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.     

CBS reductions with a fluorous prolinol immobilized in a hydrofluoroether solvent

A fluorous prolinol precatalyst bearing only 34 fluorine atoms has been immobilized in the hydrofluoroether solvent HFE-7500. The CBS reduction of acetophenone proceeded rapidly, in high yield and in high ee in the absence of any organic solvent. The organic product was stripped from the HFE-7500 phase with a polar solvent, and the HFE-7500 phase was reused "as is" with satisfactory results through eight runs. This process is an attractive prototype for the large-scale use, recovery, and reuse of fluorous organocatalysts.     

4-Substituted-alpha,alpha-diaryl-prolinols improve the enantioselective catalytic epoxidation of alpha,beta-enones

To seek novel metal-free organic catalysts for epoxidation with high stereoselectivity, a series of 4-substituted-alpha,alpha-diaryl-prolinols were synthesized in four steps from trans-4-hydroxyl-L-proline. These prolinol derivatives catalyzed the asymmetric epoxidation of alpha,beta-enones to give the corresponding chiral epoxides in good yields and high enantioselectivities under mild reaction conditions. Studies of substituent effects on enantioselectivity revealed that steric bulk and electronic effect promoted higher enantioselectivity, and prolinol 8a was found to be the best catalyst until now.     

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.     

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.     

Formation and stability of prolinol and prolinol ether enamines by NMR: delicate selectivity and reactivity balances and parasitic equilibria

Enamine key intermediates in organocatalysis, derived from aldehydes and prolinol or J?rgensen-Hayashi-type prolinol ether catalysts, were generated in different solvents and investigated by NMR spectroscopy. Depending on the catalyst structure, trends for their formation and amounts are elucidated. For prolinol catalysts, the first enamine detection in situ is presented and the rapid cyclization of the enamine to the oxazolidine ("parasitic equilibrium") is monitored. In the case of diphenylprolinol, this equilibrium is fully shifted to the endo-oxazolidine ("dead end") by the two geminal phenyl rings, most probably because of the Thorpe-Ingold effect. With bulkier and electron-withdrawing aryl rings, however, the enamine is stabilized relative to the oxazolidine, allowing for the parallel detection of the enamine and the oxazolidine. In the case of prolinol ethers, the enamine amounts decrease with increasing sizes of the aryl meta-substituents and the O-protecting group. In addition, for small aldehyde alkyl chains, Z-configured enamines are observed for the first time in solution. Prolinol silyl ether enamines are evidenced to undergo slow desilylation and subsequent rapid oxazolidine formation in DMSO. For unfortunate combinations of aldehydes, catalysts, solvents, and additives, the enamine formation is drastically decelerated but can be screened for by a rapid and facile NMR approach. Altogether, especially by clarifying the delicate balances of catalyst selectivity and reactivity, our NMR spectroscopic findings can be expected to substantially aid synthetically working organic chemists in the optimization of organocatalytic reaction conditions and of prolinol (ether) substitution patterns for enamine catalysis.     

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.     

Preparation, properties and synthetic potentials of fluorous boronates

A fluorous approach to the chemistry of boronic acids and its application in fluorous-phase techniques are described. Treatment of fluorous bromosilane 2 with allyl Grignard reagent followed by dihydroxylation provided fluorous diol 1. A series of boronic acids were attached to 1 by esterification. The formed fluorous boronates 4 were moisture sensitive and thus their synthetic potentials were limited. Thus a fluorous pinacol, 5, was designed and synthesized by treatment of fluorous bromosilane 2 with excess 2,3-dimethyl-2-butyenylmagnesium bromide 9 to afford fluorous tetramethyl ethene 8, and was dihydroxylated. Compound 5 was successfully used to prepare fluorous boronates in a one-pot process from organic bromides. We have demonstrated that olefin cross-metathesis can be carried out in a fluorous version. It is noteworthy that all of the fluorinated compounds reported in this paper were purified by simple liquid extraction.     

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.     

A fluorous Mukaiyama coupling reagent for a concise condensation reaction: utility of medium-fluorous strategy

The entire study of condensation reactions using various fluorous Mukaiyama reagents, including a novel medium-fluorous strategy, is described. A Mukaiyama reagent bearing a medium-fluorous content tag, between 40 and 60% fluorine by weight, was prepared and examined in ester and amide-forming condensation reactions. At the end of the reactions, the fluorous pyridone by-product was effectively separated from non-fluorous components by increasing the water content of the crude reaction mixture and subsequent filtration of the precipitate. It is also shown that Mukaiyama reagents bearing a fluorous tag increase the reaction rate considerably when compared to their non-fluorous tagged counterpart. Interestingly, it was observed that the longer the fluorous chain, the higher the activity of the Mukaiyama reagent.     

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.     

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.     

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.     

Performance of octene in fluorous biphasic hydroformylation: octene distribution and reversible transfer between perfluoromethylcyclohexane and nonanal

During fluorous biphasic hydroformylation 1-octene is transferred from the fluorous into the organic product phase and then from the product layer back to the fluorous layer again, due to the immiscibility of nonanal with PFMCH. The effect of the temperature and the total amount of octene on the above behaviour were also studied.     

Poly(fluoroalkyl acrylate)-bound ruthenium carbene complex: a fluorous and recyclable catalyst for ring-closing olefin metathesis

The synthesis of a fluorous olefin metathesis catalyst derived from the Grubbs second-generation ruthenium carbene complex is described. The air stable fluorous polymer-bound ruthenium carbene complex 1 shows high reactivity in effecting the ring-closing metathesis of a broad spectrum of diene and enyne substrates leading to the formation of di-, tri-, and tetrasubstituted cyclic olefins in minimally fluorous solvent systems (PhCF3/CH2Cl2, 1:9-1:49 v/v). The catalyst can be readily separated from the reaction mixture by fluorous extraction with FC-72 and repeatedly reused. The practical advantage offered by the fluorous catalyst is demonstrated by its sequential use in up to five different metathesis reactions.     

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.     

Design, synthesis, and incorporation of fluorous 5-methylcytosines into oligonucleotides

A palladium-catalyzed Negishi coupling reaction has been developed to synthesize fluorous 5-methylcytosines. These fluorous nucleosides are incorporated into the oligonucleotides that correspond to part of the promoter region of Oct4, a master gene that undergoes dynamic DNA demethylation during cellular reprogramming. The separation of the fluorous oligonucleotides from its nonfluorous analogues has been achieved through solid-phase extraction over fluorous silica, suggesting its potential use in probing DNA demethylation.     

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.     

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.     

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.