InCl3-CH3CN-H2O: an efficient catalyst-solvent combination for the synthesis of Perlin aldehydes and related compounds. Application in the synthesis of unnatural l-azasugars

InCl₃-CH₃CN-H₂O has been found to be an efficient catalyst-solvent combination for the synthesis of Perlin aldehydes and related compounds. While acetylated glycals afforded the Perlin aldehydes directly with InCl₃ and water, benzylated glycals on the other hand provided the hemiacetals under identical condition. The methodology reports a non-mercurial approach to Perlin aldehydes. Noteworthy is that this reaction is more facile as well as highly selective with glycals possessing a hydroxyl as a leaving group than with a benzyloxy group. Extension of this reaction to 2-C-hydroxymethyl glycals resulted in the formation of the corresponding hemiacetals, which were further transformed in to unsaturated azasugars with an exo-methylene group at C-2 position. Glycosidase inhibition studies reveal that these compounds display selectivity in inhibiting glucosidases rather than galactosidases.     

Homogeneous azidophenylselenylation of glycals using TMSN3-Ph2Se2-PhI(OAc)2

An improved preparative method for homogeneous azidophenylselenylation of glycals is described consisting of reaction with TMSN₃ and Ph₂Se₂ in the presence of PhI(OAc)₂. The use of TMSN₃ instead of NaN₃ as in the heterogeneous procedure, allowed both a reduced reaction time and a scale-up that was not possible in the case of the azidophenylselenylation of substituted glycals using NaN₃.     

Indium trichloride promoted stereoselective synthesis of O-glycosides from trialkyl orthoformates

A novel, highly stereoselective method for O-glycosylation of glycals and glycosylbromides is developed using orthoformates as acceptors in the presence of InCl₃ to afford the corresponding O-glycopyranosides in 66-94% yield. Both perbenzyl and peracetyl glycals afford the corresponding 2,3-unsaturated-O-glycosides with high α-selectivity. Stoichiometric amounts of orthoformates are sufficient to bring about this transformation instead of large excesses of alcohols.     

An improved synthesis of pyrimidine- and pyrazole-based acyclo-C-nucleosides as carbohybrids

The synthesis of pyrimidine- and pyrazole-based acyclo-C-nucleosides as carbohybrids was optimized and developed. The synthesis of acyclic polyol-fused pyrimidines was achieved in good to excellent yield with high purity by the cyclocondensation of 2-C-formyl glycals and various amidines using K₂CO₃ as inorganic base in co-solvent system. In comparison, the syntheses of pyrazole-based acyclo-C-nucleosides were accomplished simply by the cyclocondensation of 2-C-formyl glycals with hydrazine hydrate at room temperature and with phenyl hydrazine at refluxing temperature in ethanol.     

Direct Ferrier rearrangement on unactivated glycals catalyzed by indium(III) chloride

Anhydrous InCl₃ has been shown to efficiently catalyze the Ferrier rearrangement by a direct allylic substitution of the hydroxyl group at C-3 position of glycals to afford the corresponding 2,3-unsaturated glycosides in high yields at ambient temperature. This methodology obviates the need for protecting and/or activating the C-3 hydroxyl group of glycals. The reaction works in equal ease with both 4,6-di-O-benzyl-d-glucal and 4,6-di-O-benzyl-d-galactal. The mildness of InCl₃ makes this approach compatible for glycosyl acceptors with acid labile groups. The generality of the reaction has been demonstrated with a diversity of alcohols, phenols, and sugar nucleophiles.     

Stereoselective synthesis of 2-C-methylene glycosides and disaccharides via direct allylic substitution of hydroxy group in benzylated glycals

InCl₃ efficiently catalyzes allylic substitution of the hydroxy group of 2-C-hydroxymethyl glycals to afford a diversity of 2-C-methylene alkyl and aryl glycosides as well as disaccharides in high yields. This protocol surpasses the existing methods for the synthesis of 2-C-methylene glycosides as it obviates the need for functionalizing the allylic hydroxy group of glycals. The interest of this methodology relies on the extremely mild conditions required even with a free hydroxyl group at the allylic position of the glycals and that too only with a catalytic amount of InCl₃. The reaction is fast (30 min.), stereoselective and is compatible with a variety of oxygenated nucleophiles including those possessing acid-labile groups. A mechanistic investigation on the direct formation of an α,α-(1→1)linked disaccharide derivative from 2-C-hydroxymethyl galactal reveals that the reaction proceeds through a domino Ferrier rearrangement followed by a facile 1,3-alkoxy migration.     

Reactions of glycals with xenon fluoride: an improved synthesis of 2-deoxy-2-fluorosaccharides

The 1,2-double bond in acetylated glycals has been fluorinated with XeF₂ in the presence of BF₃ to give 1,2-deoxy-1,2-difluorosaccharides. A mechanism for this reaction has been proposed. This method represents an improvement in the synthesis of 2-deoxy-2-fluorosaccharides.     

Ferric Sulphate Hydrate–Catalyzed,Microwave‐Assisted Synthesis of 2,3‐Unsaturated O‐Glycosides via the Ferrier Reaction

Fe₂(SO₄)₃ · xH₂O catalyzes the Ferrier reaction of per‐O‐acetylated/benzylated glycals with alcohols to give 2,3‐unsaturated α‐glycosides in a few minutes under microwave irradiation.     

An efficient synthesis of 1-cyano-2,3-unsaturated sugars via the reaction of glycals with Et2AlCN

The reaction of glycals 1a-d with Et₂AlCN in benzene at room temperature leads to formation of the corresponding 1-cyano-2,3-unsaturated sugars 2a-d and 3a-d in good to excellent yields.     

Niobium(V) chloride catalyzed microwave assisted synthesis of 2,3-unsaturated O-glycosides by the Ferrier reaction

NbCl₅ catalyzes the Ferrier reaction of per-O-acetylated glycals with primary, secondary, allylic, benzylic and monosaccharide alcohols to give 2,3-unsaturated α-glycosides in short reaction times under microwave irradiation conditions.     

A Substrate‐Based Approach to Skeletal Diversity from Dicobalt Hexacarbonyl (C1)‐Alkynyl Glycals by Exploiting Its Combined Ferrier–Nicholas Reactivity

Novel substrates that combine dicobalt hexacarbonyl propargyl (Nicholas) and pyranose‐derived allylic (Ferrier) cations have been generated by treatment of hexacarbonyldicobalt (C‐1)‐alkynyl glycals with BF₃^.Et₂O. The study of these cations has resulted in the discovery of novel reaction pathways that have shown to be associated to the nature of O‐6 substituent in the starting alkynyl glycals. Accordingly, compounds resulting from ring expansion (oxepanes), ring contraction (tetrahydrofurans), or branched pyranoses, by incorporation of nucleophiles, can be obtained from 6‐O‐benzyl, 6‐hydroxy, or 6‐O‐silyl derivatives, respectively. The use of a 6‐O‐allyl alkynyl glycal led to a suitable funtionalized oxepane able to experience an intramolecular Pauson–Khand cyclization leading to a single tricyclic derivative.     

Syntheses of 5′-O-glycosylnucleosides

A general synthetic approach to 2,3-unsaturated glycosides connecting with nucleosides involving Ferrier rearrangements of glycals is discussed. The new compounds were identified by NMR and MS (HRFAB⁺). The hydroxylation of the resulting 2,3-unsaturated glycosides was completed using OsO₄ to give 5′-O-glycosylnucleosides in good yield.     

Avoiding pyran ring opening during palladium acetate catalyzed C-glycosidation of peracetylated glycals

Palladium acetate catalyzed C-glycosidation of peracetylated glycals with arylboronic acids in acetonitrile (CH₃CN) yields the desired 1-substituted 2,3-unsaturated glycal as well as a byproduct corresponding to the ring-opened pyran, present in varying proportions depending on the reaction conditions used. The byproduct is not formed when toluene/EtOH is used as reaction solvent.     

Synthesis of C-2 methylene glycosides from C-2 propargyloxymethyl glycals exploiting the alkynophilicity of AuCl3

C-2 Methylene glycosides were synthesized from C-2 propargyloxymethyl glycals in a stereoselective manner using a catalytic quantity of AuCl₃. The Au-catalyzed reaction was explored using various aglycones. The current protocol enables the preparation of C-2 methylene glycosides, tolerates diverse functional groups and is fast, catalytic and mild.     

Synthesis of and Glycosidation by 2-Deoxy-2-Fluoro-D-Mannopyranose

Abstract

With the increased biochemical interests of fluorocarbohydrates, several approaches have been establised toward the synthesis of 2-deoxy-2-fluorocarbohydrates by taking advantage of the ease of the addition reaction to readily available peracetylated glycals by employing either CF₃OF,¹ F₂,² or XeF₂,³ More stereochemically controlled approaches utilize the epoxide opening reaction with KHF₂ ⁴ or the displacement of 2-0-triflate by CsF.⁵     

A Simple and Efficient New Glycal Synthesis

Abstract

Potassium-graphite laminate (C₈K) in oxolane almost instantaneously converts O-alkyl and O-aUcylidene pyranosyl and furanosyl chlorides under extremely mild conditions and in high yields into pyranoid and furanoid glycals, which in the presence of an additional mole of C₈K, are efficiently O-alkylated or O-silylated In easily conducted one-pot reactions.     

Microwave-Assisted Regioselective Benzylation: An Access to Glycal Derivatives with a Free Hydroxyl Group at C4

D-glucal, D-galactal, and their 6-O-TBDMS derivatives were benzylated in a two-step procedure under microwave conditions. In the first step glycals were converted into dibutylstannylene acetal or tributyltin ether intermediates, which were next alkylated with benzyl bromide in the presence of Bu₄NBr. In all cases the 4-OH group stayed unsubstituted. Microwave-assisted benzylation contributes to a significant reduction of the reaction time in comparison with the classical synthesis, which requires several hours of heating. Supplemental materials are available for this article. Go to the publisher's online edition of Journal of Carbohydrate Chemistry to view the free supplemental file.     

HSAB-driven regioselectivity difference in the Lewis-acid catalyzed reactions of 2-C-substituted glycals with sulfur and oxygen nucleophiles: direct versus allylic substitution

A remarkable regioselectivity difference in the Lewis-acid catalyzed reactions of 2-C-acteoxymethyl glycals with thiophenols and phenols has been observed. The reaction with thiophenols led to preferential formation of a new class of compounds viz. 2-C-arylthiomethyl glycals via direct attack at the C-2 side chain primary carbon bearing the leaving group. In contrast, phenols were reported to afford predominantly 2-C-methylene-O-aryl glycosides via allylic attack at the anomeric carbon. The observed results correlate well with the HSAB principle proposed earlier for similar type of reactions with simple glycals. In addition, formation of an unusual bis-thioarylated product in presence of an excess of thiophenol is also reported.     

InBr3-catalyzed cyclization of glycosides with arylamines

Glycals have served as excellent substrates in the glycosidation reactions with arylamines to construct both C–C and C–N linkages simultaneously. However, the high reactivity and moisture/alcohol-sensitivity is also responsible for several side reactions. Herein we reported that 2,3-unsaturated glycosides can be used as alternatives of glycals to take part in the corresponding glycosidation as well. Therefore, with 10% of InBr₃ or InI₃ as the catalyst, 2,3-unsaturated glycosides containing various C-1 alkoxy groups reacted with arylamines smoothly and produced the glycosidation products in moderate to good yields as a pair of diastereomers with variant diastereoselectivity.     

Synthesis of C1-alkyl- and acylglycals from glycals using a B-alkyl Suzuki-Miyaura cross coupling approach

A B-alkyl Suzuki-Miyaura cross coupling approach provides a flexible, efficient means to convert glycals to C1-alkylglycals and C1-acylglycals that are versatile synthetic intermediates. This approach uses readily available glycal starting materials and overcomes major limitations associated with direct alkylation or acylation of glycals. Further, a commonly observed side reaction involving reduction of the halide coupling partner is suppressed by preincubation of the borane coupling partner with aqueous base, providing new mechanistic insights into the side reaction.