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.     

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.     

An expeditious entry to carbohydrate derived enynes and ene-diynes via Sonogashira coupling of halo-exo-glycals

Sonogashira coupling of bromo or iodo-exo-glycals, readily prepared from 1-exo-methylene furanoses and pyranoses, provides an efficient entry to furanose- and pyranose-derived enyne and ene-diyne moieties found in biologically relevant structures.     

Stereoselective iodine-induced cyclisation of alkene acetals. Application to the synthesis of 3-deoxy-exo-glycals and substituted tetrahydrofurans

2,5-Substituted tetrahydrofurans have been stereoselectively prepared by a iodine-induced cyclisation of alkene acetals, and the iodo derivatives obtained were transformed into 3-deoxy-exo-glycals and in polyhydroxy substituted tetrahydrofurans.     

Povarov reactions of exo-glycals: preparation of C-linked, quinoline analogues

A one-pot approach based upon the Povarov reaction has been efficiently employed with a number of exo-glycals and para-substituted benzanilines to synthesize novel open-ring, carbohydrate-derived quinolines. The mechanism of this reaction was studied and an explanation for the observed stereoselectivity is proposed. Treatment of the compounds with the Lewis acid, boron trichloride, successfully removes the benzyl ether protecting groups in good yields. Several of the prepared compounds have been screened in the National Cancer Institute’s (NCI’s) 60 cell line model. Moderate activity was observed for several leukemia cell lines.     

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.     

The synthesis and biological activity of novel spiro-isoxazoline C-disaccharides based on 1,3-dipolar cycloaddition of exo-glycals and sugar nitrile oxides

A series of novel spiro-isoxazoline C-disaccharides were synthesized by the key step of 1,3-dipolar cycloaddition reactions of exo-glycals and sugar nitrile oxides, and followed by catalytic debenzylation in the presence of Pd(OH)₂/C. The cycloaddition reactions were carried out stereoselectively and afforded α-isomers exclusively except in the case of galactose. The biological activities of the novel disaccharides against the glycosidases (α-amylase, α-glucosidase, and β-glucosidase) and HIV and BVDV were evaluated.     

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.     

Different reaction routes found in acid-catalyzed glycosylation of endo- and exo-glycals: competition between Ferrier rearrangement and protonation

Acid-mediated glycosylations of endo- and exo-glycals have been carried out in good to excellent yields, in which a mixture of two products is often obtained resulting from Ferrier rearrangement and protonation. The former reaction exclusively takes place with the t-butyl carbonate or hydroxyl substituent at the C3 position of endo-glycals, while the latter mainly occurs in the glycosylation of exo-glycals with allyl benzyl ether or acetate. In addition to the substituent effect, protecting groups are critical to determine the activity and favored reaction pathway. Furthermore, the method is applicable to O-, C-, and N-nucleophiles.     

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.     

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.     

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.     

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.     

Regioselective oxidation of N-alkylpyrrolidines to pyrrolidin-5-ones by RuCl3/NaIO4

RuCl₃/NaIO₄ under EtOAc/H₂O biphasic conditions, selectively oxidizes the Nα-endo-methylene group of pyrrolidine derivatives, without affecting the exo-methylene group adjacent to the N-heteroatom.     

A Julia olefination approach to the synthesis of functionalized enol ethers and their transformation into carbohydrate-derived spiroketals

A synthesis of spiroketals from carbohydrate lactones is reported. A modified Julia olefination is used to synthesize trisubstituted and highly functionalized exo-glycals, which were subsequently transformed into spiroketals under acidic conditions.     

A novel transformation of 1-exo-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones with sulfoxonium ylide to highly strained 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans

When 1-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones (1) were treated with dimethylsulfoxonium methylide, 1-endo isomers (endo-1) gave 1-substituted 3-aroyl-1,2,4a,9b-tetrahydrodibenzofuran-4-ols (2) exclusively as expected. On the other hand, 1-exo isomers (exo-1) underwent a novel transformation to 1-substituted 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans (3), together with 2.     

Me3SiCl-promoted intramolecular cyclization of aromatic compounds tethered with N,O-acetals leading to the facile preparation of 1,4-benzodiazepine skeletons

The Me₃SiCl-promoted intramolecular aminomethylation of a novel type of N,O-acetals, which were prepared via a facile three-step synthesis from N-alkylaniline derivatives and N-alkyl-2-oxazolidinones that leads to the production of pharmaceutically useful 1,4-benzodiazepine skeletons with a variety of functional groups is described. This method was successfully applied to the facile preparation of both tricyclic benzodiazepine derivatives and a 1,4-benzoxazepine derivative via 7-exo-trig cyclization.     

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.     

Stereoselective synthesis of protected (2S,3S)-N-methyl-5-hydroxyisoleucine, a component of halipeptins

The stereocontrolled synthesis of the protected (2S,3S)-N-methyl-5-hydroxyisoleucine, a component of halipeptins A and B with potent anti-inflammatory activity, has been achieved. The key steps include (i) installation of a double bond to bicyclic lactam 4 using N-tert-butyl phenylsulfinimidoyl chloride, (ii) highly exo-selective Michael reaction with lithium dimethylcuprate in the presence of chlorotrimethylsilane, and (iii) Ru-catalyzed oxidative deprotection of N,O-benzylidene acetal to the acid anhydride.     

Regioselective synthesis of phthalans via Cu(OTf)2-catalyzed 5-exo-dig intramolecular hydroalkoxylation of 2-(ethynyl)benzyl alcohols

An efficient, regioselective Cu(OTf)₂-catalyzed 5-exo-dig intramolecular hydroalkoxylation of 2-(ethynyl)benzyl alcohol, which provides a concise access to functionalized phthalan in high yields has been developed. A wide range of substrates possessing terminal, internal, and heteroaromatic alkynes can be efficiently transformed into the targeted phthalans. Substrates with primary, secondary, and tertiary benzyl alcohols also proceed well to produce the corresponding phthalans in good yields. Irrespective of the nature of the substrates, the cyclization follows highly selective 5-exo-dig regiochemistry when regioselectivity is an issue.