Synthesis of biantennary LacNAc-linked O-glycan (core 4) and glycopeptide thioester by benzyl protection strategy: rapid zinc reduction of GlcNTCA to GlcNAc by microwave irradiation

A synthetic method for the core 4 O-glycan-linked Ser and Thr was developed. Highly stereoselective 3-O- and 6-O-glycosylation was achieved by using two distinctively protected N-trichloroacetyllactosaminyl fluorides (3 and 12). Microwave-assisted Zn reduction rapidly and efficiently converted N-trichloroacetylglucosamine (GlcNTCA) to N-acetylglucosamine (GlcNAc). In order to demonstrate the usefulness of the protected core 4 O-glycan a segment (Gly³⁴-Gly⁵⁸) of emmprin (extracellular matrix metalloproteinase inducer), a cancer metastasis-related glycoprotein, was synthesized by the solid-phase method, utilizing the pentasaccharyl Thr (2) to introduce an O-glycan in place of the native N-glycan at Asn⁴⁴.     

Convergent synthesis of the tetrasaccharide repeating unit related to the O-antigenic polysaccharide of Escherichia coli 78

A convergent synthesis of the tetrasaccharide repeating unit of the O-antigenic cell wall polysaccharide of Escherichia coli 78, as the corresponding methyl glycoside (I), is being reported. It involved stereoselective glycosidation of a β-linked mannodisaccharide acceptor with a β-linked glucosamine based disaccharide thioglycoside donor, which were prepared from the corresponding functionalised monosaccharide based glycosyl donors and acceptors. The resulting tetrasaccharide derivative was finally converted to (I) by selective deprotection and also by global protection and deprotection techniques.     

New derivatives of trifluoroacetyl acetaldehyde and trifluoroaldol

The reaction of β-ethoxyvinyl trifluoromethyl ketone 1 with O-nucleophiles such as alcohols and diols leads to various derivatives of trifluoroacetyl acetaldehyde, such as β-alkoxyvinyl trifluoromethyl ketones 3 and cyclic keto acetals 4. Several derivatives synthesized contain chiral auxiliaries. Reduction of the compounds 1, 3, 4 under various reaction conditions leads to the trifluoroaldol derivatives 6, 7, 9, 10 containing a protected aldehyde group. The compounds obtained are useful building blocks in fluoroorganic synthesis.     

Solid-phase synthesis of glycopeptide carrying a tetra-N-acetyllactosamine-containing core 2 decasaccharide

A novel synthesis of tetralactosaminyl O-glycoamino acid is described. The stereoselective assemblage of a lactosaminyl unit was performed by 2-trichloroacetamido group-assisted β-glycosylation. Initial investigation into the synthesis of decasaccharyl threonine 2 showed limited success because of the low yield in the step concerning the removal of 4-O-chloroacetyl groups. In contrast, 4-O-benzylated decasaccharyl threonine 50 was efficiently synthesized from key LacNAc derivative 35 carrying a 3-O-allyl protecting group at the Gal residue by reiterative glycosylation using the (N-phenyl)trifluoroacetimidate method. Decasaccharide 50 was used as a building block in the solid-phase synthesis of a MUC1-related glycopeptide. Synthetic glycopeptide was obtained through two acidic processes: cleavage from resin with reagent K at a lowered temperature and debenzylation with a diluted cocktail of low-acidity TfOH. Desired glycopeptide 54 was isolated as the major product, while a series of the saccharide-shortened minor products were generated due to the acid-labile property of the β-GlcNAc glycosidic linkages.     

A general method for the synthesis of oligosaccharides consisting of α-(1→2)- and α-(1→3)-linked rhamnan backbones and GlcNAc side chains

A general method has been developed for the synthesis of oligosaccharides consisting of (1→2)- and (1→3)-linked rhamnans with GlcNAc side chains. As examples, highly effective and convergent syntheses of two decasaccharides in the O polysaccharide moiety of the lipopolysaccharide of the phytopathogenic bacterium Pseudomonas syringae pv. ribicola NCPPB 1010 were achieved. The two decasaccharides consist of O polysaccharide repeating units I+II and II+I, respectively. Allyl 3-O-acetyl-4-O-benzoyl-α-l-rhamnopyranoside, allyl 2-O-benzoyl-3-O-chloroacetyl-α-l-rhamnopyranoside, 2,4-di-O-benzoyl-3-O-chloroacetyl-α-l-rhamnopyranosyl trichloroacetimidate, and 3-O-acetyl-2,4-di-O-benzoyl-α-l-rhamnopyranosyl trichloroacetimidate, which were obtained by highly regioselective 3-O-acylations, were used as the key synthons to obtain the required α-(1→2)- and α-(1→3)-linked rhamnoocta saccharide acceptors with 3³- and 3⁷-free hydroxyl groups. Therefore, several disaccharides were synthesized, from which tetrasaccharides and hexasaccharides were then synthesized. Coupling of the hexasaccharide donors with the disaccharide acceptors gave the octasaccharide acceptors. Finally, the coupling of 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-d-glucopyranosyl trichloroacetimidate with the octasaccharide acceptors, followed by deprotection, afforded the two target decasaccharides. A repeating hexasaccharide unit of the cell wall polysaccharide of β-hemolytic Streptococci Group A was also synthesized in a similar way.     

Synthesis of 3,4-di-O-acylated glucose-derived furanoid sugar amino acids (Gaa): conformational analysis of a Leu-enkephalin analog containing di-O-myristoylated Gaa

3,4-Di-O-acylated derivatives 1-3 of a glucose-derived furanoid sugar amino acid (Gaa) were synthesized as novel peptide building blocks to study their effects on peptide conformation. Structural analysis of the di-O-myristoylated Gaa 3-containing Leu-enkephalin analog 4 by various NMR techniques and constrained molecular dynamics (MD) simulation studies established a well-defined β-turn structure in DMSO-d₆ with an intramolecular hydrogen bond between PheNH → TyrCO.     

Solid-phase synthesis of core 2 O-linked glycopeptide and its enzymatic sialylation

The core 2-type tetrasaccharide building blocks (1a/1b) for solid-phase synthesis of glycopeptide were synthesized via stereoselective glycosylation of the disaccharyl Ser/Thr (3a/3b) with a glycosyl fluoride (2) carrying the 2-trichloroacetamido group that was readily converted into a 2-acetamido group by reduction. A segment of glycoprotein leukosialin (215-224) was synthesized by the solid-phase protocol, the building block (1b) being utilized. Cleavage of the synthetic glycopeptide from resin was effected with reagent K and subsequent treatment of the product with a cocktail for the ‘low-acidity TfOH’ facilitated complete removal of the benzyl groups with minimum loss of glycosidic linkages. To the deprotected glycopeptide (21), were enzymatically introduced N-acetylneuraminic acid (sialic acid) residues in remarkably high efficiency by using the specific sialyltransferases.     

Synthetic studies of erythromycin derivatives: 6-O-methylation of (9S)-12,21-anhydro-9-dihydroerythromycin A derivatives

Synthetic studies on methylation of erythromycin derivatives were conducted. Methylation of 6 resulted in the formation of the C-3′ quaternary ammonium salts with a rate faster than 6-O-methylation. In dipolar aprotic solvent and under strong base conditions, 6-O-methylation, C-3′ quaternary ammonium salts formation and 2-C-methylation proceeded simultaneously to yield a mixture of three different products 7, 8 and 9. The quaternary ammonium salts were converted back to the corresponding tertiary amines 2, 10 and starting material 6 by employing sodium 4-pyridinethiolate as a N-demethylation reagent. The 6-O-methylation was eventually achieved in a good yield when a carbobenzyloxy (Cbz) group was utilized to protect the C-3′-dimethylamino group of 4. In this report, we will discuss the details of different reaction courses in the methylation of (9S)-12, 21-anhydro-9-dihydroerythromycin A derivatives.     

A convenient synthesis of the core trisaccharide of the N-glycans

A convenient synthesis of the core trisaccharide of the N-glycans was described. Orthogonal one-pot glycosylation of three monosaccharide building blocks was performed to furnish β-glucosyl chitobiose, which was then transformed to β-mannosyl chitobiose by intramolecular epimerization of the C-2 position of the β-glucoside. The key glucosyl donor 7c with differentiated 2,3-OH was prepared following the 4,6-O-benzylidene-protected 1,2-orthoester strategy.     

A versatile approach to pyrrolidine azasugars and homoazasugars based on a highly diastereoselective reductive benzyloxymethylation of protected tartarimide

A highly diastereoselective synthesis of enantio-enriched all trans-3,4-dibenzyloxyl-5-benzyloxymethyl-2-pyrrolidinone 13a was developed based on SmI₂-mediated benzyloxymethylation of O,O′-dibenzyltartarimide. The versatility of 13a and its antipode as the key building blocks for the asymmetric synthesis of pyrrolidine azasugars and homoazasugars has been demonstrated by elaborating them into naturally occurring DAB 1 (1), LAB 1 (2), N-hydroxyethyl-DAB 1 (4), 6-deoxy-DMDP 7, and 5-epi-radicamine B 36 as well as the reductive ring-opening product 35.     

Phosphoramidite building blocks for efficient incorporation of 2′-O-aminoethoxy(and propoxy)methyl nucleosides into oligonucleotides

A simple and efficient method for the preparation of eight phosphoramidite building blocks for incorporation of 2′-O-(2-aminoethoxymethyl)ribonucleosides and 2′-O-(3-aminopropoxymethyl)ribonucleosides into synthetic oligonucleotides has been developed. The synthetic routes are maximally convergent and provide sufficient amounts of phosphoramidites for several solid-phase synthesis coupling reactions. Using acyclic derivatives 17a,b the overall yields of phosphoramidites 2 and 3 were increased up to 50% for pyrimidine nucleosides and up to 30% for purine derivatives with substantial decrease of total reaction steps. The 2′-O-substituent was found to be stable during oligonucleotide synthesis. The resulting oligonucleotides are of particular interest for post-synthetic functionalization and conjugation.     

Rhodium(I) complexes with κP coordinated ω-phosphinofunctionalized alkyl phenyl sulfide, sulfoxide and sulfone ligands and their reactions with sodium bis(trimethylsilyl)amide and Ag[BF4]

Reactions of ω-diphenylphosphinofunctionalized alkyl phenyl sulfides Ph₂P(CH₂)_nSPh (n = 1, 1a; 2, 2a; 3, 3a), sulfoxides Ph₂P(CH₂)_nS(O)Ph (n = 1, 1b; 2, 2b; 3, 3b) and sulfones Ph₂P(CH₂)_nS(O)₂Ph (n = 1, 1c; 2, 2c; 3, 3c) with dinuclear chlorido bridged rhodium(I) complexes [(RhL₂)₂(μ-Cl)₂] (L₂ = cycloocta-1.5-diene, cod, 4; bis(diphenylphosphino)ethane, dppe, 5) afforded mononuclear Rh(I) complexes of the type [RhCl{Ph₂P(CH₂)_nS(O)_xPh-κP}(cod)]¹ (n/x = 1/0, 6a; 1/1, 6b; 1/2, 6c; 2/0, 8a; 2/1, 8b; 2/2, 8c; 3/0, 10a; 3/1, 10b; 3/2, 10c) and [RhCl{Ph₂P(CH₂)_nS(O)_xPh-κP}(dppe)] (n/x = 1/0, 7a; 1/1, 7b; 1/2, 7c; 2/0, 9a; 2/1, 9b; 2/2, 9c; 3/0, 11a; 3/1, 11b; 3/2, 11c) having the P^S(O)_x ligands κP coordinated. Addition of Ag[BF₄] to complexes 6-11 in CH₂Cl₂ led with precipitation of AgCl to cationic rhodium complexes of the type [Rh{Ph₂P(CH₂)_nS(O)_xPh-κP,κS/O}L₂][BF₄] having bound the P^S(O)_x ligands bidentately in a κP,κS (13a-18a, 15b-18b) or a κP,κO (13b, 14b, 13c-18c) coordination mode. Unexpectedly, the addition of Ag[BF₄] to 6a in THF afforded the trinuclear cationic rhodium(I) complex [Rh₃(μ-Cl)(μ-Ph₂PCH₂SPh-κP:κS)₄][BF₄]₂·4THF (12·4THF) with a four-membered Rh₃Cl ring as basic framework. Addition of sodium bis(trimethylsilyl)amide to complexes 6-11 led to a selective deprotonation of the carbon atom neighbored to the S(O)_x group (α-C) yielding three different types of organorhodium complexes: a) Organorhodium intramolecular coordination compounds of the type [Rh{CH{S(O)_xPh}CH₂CH₂PPh₂-κC,κP}L₂] (22a-c, 23a-c), b) zwitterionic complexes [Rh{Ph₂PCHS(O)_xPh-κP,κS/O}L₂] having κP,κS (21a, 21b) and κP,κO (20b/c, 21c) coordinated anionic [Ph₂PCHS(O)_xPh] ligands, and c) the dinuclear rhodium(I) complex [{Rh{μ-CH(SPh)PPh₂-κC:κP}(cod)}₂] (19). All complexes were fully characterized spectroscopically and complexes 15b, 15c, 12·4THF and 19·THF additionally by X-ray diffraction analysis. DFT calculations of zwitterionic complexes gave insight into the coordination mode of the [Ph₂PCHS(O)Ph] ligand (κP,κS versus κP,κO).     

Addition of secondary phosphines to N-vinylpyrroles

Secondary phosphines 1-3 react readily with N-vinylpyrroles 4 and 5 under radical initiation to give regiospecifically anti-Markovnikov adducts, diorganyl-2-(1-pyrrolyl)ethylphosphines 6a-d, highly reactive building blocks for organic synthesis, in 88-91% yields.     

Synthesis and characterization of new Rh complexes bearing CO, PPh3 and chelating P,O- or Se,Se-ligands: Application to hydroformylation of styrene

The complexes [Rh(CO)(PPh₃){Ph₂PNP(O)Ph₂-P,O}] (3), [Rh(CO)₂{Ph₂P(Se)NP(Se)Ph₂-Se,Se′}] (5), and [Rh(CO)(PPh₃){Ph₂P(Se)NP(Se)Ph₂-Se,Se′}] (6), were synthesised by stepwise reactions of CO and PPh₃ with [Rh(cod){Ph₂PNP(O)Ph₂-P,O}] (2) and [Rh(cod){Ph₂P(Se)NP(Se)Ph₂-Se,Se′}] (4), respectively. The complexes 3, 5 and 6 have been studied by IR, as well as ¹H and ³¹P NMR spectroscopy. The ν(CO) bands of complexes 3 and 6 appear at approximately 1960 cm⁻¹, indicating high electron density at the Rh^I centre. The structure of complexes 3 and 6 has been determined by X-ray crystallography, and the ³¹P NMR chemical shifts have been resolved via low temperature NMR experiments. Both complexes exhibit square planar geometry around the metal centre, with the five-membered ring of complex 3 being almost planar, and the six-membered ring of complex 6 adopting a slightly distorted boat conformation. The C-O bond of the carbonyl ligand is relatively weak in both complexes, due to strong π-back donation from the electron rich Rh^I centre. The catalytic activity of the complexes 2, 3 and 6 in the hydroformylation of styrene has been investigated. Complexes 2 and 3 showed satisfactory catalytic properties, whereas complex 6 had effectively no catalytic activity.     

Isolation of key intermediates during formation of oolongtheanins

Oolongtheanin-3′-O-gallate (2b) was obtained by treatment of (−)-EGCg (1d) with CuCl₂. This transformation was achieved over three steps, with the isolation of two intermediates; their chemical structures were determined through derivatization reactions, MS, and 1D/2D NMR techniques. One intermediate was identified as dehydrotheasinensin A (3); the other was identified as the novel dimer pro-oolongtheanin-3′-O-gallate (6). Compound 3 was converted to 6 by heating in aprotic solvent, and compound 6 was converted to 2b by addition of water.     

Synthesis of branched tri- to pentasaccharides representative of fragments of Shigella flexneri serotypes 3a and/or X O-antigens

Fragments of the {2)-[α-d-Glcp-(1→3)]-α-l-Rhap-(1→2)-α-l-Rhap-(1→3)-[Ac→2]-α-l-Rhap-(1→3)-β-d-GlcpNAc-(1→}_n ((E)AB_AcCD)_n polymer were synthesized. D(E)A, CD(E)A, _AcCD(E)A were obtained according to a linear strategy, whereas BCD(E)A and B_AcCD(E)A were derived from the condensation of appropriate BC and D(E)A building blocks. Oligosaccharides were synthesized as their propyl glycoside, relying on (i) the efficient trichloroacetimidate chemistry, (ii) a common EA allyl glycoside, and (iii) a 2-trichloroacetamido-d-glucopyranose precursor to residue D. Final Pd/C-mediated deprotection, run under a high pressure of hydrogen, ensured O-acetyl stability. All targets are parts of the O-antigen of Shigella flexneri 3a, a prevalent serotype. Non-O-acetylated oligosaccharides are shared by the S. flexneri serotype X O-antigen.     

Regioselective synthesis of triiodo-o-carboranes and tetraiodo-o-carborane

3,6-Diiodo-o-carborane 3, 3,6,9-triiodo-o-carborane 5, 3,9,12-triiodo-o-carborane 6 and 3,6,9,12-tetraiodo-o-carborane 7, which are suitable building blocks for supramolecular assemblies and carboracycles, were regioselectively synthesized by means of electrophilic iodination and introduction of iodine atoms via reconstruction of the o-carborane cage.     

Organofluorine compounds and fluorinating agents

Starting with 1,2,4,6-tetra-O-acetyl-3-O-dodecyl-β-d-glucose (1), mixed alkyl-perfluoroalkyl substituted sugar derivatives with an anomeric perfluoroalkylthio group and an O-alkyl group in the 3 position were synthesized via 2,4,6-tri-O-acetyl-3-O-dodecyl-1-thio-β-d-glucose (4). The latter was S-perfluorohexylated with 1-iodoperfluorohexane in a dithionite initiated reaction yielding perfluorohexyl 2,4,6-tri-O-acetyl-3-O-dodecyl-1-thio-β-d-glucopyranoside (5). Experiments with the aim compound 5 completely to deacetylate ended in surprising results. Thus, methanolic methanolate solution produced the orthoester 7 as the result of α-fluoride replacement by methoxy groups as well as the methyl glucoside 8 as the result of a transglycosylation reaction. Alumina supported cesium fluoride cleaved regioselectively the two acetyl groups in the 4- and 6-position yielding perfluorohexyl 2-O-acetyl-3-O-dodecyl-1-thio-β-d-glucopyranoside (10). A complete deacetylation of 5 to amphiphile 11 succeeded only with methanolic tert-butanolate. However, the products 8 and 10 were likewise formed.     

Synthesis of aluminium complexes bearing a piperazine-based ligand system

Aluminium complexes bearing the N,N-chelating ligand 1,4-bis(2-hydroxy-3,5-di-tert-butyl)piperazine (1) have been synthesised. Both monometallic and bimetallic aluminium methyl complexes (2 and 3, respectively) were prepared by treatment of 1 with the appropriate amount of AlMe₃. Complex 2 can be converted to 3 by addition of excess AlMe₃. Bimetallic aluminium-ethyl complex 4 was also prepared. Treatment of 1 with AlEt₂Cl afforded the monometallic chloride complex 5. Treatment of this latter complex with potassium alkoxides (KOR, R = Me, Et, ⁱPr, ^tBu) or AgOTf afforded the corresponding aluminium alkoxide complexes (6, R = Et; 7, R = Me; 8, R = ⁱPr; 9, R = ^tBu; 10, R = OTf) in good yields. Aluminium ethoxide complex 6 was also synthesised by treatment of 1 with AlEt₂OEt. All of these complexes were tested as potential catalysts in the ring-opening polymerisation of rac-lactide and caprolactone with limited success.     

Total synthesis of apigenin 7,4′-di-O-β-glucopyranoside, a component of blue flower pigment of Salvia patens, and seven chiral analogues

We have succeeded in the first total synthesis of apigenin 7,4′-di-O-β-d-glucopyranoside (1a), a component of blue pigment, protodelphin, from naringenin (2). Glycosylation of 2 according to Koenigs-Knorr reaction provided a monoglucoside 4a in 80% yield, and this was followed by DDQ oxidation to give apigenin 7-O-glucoside (12a). Further glycosylation of 4′-OH of 12a with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl fluoride (5a) was achieved using a Lewis acid-and-base promotion system (BF₃·Et₂O, 2,6-di-tert-butyl-4-methylpyridine, and 1,1,3,3-tetramethylguanidine) in 70% yield, and subsequent deprotection produced 1a. Synthesis of three other chiral isomers of 1a, with replacement of d-glucose at 7 and/or 4′-OH by l-glucose (1b-d), and four chiral isomers of apigenin 7-O-β-glucosides (6a,b) and 4′-O-β-glucosides (7a,b) also proved possible.