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.     

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.     

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.     

Synthesis of chlorophyll-a derivatives possessing (un)substituted 13-exo-methylene moiety and their optical properties

Chlorophyll-a derivatives possessing an un/mono/disubstituted methylene moiety at the 13¹-position were prepared by (un)substituted methylation of the 13-carbonyl group and successive dehydration. Substitution of the 13¹-oxo to the methylene group slightly blue-shifted electronic absorption and emission bands in a solution and decreased chemical stability to give an oxidation product cleaved at the E-ring. Further mono/disubstitution at the methylene terminal increased wavelengths of absorption and emission maxima as well as oxidative tolerance.     

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.     

Diastereoselective ruthenium-catalysed cycloisomerisation of diallyllactones: preparation of exo-methylene spirolactones

Diallyllactones (obtained from cyclic anhydrides via a double allylation reaction promoted by titanium tetrachloride) were cycloisomerised using 5 mol% of cyclooctadienyl ruthenium dichloride in ethanol providing the corresponding exomethylene spirolactones in good yields, with moderated to good diastereomeric excess.     

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 5-exo-trig radical cyclization in the enantioselective synthesis of Pregabalin

A practical stereoselective 5-exo-trig radical cyclization procedure was developed in order to prepare enantiomerically pure GABA derivative precursors (4-alkyl-pyrrolidin-2-ones). This procedure allows much more rapid access to optically pure GABA derivatives, such as the powerful antiepileptic agent (S)-(+)-3-aminomethyl-5-methylhexanoic acid (Pregabaline).     

Stereoselective synthesis of substituted piperazines

The treatment of allylarylamines with mercury(II) acetate in tetrahydrofuran followed by a double decomposition reaction with potassium bromide leads to trans-2,5-bis(bromomercuriomethyl)-1,4-diarylpiperazines (2). The stereochemistry of the reaction products has been elucidated by an ¹H-nmr spectroscopic study of the trans-2,5-dimethyl-1,4-diarylpiperazines (3) obtained by sodium borohydride reduction of 2 in alkaline media. The course of the reaction strongly depends on the steric demand of the groups attached to either the allylic group or the ortho-position in the aromatic ring of the starting amine (1).     

Anomeric spiroannelated 1,4-diazepine 2,5-diones from furano exo-glycals: towards a new class of spironucleosides

The first synthesis of 1,4-diazepine 2,5-dione peptides containing a β-amino acid in which the β carbon is also the anomeric carbon of a furanoid sugar is described. These new anomeric spirosugars obtained with a stereoselective control in the d-gulo, d-manno, d-allo and d-ribo series can be regarded as the first members of a new class of spironucleosides. In the course of our study, two symmetrical tetrameric cyclopeptides comprising two identical sugar β-amino acid and α-amino acid residues were also isolated, these structures could be of interest as new potential host molecules.     

Dye-sensitized photooxygenation of sugar-furans as synthetic strategy for novel C-nucleosides and functionalized exo-glycals

The methylene blue-sensitized photooxygenation of β-ribofuranosyl furan 1e followed by in situ Et₂S treatment afforded the conformationally stable β-ribofuranoside 4e almost quantitatively. The latter was converted to pyridazine C-nucleoside 6e by cyclization with NH₂NH₂ and to pyrazoline 7e through a 1,3-dipolar cycloaddition with diazomethane. Attempts to epoxidize the double bond failed both by dimethyldioxirane (DMDO), which left 4e unchanged, and by NEt₃/t-BuOOH or NaOO-t-Bu which respectively afforded the new and unexpected exo-glycals E,Z-8e and the novel furan derivative 9.     

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.     

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.     

Stereoselective synthesis of fused heterocycles from substituted o-Benzoquinones and anilines

The reaction of trisubstituted o-benzoquinones with substituted anilines gives unstable o-benzoquinone imines which undergo intramolecular cyclization to 4aH-phenoxazine derivatives. Dimerization of the latter according to Diels-Alder yields complex heterocyclic systems, 7a,14a,15a,15b-tetrahydro-14,16-dioxa-5,9-diaza-8,15-ethenohexaphenes. Effective shielding of the carbonyl groups in 3,6-di-tert-butyl-4-isopropyl-o-benzoquinone makes it inactive toward substituted anilines.     

Radical cyclization of exo-methylene furanose derivatives: an expedient approach to the synthesis of chiral tricyclic nucleosides and benzannulated oxepine derivatives

Tributyltin radical mediated cyclization of the glucose derived exo-methylene furanose derivatives 5a-c led to the highly functionalized cis-fused bicyclic ethers 6a-c. The product could subsequently be transformed to the optically active tricyclic nucleoside analogue 8 or oxepine derivative 9.     

Stereoselective tandem synthesis of oxazolo-fused pyrroloquinolines from o-alkynylaldehydes via Ag(I)-catalyzed regioselective 5-exo-dig ring closure

A tandem approach for the regio- and stereoselective synthesis of oxazolo-fused pyrroloquinolines 3a–l via the reaction of o-alkynylaldehydes 1a–i with chiral amino alcohols 2a–c under mild reaction conditions is described. The possible participation of the pyridine ring in the regioselective formation of 5-exo-dig cyclized products was supported by the controlled experiments. The structures and stereochemistry of the products were confirmed by NOESY and X-ray crystallographic studies.     

On the 6-exo-trig ring closure of substituted 5-hexen-1-oxyl radicals

Substituted 5-hexen-1-oxyl radicals have been generated from N-(5-hexen-1-oxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thiones under tin-free conditions and have been successfully applied as reactive intermediates in a mechanistic study on the formation of bromomethyl-substituted tetrahydropyrans via 6-exo-trig selective cyclizations.     

Stereoselective one-pot synthesis of highly differently substituted thiochromans

A highly stereoselective one-pot procedure to anti-configured thiochromans is described. This reaction functions at room temperature in the presence of catalytic amounts of trifluoroacetic acid. The transformation gives a selective but optional access to highly substituted thiochromans, which have been not attainable until now.     

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.     

Stereoselective synthesis of 2-C-methylene glycosides and disaccharides via direct allylic substitution of hydroxy group in benzylated glycals

InCl₃ efficiently catalyzes allylic substitution of the hydroxy group of 2-C-hydroxymethyl glycals to afford a diversity of 2-C-methylene alkyl and aryl glycosides as well as disaccharides in high yields. This protocol surpasses the existing methods for the synthesis of 2-C-methylene glycosides as it obviates the need for functionalizing the allylic hydroxy group of glycals. The interest of this methodology relies on the extremely mild conditions required even with a free hydroxyl group at the allylic position of the glycals and that too only with a catalytic amount of InCl₃. The reaction is fast (30 min.), stereoselective and is compatible with a variety of oxygenated nucleophiles including those possessing acid-labile groups. A mechanistic investigation on the direct formation of an α,α-(1→1)linked disaccharide derivative from 2-C-hydroxymethyl galactal reveals that the reaction proceeds through a domino Ferrier rearrangement followed by a facile 1,3-alkoxy migration.