Preparative fluorous mixture synthesis of diazonium-functionalized oligo(phenylene vinylene)s

[structure: see text] A series of building blocks for the synthesis of oligo(phenylene vinylene)s (OPVs) and hybrid oligomers were prepared, and alternating Heck coupling and Horner-Wadswoth-Emmons (HWE) reactions were used to couple the building blocks. Model studies were carried out to optimize the reaction strategies. The products were made to bear aryl diazonium functionalities that allow them to be used as surface grafting moieties in hybrid silicon/molecule assemblies. A library of OPV and hybrid oligomer tetramers was synthesized using fluorous mixture synthesis (FMS). The fluorous tags, which are secondary amines bearing different numbers of fluorine atoms, were synthesized and used as phase tags in mixture synthesis. The tags and substrates were anchored together by triazene linkages. The mixture synthesis was monitored by analytical HPLC on a fluorous column, and isolation of final OPV and hybrid oligomer tetramers was achieved by preparative HPLC. At the end of the FMS, after demixing, the tagged products were detagged by cleaving the triazene linkage and generating a series of aryl diazonium compounds. The fluorous tags could be recovered and reused. The NMR spectra of the 1-aryl-3,3-dialkyltriazenes are discussed.     

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.     

Separation of "light fluorous" reagents and catalysts by fluorous solid-phase extraction: synthesis and study of a family of triarylphosphines bearing linear and branched fluorous tags

Practical syntheses of new triarylphosphines bearing both linear and branched fluorous tags (Rf) are reported. The phosphines have one, two, or all three aryl rings bearing fluorous tags: (Ph)(3)(-)(n)()P(C(6)H(4)(CH(2))(m)()Rf)(n)(). Fluorous-organic partition coefficients have been measured and the retention properties of both the phosphines and the derived phosphine oxides on fluorous reverse phase silica have been studied. While applications relying on liquid-liquid extractive separations of these phosphines may be limited to those bearing three fluorous chains, the technique of solid phase extraction should be broadly applicable to phosphines, phosphine oxides, and derived metal complexes. A parallel platinum-catalyzed allylation of aldehydes with fluorous allyl stannanes illustrates the usefulness of the new fluorous ligands in small-scale synthesis.     

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.     

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.     

Towards oligosaccharide library synthesis by fluorous mixture method

The synthesis of an oligosaccharide library by a fluorous tag method is reported here. Several acceptors and donors were mixed and glycosylated. The reaction mixture was purified by chromatography over fluorous HPLC to provide disaccharides in order of increasing fluorine content of the tag. This method could be applied to oligosaccharide libraries consisting of two sets of structural isomers.     

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.     

A highly efficient and recyclable fluorous palladium catalyst for Heck reactions in water

Abstract  

A fluorous nano-palladium catalyst has been synthesized and characterized. The catalyst is highly active for the Heck reaction of aryl halides with substituted styrenes in water under air. The corresponding Heck products were obtained in high yields with good stereoselectivity (E/Z up to 98:2). In addition, the catalyst could be recovered by fluorous liquid–liquid separation and reused four times without significant loss of activity or stereoselectivity.     

Reverse fluorous solid-phase extraction: a new technique for rapid separation of fluorous compounds

Fluorous-tagged compounds can rapidly be separated from organic (non-tagged) compounds by the new separation technique of reverse fluorous solid-phase extraction (r-fspe). In a reversal of the roles of solid and liquid phases in standard fluorous spe, a mixture is charged to a polar solid phase (standard silica gel) and then eluted with a fluorous solvent or solvent mixture. The organic components of the mixture are retained, while the fluorous components pass. [structure: see text]     

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.     

Probing the limitations of the fluorous content for tag-mediated microarray formation

The synthesis of a di-perfluorohexyl tag is reported for use in a fluorous-based carbohydrate microarray. A comparative microarray study with this di-perfluorohexyl tag and a mono-perfluorooctyl and mono-perfluorohexyl tag found the increased fluorous content conducive to better spot morphology and easier washing protocols without precluding reuse of the fluorous slide.     

Second-generation tags for fluorous chemistry exemplified with a new fluorous Mitsunobu reagent

A new fluorous DEAD reagent bearing two perfluoro-tert-butyloxy groups with propylene spacers shows excellent promise for use in fluorous Mitsunobu reactions. Pure target products were obtained in good yields after removing fluorous byproducts by FSPE. The new reagent serves as a prototype for a greener second generation of fluorous reagents bearing tags that are not expected to degrade in the environment to compounds that are highly persistent or that bioaccumulate in higher organisms.     

Practical synthesis of fluorous oxazolidinone chiral auxiliaries from alpha-amino acids

[reaction: see text] A series of new fluorous-supported oxazolidinone chiral auxiliaries has been prepared using a versatile and general five-step pathway, starting from readily available chiral alpha-amino acids. The key feature of this synthesis is the efficient generation of a suitably active perfluoroalkyllithium species. By use of this protocol, the auxiliaries can be obtained in high enantiomeric purity and on multigram scales from L-phenylalanine and L-valine with overall yields as high as 55%. The new methodology also incorporates fluorous solid-phase extraction on the large scale, allowing bulk quantities (up to 25 g) of fluorous compounds to be purified from the crude reaction mixture.     

Synthesis of a fluorous ligand and its application for asymmetric addition of dimethylzinc to aldehydes

A new fluorous ligand was synthesized from the acetonide of dimethyl tartarate, which showed excellent asymmetric induction on the addition of dimethylzinc to aldehydes. This ligand will be useful for synthesis of bioactive compounds with a methyl carbinol moiety. It could be recycled without using a fluorous solvent or a fluorous column.     

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.     

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.     

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]     

Highly efficient microwave-assisted fluorous Ugi and post-condensation reactions for benzimidazoles and quinoxalinones

The efficiency of an Ugi/de-Boc/cyclization strategy for construction of heterocyclic compounds has been improved through the incorporation of microwave and fluorous technologies. In the synthesis of substituted quinoxalinones and benzimidazoles, a fluorous-Boc protected diamine is employed for the Ugi reactions. Both the Ugi and the post-condensation reaction proceed rapidly under microwave irradiation and the reaction mixtures are purified by solid-phase extraction (SPE) over FluoroFlash^TM cartridges.     

Synthesis, reaction, and recycle of fluorous palladium catalysts for an asymmetric allylic alkylation without using fluorous solvents

[Chemical reaction: See text] Chiral fluorous aminophosphine 4c bearing two fluorous ponytails was prepared from (S)-prolinol and applied to palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate (7) with a dialkyl malonate-BSA-LiOAc system with high enantioselectivities (up to 97% ee). Results indicated that the chiral fluorous palladium catalyst from ligand 4c was easily separated from the reaction mixture by simple solid/liquid separation and could be reused up to five times.     

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.