using fluorine-rich (fluorous) soluble supports

A convenient new strategy for producing radiolabeled compounds in high effective specific activity was developed using soluble fluorous supports. The reported methodology involves a fluorous linker group that is released from the substrate of interest upon reaction with radioiodine. The desired product can then be selectively separated from unreacted starting material and reaction byproducts using a simple fluorous solid-phase extraction procedure. The utility of this approach was demonstrated by labeling a series of benzoic acid derivatives which are commonly used to prepare molecular imaging agents. All compounds were produced in high radiochemical yields, purities, and effective specific activities. The strategy was further elaborated in that it was used to prepare a small collection of radiolabeled benzamides as a way of demonstrating the potential utility of this method for creating libraries of molecular imaging agents.     

Towards functional fluorous surfactants. Synthesis of hydrophilic fluorous 1,2,3-triazolylmethyl ethers and di(1,2,3-triazolylmethyl) ethers

Copper(I)-accelerated Huisgen–Meldal dipolar cycloaddition reactions between polyfluoroalkyl azides and propargyl ethers of n-octanol and of triethyleneglycol monomethyl ether exhibited variation in yield of 1,2,3-triazol-4-ylmethyl ethers. Microwave acceleration, and in situ generation of the azides, provided improvements in yield and efficiency. In contrast, very good yields of equivalent fluorous triazoles were obtained from a range of n-alkyl azides with propargyl ethers of perfluorohexylethanol and of perfluoroheptylmethanol through conventional copper(I)-promoted reactions. Together, the resulting substances with systematic variations in polyfluoroalkyl and alkyl substituent length and position of substitution, and degree of oxygen content, make up small libraries of hybrid fluorous 1,2,3-triazol-4-ylmethyl ethers as candidates for study as hydrophilic fluorous surfactants. In addition, a pilot sample of di(1,2,3-triazol-4-ylmethyl) ethers with 1′-octyl-1-polyfluoroalkyl-substituents and 1′-nonyl-1-perfluorooctylethyl substituents were synthesised for the first time in an effort to develop more functional, fluorous surfactants.     

Increasing fluorous partition coefficients by solvent tuning

Low partition coefficients of fluorous components have been a persistent problem in liquid-liquid separations using perfluoroalkanes as the fluorous phase. Solvent tuning of both the nonfluorous and the fluorous phase dramatically enhances the partitioning of light or polar fluorous molecules into the fluorous liquid phase, while minimally effecting partition coefficients of nonfluorous molecules. These findings suggest an expanded scope for liquid-based separations in fluorous biphasic catalysis, fluorous-tagged reagents, fluorous-supported oligomer synthesis, and related areas. [reaction: see text]     

Polymer-supported ytterbium perfluorooctanesulfonate [Yb(OPf)3]: A recyclable catalyst for organic reactions

Amberlyst A-21, a kind of well-known and cheap polymeric material, was treated with ytterbium perfluorooctanesulfonate [Yb(OPf)₃] giving a reagent with a ytterbium loading of 1.34 (wt%). The polymer-supported fluorous ytterbium catalyses the highly efficient nitration, esterification, Fridel-Crafts acylation, and aldol condensation. The catalyst can be recovered by simple filtration and used again without a significant loss of catalytic activity. The protocol avoids the use of fluorous solvents during the reaction or workup, which are expensive and can leach in small amounts.     

Recoverable fluorous CBS methodology for asymmetric reduction of ketones

[reaction: see text]. An operationally simple and recoverable fluorous CBS methodology was developed. The in situ-generated fluorous oxazaborolidine efficiently catalyzed the reduction of ketones with high enantioselectivity and reactivity. The subsequent recycling of the fluorous prolinol precatalyst was achieved by fluorous solid-phase extraction.     

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.     

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.     

Hydroformylation in fluorous solvents

Triaryl-phosphines and -phosphites bearing fluorous ponytails give high rates, good linear selectivity and good retention of catalyst in the fluorous phase during hydroformylation of alkenes in fluorous solvents.     

Synthesis of aminoglycoside derivatives on a Cbz-type heavy fluorous tag

Four aminoglycoside derivatives containing a 2,6-diamino-2,6-dideoxy-d-glucopyranose disaccharide structure were successfully prepared by using a Cbz-type heavy fluorous tag in a fluorous synthesis. A Cbz-type heavy fluorous tag was prepared using the hexakis(fluorous chain)-type alcohol 11, and the fluorous alcohol 11 was recovered in good yield after the synthesis of aminoglycoside derivatives.     

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.     

Peptide synthesis on fluorous support

New fluorous supports were synthesized and used to prepare a peptide having a C-terminal COOH based on fluorous chemistry. The hexakisfluorous chain-type support was suitable for the synthesis of a pentapeptide or a peptide derivative on a fluorous support whose fluorine content is over 40 w/w%. A bioactive peptide, Leu-enkephalin, was easily synthesized using an Fmoc-strategy based on fluorous chemistry.     

Recyclable benzyl-type fluorous tags: Preparation and application in oligosaccharide synthesis

We herein described the design, synthesis and application of two recyclable benzyl-type fluorous tags with double fluorous chains. The benzyl-type fluorous tags were prepared in 3 steps from a commercially available fluorous alcohol. The glycosylation of the benzyl-type tags with imidate donors proceeded smoothly to provide the corresponding fluorous-tagged carbohydrates in good to excellent yields, which were readily purified by fluorous solid-phase extraction(FSPE). Efficient removal of the tags from tagtethered carbohydrates were conducted under the common catalytic hydrogenation condition and the initial benzyl-type fluorous tags could be regenerated [5_TD$IF]via a 2-step simple procedure in 69%–93% yields.The utility of the new benzyl-fluorous tag was demonstrated [7_TD$IF]via the FSPE-assisted synthesis of oligosaccharides Gb3.     

Stereoselective conjugate radical additions: application of a fluorous oxazolidinone chiral auxiliary for efficient tin removal

[reaction: see text] A series of asymmetric free-radical-mediated intermolecular conjugate additions using a fluorous oxazolidinone chiral auxiliary has been completed. The fluorous auxiliary facilitated product isolation using fluorous solid phase extractions (FSPE), effectively removing excess organic and organometallic reagents. Parallel reactions carried out with a similar but nonfluorous norephedrine-derived oxazolidinone demonstrated the superior stereoselectivity and purification obtainable with the fluorous chiral auxiliary.     

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.     

Use of fluorous chemistry in the solubilization and phase transfer of nanocrystals, nanorods, and nanotubes

Fluorous chemistry, involving the use of a fluorous label for the functionalization of a substrate and a fluorous solvent for extraction of the functionalized substrate, is shown to be effective in solubilizing gold and CdSe nanoparticles in a fluorous medium, through phase transfer from an aqueous or a hydrocarbon medium. While these nanoparticles were functionalized with a fluorous thiol, single-walled carbon nanotubes and ZnO nanorods could be solubilized in a fluorous medium by reacting them with a fluorous amine. Fluorous chemistry enables the solubilization of the nanostructures in the most nonpolar liquid medium possible.