Heck-type cross-coupling between halo-exo-glycals and endo-glycals: a practical way to achieve C-glycosidic disaccharides

An effective Heck-type cross-coupling reaction between halo-exo-glycals and endo-glycals to achieve C-glycosidic disaccharides has been developed. Using Pd(OAc)₂ as the catalyst, dppp as ligand and K₂CO₃ as base, the reactions gave C-glycosidic products in good to excellent yields with exclusive stereochemistry.     

Stereoselective synthesis of substituted exo-glycals from 1-exo-methylene pyranoses

Halo-exo-glycals of the gluco-, manno- and galacto- series, readily prepared by reaction of 1-exo-methylene pyranoses with iodonium dicollidinium triflate (IDCT), undergo Suzuki or B-alkyl Suzuki cross-coupling reactions with boronic acids or alkyl boranes to yield, in a stereoselective manner, functionalized exo-glycals.     

Substituent control in the diastereoselectivity of dipolar cycloadditions of nitrones and their Zn(II) complexes with N-arylmaleimides

The π-π stacking interactions between maleimide's and nitrone's aromatic rings during the 1,3-dipolar cycloaddition were assumed to control the exo-endo selectivity of the reaction. The exo-endo ratios change during the reactions until they reach a constant value, which depends on the substituent. Electron-withdrawing groups favour the exo adduct while electron-donating groups favour the endo adduct. The nitrone ZnBr₂ complexes react much more slowly than the free nitrone and the cycloaddition is exo selective in all cases independent of the substituents on the maleimide's aromatic ring. Thermal retrocycloaddition of the cycloadducts produce the corresponding nitrones. The ring opening in the presence of secondary amines did not induce imine formation. endo Adducts were shown for the first time to be the stable paramagnetic compounds.     

Efficient access to disubstituted exo-glycals. Application to the preparation of C-glycosyl compounds

Efficient methods of preparation of disubstituted exo-glycals by palladium cross-coupling reaction on the readily available dibromo exo-glycal and methoxycarbonyl exo-glycal have been developed. Hydrogenation of these new monosubstituted and disubstituted exo-glycals proceeded with a high stereocontrol and led to original C-glycosyl compounds.     

Stereoselective glycosylation of exo-glycals by microwave-assisted Ferrier rearrangement

exo-Glycosyl carbonates were shown to be efficient glycosyl donors in microwave-assisted glycosylation. In these reactions α-glycosyl additions occurred with excellent stereoselectivity and were complete in 4–8 min with 75–92% yield. Interestingly exo-glycals were found to have higher activity than endo-glycals and common glycosides, the reactions of which can be improved by the addition of Lewis acid to result in a higher yield and enhanced stereoselectivity.     

Rh-catalyzed π-facial selective intermolecular hydroacylation of norbornenes

Rh-catalyzed π-facial selective intermolecular hydroacylations of norbornenes with salicylaldehyde have been attained. In the reaction with norbornylene, the exo-hydroacylated product was produced because of steric hindrance. In the case of norbornadiene, the endo-product was obtained because of chelation effect. Lastly, because of chelation and remote substituent effects, the product formed in the reaction of 7-tert-butoxynorbornadiene was the endo,syn-product. Deuterium-labeling experiments revealed that the hydroacylation stereoselectively proceeded via endo- and exo-intermediates.     

Azabrendanes IV. Synthesis and characterization of N-(alkyl- and benzylsulfonyl)-exo-2-hydroxy-4-azatricyclo[4.2.1.0]nonanes

exo- and endo-5-Aminomethylbicyclo[2.2.1]hept-2-enes have been obtained from stereoisomeric exo- and endo-5-cyanobicyclo[2.2.1]hept-2-enes and the corresponding sulfonamides were obtained through reaction of amines with methyl-, n-propyl-, n-butyl-, benzyl-, and cyclohexylsulfonyl chlorides. From the stereoisomeric sulfonamides with peroxy acids, various products were obtained: exo-sulfonamides were transformed into epoxy derivatives, and, in contrast, most of the endo-stereoisomers underwent heterocyclization resulting in substituted exo-2-hydroxy-4-azatricyclo[4.2.1.0^3,7]nonanes. The type of the products obtained did not depend on the type of peroxy acid used (peroxyacetic, peroxyphthalic, and m-chloroperoxybenzoic one). In contrast to other endo-sulfonamides, N-(cyclohexylsulfonyl)-endo-5-aminomethylbicyclo[2.2.1]hept-2-ene in reaction with peroxyacetic acid did not undergo heterocyclization, probably, due to steric factors. The structure and stereochemical homogeneity of the sulfonamides and the structure of the products of their oxidation with peroxy acids were confirmed by spectroscopic methods. The molecular structure of N-(cyclohexylsulfonyl)-endo-5-aminomethyl-exo-2,3-epoxybicyclo[2.2.1]heptane was determined by X-ray diffraction analysis. The mechanism of the intramolecular heterocyclization reaction of N-substituted endo-5-aminomethyl-exo-2,3-epoxybicyclo[2.2.1]heptanes was studied at the BHandHLYP/6-31G(d) level of theory.     

Synthesis of exo-glycals and their biochemical applications

exo-Glycals are both valuable synthetic tools and biologically relevant structures. This article reviews the novel synthetic approaches that have been reported to synthesize sugar based tri- or tetrasubstituted exocyclic enol ethers. Among those, the Julia modified olefinations as well as the transition metal catalyzed cross-couplings have been extensively developed. The synthesis of unprecedented fluorinated and sulfonylated phosphono-exo-glycals are also described. An overview of the biological applications in which exo-glycals acts as inhibitors or inactivator of relevant enzymes is finally presented.     

Stereoselective glycosylation of endo-glycals by microwave- and AlCl3-assisted catalysis

α-2-Deoxyglycosides were synthesized in good to excellent yields by microwave-assisted reaction of endo-glycals with various O-nucleophiles in the presence of catalytic amount of AlCl₃. These glycosyl additions occurred with high α-stereoselectivity and were complete in 5-35 min in 65-93% yield.     

Photoinitiated Thiol-ene Reactions of Enoses: A Powerful Tool for Stereoselective Synthesis of Glycomimetics with Challenging Glycosidic Linkages

Thioglycosides and C-glycosides represent pharmacologically useful classes of glycomimetics that possess a high degree of biological stability. One emerging tool for the stereoselective synthesis of thioglycosides is the photoinitiated addition of thiols to unsaturated sugars. Moreover, thiyl radical-mediated reactions of exo-glycals and 1-substituted endo-glycals offer facile routes to β-C-glycosidic structures. This Concept article summarizes the thiol-ene coupling strategies developed recently by our group and Somsák's group for the synthesis of several kinds of glycomimetics which are difficult to synthesize by conventional methods. One unusual characteristic of the thiol-ene reactions of endo-glycals is that heating inhibits, whereas cooling promotes the reaction. This unique temperature dependence as well as the effects of the enose structures and thiol configurations on the efficacy and stereoselectivity of the reactions are also discussed.     

Wittig reaction of glycosyl phosphonium salts: a stereoselective route to C-disaccharides and C,O-trisaccharides

C-Disaccharides and C,O-trisaccharides, with a quaternary anomeric center, were prepared in good yields and excellent stereoselectivity by a route involving the Wittig reaction of glycosyl phosphonium salts and hydrogenation or glycosidation of exo-glycals as key steps.     

A novel entry to C-glycals via diethylzinc-mediated umpolung of π-allyl palladium derived from 1-exo-methylene 2,3-anhydrofuranoses

The reaction of aldehydes with allylzinc reagents resulting from the umpolung of π-allyl palladium complexes from 1-exo-methylene 2,3-anhydrofuranoses provides a novel entry to C-glycals.     

Stereochemistry of dihydroxylation of <Emphasis Type="Italic">N</Emphasis>-arylbicyclo[2.2.1]-hept-5-ene-<Emphasis Type="Italic">endo</Emphasis>- and -<Emphasis Type="Italic">exo</Emphasis>-2,3-dicarboximides

Stereochemistry of the oxidation of N-arylbicyclo[2.2.1]hept-5-ene-endo-and-exo-2,3-dicarboximides at the double bond with peroxyacetic acid generated in situ in the presence of sulfuric acid and with an anhydrous dioxane solution of peroxyacetic acid was studied. In both cases, the reaction was stereospecific, regardless of the substituent in the N-aryl group and configuration of the imide ring, but the reaction direction depended on the presence of water in the system. In the first case, the corresponding trans-5,6-dihydroxy derivatives were formed, while in the second, exo-5,6-epoxy derivatives. The oxidation of N-arylbicyclo[2.2.1]-hept-5-ene-endo-and-exo-2,3-dicarboximides with a solution of potassium permanganate in aqueous acetone gave the corresponding N-aryl-cis-5,6-dihydroxybicyclo[2.2.1]heptane-endo-and-exo-2,3-dicarboximides. The exo,cis,exo and exo,cis,endo configurations of the synthesized compounds were determined by ¹H NMR spectroscopy.     

Convergent stereocontrolled synthesis of substituted exo-glycals by Stille cross-coupling of halo-exo-glycals and stannanes

(Z)-exo-Glycals can be conveniently prepared in a convergent manner by Stille cross-coupling of (Z)-halo(Br,I)-exo-glycals and aryl or alkenyl stannanes, the latter are readily obtained by addition of tributylstannyl radicals to terminal alkynes.     

Additions to bicyclic olefins—X: Stereochemistry of the oxymercuration-demercuration of cis-bicyclo[3.3.0]oct-2-ene,endo-trimethylene-norborn-8-ene and related olefins

The stereochemistry of the oxymercuration-demercurarion (OM-DM) of olefins related to the cis-bicyclo(3.3.0]octane and endo-2,3-trimethylenenorboniane structures was determined. In the case of cis-bicyclo(3.3.0]oct-2-ene, hydration occurs preferentially at the less hindered 3-position, with little preference shown for exo vs endo. The more hindered 2-product shows a 11:1 preference for the exo-product. The presence of Me groups at positions 2- or 3-, results in the formation of the tertiary alcohols with approximately a 4:1 favoring of the exo-isomer. (The oxymercuration intermediate exhibits a rapid equilibration with time. Consequently, the 4:1 ratios may not represent the true limit for the isomer distribution in the initial kinetic product.) Similarly, 2-methylenebicyclo[3.3.0]octane reveals an 8:1 preferential formation of the exo-alcohol. In the case of endo-trimethylene-norborn-8-ene, the oxymercuration stage is extraordinarily slow and the results do not fit this pattern. Possibly the very slow oxymercuration stage permits equilibration of the initial reaction product. On the other hand, the reaction is fast with 8-methylene-endo-trimethylenenorbornane and the product is 100% of the tertiary exo-alcohol. The same behavior is observed for 2-methylenenorbornane. Surprisingly, 2-methylene-endo-trimethy-lenenorbornane fails to undergo oxymercuration. Consequently, both endo-trimethylenenorborn-8-ene and 2-methylene-endo-trimethylenenorbornane exhibit an exceptional inertness toward oxymercuration, presumably related to the highly rigid U-shaped structure of the parent system.     

Convenient switching of 7-endo/6-exo radical cyclization

7-endo/6-exo Selectivity of radical cyclization to α,β-unsaturated amides was readily controlled by the presence or absence of a temporary substituent, a phenylthio or chlorine group, at the α-position of the acceptor.     

Epoxidation of Bicyclo[2.2.1]hept-5-ene-2,3-endo- and Exodicarboxylic Acid N-Arylimides

Epoxidation of endo- and exo-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid N-arylimides with a solution of peracetic acid in anhydrous dioxane affords 5,6-exo-epoxybicycloheptanedicarboxylic acid N-arylimides. The epoxidation reaction is not sensitive to the configuration of the imide fragment, to the character and position of the substituent in the aromatic ring. The reaction is determined only by oxidation conditions.     

Synthesis of nitrogen-containing heterocycles using exo- and endo-selective radical cyclizations onto enamides

The effect of positional change of the carbonyl group of enamides on Bu₃SnH-mediated alkyl radical cyclization leading to five-, six-, seven-, and eight-membered nitrogen-containing heterocycles was examined. A 5-exo cyclization is generally preferred over a 6-endo ring closure in systems having an alkyl radical center on the enamide-acyl side chain, whereas enamides having an alkyl radical center opposite to the acyl side chain predominantly gave 6-endo cyclization products. These results suggest that the exo or endo selectivity of radical cyclization onto the alkenic bond of enamides can be controlled by positional change of the carbonyl group. For an understanding of these selectivities, heat of formation for each transition state was calculated. 6-endo-Selective radical cyclization was applied to the radical cascade, enabling a concise synthesis of a cylindricine skeleton. A 7- or 8-endo alkyl radical cyclization, however, predominated over a corresponding 6- or 7-exo ring closure regardless of the positional change of the carbonyl group of enamides.     

Synthesis and some reductions of endo- and exo-3,6-epoxy-Δ4-tetrahydrophthalic anhydride

The synthesis of endo-3,6-epoxy-Δ⁴-tetrahydrophthalic anhydride from the endo-adduct of furan and maleic acid is described. Reduction of endo- and exo-3,6-epoxy-Δ⁴-tetrahydrophthalic anhydride with sodium borohydride gave the corresponding lactones, while catalytic hydrogenation over 10% Pd/C gave anhydride and/or hemi-acylals, depending on the solvent.     

Experimental and DFT study of the aza-Diels-Alder reaction between cyclopentadiene and protonated benzylimine derivated from glyoxylates

The Diels-Alder reaction of protonated N-benzyl imine of methyl glyoxylate with cyclopentadiene in different solvents gave mixtures of exo/endo adducts. The exo/endo selectivity of the reaction was elucidated by NMR experiments. Theoretical calculations by means of density functional theory (DFT) at the B3LYP/6-31G(d) level have also been performed to elucidate the molecular mechanism of this reaction. The DFT results suggest a highly asynchronous concerted mechanism, which in turn can explain the preferred exo stereoselectivity of the reaction. Inclusion of solvent effects enhances the exo selectivity, and this effect increases with the polarity of the solvent, in good agreement with the experimental findings.