Palladium-catalyzed Glycosylation Research Articles

Stereospecific Palladium-Catalyzed Direct Glycosylation of Oximes: Access to N-O-Linked Glycosides.

A highly efficient, palladium-catalyzed glycosylation between 3,4-O-carbonate glycals and acid-labile oximes is disclosed. This approach features broad substrate scope, high functional group tolerance, and easy scalability, delivering glycosyl oximes in excellent yields with exclusive β-selectivity and retention of Z/E geometries. The power of this method is demonstrated by a set of site-selective transformations of glycosylation products and late-stage glycodiversification of bioactive molecules. Overall, our strategy provides an efficient toolkit for facile access to valuable N-O-linked glycosides.

The Palladium-Catalyzed Glycosylation of Halotropones

A range of mono- and disaccharides, including glucose derivative 10, has been cleanly coupled, in the presence of a Pd catalyst, with various halogenated and structurally distinctive tropones, including "parent" compound 11, to afford the corresponding α- and β-anomeric forms of the tropolone glycosides, e.g., 12 and 13, respectively. Varying the ligand used influences the anomer distribution significantly and such that either the α- or β-form predominates. Notable chemo- and regioselectivities are observed when dihalogenated troponoids are employed as coupling partners.

Achmatowicz approach to the asymmetric synthesis of (+)- and (−)-monanchorin

The full account of our development of a de novo asymmetric total synthesis of (+)-monanchorin has been reported. The optimized synthesis provided access to either enantiomer of the guanidine alkaloid natural product in nine steps from the commodity chemicals furan and caproic acid. The route relied upon the asymmetric Noyori hydrogen transfer reduction of an achiral acylfuran to introduce the absolute stereochemistry. In addition, an Achmatowicz rearrangement, a diastereoselective palladium-catalyzed glycosylation, a reductive amination and an acid-catalyzed bicyclic guanidine mixed acetal formation were used to complete the synthesis.

2, 4, 5-Trideoxyhexopyranosides Derivatives of 4'-Demethylepipodophyllotoxin: De novo Synthesis and Anticancer Activity.

Podophyllotoxin is a natural lignan which possesses anticancer and antiviral activities. Etoposide and teniposide are semisynthetic glycoside derivatives of podophyllotoxin and are increasingly used in cancer medicine. The present work aimed to design and synthesize a series of 2, 4, 5-trideoxyhexopyranosides derivatives of 4'-demethylepipodophyllotoxin as novel anticancer agents. A divergent de novo synthesis of 2, 4, 5-trideoxyhexopyranosides derivatives of 4'- demethylepipodophyllotoxin has been established via palladium-catalyzed glycosylation. The abilities of synthesized glycosides to inhibit the growth of A549, HepG2, SH-SY5Y, KB/VCR and HeLa cancer cells were investigated by MTT assay. Flow cytometric analysis of cell cycle with propidium iodide DNA staining was employed to observe the effect of compound 5b on cancer cell cycle. Twelve D and L monosaccharide derivatives 5a-5l have been efficiently synthesized in three steps from various pyranone building blocks employing de novo glycosylation strategy. Dmonosaccharide 5b showed the highest cytotoxicity on five cancer cell lines with the IC50 values ranging from 0.9 to 6.7 μM. It caused HepG2 cycle arrest at G2/M phase in a concentrationdependent manner. The present work leads to the development of novel 2, 4, 5-trideoxyhexopyranosides derivatives of 4'-demethylepipodophyllotoxin. The biological results suggest that the replacement of the glucosyl moiety of etoposide with 2, 4, 5-trideoxyhexopyranosyl is favorable to their cytotoxicity. D-monosaccharide 5b was observed to cause HepG2 cycle arrest at the G2/M phase in a concentration- dependent manner.

Palladium-Catalyzed Glycosylation of Arginine

Key words arginine - palladium catalysis - glycosylation - glycals

General Strategy for Stereoselective Synthesis of β- N-Glycosyl Sulfonamides via Palladium-Catalyzed Glycosylation.

A highly efficient and mild glycosylation reaction between 3,4- O-carbonate glycal and N-tosyl functionalized aliphatic and aromatic amines via palladium-catalyzed decarboxylative allylation is disclosed. A wide range of highly functionalized 2,3-unsaturated β- N-glycosides are furnished in good to excellent yields and complete regioselectivity and stereoselectivity. In addition, applications of the glycosyl sulfonamides as the precursor to assemble functional derivatives have also been explored, including glycosylation, dihydroxylation, and nucleophilic addition to the N-glycosides.

Synthesis of the C1-C10 Fragment of Madeirolide A.

The synthesis of a fully elaborated C1-C10 fragment of madeirolide A has been achieved via a strategy based on a series of stereospecific processes. The concise synthetic route also features an iridium-catalyzed visible light induced radical cyclization for construction of the THP ring and a palladium-catalyzed glycosylation for formation of the α-cineruloside linkage.

Palladium-catalyzed glycosylation: novel synthetic approach to diverse N-heterocyclic glycosides.

An efficient and highly stereoselective method for the construction of N-heterocyclic glycosides is reported. This method is based on a palladium-catalyzed allylation which proceeded to provide N-heterocyclic glycosyl compounds in good-to-excellent yields with β- or α-selectivity. Various N-nucleophiles were examined for this reaction and selected N-glycosyl isatin substrates were further elaborated to bis-indole sugars which have potential as antiproliferative drugs.

ChemInform Abstract: De novo Asymmetric Synthesis of the Pyranoses: From Monosaccharides to Oligosaccharides

The various methods for the de novo asymmetric synthesis of the pyranose sugars are surveyed. The presentation begins with the work of Masamune and Sharpless with the use of the Sharpless asymmetric epoxidation for the synthesis of all eight l-hexoses. The development of other asymmetric reactions and their application for the synthesis of specific hexopyranoses are further discussed. The broad application of the Achmatowicz rearrangement with asymmetric catalysis, for the synthesis of various pyranones and imino sugars, is also presented. Finally, the use of a diastereoselective palladium-catalyzed glycosylation with the Achmatowicz approach for the synthesis of oligosaccharides and applications to medicinal chemistry are discussed.

C3′/C4′‐Stereochemical Effects of Digitoxigenin α‐L‐/α‐D‐Glycoside in Cancer Cytotoxicity

Sweet'n low in stereo: A Wharton reaction was employed along with a diastereoselective palladium-catalyzed glycosylation and other post-glycosylation transformations to synthesize digitoxin analogues. Cytotoxic evaluation against a panel of cancer cell lines uncovered the stereochemical and substitutional limits of the C3'/C4'-hydroxy functionality in digitoxin monosaccharide.

Synthesis and Evaluation of the α-d-/α-l-Rhamnosyl and Amicetosyl Digitoxigenin Oligomers as Antitumor Agents

A highly regio- and stereo-selective asymmetric synthesis of rhamnosyl- and amicetosyl-digitoxigenin analogues has been established via palladium-catalyzed glycosylation followed by bis-/tris-dihydroxylation or bis-/tris-diimide reduction. The α-l-rhamnose and α-l-amicetose digitoxin monosaccharide analogues displayed stronger apoptosis inducing activity and cytotoxicity against non-small cell human lung cancer cells (NCI-H460) than its d-diastereomeric isomers in a sugar-chain length dependent manner.

C5′-Alkyl Substitution Effects on Digitoxigenin α-l-Glycoside Cancer Cytotoxicity

A highly regio- and stereo-selective asymmetric synthesis of various C5'-alkyl side chains of rhamnosyl- and amicetosyl-digitoxigenin analogs has been established via palladium-catalyzed glycosylation with post-glycosylated dihydroxylation or diimide reduction. The C5'-methyl group in both α-l-rhamnose and α-l-amicetose digitoxin analogs displayed a steric directed apoptosis induction and tumor growth inhibition against non-small cell human lung cancer cells (NCI-H460). The anti-tumor activity is significantly reduced when the steric hindrance is increased at C5'-stereocenter.

Synthesis of Several Cleistrioside and Cleistetroside Natural Products via a Divergent De Novo Asymmetric Approach

The de novo asymmetric syntheses of several partially acylated dodecanyl tri- and tetra-rhamnoside natural products (cleistriosides-5 and 6 and cleistetrosides-2 to 7) have been achieved (19-24 steps). The divergent route requires the use of three or less protecting groups. The asymmetry was derived via Noyori reduction of an acylfuran. The rhamno-stereochemistry was installed by a diastereoselective palladium-catalyzed glycosylation, ketone reduction and dihydroxylation.

Synthesis of 2,3,4-Trideoxy-4,4-difluoro-d-ribo-hexopyranose Adenosines

A novel synthetic route to 2,3,4-trideoxy-4,4-difluoro-β-d-ribo-hexopyranose adenosine and 2,3,4-trideoxy-2,3-didehydro-4,4-difluoro-β-d-ribo-hexopyranose adenosine has been developed. The approach highlights the highly regio- and stereoselective palladium-catalyzed glycosylation of Boc-protected pyranose, which was prepared from the oxidation-cyclization of a difluorinated diol. The diol was provided through ozonization and Lindlar reduction of optically pure enynic alcohol.

De Novo Asymmetric Synthesis and Biological Evaluation of the Trisaccharide Portion of PI-080 and Vineomycin B2

A highly enantio- and diastereoselective synthesis of an alpha-L-aculose, alpha-L-rhodinose, and beta-D-olivose trisaccharide is described. The key transformations include the palladium-catalyzed glycosylation, Myers' reductive rearrangement, diastereoselective dihydroxylation, and regioselective Mitsunobu inversion. Significant apoptotic antitumor activity was found for this trisaccharide, which has implication for vineomycin B2 and PI-080 structure-activity relationship.

De Novo Asymmetric Synthesis of Anthrax Tetrasaccharide and Related Tetrasaccharide

A de novo asymmetric approach to the natural product anthrax tetrasaccharide 1 and an analogue 2 with an anomeric hexyl azide group has been developed from acetylfuran. The construction of the tetrasaccharide was achieved by a traditional [3 + 1] glycosylation strategy. An iterative diastereoselective palladium-catalyzed glycosylation, Luche reduction, diastereoselective dihydroxylation, and regioselective acylation were employed for the assembly of the L-rhamno-trisaccharide building block. The anthrose building block also required a palladium-catalyzed azide allylation and a triflate inversion to set the gluco-stereochemistry in addition to Luche reduction and dihydroxylation.

De Novo Synthesis of the Trisaccharide Subunit of Landomycins A and E

A highly enantio- and diastereoselective synthesis of alpha- -rhodinose, beta-d-olivose as well as the trisaccharide portion of landomycin A from achiral acetyl furan has been developed. The key transformations include the palladium-catalyzed glycosylation, Myers' reductive rearrangement, diastereoselective dihydroxylation, and regioselective Mitsunobu inversion. A Mitsunobu reaction on a six member ring cis-1,2-diol was found to chemoselectively discriminate between equatorial and axial alcohols and to stereoselectively convert cis-1,2-diol into anti-1,2-diol.

De Novo Asymmetric Synthesis of 8a-epi-Swainsonine

An enantioselective and diastereocontrolled approach to 8a-epi-d-swainsonine has been developed from achiral furfural. The key step to this synthesis was a one-pot procedure for the hydrogenolytic removal of two protecting groups and two intramolecular reductive amination reactions. The absolute stereochemistry was introduced by asymmetric Noyori reduction of furfuryl ketone. This route relies on diastereoselective palladium-catalyzed glycosylation to install the anomeric bond, and Luche reduction, diastereoselective dihydroxylation to set up the manno-stereochemistry of the indolizidine precursor.

The De Novo Synthesis of Oligosaccharides: Application to the Medicinal Chemistry SAR-Study of Digitoxin

To address the medicinal chemist's need for new synthetic methods for the preparation of unnatural carbohydrates, a new de novo method for carbohydrate synthesis has been developed. These routes use a palladium catalyzed glycosylation reaction to stereoselectively control the anomeric center and subsequent diastereoselective post glycosylation to install the remaining sugar stereocenters. The utility of this method was demonstrated by the syntheses and biological evaluation of several digitoxin oligosaccharide analogues.

De novo asymmetric syntheses of d-, l- and 8- epi- d-swainsonine

A highly enantioselective and stereocontrolled approach to d-, l- and 8- epi- d-swainsonine has been developed from achiral furan and γ-butyrolactone. A one-pot hydrogenolysis of both azide and benzyl ether followed by an intramolecular reductive amination has been employed as key step to establish the indolizidine ring system. The absolute stereochemistry was installed by the Noyori reduction and the relative stereochemistry by the use of several highly diastereoselective palladium-catalyzed glycosylation, Luche reduction, dihydroxylation, and palladium-catalyzed azide allylation reactions. This practical approach provide multigram quantities of indolizidine natural product d-swainsonine in 13 steps and 25% overall yield.