Cerium(IV)-mediated C-C bond formations in carbohydrate chemistry

We provide a comprehensive study on the addition of radicals to unsaturated carbohydrates in the presence of cerium(IV) ammonium nitrate (CAN). The method is applicable to hexoses, pentoses, and disaccharides, tolerates different protecting groups, and is characterized by mild reaction conditions. Best substrates are malonates and glycals, which afford 2-C-branched carbohydrates in high yields and stereoselectivities. For the first time, the anomeric radicals were trapped with nucleophiles after oxidation and thus the 1- and 2-position of glucose were functionalized in one step. Nitro compounds are suitable CH acidic radical precursors as well, offering an easy access to C-analogs of glycosamines in moderate to good yields. Finally, selective reductions demonstrate the synthetic potential of cerium(IV)-mediated radical reactions in carbohydrate chemistry.     

Recent advances in the stereoselective synthesis of carbohydrate 2-C-analogs

C-branched carbohydrates are of current interest for glycochemistry, are widely found in nature and serve as important subunits in many antibiotics, bacterial polysaccharides and macrolides. Among C-functionalized saccharides, 2-C-branched carbohydrates represent challenging structures for synthetic chemists, since in contrast to C-glycosides they are not easily accessible from glycosyl bromides or other simple precursors. In this perspective we want to summarize recent approaches to 2-C-branched carbohydrates over the past fifteen years. The two main strategies are based on ring-opening of 1,2-cyclopropanated carbohydrates by various reagents, as well as radical additions to glycals and further transformations, developed in our group. Both methods are characterized by high stereoselectivities and good yields and give access to a broad variety of functionalized carbohydrate 2-C-analogs.     

Barton radical reactions of 2-C-branched carbohydrates

Barton esters have been introduced into the side chain of carbohydrates with high yields in only a few steps from easily available glycals. Their radical reactions afford 2-C-methyl and 2-C-bromomethyl hexoses, pentoses and disaccharides in good yields in analytically pure form. Since the Barton esters have been synthesized by an oxidative radical addition and their transformations by reductive radical processes, our results demonstrate the power of such reactions in carbohydrate chemistry.     

Remarkable oxidation stability of glycals: excellent substrates for cerium(IV)-mediated radical reactions

The remarkable stability of glycals under oxidative conditions becomes apparent by their redox data in solution, computed HOMO energies, and behavior on the addition of electrophilic radicals generated in the presence of cerium(IV) ammonium nitrate. Oxidation potentials up to 2.03 V vs ferrocene were obtained, which are exceptionally high for cyclic enol ethers but correlate nicely with the reaction times of the radical reactions. Protecting groups have a strong influence on the oxidation stability and HOMO energies of glycals as E(ox) is shifted from O-silyl over O-benzyl to O-acetyl by more than 500 mV. Interestingly, this effect must be transmitted through sigma-bonds, even up to the para-position of a benzoate group, as verified by a wide variation of remote substituents in the carbohydrate. Favorable interactions of the sigma*-orbital of the adjacent C-O bond with the HOMO of the double bond are proposed as a mechanistic rationale, which might be important for the redox behavior of other allylic systems. Finally, donors and acceptors in the 1-position exert the strongest influence on the oxidation stability, shifting the potentials by almost 1 V and resulting in different follow-up reactions of the cerium(IV)-mediated additions of malonates. It is the remarkable oxidation stability of glycals that makes them valuable building blocks in carbohydrate chemistry.     

Palladium-catalyzed direct cross-coupling reaction of glycals with activated alkenes

An efficient method for a Pd(OAc)(2)-catalyzed cross-coupling reaction of glycals with activated alkenes under mild conditions has been developed. This transformation provides an expedient synthetic method to C(2)-functionalized glycals, which are common structural building blocks in natural products and other biologically active compounds. The reaction scope includes different kinds of carbohydrates, protecting groups and substituents on alkene. Moderate to excellent yields and pure E configuration selectivity were obtained.     

Ionic liquids as phase transfer catalysts: Enhancing the biphasic extractive epoxidation reaction for the selective synthesis of β-O-glycosides

Ionic liquids promoted the direct epoxidation of glycals acting as PTC. 1,2-anhydrosugars were prepared by the oxidation of glycals under biphasic conditions with dimethydioxirane generated in situ from oxone/acetone and amphiphilic IL’s as catalysts. β-O-glycosides were synthesized in good yields by the nucleophilic ring opening of epoxy carbohydrate derivatives. Also, 3,4,6-benzyl protected carbohydrates and β-N-glycosides could be prepare by this method.     

Lewis acid-catalyzed stereoselective lactonization and subsequent glycosidation of 2-C-malonyl carbohydrates

Gold(III) bromide is a suitable catalyst for the stereoselective cyclization of 2-C-malonyl carbohydrates to the anomeric center under retention of one ester group. Reopening of the lactones with alcohols in the presence of TMSOTf affords allyl, propargyl and benzyl glycosides with high α-selectivity.     

InCl3/IBX: a novel reagent system for the conversion of glycals into α,β-unsaturated δ-lactones

The combination of indium trichloride with iodoxybenzoic acid (IBX) has been utilized for the first time as a novel reagent system for the one-pot synthesis of 2,3-dideoxy-d-hex-2-enono-1,5-lactones from glycals. The reaction proceeds smoothly in aqueous media and the products are obtained in good yields. This method is suitable for the oxidation of glycals bearing olefin functionality.     

Diastereoselective synthesis of branched 2-deoxy sugars via radical c-c bond formation reactions

From glycals 1 and 6, 2-deoxy sugars can be synthesized in 40–72% yields. With 1,2-disubstituted alkenes 3 this radical C-C bond formation reaction leads with high stereoselectivity to the isomers 4 and 8.     

The homologous conjugate addition of thiols to electron-deficient cyclopropanes catalyzed by a calcium(II) complex

The synthesis of γ-sulfanyl malonates was achieved through the addition of thiols to electron deficient cyclopropanes. These reactions are catalyzed by calcium acetylacetonate, Ca(acac)₂. A variety of electron rich and electron deficient thiols were added without the need for prior activation or exogenous base. The thiol additions to donor–acceptor cyclopropanes bearing electron-rich and electron-deficient aromatic and heteroaromatic groups proceeded in good to excellent yields.     

General method for synthesizing pyranoid glycals. A new route to allal and gulal derivatives

[reaction: see text] Pyranoid glycals of all configurations can be obtained from pentoses through an olefination-cyclization-elimination sequence. The elimination can be carried out with excellent yields under radical conditions or by using common reductive reagents such as Zn/Cu, TiCl(4)/LiAlH(4), or lithium naphthalenide. The proposed method is appropriate for the synthesis of glycals with allo or gulo configurations because the cyclization step is more efficient for these substrates.     

Radical addition approach to asymmetric amine synthesis: design, implementation, and comparison of chiral N-acylhydrazones

Intermolecular radical addition to C=N bonds with acyclic stereocontrol offers excellent potential as a mild, nonbasic carbon-carbon bond construction approach to chiral amines. Here, complete details of the first radical additions to chiral N-acylhydrazones as an approach to asymmetric amine synthesis are disclosed. Novel N-acylhydrazones were designed as chiral C=N radical acceptors with Lewis acid activation, restriction of conformational mobility, and commercial availability of precursors. Amination of 4-alkyl-2-oxazolidinones with O-(mesitylenesulfonyl)hydroxylamine or O-(p-nitrobenzoyl)hydroxylamine afforded N-aminooxazolidinones which were condensed with aldehydes to afford N-acylhydrazones 3-8. Three synthetic methods were developed, implementing these N-acylhydrazones in Lewis acid-promoted intermolecular radical additions to C=N bonds. First, additions of various secondary and tertiary alkyl iodides to propionaldehyde and benzaldehyde hydrazones (3 and 7) under tin hydride radical chain conditions in the presence of ZnCl2 gave N-acylhydrazine adducts with diastereomeric ratios ranging from 93:7 to 99:1. Radical additions to a series of N-acylhydrazones with different substituents on the oxazolidinone revealed that benzyl and diphenylmethyl were more effective stereocontrol elements than those with the aromatic ring directly attached to the oxazolidinone. Second, a tin-free method, exploiting dual functions of triethylborane for both initiation and chain propagation, enabled improved yields in addition of secondary alkyl iodides. Third, under photolytic conditions with hexamethylditin, primary radical addition could be achieved with ethyl iodide in the presence of diethyl ether as cosolvent; the 1-ethoxyethyl adduct was observed as a minor product. Chloromethyl addition was achieved under both the tin-free and photolytic conditions; in this case, the adduct bears alkyl chloride functionality with potential for further elaboration.     

Asymmetric conjugate addition of malonate to α,β-unsaturated ketones in water using a perfluoroalkanesulfonamide organocatalyst

Perfluoroalkanesulfonamide organocatalyst 7 efficiently promotes asymmetric Michael additions of malonates to enones in cyclohexane or water to produce the corresponding addition products with excellent yields and with up to 99% ee.     

Catalytic radical addition of carbonyl compounds to alkenes by Mn(II)/Co(II)/O(2) system

The radical addition of enolizable carbonyl compounds such as malonates and malononitrile to alkenes was successfully achieved through a catalytic process using the Mn(II)/Co(II)/O(2) system to afford the corresponding adducts in fair to good yields. Dimethyl malonate added to 1,5-cyclooctadiene to produce a fused bicycle compound.     

Cobalt(II)-Catalyzed C(sp3)−C(sp3) Coupling for the Direct Stereoselective Synthesis of 2-Deoxy-C-Glycosides from Glycals

We report a ligand-controlled Co^II-catalyzed C(sp³)−C(sp³) coupling hydroalkylation for direct and β-selective synthesis of 2-deoxy-C-glycosides from glycals. This reaction proceeds by a radical pathway for alkyl halide activation and is β-selective through ligand control. This approach may inspire the development of further stereoselective coupling reactions with potential application in the field of carbohydrates.     

Stereoselective diversity-oriented syntheses of functionalized saccharides from bicyclic carbohydrate 1,2-lactones

Bicyclic carbohydrate 1,2-lactones have been synthesized in only two steps and high yields by saponification and subsequent cyclization from known malonate addition products to glycals. The gluco-configured lactone serves as an important precursor for diversity-oriented syntheses. Thus, stereoselective opening of the lactone ring was realized with various nucleophiles in the presence of Sc(OTf)₃. This enabled the introduction of different substituents at the anomeric position, to afford a broad variety of 1-functionalized carbohydrates. On the other hand, stereoselective α-substitution of the gluco-configured lactone with different electrophiles and subsequent ring opening gives a collection of 2-functionalized saccharides. More than 30 products have been isolated in analytically pure form, and their configurations were unequivocally established by various NMR methods. Thus, carbohydrate 1,2-lactones are attractive precursors for the stereoselective synthesis of diverse saccharides.     

Copper-mediated controlled/"living" radical polymerization in polar solvents: insights into some relevant mechanistic aspects

The field of transition-metal-mediated controlled/"living" radical polymerization (CLRP) has become the subject of intense discussion regarding the mechanism of this widely-used and versatile process. Most mechanistic analyses (atom transfer radical polymerization (ATRP) vs. single-electron transfer living radical polymerization (SET-LRP)) have been based on model experiments, which cannot correctly mimic the true reaction conditions. We present, for the first time, a determination of the [Cu(I)Br]/[L] (L=nitrogen-based chelating ligand) ratio and the extent of Cu(I)Br/L disproportionation during CLRP of methyl acrylate (MA) in dimethylsulfoxide (DMSO) with Cu(0) wire as a transition-metal catalyst source. The results suggest that Cu(0) acts as a supplemental activator and reducing agent of Cu(II)Br(2)/L to Cu(I)Br/L. More importantly, the Cu(I)Br/L species seem to be responsible for the activation of SET-LRP.     

Intermolecular radical addition and addition/cyclization reactions of alkoxyamines onto nonactivated alkenes

[reaction: see text] Alkoxyamines A, which are readily prepared from commercially available starting materials, undergo efficient thermal radical carboaminoxylations onto various nonactivated alkenes to provide 1,4-functionalized malonates B in good to excellent yields. The experiments are very easy to conduct. The carboaminoxylations can be combined with radical cyclization and fragmentation processes.     

Synthesis and characterization of piperazine-substituted dihydrofuran derivatives viaMn(OAc) 3 mediated radical cyclizations

The aim of this study is to synthesize novel piperazine-containing dihydrofuran compounds (3a-n)from radical additions and cyclizations of diacyl and alkyl-acyl piperazine derivatives (1a-h) with 1,3-dicarbonyl compounds (2a-c) mediated by Mn(OAc) ₃ for the first time. From the reactions of 1a-c with dimedone (2a);1a, 1c, and 1d with acetylacetone (2b); and 1a with ethylacetoacetate(2c) ,the dihydrofuran-piperazine compounds 3a-c, 3d-f, and 3g were obtained in medium to high yields (31%–81%), respectively. In addition, dihydrofuran-piperazine compounds 3h-j and 3k-n were prepared at low to medium yields (20%–40%) from the reactions of 1e-g with 2a and 1e-h with 2c , respectively.     

The Synthesis of New Type Bisazo Compounds Using 4-Hydroxy-2,2,6,6-Tetramethyl-l-Piperidinyloxyl as The Phase-Transfer Dehydrogenation Catalyst

Using 4-hydroxy-2, 2, 6, 6-tetramethyl-l -piperidinyloxyl as the phase-transfer dehydrogenation catalyst to prepare bisazo compounds is reported for the first time. Nine bisaryl carbodiazones were synthesized in high yields under mild conditions. This method was efficient, convenient and rapid. A possible mechanism was suggested by a nitroxide free radical which acted on aryl substituted carbazides to form azo compounds.