Oscar Varela - Academia.edu (original) (raw)

Papers by Oscar Varela

Research paper thumbnail of Synthesis of Enantiomeric Polyhydroxyalkylpyrrolidines from 1,3-Dipolar Cycloadducts. Evaluation as Inhibitors of a β-Galactofuranosidase

Journal of Organic Chemistry, May 10, 2016

Research paper thumbnail of Synthesis of a New Chiral Bis-Arsine Ligand Based on Natural Carbohydrates

Proceedings of the 15th Brazilian Meeting on Organic Synthesis Proceedings, 2013

Research paper thumbnail of Design and Synthesis of 2-Acetamido-2,3-dideoxythiodisaccharides via Diastereoselective Conjugate Addition to Sugar Enone O-Acetyl Oximes. Galactosidase Inhibition Studies

Organic Letters, 2018

The key step in a new synthesis of 2-acetamido-2,3-dideoxy-(1→4)-thiodisaccharides was the conjug... more The key step in a new synthesis of 2-acetamido-2,3-dideoxy-(1→4)-thiodisaccharides was the conjugate addition of a 1-thiogalactose derivative to E and Z acetyl oximes derived from sugar enones. This reaction was shown to be completely diastereoselective for both the formation of the thioglycosidic linkage and the configuration of acetyl oxime. The thiodisaccharides have been designed as inhibitors of the β-galactosidase from E. coli, and they have been shown to successfully meet such requirements.

Research paper thumbnail of Non-Conventional Glycosidic Linkages: Syntheses and Structures of Thiooligosaccharides and Carbohydrates with Three-Bond Glycosidic Connections

Research paper thumbnail of Synthesis, characterization and chemical degradation of poly(ester-triazole)s derived from d-galactose

RSC Advances, 2019

Carbohydrate-derived poly(ester-triazoles), soluble in organic solvents and degradable in aqueous... more Carbohydrate-derived poly(ester-triazoles), soluble in organic solvents and degradable in aqueous media, have been synthesized by CuAAC or thermal polymerization.

Research paper thumbnail of Photooxidation of thiosaccharides mediated by sensitizers in aerobic and environmentally friendly conditions

RSC Advances, 2021

An environmentally friendly and simple sensitized photooxidation methodology to obtain glycosyl s... more An environmentally friendly and simple sensitized photooxidation methodology to obtain glycosyl sulfoxides with outstanding chemoselectivity in aerobic conditions is described.

Research paper thumbnail of Synthesis and antitumor activity of anthracycline disaccharide glycosides containing daunosamine

The Journal of Antibiotics, 1993

Daunosamine, as its 4-0-acetyl-3-JV-trin'uoroacetyl glycosyl chloride derivative (lb), has been c... more Daunosamine, as its 4-0-acetyl-3-JV-trin'uoroacetyl glycosyl chloride derivative (lb), has been coupled a-L-glycosidically to the 3-and 4-mono-O-acetyl derivatives of L-rhamnal to afford disaccharide glycal derivatives, whose conversion into the corresponding 2-deoxyglycosides by sequential alkoxyiodination-tributylstannane reduction has been evaluated. The sequence successfully demonstrated with the methyl glycosides was successfully extended with daunomycinone as the aglycon, providing a preparative route to 7-O-[3-O-(3-amino-2,3,6-trideoxy-a-L-(y.x0hexopyranosyl)-2,6-dideoxy-a-L-flra6mo-hexopyranosyl]daunomycinone hydrochloride (15), an analogue of natural anthracycline antibiotics containing daunosamineand a 2,6-dideoxy-L-hexose. Most of the natural anthracycline antibiotics with oligosaccharide side chains, as in the rhodomycin and cinerubin series, contain daunosamine as the sugar directly attached to the anthracyclinone and are of interest as antitumor agents1*. Only in a few cases, daunosamine appears as the non reducing terminal sugar2>3). These compounds also showed high degree of antitumor activity. As part of our program to obtain new anthracycline antibiotics, we decided to synthesize derivatives having daunosamine as the terminal non reducing sugar, in order to compare their biological activity with the natural products, and to be able to make conclusions about the importance of the sequence of sugars in the oligosaccharide side chain. Synthetic analogs of daunorubicin and doxorubicin have been extensively investigated in our laboratory4'5). Conventional Koenigs-Knorr coupling between daunomycinone or 14-protected adriamycinone and appropriate glycosyl halides is sometimes complicated by low yields and mixtures of anomers. An alternative two-step synthesis6) offers significant advantage. The first step involves

Research paper thumbnail of Synthesis and antitumor activity of 3'-deamino-3'-hydroxydoxorubicin. A facile procedure for the preparation of doxorubicin analogs

The Journal of Antibiotics, 1984

Two successful routes have been developed for preparation of 3'-deamino-3'-hydroxydoxorubicin (11... more Two successful routes have been developed for preparation of 3'-deamino-3'-hydroxydoxorubicin (11), based on protection of the 14-hydroxyl group of the aglycon by using tertbutylchlorodimethylsilane. The key intermediate, 14-O-tert-butyldimethylsilyl-7-O-(3,4-di-Oacetyl-2,6-dideoxy-n-L-lyxo-hexopyranosyl)adriamycinone (9), was successively deacetylated and desilylated in high yield to give the desired product 11. This route constitutes a general method of access to glycon-modified doxorubicin analogs. Compound 11 showed high antitumor activity in vivo in the murine P388 lymphocytic leukemia assay. THE JOURNAL OF ANTIBIOTICS AUG.

Research paper thumbnail of Synthesis of linear D-alt-L peptidomimetics starting from a carbohydrate precursor

Proceedings of the 14th Brazilian Meeting on Organic Synthesis Proceedings, 2013

Research paper thumbnail of Efficient Synthesis of Thiolactoside Glycoclusters by Ruthenium-Catalyzed Cycloaddition Reaction of Disubstituted Alkynes on Carbohydrate Scaffolds

European Journal of Organic Chemistry, 2013

Lectin-carbohydrate interactions are responsible for several cellular processes involved in the i... more Lectin-carbohydrate interactions are responsible for several cellular processes involved in the immune system and the development of certain types of cancer. To further understanding of the cellular responses triggered by these interactions, complex carbohydrates are designed and prepared. Here, we describe the synthesis of a family of multivalent glycoclusters based on carbohydrate cores bearing thiolactosides or thiogalactosides as recognition elements with structural valencies ranging from 2 to 8. The synthetic strategy involves a key ruthenium-catalyzed cycloaddition reaction between symmetric disubstituted alkynes bearing two thiosugar units and azide-containing carbohydrate scaffolds. This methodology afforded high-valency glycoconjugates in good to excellent yields. Binding affinities of the synthetic β-thiolactosides for peanut lectin were measured by isothermal titration calorimetry. These titrations revealed micromolar affinities as well as a multivalent effect. A tetravalent glycoconjugate based on a trehalose scaffold displayed the highest binding affinity.

Research paper thumbnail of Non-conventional Glycosidic Linkages: Syntheses and Structures of Thiooligosaccharides and Carbohydrates with Three-bond Glycosidic Connections

Current Organic Chemistry, 2006

Research paper thumbnail of Synthesis of antitumor-active (7S,9S)-4-demethoxy-7-O-(2,6-dideoxy-2-iodo-α-l-mannopyranosyl)adriamycinone: Preparative resolution of a racemic anthracyclinone by alkoxyhalogenation of a glycal

Carbohydrate Research, 1984

Various 2'-halo-3'-hydroxy analogs' of daunorubicin2, doxorubicin' , and 4-demethoxydaunorubicin'... more Various 2'-halo-3'-hydroxy analogs' of daunorubicin2, doxorubicin' , and 4-demethoxydaunorubicin' have demonstrated high antitumor activity in viva, and low cardio-toxicity1. We demonstrate here how L-rhamnal diacetate may be used in oxyio~nation of a derivative of racemic 4-demethoxydaunomy~inone3-5 to resolve the aglycon and furnish the optically pure, crystalline, title compound 6; its 7R,9R isomer (8) was biologically inactive. Racemic Cdemethoxydaunomycinone 3-5 (1) was converted by the general procedure of Smith et al, 6 into its 14-bromo derivative, which was then readily hydrolyzed by aqueous potassium carbonate', or by heating for 0.5-l h at-80' in dimethyl sulfoxide.-water solution, to afford racemic 4-demethoxyadriamyc~one. The latter was then silylated with ~e~#-butylchioro~methyl~lane in ~,~-dimethylformamide in the presence of i~dazole to give racemic 14-O-(terb-butyldimethylsilyl)-4-demethoxyadriamycinone (2) in 54% yield as red crystals** having m.p. 193-195'. Solutions of compound 2 (1.26 mmol) in oxolane and of 3,4-di-O-ace@& rhamnal(1.95 mmol) in acetonitrile were mixed under dry argon, and N-iodosuccinimide (NIS; 2.68 mmol) was added with stirring'. After 3 h, further portions of 3,4-di-Uacetyl-Lrhamnal(1.91 mmol) and ~-iodosucc~imide (2.64 mmol) were added. The reaction was terminated after a further 3 h. Chromatography of the product-mixture on a column of silica gel, with 50: 1 toluene-acetone as the eluant, and crystallization, afforded 27% of (7~9R)-I#~O-(tert-butyldimethylsi~yyl)4-deme~hoxy-7-0-(3,4~i-O-acebyl-2,6-dideoxy-2-iod~cr.L-muPulopyrunrosyl)adTiawaycinone (4) as the less-polar component; m.p. 153"; [rx]:

Research paper thumbnail of L-Glutamic acid and L-alanine derivatives as building blocks for the synthesis of a chiral monomer precursor of AABB-type polyamide

Research paper thumbnail of Synthesis of non-glycosidic 4,6′-thioether-linked disaccharides as hydrolytically stable glycomimetics

Carbohydrate Research, 2007

Michael addition of 1,2:3,4-di-O-isopropylidene-6-thio-alpha-D-galactose (2) to 2-propyl 6-O-acet... more Michael addition of 1,2:3,4-di-O-isopropylidene-6-thio-alpha-D-galactose (2) to 2-propyl 6-O-acetyl-3,4-dideoxy-alpha-D-glycero-hex-3-enopyranosid-2-ulose (1) afforded, as the major diastereoisomer, 2-propyl 6-O-acetyl-3-deoxy-4-S-(6-deoxy-1,2:3,4-di-O-isopropylidene-alpha-D-galactopyranos-6-yl)-4-thio-alpha-D-threo-hexopyranosid-2-ulose (3, 91% yield). Reduction of the carbonyl group of 3, followed by O-deacetylation gave the two epimers 7 (alpha-D-lyxo) and 8 (alpha-D-xylo) in a 1:2 ratio. On removal of the protecting groups of 8 by acid hydrolysis, formation of an 1,6-anhydro bridge was observed in the 3-deoxy-4-thiohexopyranose unit (10). The free non-glycosidic thioether-linked disaccharide 3-deoxy-4-S-(6-deoxy-alpha,beta-D-galactopyranos-6-yl)-4-thio-alpha,beta-D-xylo-hexopyranose (11) was obtained by acetolysis of 10 followed by O-deacetylation. A similar sequence starting from the enone 1 and methyl 2,3,4-tri-O-benzoyl-6-thio-alpha-D-glucopyranoside (12) led successfully to 2-propyl 3-deoxy-4-S-(methyl 6-deoxy-alpha-D-glucopyranos-6-yl)-4-thio-alpha-D-lyxo-hexopyranoside (17) and its alpha-D-xylo analog (19, major product). In this synthetic route, orthogonal sets of protecting groups were employed to preserve the configuration of both reducing ends and to avoid the formation of the 1,6-anhydro ring.

Research paper thumbnail of Synthesis and polymerization of conveniently substituted 6-amino-6-deoxy-D-galactonic acid derivatives

Arkivoc, 2005

Methyl 6-azido-6-deoxy-2,3:4,5-di-O-isopropylidene-D-galactonate (1), prepared in two steps from ... more Methyl 6-azido-6-deoxy-2,3:4,5-di-O-isopropylidene-D-galactonate (1), prepared in two steps from D-galactono-1,4-lactone, was hydrolyzed to the corresponding acid 2, which was esterified with phenol (PhOH) in the presence of dicyclohexylcarbodiimide (DCC) to give the phenyl ester 3. Hydrogenolysis of the azide function of 3 yielded the hydrochloride derivative of the amino acid 4. Compound 4 is conveniently substituted for the polycondensation; therefore, this reaction was conducted using DMF as solvent and N,N-diisopropylethylamine as a basic catalyst. The MALDI-TOF mass spectrum of the isolated product (5) indicated that this was a mixture of the cyclic trimer (M + Na + , 793.7) and linear oligomers (from the tetramer to the tetradecamer). To favor the linear polymerization the dimeric amino acid 10 was prepared starting from 2. Thus, hydrogenation of 2 gave the amino acid 6, and treatment of 2 with pentachlorophenol-DCC gave the pentachlorophenyl ester 7. Coupling of 6 with 7 in the presence of DCC gave the dimer 8, which was converted (PhOH, DCC) into 9. Hydrogenolysis of 9 afforded the dimeric amino acid 10, which was polymerized under the conditions employed for 4. The resulting polyamide 11 was highly soluble in common organic solvents, and its molecular weight was established by MALDI-TOF MS and size exclusion chromatography (M w = 2700).

Research paper thumbnail of Michael Addition of Thiols to Sugar Enones. Synthesis of 3-Deoxy-4-Thiohexopyranosid-2-uloses as Key Precursors of 3-Deoxy- and C-2 Branched-Chain 4-Thiosugars

Australian Journal of Chemistry

Benzyl and 2-propyl 6-O-acetyl-3,4-dideoxy-α -D-glycero-hex-3-enopyranosid-2-uloses (2) and (3) w... more Benzyl and 2-propyl 6-O-acetyl-3,4-dideoxy-α -D-glycero-hex-3-enopyranosid-2-uloses (2) and (3) were readily prepared by the tin(IV) chloride-promoted glycosylation of glycal (1). The enone system of (2) and (3) underwent a highly diastereoselective Michael addition of thiols (ethanethiol, propane-2-thiol, and benzenemethanethiol) to afford the sulfur-containing hexopyranosid-2-ulose derivatives (4a-c) and (5a-c) in good yields. Sodium borohydride reduction of the carbonyl functionalities of (4b,c) and (5b) led to the corresponding 3-deoxy-4-thiohexopyranosides having the D-xylo (6b), (6c), and (8b) or the D-lyxo (7b), (7c), and (8c) configuration. Standard acetylation of these compounds gave the corresponding per-O-acetyl derivatives (10b), (10c), and (12b) and (11b), (11c), and (13b), useful for confirming all the previous configurational assignments by means of their 1H and 13C nuclear magnetic resonance spectra. Furthermore the 2-ulose (5b) proved to be a key intermediate for th...

Research paper thumbnail of Synthesis, Secondary Structure, and Anion Binding of Acyclic Carbohydrate-Derived Oligo(amide-triazole)s

European Journal of Organic Chemistry

A family of linear, carbohydrate-derived oligo(amidetriazole)s has been designed and synthesized.... more A family of linear, carbohydrate-derived oligo(amidetriazole)s has been designed and synthesized. These molecules possess a regular distribution of triazole rings (from one to four) linking the carbohydrate units to give dimer to pentamer derivatives. Their binding to halide anions was qualitatively analyzed by means of NMR spectroscopy and mass spectrometry. All the compounds were able to bind chloride anions, with a stoichiometry that depended on the chain length. The dimer and trimer gave 2:1 host:chloride ratio, while the tetramer and pentamer gave 1:1 complexes. The secondary structure of the oligo(amide-triazole)s was studied using NMR spectroscopy and circular dichroism. These studies showed that the larger host molecules (tetramer and pentamer) adopted a stabilized U-turn and were able to bind just one chloride anion. Only the pentamer displayed a helical conformation, which was slightly distorted in the presence of chloride salts. Interestingly, chloride binding involves not only the triazole-CH but also H atoms from the carbohydrate moieties. These compounds could be applied for chloride sensing by ESI-MS.

Research paper thumbnail of ChemInform Abstract: Synthesis of (2S,4R,5R)-4,5,6-Trihydroxynorleucine and 5- Hydroxynorvaline from Precursors Obtained by an Unusual Rearrangement in a 5,6-Dihydro-2-pyrone

ChemInform

ABSTRACT 2-Acetamido-4,6-O-benzylidene-2,3-dideoxy-d-erythro-hex-2-enono-1,5-lactone (2), readily... more ABSTRACT 2-Acetamido-4,6-O-benzylidene-2,3-dideoxy-d-erythro-hex-2-enono-1,5-lactone (2), readily prepared from d-glucosamine, undergoes a rearrangement on treatment with tin(IV) chloride which leads to 3-acetamido-2-pyrone (3) and 2-acetamido-2,3-dideoxy-4,6-O-formylidene-d-threo-hex-2-enono-1,5-lactone (4). A mechanism is proposed for this unusual rearrangement, which was not observed for other analogous hex-2-enono-1,5-lactones. For example, the 2-acetoxy analog of 2 (2-acetoxy-4,6-O-benzylidene-3-deoxy-d-erythro-hex-2-enono-1,5-lactone, 7) was synthesized and treated with tin(IV) chloride affording 3-acetoxy-6-chloromethyl-2-pyrone (8) as main product. The 2-pyrone derivatives 3 and 4 are convenient precursors for the synthesis of 5-hydroxynorvaline (12) and (2S,4R,5R,)-4,5,6-trihydroxynorleucine (14), respectively. The latter was prepared by diastereoselective hydrogenation of 4, followed by deprotection.

Research paper thumbnail of Internal asymmetric induction by the C-6 substituent on the oxidation reaction of interglycosidic sulfur atom of thiodisaccharides

RSC Adv.

Complete diastereoselectivity was archived in the oxidation of 3-deoxy-S-(1-4)-disaccharides due ... more Complete diastereoselectivity was archived in the oxidation of 3-deoxy-S-(1-4)-disaccharides due to anchimeric assistance of the terminal CH2OH group.

Research paper thumbnail of Synthesis of β-galactosylamides as ligands of the peanut lectin. Insights into the recognition process

Carbohydrate research, Jan 23, 2017

The synthesis of mono and divalent β-galactosylamides linked to a hydroxylated chain having a C2 ... more The synthesis of mono and divalent β-galactosylamides linked to a hydroxylated chain having a C2 symmetry axis derived from l-tartaric anhydride is reported. Reference compounds devoid of hydroxyl groups in the linker were also prepared from β-galactosylamine and succinic anhydride. After functionalization with an alkynyl residue, the resulting building blocks were grafted onto different azide-equipped scaffolds through the copper catalyzed azide-alkyne cycloaddition. Thus, a family of structurally related mono and divalent β-N-galactopyranosylamides was obtained and fully characterized. The binding affinities of the ligands towards the model lectin PNA were measured by the enzyme-linked lectin assay (ELLA). The IC50 values were significantly higher than that of galactose but the presence of hydroxyl groups in the aglycone chain improved lectin recognition. Docking and molecular dynamics experiments were in accordance with the hypothesis that a hydroxyl group properly disposed in th...

Research paper thumbnail of Synthesis of Enantiomeric Polyhydroxyalkylpyrrolidines from 1,3-Dipolar Cycloadducts. Evaluation as Inhibitors of a β-Galactofuranosidase

Journal of Organic Chemistry, May 10, 2016

Research paper thumbnail of Synthesis of a New Chiral Bis-Arsine Ligand Based on Natural Carbohydrates

Proceedings of the 15th Brazilian Meeting on Organic Synthesis Proceedings, 2013

Research paper thumbnail of Design and Synthesis of 2-Acetamido-2,3-dideoxythiodisaccharides via Diastereoselective Conjugate Addition to Sugar Enone O-Acetyl Oximes. Galactosidase Inhibition Studies

Organic Letters, 2018

The key step in a new synthesis of 2-acetamido-2,3-dideoxy-(1→4)-thiodisaccharides was the conjug... more The key step in a new synthesis of 2-acetamido-2,3-dideoxy-(1→4)-thiodisaccharides was the conjugate addition of a 1-thiogalactose derivative to E and Z acetyl oximes derived from sugar enones. This reaction was shown to be completely diastereoselective for both the formation of the thioglycosidic linkage and the configuration of acetyl oxime. The thiodisaccharides have been designed as inhibitors of the β-galactosidase from E. coli, and they have been shown to successfully meet such requirements.

Research paper thumbnail of Non-Conventional Glycosidic Linkages: Syntheses and Structures of Thiooligosaccharides and Carbohydrates with Three-Bond Glycosidic Connections

Research paper thumbnail of Synthesis, characterization and chemical degradation of poly(ester-triazole)s derived from d-galactose

RSC Advances, 2019

Carbohydrate-derived poly(ester-triazoles), soluble in organic solvents and degradable in aqueous... more Carbohydrate-derived poly(ester-triazoles), soluble in organic solvents and degradable in aqueous media, have been synthesized by CuAAC or thermal polymerization.

Research paper thumbnail of Photooxidation of thiosaccharides mediated by sensitizers in aerobic and environmentally friendly conditions

RSC Advances, 2021

An environmentally friendly and simple sensitized photooxidation methodology to obtain glycosyl s... more An environmentally friendly and simple sensitized photooxidation methodology to obtain glycosyl sulfoxides with outstanding chemoselectivity in aerobic conditions is described.

Research paper thumbnail of Synthesis and antitumor activity of anthracycline disaccharide glycosides containing daunosamine

The Journal of Antibiotics, 1993

Daunosamine, as its 4-0-acetyl-3-JV-trin'uoroacetyl glycosyl chloride derivative (lb), has been c... more Daunosamine, as its 4-0-acetyl-3-JV-trin'uoroacetyl glycosyl chloride derivative (lb), has been coupled a-L-glycosidically to the 3-and 4-mono-O-acetyl derivatives of L-rhamnal to afford disaccharide glycal derivatives, whose conversion into the corresponding 2-deoxyglycosides by sequential alkoxyiodination-tributylstannane reduction has been evaluated. The sequence successfully demonstrated with the methyl glycosides was successfully extended with daunomycinone as the aglycon, providing a preparative route to 7-O-[3-O-(3-amino-2,3,6-trideoxy-a-L-(y.x0hexopyranosyl)-2,6-dideoxy-a-L-flra6mo-hexopyranosyl]daunomycinone hydrochloride (15), an analogue of natural anthracycline antibiotics containing daunosamineand a 2,6-dideoxy-L-hexose. Most of the natural anthracycline antibiotics with oligosaccharide side chains, as in the rhodomycin and cinerubin series, contain daunosamine as the sugar directly attached to the anthracyclinone and are of interest as antitumor agents1*. Only in a few cases, daunosamine appears as the non reducing terminal sugar2>3). These compounds also showed high degree of antitumor activity. As part of our program to obtain new anthracycline antibiotics, we decided to synthesize derivatives having daunosamine as the terminal non reducing sugar, in order to compare their biological activity with the natural products, and to be able to make conclusions about the importance of the sequence of sugars in the oligosaccharide side chain. Synthetic analogs of daunorubicin and doxorubicin have been extensively investigated in our laboratory4'5). Conventional Koenigs-Knorr coupling between daunomycinone or 14-protected adriamycinone and appropriate glycosyl halides is sometimes complicated by low yields and mixtures of anomers. An alternative two-step synthesis6) offers significant advantage. The first step involves

Research paper thumbnail of Synthesis and antitumor activity of 3'-deamino-3'-hydroxydoxorubicin. A facile procedure for the preparation of doxorubicin analogs

The Journal of Antibiotics, 1984

Two successful routes have been developed for preparation of 3'-deamino-3'-hydroxydoxorubicin (11... more Two successful routes have been developed for preparation of 3'-deamino-3'-hydroxydoxorubicin (11), based on protection of the 14-hydroxyl group of the aglycon by using tertbutylchlorodimethylsilane. The key intermediate, 14-O-tert-butyldimethylsilyl-7-O-(3,4-di-Oacetyl-2,6-dideoxy-n-L-lyxo-hexopyranosyl)adriamycinone (9), was successively deacetylated and desilylated in high yield to give the desired product 11. This route constitutes a general method of access to glycon-modified doxorubicin analogs. Compound 11 showed high antitumor activity in vivo in the murine P388 lymphocytic leukemia assay. THE JOURNAL OF ANTIBIOTICS AUG.

Research paper thumbnail of Synthesis of linear D-alt-L peptidomimetics starting from a carbohydrate precursor

Proceedings of the 14th Brazilian Meeting on Organic Synthesis Proceedings, 2013

Research paper thumbnail of Efficient Synthesis of Thiolactoside Glycoclusters by Ruthenium-Catalyzed Cycloaddition Reaction of Disubstituted Alkynes on Carbohydrate Scaffolds

European Journal of Organic Chemistry, 2013

Lectin-carbohydrate interactions are responsible for several cellular processes involved in the i... more Lectin-carbohydrate interactions are responsible for several cellular processes involved in the immune system and the development of certain types of cancer. To further understanding of the cellular responses triggered by these interactions, complex carbohydrates are designed and prepared. Here, we describe the synthesis of a family of multivalent glycoclusters based on carbohydrate cores bearing thiolactosides or thiogalactosides as recognition elements with structural valencies ranging from 2 to 8. The synthetic strategy involves a key ruthenium-catalyzed cycloaddition reaction between symmetric disubstituted alkynes bearing two thiosugar units and azide-containing carbohydrate scaffolds. This methodology afforded high-valency glycoconjugates in good to excellent yields. Binding affinities of the synthetic β-thiolactosides for peanut lectin were measured by isothermal titration calorimetry. These titrations revealed micromolar affinities as well as a multivalent effect. A tetravalent glycoconjugate based on a trehalose scaffold displayed the highest binding affinity.

Research paper thumbnail of Non-conventional Glycosidic Linkages: Syntheses and Structures of Thiooligosaccharides and Carbohydrates with Three-bond Glycosidic Connections

Current Organic Chemistry, 2006

Research paper thumbnail of Synthesis of antitumor-active (7S,9S)-4-demethoxy-7-O-(2,6-dideoxy-2-iodo-α-l-mannopyranosyl)adriamycinone: Preparative resolution of a racemic anthracyclinone by alkoxyhalogenation of a glycal

Carbohydrate Research, 1984

Various 2'-halo-3'-hydroxy analogs' of daunorubicin2, doxorubicin' , and 4-demethoxydaunorubicin'... more Various 2'-halo-3'-hydroxy analogs' of daunorubicin2, doxorubicin' , and 4-demethoxydaunorubicin' have demonstrated high antitumor activity in viva, and low cardio-toxicity1. We demonstrate here how L-rhamnal diacetate may be used in oxyio~nation of a derivative of racemic 4-demethoxydaunomy~inone3-5 to resolve the aglycon and furnish the optically pure, crystalline, title compound 6; its 7R,9R isomer (8) was biologically inactive. Racemic Cdemethoxydaunomycinone 3-5 (1) was converted by the general procedure of Smith et al, 6 into its 14-bromo derivative, which was then readily hydrolyzed by aqueous potassium carbonate', or by heating for 0.5-l h at-80' in dimethyl sulfoxide.-water solution, to afford racemic 4-demethoxyadriamyc~one. The latter was then silylated with ~e~#-butylchioro~methyl~lane in ~,~-dimethylformamide in the presence of i~dazole to give racemic 14-O-(terb-butyldimethylsilyl)-4-demethoxyadriamycinone (2) in 54% yield as red crystals** having m.p. 193-195'. Solutions of compound 2 (1.26 mmol) in oxolane and of 3,4-di-O-ace@& rhamnal(1.95 mmol) in acetonitrile were mixed under dry argon, and N-iodosuccinimide (NIS; 2.68 mmol) was added with stirring'. After 3 h, further portions of 3,4-di-Uacetyl-Lrhamnal(1.91 mmol) and ~-iodosucc~imide (2.64 mmol) were added. The reaction was terminated after a further 3 h. Chromatography of the product-mixture on a column of silica gel, with 50: 1 toluene-acetone as the eluant, and crystallization, afforded 27% of (7~9R)-I#~O-(tert-butyldimethylsi~yyl)4-deme~hoxy-7-0-(3,4~i-O-acebyl-2,6-dideoxy-2-iod~cr.L-muPulopyrunrosyl)adTiawaycinone (4) as the less-polar component; m.p. 153"; [rx]:

Research paper thumbnail of L-Glutamic acid and L-alanine derivatives as building blocks for the synthesis of a chiral monomer precursor of AABB-type polyamide

Research paper thumbnail of Synthesis of non-glycosidic 4,6′-thioether-linked disaccharides as hydrolytically stable glycomimetics

Carbohydrate Research, 2007

Michael addition of 1,2:3,4-di-O-isopropylidene-6-thio-alpha-D-galactose (2) to 2-propyl 6-O-acet... more Michael addition of 1,2:3,4-di-O-isopropylidene-6-thio-alpha-D-galactose (2) to 2-propyl 6-O-acetyl-3,4-dideoxy-alpha-D-glycero-hex-3-enopyranosid-2-ulose (1) afforded, as the major diastereoisomer, 2-propyl 6-O-acetyl-3-deoxy-4-S-(6-deoxy-1,2:3,4-di-O-isopropylidene-alpha-D-galactopyranos-6-yl)-4-thio-alpha-D-threo-hexopyranosid-2-ulose (3, 91% yield). Reduction of the carbonyl group of 3, followed by O-deacetylation gave the two epimers 7 (alpha-D-lyxo) and 8 (alpha-D-xylo) in a 1:2 ratio. On removal of the protecting groups of 8 by acid hydrolysis, formation of an 1,6-anhydro bridge was observed in the 3-deoxy-4-thiohexopyranose unit (10). The free non-glycosidic thioether-linked disaccharide 3-deoxy-4-S-(6-deoxy-alpha,beta-D-galactopyranos-6-yl)-4-thio-alpha,beta-D-xylo-hexopyranose (11) was obtained by acetolysis of 10 followed by O-deacetylation. A similar sequence starting from the enone 1 and methyl 2,3,4-tri-O-benzoyl-6-thio-alpha-D-glucopyranoside (12) led successfully to 2-propyl 3-deoxy-4-S-(methyl 6-deoxy-alpha-D-glucopyranos-6-yl)-4-thio-alpha-D-lyxo-hexopyranoside (17) and its alpha-D-xylo analog (19, major product). In this synthetic route, orthogonal sets of protecting groups were employed to preserve the configuration of both reducing ends and to avoid the formation of the 1,6-anhydro ring.

Research paper thumbnail of Synthesis and polymerization of conveniently substituted 6-amino-6-deoxy-D-galactonic acid derivatives

Arkivoc, 2005

Methyl 6-azido-6-deoxy-2,3:4,5-di-O-isopropylidene-D-galactonate (1), prepared in two steps from ... more Methyl 6-azido-6-deoxy-2,3:4,5-di-O-isopropylidene-D-galactonate (1), prepared in two steps from D-galactono-1,4-lactone, was hydrolyzed to the corresponding acid 2, which was esterified with phenol (PhOH) in the presence of dicyclohexylcarbodiimide (DCC) to give the phenyl ester 3. Hydrogenolysis of the azide function of 3 yielded the hydrochloride derivative of the amino acid 4. Compound 4 is conveniently substituted for the polycondensation; therefore, this reaction was conducted using DMF as solvent and N,N-diisopropylethylamine as a basic catalyst. The MALDI-TOF mass spectrum of the isolated product (5) indicated that this was a mixture of the cyclic trimer (M + Na + , 793.7) and linear oligomers (from the tetramer to the tetradecamer). To favor the linear polymerization the dimeric amino acid 10 was prepared starting from 2. Thus, hydrogenation of 2 gave the amino acid 6, and treatment of 2 with pentachlorophenol-DCC gave the pentachlorophenyl ester 7. Coupling of 6 with 7 in the presence of DCC gave the dimer 8, which was converted (PhOH, DCC) into 9. Hydrogenolysis of 9 afforded the dimeric amino acid 10, which was polymerized under the conditions employed for 4. The resulting polyamide 11 was highly soluble in common organic solvents, and its molecular weight was established by MALDI-TOF MS and size exclusion chromatography (M w = 2700).

Research paper thumbnail of Michael Addition of Thiols to Sugar Enones. Synthesis of 3-Deoxy-4-Thiohexopyranosid-2-uloses as Key Precursors of 3-Deoxy- and C-2 Branched-Chain 4-Thiosugars

Australian Journal of Chemistry

Benzyl and 2-propyl 6-O-acetyl-3,4-dideoxy-α -D-glycero-hex-3-enopyranosid-2-uloses (2) and (3) w... more Benzyl and 2-propyl 6-O-acetyl-3,4-dideoxy-α -D-glycero-hex-3-enopyranosid-2-uloses (2) and (3) were readily prepared by the tin(IV) chloride-promoted glycosylation of glycal (1). The enone system of (2) and (3) underwent a highly diastereoselective Michael addition of thiols (ethanethiol, propane-2-thiol, and benzenemethanethiol) to afford the sulfur-containing hexopyranosid-2-ulose derivatives (4a-c) and (5a-c) in good yields. Sodium borohydride reduction of the carbonyl functionalities of (4b,c) and (5b) led to the corresponding 3-deoxy-4-thiohexopyranosides having the D-xylo (6b), (6c), and (8b) or the D-lyxo (7b), (7c), and (8c) configuration. Standard acetylation of these compounds gave the corresponding per-O-acetyl derivatives (10b), (10c), and (12b) and (11b), (11c), and (13b), useful for confirming all the previous configurational assignments by means of their 1H and 13C nuclear magnetic resonance spectra. Furthermore the 2-ulose (5b) proved to be a key intermediate for th...

Research paper thumbnail of Synthesis, Secondary Structure, and Anion Binding of Acyclic Carbohydrate-Derived Oligo(amide-triazole)s

European Journal of Organic Chemistry

A family of linear, carbohydrate-derived oligo(amidetriazole)s has been designed and synthesized.... more A family of linear, carbohydrate-derived oligo(amidetriazole)s has been designed and synthesized. These molecules possess a regular distribution of triazole rings (from one to four) linking the carbohydrate units to give dimer to pentamer derivatives. Their binding to halide anions was qualitatively analyzed by means of NMR spectroscopy and mass spectrometry. All the compounds were able to bind chloride anions, with a stoichiometry that depended on the chain length. The dimer and trimer gave 2:1 host:chloride ratio, while the tetramer and pentamer gave 1:1 complexes. The secondary structure of the oligo(amide-triazole)s was studied using NMR spectroscopy and circular dichroism. These studies showed that the larger host molecules (tetramer and pentamer) adopted a stabilized U-turn and were able to bind just one chloride anion. Only the pentamer displayed a helical conformation, which was slightly distorted in the presence of chloride salts. Interestingly, chloride binding involves not only the triazole-CH but also H atoms from the carbohydrate moieties. These compounds could be applied for chloride sensing by ESI-MS.

Research paper thumbnail of ChemInform Abstract: Synthesis of (2S,4R,5R)-4,5,6-Trihydroxynorleucine and 5- Hydroxynorvaline from Precursors Obtained by an Unusual Rearrangement in a 5,6-Dihydro-2-pyrone

ChemInform

ABSTRACT 2-Acetamido-4,6-O-benzylidene-2,3-dideoxy-d-erythro-hex-2-enono-1,5-lactone (2), readily... more ABSTRACT 2-Acetamido-4,6-O-benzylidene-2,3-dideoxy-d-erythro-hex-2-enono-1,5-lactone (2), readily prepared from d-glucosamine, undergoes a rearrangement on treatment with tin(IV) chloride which leads to 3-acetamido-2-pyrone (3) and 2-acetamido-2,3-dideoxy-4,6-O-formylidene-d-threo-hex-2-enono-1,5-lactone (4). A mechanism is proposed for this unusual rearrangement, which was not observed for other analogous hex-2-enono-1,5-lactones. For example, the 2-acetoxy analog of 2 (2-acetoxy-4,6-O-benzylidene-3-deoxy-d-erythro-hex-2-enono-1,5-lactone, 7) was synthesized and treated with tin(IV) chloride affording 3-acetoxy-6-chloromethyl-2-pyrone (8) as main product. The 2-pyrone derivatives 3 and 4 are convenient precursors for the synthesis of 5-hydroxynorvaline (12) and (2S,4R,5R,)-4,5,6-trihydroxynorleucine (14), respectively. The latter was prepared by diastereoselective hydrogenation of 4, followed by deprotection.

Research paper thumbnail of Internal asymmetric induction by the C-6 substituent on the oxidation reaction of interglycosidic sulfur atom of thiodisaccharides

RSC Adv.

Complete diastereoselectivity was archived in the oxidation of 3-deoxy-S-(1-4)-disaccharides due ... more Complete diastereoselectivity was archived in the oxidation of 3-deoxy-S-(1-4)-disaccharides due to anchimeric assistance of the terminal CH2OH group.

Research paper thumbnail of Synthesis of β-galactosylamides as ligands of the peanut lectin. Insights into the recognition process

Carbohydrate research, Jan 23, 2017

The synthesis of mono and divalent β-galactosylamides linked to a hydroxylated chain having a C2 ... more The synthesis of mono and divalent β-galactosylamides linked to a hydroxylated chain having a C2 symmetry axis derived from l-tartaric anhydride is reported. Reference compounds devoid of hydroxyl groups in the linker were also prepared from β-galactosylamine and succinic anhydride. After functionalization with an alkynyl residue, the resulting building blocks were grafted onto different azide-equipped scaffolds through the copper catalyzed azide-alkyne cycloaddition. Thus, a family of structurally related mono and divalent β-N-galactopyranosylamides was obtained and fully characterized. The binding affinities of the ligands towards the model lectin PNA were measured by the enzyme-linked lectin assay (ELLA). The IC50 values were significantly higher than that of galactose but the presence of hydroxyl groups in the aglycone chain improved lectin recognition. Docking and molecular dynamics experiments were in accordance with the hypothesis that a hydroxyl group properly disposed in th...