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.     

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.     

The synthesis and application of fluorous boronates without perfluorinated solvents

The synthesis of a fluorous diol 4 bearing a perfluorodecyl chain was described. A series of boronic acid were attached to 4 by esterification. The purification of the products was fulfilled by facile filtration instead of expensive and environmental troublesome fluorous liquid-liquid extraction. The Suzuki cross-coupling reactions of the formed fluorous boronates 5 underwent smoothly and the fluorous diol 4 was recycled in good yields.     

Solution and fluorous phase synthesis of β,β-difluorinated 1-amino-1-cyclopentane carboxylic acid derivatives

An efficient protocol for the preparation of β,β-difluorinated 1-amino-1-cyclopentane carboxylic acid derivatives was developed. 2,2-Difluro-4-phenyl-3-butenoic acid 6 was used as substrate for the preparation of the starting vinyl difluoro imino esters 8. The key steps of this methodology rely on the chemo- and diastereoselective addition of allylzinc bromides over the iminic functionality of 8 and subsequent RCM reaction. This synthetic sequence was successfully applied to fluorous synthesis.     

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.     

Catalytic enantioselective cyclopropanation of allylic alcohols using recyclable fluorous disulfonamide ligand

Cyclopropanation of allylic alcohols with Et₂Zn and CH₂I₂ in the presence of a catalytic amount of fluorous disulfonamide 3 afforded the corresponding cyclopropylmethanols in 69-96% yield with 49-83% ee. The fluorous ligand 3 was readily recovered from the reaction mixture by the fluorous solid-phase extraction (FSPE) and could be reused without a significant loss of the catalytic activity and enantioselectivity.     

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.     

Efficient syntheses of (±)-hydrangenol, (±)-phyllodulcin and (±)-macrophyllol

In this paper we report on a efficient and flexible synthetic route towards the total syntheses of the dihydrocoumarine derivatives hydrangenol (1), phyllodulcin (1a) and macrophyllol (6b). The syntheses started with a readily available phosphonium salt 2 and suitable modified benzaldehydes 3/3a/3b resulting in 46 to 61% overall yields in three to four-steps sequences. The racemic products could be separated by chiral HPLC. The evidence of the (R)-enantiomer for sweetness could be demonstrated for 1a.     

Efficient, recoverable, copper-catalyzed aerobic oxidation of alcohols under FBS and thermomorphic mode

A series of fluorinated bipyridine derivatives, (4,4′-bis(R_fCH₂OCH₂)-2,2′-bpy) {R_f = n-C₈F₁₇ (1a), n-C₉F₁₉ (1b), n-C₁₀F₂₁ (1c), n-C₁₁F₂₃ (1d)} have been successfully synthesized using 4,4′-bis(bromomethylene)-2,2′-bpy and fluorinated alkoxides. Bpy 1a-d have been characterized by multi-nuclei (¹H, ¹⁹F, and ¹³C) NMR, GC/MS and FTIR. The Cu complexes 2a-d could be generated in situ by stirring ligands 1a-d with CuBr·Me₂S at room temperature, respectively. The 3-component systems 3c-d, CuBr·Me₂S/Bpy (1c-d)/2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO), were successfully used to the aerobic oxidation of alcohols under the fluorous biphasic system (FBS). The resulting products from FBS could be easily recovered by two phase separation with high yields up to 8 runs (>90%). In order to avoid using the expensive fluorous solvents, systems 3a-d, CuBr·Me₂S/Bpy (1a-d)/TEMPO, were also successfully shown to catalyze the aerobic alcohol oxidation under the thermomorphic condition (in C₆H₅Cl), and the yields of oxidation of 4-nitrobenzyl alcohol were close to 100% even after 8 runs. In particular, 3a was most effective under the thermomorphic mode in the chemoselectivity of aerobic oxidation of aliphatic primary alcohols to aldehydes without any overoxidized acids.     

Oxidative synthesis of azacyclic derivatives through the nitrenium ion: application of a hypervalent iodine species electrochemically generated from iodobenzene

Oxidation of the methoxyamide derivatives 1, 4, and 7 has been examined to elaborate efficient synthetic methodology of the azacyclic derivatives 2, 3, 5, 6, and 8, which would be applicable as synthetic intermediates of complicated bioactive substances. In addition to direct anodic and PIFA [phenyliodine(III) bis(trifluoroacetate)] oxidations, an active species derived from iodobenzene generated under electrolytic conditions was examined as an oxidant, and its synthetic efficacy was demonstrated in comparison of the reaction outcomes with other oxidation methods. In the oxidation, the methoxy substitution of substrates modulated the cyclization mode to provide the azaspiro- (2, 8) or quinolinone-type (3, 5, 6) products.     

Fluorous glycol derivatives: novel carbonyl protective groups

Fluorous glycol derivatives 5 were prepared and evaluated as reagents for the protection of carbonyl groups for use in fluorous synthesis. The acetals formed from fluorous diol 5b (Rf=n-C₈F₁₇) with carbonyl compounds can be separated and purified by simple fluorous-organic extraction.     

Fluorous chiral bisoxazolines. Synthesis and applications to an asymmetric allylic alkylation

The easily accessible fluorous bisoxazolines 3a-b bearing two fluorous ponytails are efficient ligands in the palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenylprop-2-enyl acetate with carbonucleophiles in benzotrifluoride or CH₂Cl₂, enantioselectivities of up to 95% being obtained. The ligand is easily separated from the reaction mixture by simple extraction with a fluorous solvent.     

Convergent synthesis of the IJKLM-ring part of ciguatoxin CTX3C

Convergent synthesis of the IJKLM-ring part (2) of ciguatoxin CTX3C has been achieved from the I-ring and the L-ring parts (4 and 5) in total eight steps in 27% overall yield. The carbanion derived from 4, stabilized by a dimethyldithioacetal S-oxide group, was readily reacted with aldehyde 5 to give an adduct, which was facilely transformed into the corresponding α,ε-dihydroxy ketone 3. The JK-ring formation from 3 under reductive conditions followed by oxidative M-ring cyclization efficiently led to the pentacyclic ether 2. Improved synthesis of 6, a synthetic intermediate for 4, was also established.     

A novel Birch reduction of aromatic compounds using aqueous titanium trichloride: anions of trans-10b,10c-dimethyl-2,7,10b,10c-tetrahydropyrene

The Birch reduction of 10b,10c-dimethyl-10b,10c-dihydropyrene 1 and anthracene could be predicted on the basis of their reduction potentials and achieved readily with aqueous titanium trichloride in near quantitative yields. Controlled reduction of a nitro group could be achieved under these conditions with the aromatic hydrocarbon remaining intact. The anion derived from the hexane obtained from reduction of 1 provided synthetic routes to derivatives of 1 inaccessible from direct substitution reactions of 1. Oxidative dimerization of the anion led to the formation of a series of interesting products.     

Greener fluorous chemistry: Convenient preparation of new types of ‘CF3-rich’ secondary alkyl mesylates and their use for the synthesis of azides, amines, imidazoles and imidazolium salts

2,2,2-Trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, and nonafluoro-tert-butyl alcohol were used as precursors for the preparation of the appropriate bis(polyfluoroalkoxymethyl)carbinols [(R_FHOCH₂)₂CHOH, 1a-c, R_FH = (a) CF₃CH₂, (b) (CF₃)₂CH, and (c) (CF₃)₃C] and the corresponding mesylates [(R_FHOCH₂)₂CHOSO₂CH₃, 2a-c]. This novel design paradigm is introduced to eliminate the persistence and bioaccumulation problems of fluorous chemistry, which are associated with the use of longer linear perfluoroalkyl groups (e.g. R_fn ≥ n-C₈F₁₇, n-C₇F₁₅). Secondary mesylates 2a,b and the primary tosylate [(CF₃)₃COCH₂CH₂OTs, 2d] displayed acceptable reactivity towards azide and imidazole nucleophiles to allow the syntheses of novel fluorous azides, which on hydrogenolysis with H₂/Pd-C offered fluorous amines [(R_FHOCH₂)₂CHNH₂, 8a,b], and 1-(polyfluoroalkyl)imidazoles (5a,b,d), respectively, while 2c showed no reactivity due to steric hindrance. The reaction of 8a,b with formaline, glyoxal and hydrochloric acid gave symmetrical 1,3-dialkylated imidazolium chlorides (9a,b), while 5a,b,d were effectively alkylated using n-C₈F₁₇(CH₂)₃I, methyl iodide, 2-bromoethanol, and 2d to yield the corresponding 1,3-dialkylimidazolium iodides, bromides, and tosylates (7aa-ec). Some physical properties of new compounds including mp, bp and solubility patterns were also analyzed; and the fluorophilicity values of 1a-c, and 2a-c were experimentally determined by GC and/or ¹⁹F NMR spectroscopy.     

Synthesis of 11-aza-artemisinin derivatives using the Ugi reaction and an evaluation of their antimalarial activity

A series of new 11-aza-artemisinin derivatives were prepared from 11-aza-artemisinin using the Ugi reaction. An antimalarial activity evaluation against the FcB1 strain indicated that compounds 7, 10, and 16 had very strong inhibitory activity. Comparison of the activity among the synthetic derivatives of this series revealed that the length of the side chain R group on the amide nitrogen could be critical for their antimalarial properties.     

Recycling of fluorinated axially dissymmetric ligand with fluorous solvent

Axially dissymmetric ligand, (Ra)-2,2′-bis[(R)-1-hydroxy-1H-perfluorooctyl]-biphenyl (1), showing a high asymmetric induction, was found to be recovered quantitatively with a fluorous solvent from the reaction mixture owing to its high fluorine content. The recovered ligand 1 was pure enough to be reused without purification. The efficiency of 1 as the chiral ligand was not reduced at all even after seven times recycling.     

Unexpected regiospecific reactivity of a substituted phthalic anhydride

Regioselective nucleophilic addition at C1 of anhydride 7 by a range of nucleophiles occurs to produce amide, ester and thioester derivatives 8-15 (60-99%). The increased electrophilic reactivity of the C1 carbonyl group of anhydride 7 is supported by a competition experiment with phthalic anhydride. Unexpected formation of lactams 18 and 19 from amides 12 and 13 was shown to proceed via the lactamols 16 and 17 and could be controlled by the reaction conditions. The solid-state structure of 19 is reported.     

Synthesis of poinsettifolin A

A synthesis of poinsettifolin A (1), a prenylated flavonol isolated from Dorstenia poinsettifolia, is described. Two routes starting from quercetin were explored, and 1 could be prepared if a prenyl group first was incorporated at C-6 of the protected quercetin followed by a condensation with citral at C-8. The key synthetic steps are a Mitsunobu reaction, an europium (III)-catalysed Claisen rearrangement coupled with cross-metathesis, and a benzopyran-forming geranylation. The two geranylated 3,5,3′,4′-tetrahydroxyflavonols prepared, 1 and 3, were assayed for antileishmanial activity against Leishmania amazonensis and Leishmania braziliensis, and found to be active. Compound 3 showed cytotoxic activity against leukaemia and lung cancer cells while 1 lacked cytotoxicity.