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.     

Convenient synthesis of N-isobutyryl-2′-O-methyl guanosine by efficient alkylation of O-trimethylsilylethyl-3′,5′-di-tert-butylsilanediyl guanosine

We present a novel route for the synthesis of N²-isobutyryl-2′-O-methyl guanosine, introducing 3′,5′-di-tert-butylsilyl and O⁶-trimethylsilylethyl groups as efficient protections during the 2′-O-methylation step with NaH/CH₃I. These protections were then removed simultaneously in a single step with TBAF. The eight-step synthesis is easy to perform, employing convenient commercially available reagents; crude mixtures are of satisfying purity, so only three chromatography purifications were required. Title compound was obtained in 25% overall yield from guanosine.     

On the conformational characteristics of the O,O,O-trimethyl selenophosphate molecule

Spectroscopic and theoretical studies were carried out for O,O,O-trimethyl selenophosphate molecule. DFT structural and vibrational calculations were performed at 6-311++G^∗∗ level. Ar/matrix-FTIR spectra were recorded. A coexistence of different conformers with C₃ and C₁ symmetries was detected at different temperatures. Spectral evidence of a lower energy C_s conformer was found. These conclusions are consistent with the results from DFT calculations. A tentative assignment of the features observed in the Ar/matrix-FTIR spectra is proposed.     

‘O-Acyl isopeptide method’ for the efficient synthesis of difficult sequence-containing peptides: use of ‘O-acyl isodipeptide unit’

A novel ‘O-acyl isodipeptide unit’, Boc-Thr(Fmoc-Val)-OH 5 has been successfully used for the efficient synthesis of a difficult sequence-containing pentapeptide based on the ‘O-acyl isopeptide method’, in which racemization-inducible esterification could be omitted, suggesting that the use of O-acyl isodipeptide units allows the application of this method to fully automated protocols for the synthesis of long peptides or proteins.     

BF3·Et2O catalyzed diastereoselective nucleophilic reactions of 3-silyloxypiperidine N,O-acetal with silyl enol ether and application to the asymmetric synthesis of (+)-febrifugine

The asymmetric BF₃·Et₂O catalyzed nucleophilic reactions of 3-silyloxypiperidine N,O-acetal 10 with silyl enol ethers derived from ketones are described. (+)-Febrifugine 1, an antimalarial alkaloid, was successfully synthesized based on this nucleophilic substitution. In addition, N,O-acetal 10 was synthesized from l-benzyl glutamate in 11 steps.     

Solid-phase synthesis of 3-alkyl-2-arylamino-3,4-dihydroquinazolines

The solid-phase synthesis of 3-alkyl-2-arylamino-3,4-dihydroquinazolines using an N-Fmoc-β-amino-2-nitrobenzenepropanoic acid scaffold is described. The resin-bound scaffold was reductively alkylated with aldehydes or ketones after Fmoc deprotection, followed by reduction of the nitro group with tin(II) chloride. Subsequent cyclization of the 1,3-diamine intermediates with aryl isothiocyanates in the presence of 1,3-diisopropylcarbodiimide (DIC) afforded the desired products in high purity with moderate to good yield after trifluoroacetic acid (TFA) cleavage.     

Sm(OTf)3 as a highly efficient catalyst for the synthesis of 2,3-unsaturated O- and S-pyranosides from glycals and the temperature-dependent formation of 4-O-acetyl-6-deoxy-2,3-unsaturated S-pyranosides and 4-O-acetyl-6-deoxy-3-alkylthio glycals

By using Sm(OTf)₃ as the catalyst, synthesis of 2,3-unsaturated-glycosides has been performed. A series of 2,3-unsaturated glycosides were obtained from 3,4,6-tri-O-acetyl–d-glucal or 3,4-di-O-acetyl-l-rhamnal under mild reaction conditions in good yield and high anomeric selectivity. It was found that under certain conditions, reaction of 3,4-di-O-acetyl-l-rhamnal with thiol leads to temperature-dependent formation of C-1-S and C-3-S product. A temperature-dependent profile of the yield of these two products is given.     

Y(OTf)3 as a highly efficient catalyst in Ferrier Rearrangement for the synthesis of O- and S-2,3-unsaturated glycopyranosides

By using Y(OTf)₃ as the catalyst, a series of 2,3-unsaturated-glucosides have been synthesized from 3,4,6-tri-O-acetyl-d-glucal, 3,4-di-O-acetyl-l-rhamnal, and 3,4,6-tri-O-benzyl-d-glucal under mild reaction conditions in good yields with high anomeric selectivities. It was found that, in this reaction, 3,4,6-tri-O-benzyl-d-glucal behaved differently from the other two glucals when it was reacted with phenol, O-benzyl glucoside instead of O-phenyl glucoside formed as the sole product. An explanation is given for this phenomenon.     

Construction of a novel molecularly imprinted sensor for the determination of O,O-dimethyl-(2,4-dichlorophenoxyacetoxyl)(3′-nitrophenyl)methinephosphonate

A novel voltammetric sensor for O,O-dimethyl-(2,4-dichlorophenoxyacetoxyl)(3′-nitrophenyl)methinephosphonate (Phi-NO₂) based on molecularly imprinted polymer (MIP) film electrode is constructed by using sol-gel technology. The sensor responds linearly to Phi-NO₂ over the concentration range of 2.0 × 10⁻⁵ to 1.0 × 10⁻⁸ mol L⁻¹ and the detection limit is 1.0 × 10⁻⁹ mol L⁻¹ (S/N = 3). This sensor provides an efficient way for eliminating interferences from coexisting substances in the solution. The high sensitivity, selectivity and stability of the sensor demonstrates its practical application for a simple and rapid determination of Phi-NO₂ in cabbage samples.     

Design, synthesis and utilization of a novel coupling reagent for the preparation of O-alkyl hydroxamic acids

An efficient novel reagent, phosphoric acid diethyl ester 2-phenyl-benzimidazol-1-yl ester, was designed, and synthesized and its applicability was demonstrated for the preparation of O-alkyl hydroxamic acids. The O-alkyl hydroxamic acids of N-protected amino acids were also synthesized. The enantiomeric purity of the synthesized compounds were measured using chiral HPLC and the degree of racemization was found to be negligible.     

Solid-phase synthesis of 2,6- and 2,7-diamino-4(3H)-quinazolinones via palladium-catalyzed amination

A new procedure for the solid-phase synthesis of 2,6- and 2,7-diamino-4(3H)-quinazolinones is described. The method involves coupling of 2,4,6- and 2,4,7-trichloroquinazoline to a solid support via benzyl alcohol type linkers, subsequent displacement of chlorine at C-2 then at the C-6 or C-7 positions by amines (Fig. 1) and the cleavage of the products from the resin. The palladium-catalyzed amination of C-6 and C-7 positions with a representative set of amines in the presence of 2-(di-t-butylphosphino)biphenyl (DTBPBP), P(t-Bu)₃ and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) ligands has been investigated. This method should prove to be a useful tool for constructing combinatorial libraries containing the 4(3H)-quinazolinone moiety.     

Solid-phase synthesis of fused [2,1-b]quinazolinone alkaloids

Solid-phase synthesis of fused [2,1-b]quinazolinone alkaloids has been developed for the preparation of vasicinone and deoxyvasicinone by two approaches. The derivative of polymer-supported p-nitrophenyl carbonate was attached to anthranilic acid and then coupled with various bromo-lactams. This resin-linked bromo intermediate upon acetylation, hydrolysis and resin cleavage gave the cyclized [2,1-b]quinazolinones (vasicinone). Alternatively, resin-linked azido-benzoic acids were coupled with bromo-substituted lactams followed by cyclization in an aza-Wittig reductive cyclization process giving the bromo-substituted quinazolinone intermediates, with subsequent acetylation, hydrolysis and resin cleavage affording the fused [2,1-b]quinazolinones.     

Traceless solid-phase synthesis of 1,4-disubstituted-6-nitro-3,4-dihydro-1H-quinoline-2-ones

A traceless solid-phase route to 1,4-disubstituted-6-nitro-3,4-dihydro-1H-quinazolin-2-ones is described. N-Alloc-3-amino-3-(2-fluoro-5-nitrophenyl)propionic acid was tethered to Rink resin via its carboxylic group. The protected amine was coupled with an organic acid after Alloc-deprotection and the arylfluorine was displaced with a primary amine to generate a resin-bound aniline with two diversity points. The aniline was released via cleavage to produce the desired products in high yield and purity.     

Diastereoselective synthesis of homo-N,O-nucleosides

A new class of homo-N,O-nucleosides has been designed, based on the 1,3-dipolar cycloaddition of C-substituted nitrones with allyl nucleobases. The N-methyl-C-ethoxycarbonyl nitrone 1, and the C-α-silyloxymethyl-N-methyl nitrone 7 have been exploited: the stereochemical features of the obtained nucleosides are dependent on the nature of the dipole. The results obtained with DFT calculations fully agree with the experimental results and successfully reproduce the experimentally observed reversal of endo/exo selectivity for nitrones 1 and 7.     

Synthesis of glycopeptide dendrimer by a convergent method

Glycopeptide thioester comprising the sequence of extracellular matrix metalloproteinase inducer (emmprin) (34-58) was prepared and condensed with a dendrimer core having eight amino groups by the thioester method. The desired product, a glycopeptide dendrimer carrying an N-linked core pentasaccharide of about 30 kDa, was successfully isolated by preparative electrophoresis and characterized by mass analysis.     

One-pot three components synthesis of O-acetylcyanohydrins with TMSCN, acetic anhydride and carbonyl compounds under solvent-free condition

One-pot three components synthesis of O-acetylcyanohydrins has been developed in the presence of B(C₆F₅)₃ as the catalyst. Variety of aldehydes or ketones reacts with TMSCN and acetic anhydride (Ac₂O) under the influence of 1 mol % of B(C₆F₅)₃ to give good to excellent yield of the products without solvent at rt.     

A new synthesis of key intermediates for the assembly of polycyclic ethers: Yb(OTf)3-promoted formation of O,S-acetals from α-fluorosulfides and alcohols

We report a new reaction for the direct construction of O,S-acetals, key intermediates in the assembly of fused polycyclic ethers. α-Fluorosulfides and secondary alcohols were coupled by the action of Yb(OTf)₃ to generate O,S-acetals in high yield. The neutral and selective nature of the reaction should be useful for synthesizing natural and artificial polyethers with multisensitive functionalities.     

Solid-phase synthesis of 1,5-substituted 2-(N-alkylamino)-imidazolidin-4-ones

The solid-phase synthesis of 1,5-substituted 2-(N-alkylamino)-imidazolidin-4-one from resin-bound amino acid is described. Using a guanidinylating reagent in solution to form the guanidine moiety instead of resin-bound carbodiimide, an N-alkyl substitution is introduced specifically onto the 2-amino position. Combined with an alkylation step of the resin-bound amino acid prior to guanidinylation, all desired substitutions of the final products are achieved without racemization at chiral centers. This reaction sequence is also compatible with a variety of protected amino acid side chains.     

Spectroscopic and structural characterization of O,O′-(diphenylphosphineoxide)amidate and acetylacetonate complexes of pentacoordinate nickel(II)

Heteroleptic nickel pentacoordinate complexes with the macrocyclic ligands 2,4,4-trimethyl-1,5,9-triazacyclododec-1-ene (Me₃-mcN₃) or its 9-methyl derivative (Me₄-mcN₃), as ancillary ligands, and O,O′-(diphenylphosphineoxide)amidate ligands, [RC(O)NP(O)Ph₂]^¯ (R = C₆H₆ (1), C₅H₄N (2), C₄H₃S (3)), have been prepared as well as related acetylacetonate derivatives. The complexes have been studied by spectroscopic methods (IR, UV-Vis and ¹H NMR). In acetone solution, the complexes exhibit isotropically shifted ¹H NMR resonances. The full assignment of these resonances has been achieved using one- and two-dimensional ¹H NMR techniques. The single-crystal structures of {(Me₄-mcN₃)Ni[OP(Ph₂)NC(Tf)O]}[PF₆] (9) and {(Me₃-mcN₃)Ni(acac)}[PF₆] (10) have been established by X-ray diffraction.