Chemical synthesis of bioactive siRNA in solution phase by using 2-(azidomethyl)benzoyl as 3′-hydroxyl group protecting group

A protecting group AZMB was introduced to ribonucleosides 3′-hydroxyl group to facilitate solution phase synthesis of siRNA. The protection and cleavage reaction were carried out in mild conditions, that is protection by acyl chloride and cleavage by triphenylphosphine. The synthesized siRNA showed good biological activity to suppress targeted superoxide dismutase gene expression.     

Preparation of 1,1-disubstituted silacyclopentadienes

Several new 1,1-disubstituted siloles containing substituents on the ring carbon atoms have been synthesized. The new siloles: 1,1-dihydrido-2,5-bis(trimethylsilyl)-3,4-diphenylsilole (5), 1,1-dihydrido-2,5-dimethyl-3,4-diphenylsilole (6), 1,1-dimethoxy-2,5-bis(trimethylsilyl)-3,4-diphenylsilole (7), 1,1-bis(4-methoxyphenyl)-2,5-bis(trimethylsilyl)-3,4-diphenylsilole (8), 1,1-dipropoxy-2,5-bis(trimethylsilyl)-3,4-diphenylsilole (9), and 1,1-dibromo-2,5-bis(trimethylsilyl)-3,4-diphenylsilole (13) were prepared from reactions originating from the previously reported, 1,1-bis(diethylamino)-2,5-bis(trimethylsilyl)-3,4-diphenylsilole (1) or 1,1-bis(diethylamino)-2,5-dimethyl-3,4-diphenylsilole (2). In addition, three other new organosilane byproducts were observed and isolated during the current study, bis(4-methoxyphenyl)bis(phenylethynyl)silane (11), bis(4-methoxyphenyl)di(propoxy)silane (12) and 1-bromo-4-bromodi(methoxy)silyl-1,4-bis(trimethylsilyl)-3,4-diphenyl-1,3-butadiene (14). Compounds 13 and 14 were characterized by X-ray crystallography and 14 is the first 1,1-dibromosilole whose solid state structure has been determined.     

Preparation of aminals in water

Aminals, which are used as protecting groups in syntheses and are part of many biologically active compounds, are normally prepared from aldehydes and diamines under conditions that remove water in order to shift the equilibrium to the side of the aminal. Here we report for the first time that aminals can be prepared and isolated in pure water without a catalyst in high yield and purity.     

1-Methyl 1′-cyclopropylmethyl (MCPM) as an anomeric protecting group

A pragmatic approach for preparing glycoconjugates of complex oligosaccharides is to prepare the oligosaccharide as a building block with most of its protecting groups exchanged to protecting groups whose cleavage and other manipulations are highly compatible with the functional groups of complex aglycones. For such an approach the reducing end sugar of the building bloc must be protected with a cleavable protecting group during the oligosaccharide synthesis. We demonstrate that the acid labile 1-methyl 1′-cyclopropylmethyl (MCPM) can be effectively used for this purpose. A trisaccharide glycolipid and a disaccharide glycoamino acid are prepared. The absolute chirality of the MCPM in one key acceptor is determined by a combination of NMR NOE measurements, DFT molecular modeling and Noyori catalyst catalyzed asymmetric reduction.     

Structure of 4-sila-3-platinacyclobutene and its formation via Pt-promoted gamma-Si-H bond activation of 3-sila-1-propenylplatinum precursor

4-Sila-3-platinacyclobutene was isolated from the reaction of Pt(SiHPh2)2(PMe3)2 with dimethyl acetylenedicarboxylate (DMAD) and characterized by X-ray crystallography. The formation pathway was found to involve gamma-Si-H bond activation of the 3-sila-1-propenylplatinum intermediate that is formed by the insertion of a DMAD into a Pt-Si bond of Pt(SiHPh2)2(PMe3)2.     

Preparation of substituted 9,10-dihydro-9-sila-3-azaanthracenes and their derivatives

3-Methyl-4-dimethylphenylsilylpyridine and 3-methyl-4-methyldiphenylsilylpyridine, which were obtained from -picoline and dimethylphenylchlorosilane and methyldiphenylchlorosilane, respectively, were converted by catalytic dehydrocyclization to 9,9-dimethyl-9,10-dihydro-9-sila-3-azaanthracene and 9-methyl-9-phenyl-9,10-dihydro-9-sila-3-azaanthracene. The corresponding silaazaanthrones were obtained from them and were converted to tertiary silaazaanthrols with a methyl or phenyl group attached to the C₁₀ atom. On the basis of an analysis of data from the PMR spectra of the silaazaanthracenes it was assumed that they exist in the form of an equilibrium mixture of boat conformations. 9-Methyl-9-phenyl-10-methylene-9,10-dihydro-9-sila-3-azaanthracene was obtained in the form of a stable crystalline substance by dehydration of the corresponding silaazaanthrol. Potassium tert-butoxide cleaves the Si-C bond in the silaazaanthrone system; this was confirmed by isolation of 1,2-dimethyl-1,2-diphenyl-1,2-bis (2-nicotinoylphenyl)disiloxane.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 240–244, February, 1981.     

Oligoribonucleotide synthesis by the use of 1-(2-cyanoethoxy)ethyl (CEE) as a 2′-hydroxy protecting group

A novel method for the synthesis of oligoribonucleotides using 1-(2-cyanoethoxy)ethyl (CEE) as a 2′-hydroxy protecting group has been developed. A CEE group was introduced to the 2′-position of N-acyl-3′,5′-O-silyl-protected ribonucleosides under acidic conditions in good yields. The 2′-O-CEE group was found to be stable in an aqueous or ethanolic ammonia and was quickly removed by treatment with anhydrous tetrabutylammonium fluoride (TBAF). A combination of the use of N-acyl and 2′-O-CEE protecting groups enabled a reliable and complete two-step deprotection, first with NH₃–EtOH, then with TBAF in THF, without cleavage of internucleotidic linkages.     

Strategies for protecting and manipulating triazine derivatives

Aminotriazine derivatives are available in two steps by treating chlorotriazines with acid-labile benzylic amines including triphenylmethylamine, diphenylmethylamine, and 2,4-dimethoxybenzyl-amine (Dmb-amine), followed by deprotection using trifluoroacetic acid. This high yielding (85-99%) protocol is a milder alternative to the traditional method that uses ammonia and high temperature as a route to aminotriazine derivatives. The nucleophilic substitution reaction that installs the benzylic amine on monochlorotriazine herbicide derivatives may be performed using conventional heating. Alternatively, a microwave reactor can be used to decrease the reaction times 100-fold. The intermediates in these syntheses are soluble in a range of organic solvents and amenable to chromatography. In some cases when dimethoxybenzyl groups are used, oligomerization of the dimethoxybenzyl side product upon treatment with trifluoroacetic acid yields a precipitate that facilitates purification by simple filtration.     

Synthesis and hydrolytic stability of novel 3-[F]fluoroethoxybis(1-methylethyl)silyl]propanamine-based prosthetic groups

Two new silicon-based prosthetic groups, derived from 3-[ethoxybis(1-methylethyl)silyl]propanamine, have been prepared in good yields. These silicon groups bearing an acid or an azide group were coupled to a model tripeptide (Leu-Gly-Gly) either through a classical amide bond formation or through “click chemistry” via the Huisgen cycloaddition. The radiolabelling with fluorine-18 by substitution of the ethoxy group at silicon has been carried out with success in 51-54% decay corrected radiochemical yields. Radiolabelled peptides were easily prepared by direct ¹⁸F-fluorination of the silicon-bearing tripeptide or by coupling the peptide with a radiolabelled silicon-based prosthetic group. Their stabilities in physiological medium were studied and proved poor.     

A benzyloxy group migration under Mitsunobu reaction conditions

When compounds 3a and 3b were subjected to a Mitsunobu reaction with benzoylthymine, the expected substitution products were formed together with the regioisomers corresponding to benzyloxy group migrations.     

Routes to highly substituted thiophenol derivatives

Syntheses of highly substituted thiophenol derivatives that incorporate steric bulk into the ligand framework via ortho and para tert-butyl substituents are reported. S-Benzyl and trityl protection were investigated and the effects of substituents on the Newman-Kwart rearrangement of the thiocarbamate discussed. Single crystal X-ray structures are reported for three compounds and demonstrate the role of hydrogen bonding in stabilising the thiophenol to oxidation.     

Solid-Phase Enzymatic Synthesis of a Lewis a Trisaccharide Using an Acceptor Reversibly Bound to Sepharose

Abstract

The disaccharide 2-aminoethyl O-β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-glucopyranoside was reacted with thiobutyrolactone to give a disaccharide with a thiol group on the aglycone. This disaccharide was reacted with activated Thiopropyl Sepharose, which gave a disaccharide bound to Sepharose via a disulphide bond. Enzymatic fucosylation, using GDP-fucose and partially purified human milk fucosyltransferase, gave a trisaccharide in good yield, which was cleaved from Sepharose by treatment with mercaptoethanol or dithiothreitol.     

Simple and rapid p-methoxybenzylation of hydroxy and amide groups at room temperature by NaOt-Bu and DMSO

The p-methoxybenzylation of hydroxy and amide groups by p-methoxybenzyl chloride utilizing NaOt-Bu in DMSO is described. p-Methoxybenzylation of sterically hindered menthol using NaOt-Bu in DMSO proceeded faster than the commonly used methods which use NaH in THF or DMF for p-methoxybenzylation of hydroxy and amide groups. The described method was applicable for sterically hindered substrates at room temperature without adding any activating reagents such as tetrabutylammonium iodide.     

Thermoinitiated polymerization of 1,1,3,3-tetramethyl-1-sila-3-germacyclobutane and the polymer chain structure

Russian Chemical Bulletin -     

Protecting Group Manipulations on Glycosyl Phosphate Triesters

Glucosyl and mannosyl phosphate triester building blocks were differentially protected by protecting group manipulations on competent glycosyl donors. Dibutyl 3,4‐di‐O‐benzyl‐6‐O‐(fluorenylmethoxycarbonyl)‐2‐O‐pivaloyl‐β‐D‐glucopyranoside phosphate, not accessible by other methods, was prepared this way.     

A novel redox-sensitive protecting group for boronic acids, MPMP-diol

A new boronic acid protecting group, 1-(4-methoxyphenyl)-2-methylpropane-1,2-diol (MPMP-diol), has been developed. Both protection and deprotection can be accomplished under mild conditions with quantitative conversions. The deprotection can be carried out using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).     

2‐[(Acetyloxy)methyl]‐4‐(acetylsulfanyl)‐2‐(ethoxycarbonyl)‐3‐oxobutyl Group: A Thermolabile Protecting Group for Phosphodiesters

The phosphodiester linkage of 3′‐O‐levulinoylthymidine 5′‐methylphosphate ( 5 ) has been protected with 2‐[(acetyloxy)methyl]‐4‐(acetylsulfanyl)‐2‐(ethoxycarbonyl)‐3‐oxobutyl group (to give 1 ) to study the potential of this group as an esterase‐ and thermolabile protecting group. The group turned out to be unexpectedly thermolabile, being removed as ethyl 3‐(acetyloxy)‐4‐(acetylsulfanyl)‐2‐methylidenebut‐3‐enoate ( 10 ) without accumulation of any intermediates. The half‐life of this reaction at pH 7.5 and 37° is 14 min. Hog liver esterase (HLE), in turn, removes the protecting group as ethyl 4‐(acetylsulfanyl)‐2‐methylidene‐3‐oxobutanoate ( 12 ). On using 2.6 units of HLE in 1 ml, the rate of the enzymatic deprotection was still only one third of that of the nonenzymatic reaction. The mechanisms of both reactions have been studied and discussed. The crucial step seems to be removal of the O‐bound Ac group, either by esterase or by migration to the neighboring 3‐oxo group (nonenzymatic removal). This triggers the removal by retro‐aldol condensation/elimination mechanism. No alkylation of glutathione (GSH) upon the deprotection of 1 could be detected.