Synthesis of Selectively Protected Chitobiose and Chitotriose Derivatives from one Precursor. Versatile Building Blocks for Oligosaccharide Synthesis

Abstract

The inner core region of cell surface N-glycoproteins consists of a chitobiose substructure², containing β-(1,4)-linked disaccharides of glucosamine. Such carbohydrate structures are also found as repeating units of the bacterial cell wall peptidoglycan³ and in novel tetra- and pentasaccharide plant hormones, which are nodulation factors on legume roots.⁴ Since the first synthesis of a chitobiose derivative in 1966 by Paulsen,⁵ approaches to these compounds have relied mainly on the oxazoline method.⁶ The coupling reactions of aminosugar chlorides,⁷ bromides,⁸ acetates⁹ and trichloroacetimidates¹⁰ to suitable glycosyl acceptors have also been described. Most of these syntheses¹¹ require two completely different coupling partners; only in very few examples could the glycosyl donor and acceptor be obtained from the same starting material.¹² During our investigations into the stereocontrolled synthesis of glucosamine oligosaccharides, we required an economical synthetic route to protected derivatives of chitotriose. For the purpose of easy oligomerization, the anomeric protecting group of every building block had to be exchangeable selectively with the activating group for the next glycosylation. In this paper, we report an efficient approach to chitobiose and chitotriose from a single precursor. Furthermore, the hydroxyl groups at C-1, C-3, C-4, C-6 of these oligosaccharides are differentially protected. This protecting group scenario allows a specific access to any of these functionalities by regioselective deblocking. The N-phthalimide group was chosen out of several possible amino protecting groups to ensure β-selectivity and simultaneous activation in the coupling.¹³     

Spin-Labeled Riboswitch Synthesized from a Protected TPA Phosphoramidite Building Block

The nitroxide TPA (2,2,5,5-tetramethyl-pyrrolin-1-oxyl-3-acetylene) is an excellent spin label for EPR studies of RNA. Previous synthetic methods, however, are complicated and require special equipment. Herein, we describe a uridine derived phosphoramidite with a photocaged TPA unit attached. The light sensitive 2-nitrobenzyloxymethyl group can be removed in high yield by short irradiation at 365 nm. Based on this approach, a doubly spin-labeled 27mer neomycin sensing riboswitch was synthesized and studied by PELDOR. The overall thermal stability of the fold is not much reduced by TPA. In-line probing nevertheless detected changes in local mobility.     

Synthesis of Selectively gem-Difluorinated Molecules; Chiral gem-Difluorocyclopropanes via Chemo-Enzymatic Reaction and gem-Difluorinated Compounds via Radical Reaction

The incorporation of fluorine atoms into an organic compound can alter the chemical reactivity or biological activity of the resulting compound due to the strong electron withdrawing nature of the fluorine atom. We have synthesized many original gem-difluorinated compounds and described the results in four sections. The first section describes the synthesis of optically active-gem-difluorocyclopropanes via the chemo-enzymatic reaction; we applied these compounds to liquid crystalline molecules, then further discovered a potent DNA cleavage activity for the gem-difluorocyclopropane derivatives. The second section describes the synthesis of selectively gem-difluorinated compounds via a radical reaction; we synthesized fluorinated analogues of a sex pheromone of the male African sugarcane borer, Eldana saccharina, and used the compounds as proof for investigating the origin of pheromone molecule recognition on the receptor protein. The third involves the synthesis of 2,2-difluorinated-esters by visible light-driven radical addition of 2,2-difluoroacetate with alkenes or alkynes in the presence of an organic pigment. The last section describes the synthesis of gem-difluorinated compounds via the ring-opening of gem-difluorocyclopropanes. We further developed a novel method of synthesizing gem-difluorohomoallylic alcohols via the ring-opening of gem-difluorocyclopropane and aerobic oxidation by photo-irradiation in the presence of an organic pigment. Since gem-difluorinated compounds that were prepared by the present method have two olefinic moieties with a different reactivity at the terminal position, we accomplished the synthesis of four types of gem-difluorinated cyclic alkenols via the ring-closing-metathesis (RCM) reaction.     

PUVA Treatment Selectively Induces a Cell Cycle Block and Subsequent Apoptosis in Human T-Lymphocytes

Psoralen plus UVA (320–400 nm radiation; PUVA) is a highly effective therapy for cutaneous diseases caused by skin infiltration with normal or neoplastic T-lympho-cytes. In comparing the effects of pharmacologically relevant, low-dose PUVA treatment on growth of human keratinocytes, peripheral blood leukocytes (PBMC), and T-lymphocyte cell lines, we determined that PBMC or T-lymphocytes were >50-fold more sensitive to cytotoxic effects of PUVA, while antiproliferative effects were produced by similar PUVA levels in all cell types. Low doses of PUVA (10 ng/mL 8-methoxypsoralen and 1–2 J/cm²) were highly cytotoxic for phytohemagglutinin-activated normal lymphocytes or transformed T-lymphocytes as assessed by two viability assays and by flow cytofluo-rometry. Altered lymphocyte morphology, nuclear fragmentation, TUNEL+ nuclei or nuclear fragments, and the appearance of a sub-G, DNA peak indicated that cell death occurred by apoptosis, beginning about 1 day after PUVA treatment and continuing for several days thereafter. From assessment of cell cycle progression in mi-mosine-synchronized cells, PUVA treatment markedly slowed cell cycle progression, eventually producing cell cycle arrest and apoptotic entry. We propose that the probable basis for disease remissions (psoriasis, cutaneous T-cell lymphoma) produced by PUVA treatment is through selective cytotoxic effects on clonal T-lymphocyte populations that are concentrated in diseased skin.     

Efficient Synthesis of a Benzo[b]furan Building Block

Unexpected difficulty in the conversion of a bromobenzofuran to the corresponding formylbenzofuran led us to develop a new synthesis for 5-formylbenzo[b]furan-2-carbonitrile (1).     

Maleimides As a Building Block for the Synthesis of High Performance Polymers

Maleimides are gaining a great deal of attention in both scientific and industrial communities since they can be used in high performance macromolecular systems: thermosets with high temperature stability, self-healing systems, or in click chemistry reactions. After an introduction, this review reports in the first part the different routes to synthesize maleimides. In the second part, this review focuses on the use of maleimides in polymer synthesis, first through nucleophilic reactions, second via cycloaddition to yield remendable systems, and then via radical polymerization. Finally, the industrial availability of maleimides is discussed.     

A Convenient Synthesis of Azafulleroid of Erythronate as a New Chiral Building Block

Azafulleroid of erythronate 3 as a chiral building block was synthesized conveniently in thermal condition from the reaction of fullerene with azidoerythronate 2.     

Unexpected but Easy Synthesis of a Dihydrophosphadiazaazulene

Abstract

The title compound is the main product of the 2:1 reaction of DMAD with diazaphosphinines. The supposed mechanisms with intermediates and related products will be presented.     

High-Performance Quinoline-Malononitrile Core as a Building Block for the Diversity-Oriented Synthesis of AIEgens

In vivo fluorescent monitoring of physiological processes with high-fidelity is essential in disease diagnosis and biological research, but faces extreme challenges due to aggregation-caused quenching (ACQ) and short-wavelength fluorescence. The development of high-performance and long-wavelength aggregation-induced emission (AIE) fluorophores is in high demand for precise optical bioimaging. The chromophore quinoline-malononitrile (QM) has recently emerged as a new class of AIE building block that possesses several notable features, such as red to near-infrared (NIR) emission, high brightness, marked photostability, and good biocompatibility. In this minireview, we summarize some recent advances of our established AIE building block of QM, focusing on the AIE mechanism, regulation of emission wavelength and morphology, the facile scale-up and fast preparation for AIE nanoparticles, as well as potential biomedical imaging applications.     

以苯为模块自组装合成碳纳米片

在300 ℃苯溶剂中, 以无水三氯化铝为催化剂, 以苯和六氯乙烷为碳源, 基于傅克烷基化反应生成三氯乙烯苯, 并以之为模块自组装合成了具有叠层结构的碳微米颗粒, 其层片厚度为300～500 nm. 进而在反应体系和反应条件不变的情况下, 通过引入铝粉颗粒作为基底成功地诱导出厚度为30～50 nm的碳纳米片. 实验结果表明, 所得碳材料由纳米石墨微晶和非晶碳组成. 文中探讨了叠层结构的台阶长大机制, 以及碳纳米片在铝粉表面的异质形核机制.     

Synthesis of an Anti-1,3-Diol Type Chiral Building Block

Duringthelastdecade,1,3-dioltypechiralbuildingbIocksofvariousconfigurationshavebeensynthesizedandappliedwidelyinthetotalsynthesisofnaturalpolyenemacrolideantibiotics1'2andla,25-dihydroxyvitaminD3analogues'.RecentlyWeigandandBrucker4synthesizedachiralbuildingblock(4R,6R)-2,2-dimethyl-5-tert-butyldip4-hydroxymethyl-l,3-dioxane1inlOsteps.Herein,wereportasyntheticrouteofnewbuildingblock(4S,6S)-2,2-dimethyl-5-tert-butyldip2,anenantiomerofl,startingfromreadilyavailableandinexpensiveD( )-xylose3i…     

Synthesis of a Building Block for a Nucleic-Acid Analog with a Chiral,Flexible Peptide Backbone

We present here a nine-step synthesis of the thymine-containing amino ester 1 , starting from commercially available methyl N-[(tert-butoxy)carbonyl]-L -serinate. Amino ester 1 is considered as a building block for the preparation of a new nucleic-acid analog with a chiral, flexible polyamide backbone. Key steps in the synthesis are the vitamin-B₁₂-catalyzed addition of 3-bromo-N-[(tert-butoxy)carbonyl]-L -alaninate 2 to ethyl acrylate and the homologation of the corresponding N-protected α-amino acid 4 into the β-amino ester 6 by Arndt-Eistert chemistry. The latter was found to proceed with 10% inversion of configuration at the asymmetric center in 6. Resolution to enantiomerically pure material, however, was easily achieved by simple crystallization of 1 .     

Synthesis of Differentially Protected Glucosamine Building Blocks and Their Evaluation as Glycosylating Agents

The modular assembly of heparin oligosaccharides requires glucosamine building blocks with amine protecting groups for α-selective glycosylations that can be readily removed. The synthesis of N-4-nitrobenzensulphonamide (nosyl)- and N-2,4-dinitrophenyl (DNP)-protected glucosamine building blocks and their evaluation as glycosylating agents is described. The N-nosyl-protected glucosamine building blocks were challenging to prepare and their glycosylations resulted in inseparable mixtures of products. The N-DNP-protected glucosamines, however, were readily synthesized and resulted in α-selective couplings to protected l-iduronic acid derivatives.     

Concise Synthesis of 6-Cyanobenzo[b]furan,a Useful Building Block

A new three-step synthesis of 6-cyanobenzo[b]furan (6) was developed, starting from commercially available 6-hydroxybenzo[b]furan-3-one (18). Key steps in this process were the first step, which was the reductive dehydration of 18 to produce 6-hydroxybenzo[b]furan (19), and the last step, which converted the aryl triflate 20 to the aryl cyanide 6 in a palladium-catalyzed cross-coupling protocol. Overall yield for this new synthesis was 49%.