Unprotected Glycosides Research Articles

Stereoselective and site-divergent synthesis of C-glycosides.

Carbohydrates play important roles in medicinal chemistry and biochemistry. However, their synthesis relies on specially designed glycosyl donors, which are often unstable and require multi-step synthesis. Furthermore, the catalytic and stereoselective installation of arylated quaternary stereocentres on sugar rings remains a formidable challenge. Here we report a facile and versatile method for the synthesis of diverse C-R (where R is an aryl, heteroaryl, alkenyl, alkynyl or alkyl) glycosides from readily available and bench-stable 1-deoxyglycosides. The reaction proceeds under mild conditions and exhibits high stereoselectivity across a broad range of glycosyl units. This protocol can be used to synthesize challenging 2-deoxyglycosides, unprotected glycosides, non-classical glycosides and deuterated glycosides. We further developed the catalyst-controlled site-divergent functionalization of carbohydrates for the synthesis of various unexplored carbohydrates containing arylated quaternary stereocentres that are inaccessible by existing methods. The synthetic utility of this strategy is further demonstrated in the synthesis of pharmaceutically relevant molecules and carbohydrates.

Site-selective introduction of thiols in unprotected glycosides.

Thioglycosides or S-linked-glycosides are important glycomimetics. These thioglycosides are often prepared by glycosylating deoxythio sugar acceptors, which are synthesized via elaborate protecting group manipulations. We discovered that a carbonyl group, formed by site-selective oxidation of unprotected saccharides, can be converted into a thiol moiety. The transformation involves SN1-substitution of a chloro-azo intermediate, formed by oxidation of the corresponding trityl hydrazone, with a thiol. The prepared deoxythio sugars provide, in combination with the recently developed protecting group-free glycosylation of glycosyl fluorides, a protecting group-free synthesis of thioglycosides.

Substrate specific closed-loop optimization of carbohydrate protective group chemistry using Bayesian optimization and transfer learning.

A new way of performing reaction optimization within carbohydrate chemistry is presented. This is done by performing closed-loop optimization of regioselective benzoylation of unprotected glycosides using Bayesian optimization. Both 6-O-monobenzoylations and 3,6-O-dibenzoylations of three different monosaccharides are optimized. A novel transfer learning approach, where data from previous optimizations of different substrates is used to speed up the optimizations, has also been developed. The optimal conditions found by the Bayesian optimization algorithm provide new insight into substrate specificity, as the conditions found are significantly different. In most cases, the optimal conditions include Et3N and benzoic anhydride, a new reagent combination for these reactions, discovered by the algorithm, demonstrating the power of this concept to widen the chemical space. Further, the developed procedures include ambient conditions and short reaction times.

Site-Selective Dehydroxy-Chlorination of Secondary Alcohols in Unprotected Glycosides.

To circumvent protecting groups, the site-selective modification of unprotected glycosides is intensively studied. We show that site-selective oxidation, followed by treatment of the corresponding trityl hydrazone with tert-butyl hypochlorite and a H atom donor provides an effective way to introduce a chloride substituent in a variety of mono- and disaccharides. The stereoselectivity can be steered, and a new geminal dichlorination reaction is described as well. This strategy challenges existing methods that lead to overchlorination.

Final-stage Site-selective Acylation for the Total Synthesis of Natural Glycosides.

The first total syntheses of multifidosides A-C are reported. The prominent feature is an unconventional retrosynthesis based on organocatalytic site-selective acylation of unprotected glycosides at the final stage of synthesis. A notable advantage of this strategy is that it avoids the risks of undesired side reactions during the removal of the protecting groups at the final stage of total synthesis. The proposed synthetic strategy has another advantage in terms of efficient late-stage derivatization of natural products. Due to the predictability and reliability of the catalytic site-selective introduction of various functionalized acyl groups, the present synthetic strategy could provide a general synthetic route to 4-O-acylglycosides, such as phenylethanoid glycosides and ellagitannins, which are of biological interest.

Regioselective modification of unprotected glycosides.

Selective modification of unprotected carbohydrates is difficult due to the similar reactivity of the hydroxyl groups. In carbohydrate synthesis, therefore, even straightforward transformations often require multiple synthetic steps. The development of selective methods for carbohydrate modification is consequently highly desired. This review describes the methods for the regio- and chemoselective carbohydrate modification, with a focus on novel approaches that mainly apply transition metal catalysis and organocatalysis, and discusses the challenges and opportunities in this field.

Catalytic Regioselective Oxidation of Glycosides

Discrimination among equals: A catalytic method for the selective oxidation of unprotected glycosides, both monosaccharides and disaccharides, has been developed. The resulting ketosaccharides are isolated in moderate to excellent yields. This approach provides a basis for protecting-group-free synthetic transformations of carbohydrates.

A high-yielding synthesis of allyl glycosides from peracetylated glycosyl donors

β-Configured peracetylated sugars are often used as easily accessible glycosyl donors that are typically activated with common Lewis acids such as boron trifluoride or trimethylsilyltrifluoromethane sulfonate. Often these glycosylations occur with unsatisfactory yields due to incomplete reactions or extensive byproduct formation, primarily as a result of loss of an additional acetyl group generating partially unprotected glycosides. Here we report a simple glycosylation–reacetylation protocol for the generation of predominantly β-configured peracetylated allyl glucoside, -galactoside, -lactoside, and -maltoside with substantially improved reaction yields.

ChemInform Abstract: Efficient Synthesis of Deoxy and Dideoxy Sugars by a Thio-Mitsunobu Reaction on Unprotected Glycosides.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Direct, Mild, and Selective Synthesis of Unprotected Dialdo‐Glycosides

AbstractA direct and highly convenient organocatalytic method for the preparation of 1,5‐dialdo‐pyranosides and 1,4‐dialdo‐furanosides is presented. The method relies on the chemoselective properties of TEMPO in combination with trichloroisocyanuric acid under very mild, basic conditions. Unprotected glycosides are prepared in a single step in high yields and are efficiently purified with the use of solid‐phase imine capture. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Temporary Protection and Activation in the Regioselective Synthesis of Saccharide Sulfates

AbstractRegioselective sulfation with Et3N · SO3 of partially protected or unprotected glycosides via stannanediyl acetals or stannyl ethers, combined with persistent or temporary protecting groups is described. Stannylation of phenylboronates, followed by sulfation and aqueous workup, is an efficient way for the synthesis of monosulfated monosaccharides. The stannanediyl acetal 2 led in high yields to 3a, while sulfation of the diol 1 proceeded more slowly and led in lower yield to a mixture 1/3a/4a/5a (Scheme 1). The trehalose disulfate 8a was obtained in high yields from 7; reducing the amount of sulfating agent led to a mixture 6/8a/9a. Stannylation and sulfation of the galactoside 11 afforded 13a, while direct sulfation of 11 gave a mixture of the 2‐and 3‐sulfates 13a/14a besides some disulfate 15a. Sulfation of the lactose derivative 16 and the stannanediyl acetal 17 gave the 3‐sulfate 18a, with some disulfate 19a being formed from 16. The mannopyranoside 21 was selectively sulfated at OH–C(2), leading to 22a, while the corresponding diol 20 yielded mostly the isomer 23a and some disulfate 24a. Sulfation of the stannyl ethers derived from the gluco‐and galactopyranosides 25 and 28 and (Bu3Sn)2O afforded high yields of the 2,6‐disulfate 26a and the 3,6‐disulfate 29a, respectively. Stannylation of 25 and 28 with Bu2SnO and sulfation proceeded less satisfactorily. Stannylation of the phenylboronate 32 (Bu2SnO) and sulfation gave good yields of the 2‐sulfate 27a; stannylation and benzoylation yielded the 2‐benzoate 34 (Scheme 2). Similarly, the galactose‐derived 37 provided high yields of the 3‐sulfate 30a and of the 3‐benzoate 39. Direct sulfation of the phenylboronates 32 and 37 proceeded in lower yields and gave mixtures.

Stepwise synthesis of a GalNAc‐containing cluster glycoside ligand of the asialoglycoprotein receptor

A series of peptidylglycoside derivatives, including the tris(GalNAc-aminohexyl) glycoside of tyrosyl(glutamyl)-glutamate (1) which is known to have sub-nanomolar affinity for the asialoglycoprotein receptor (ASGPr), have been synthesized using the protected tetra-O-acetyl aminohexyl glycoside (9) of N-acetylgalactosamine. The N-succinyl derivative of 1 was also prepared, providing a derivative for bioconjugate formation via carboxyl activation of the glycopeptide. Use of the protected glycoside 9 affords synthetic intermediates with increased solubility in organic solvents that are easier to purify and use in subsequent synthetic manipulations in comparison with compounds containing unprotected glycosides. These synthetic procedures will be generally applicable to the preparation of related compounds to probe binding to the ASGPr and the use of these cluster glycosides as ligands for targeted delivery to the liver.

ChemInform Abstract: Synthesis of 6‐Deoxy and 3,6‐Dideoxy Derivatives from Unprotected Glycosides Employing the Mitsunobu Reaction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of 6‐Deoxy and 3,6‐Dideoxy Derivatives from Unprotected Glycosides Employing the Mitsunobu Reaction

AbstractStarting with unprotected hexopyranoside derivatives, an efficient synthesis of 6‐deoxy‐ and 3,6‐dideoxyhexopyranosides was achieved in two consecutive steps involving a highly regioselective Mitsunobu reaction and subsequent desulfurization.

Efficient Synthesis of Deoxy and Dideoxy Sugars by a Thio-Mitsunobu Reaction on Unprotected Glycosides

6-Deoxy-gluco- and 3,6-dideoxy-ribo-hexopyranosides were synthesized in two consecutive steps from unprotected β-glucopyranoside derivatives by a highly regioselective thio-Mitsunobu reaction and subsequent desulfurization. In contrast,the α-anomer reacted only at position 6.

Carbohydrate protein interactions. Syntheses of agglutination inhibitors of wheat germ agglutinin by phase transfer catalysis

Starting from chloride 1, a series of para-substituted aryl 2-acetamido-2-deoxy-β-D-glucopyranosides were prepared using phase transfer catalysis conditions with tetrabutylammonium hydrogen sulfate in 1 M sodium hydroxide and methylene chloride at room temperature. Zemplén de-O-acetylation afforded the unprotected glycosides. Optimization of reaction conditions was evaluated. Several functional group manipulations were effected to widen the number and nature of the para-substituents. Key words: phase transfer catalysis, aryl 2-acetamido-2-deoxy-β-D-glucopyranosides.

The substrate specificity of the enzyme amyloglucosidase (AMG). Part I. Deoxy derivatives.

The eight possible monodeoxy derivatives of methyl beta-maltoside and two bisdeoxy derivatives have been synthesized. The unprotected glycosides have all been investigated by NMR (1H and 13C) spectroscopy in order to confirm their structures and to obtain supporting information about their preferred solution conformations. The compounds have all been tested as substrates toward the hydrolase, amyloglucosidase (AMG) and it has been demonstrated that three hydroxy groups (3, 4' and 6') are essential for the compounds to act as substrate for the enzyme. The kinetic parameters KM (Michaelis-Menten constant) and VM (maximum rate for the reaction) have been determined using 1H NMR spectroscopy at 500 MHz.

Synthese regioselective de sulfites cycliques osidiques

Sugar cyclic sulfites are prepared through a two step reaction including the synthesis of dibutylstannylidene derivatives followed by their reaction with thionyl chloride under mild conditions. This reaction gives high yields of cyclic sulfites from unprotected glycosides.

Preparative syntheses of 2,6-dideoxy-α- L- lyxo-hexose (2-deoxy-α- L-fucose) and its D- ribo epimer (digitoxose)

Methyl 4,6- O-benzylidene-2-deoxy-α- D- ribo-hexopyranoside ( 1) is converted into methyl 3,4-di- O-benzoyl-6-bromo-2,6-dideoxy-α- D- ribo-hexopyranoside ( 3) via the 3- O-benzoyl derivative ( 2) of 1 by subsequent treatment with N-bromosuccinimide. Compound 3 is the key intermediate in high-yielding, preparative syntheses of the title dideoxy sugars, which are constituents of many antibiotics. Dehydrohalogenation of 3 affords the 5,6-unsaturated glycoside 7. which undergoes stereospecific reduction by hydrogen with net inversion at C-5 to give methyl 3,4-di- O-benzoyl-2,6-dideoxy-β- L- lyxo-hexopyranoside ( 8), whereas reductive dehalogenation of 3 provides the corresponding D- ribo derivative 4. The unprotected glycosides 9 ( L- lyxo) and 5 ( D- ribo) are readily obtained by catalytic transesterification, and mild, acid hydrolysis gives the crystalline title sugars 10 ( L- lyxo) and 6 ( D- ribo) in 45 and 57% overall yield from 1 without the necessity of chromatographic purification at any of the steps.