Ferrier Rearrangement Research Articles

Chemical Synthesis of 6-Azido-6-Deoxy Derivatives of Phosphatidylinositol Containing Different Fatty Acid Chains

This paper describes the synthesis of two 6-azido-6-deoxy derivatives of phosphatidylinositol (PI), which contained different fatty acid chains. These syntheses, starting from methyl α-d-glucopyranoside, employed multiple regioselective transformations with Ferrier rearrangement as one of the key steps. The PI derivatives contained different fatty acid chains in the lipids and an azido group in the inositol residue to facilitate their further functionalization under bioorthogonal conditions. Therefore, they should be useful probes for the investigation of PI and related biology, such as PI phosphorylation, PI interaction with other molecules in cells, and the functions of lipid structures in these processes.

Electrochemical Ferrier Rearrangement of Glycals.

The Ferrier rearrangement (FR) is a well-documented reaction that relies on strong acids or oxidants to convert glycals into unsaturated glycosyl derivatives. In this work, we introduce an electrochemical variant of the FR, offering a broad substrate compatibility. Various nucleophiles and glycal derivatives afford 2,3-unsaturated glycosyl derivatives in high yields with excellent diastereoselectivities. This sustainable method promises to expand the electrochemistry applications in sugar chemistry.

Insight into the Course of the Ferrier Rearrangement Used to Obtain Untypical Diosgenyl Saponins.

The Ferrier rearrangement was utilized to obtain 2,3-unsaturated diosgenyl glycosides. This reaction proceeded with high stereoselectivity, yielding mostly saponins with an α configuration (hexoses) or predominantly with a β configuration (pentoses). The diversity of the glycals used and the glycosides obtained enabled a deep discussion of the Ferrier rearrangement mechanism. The mechanism was supported by DFT calculations concerning the intermediate ions. It was concluded that the vinylogous anomeric effect may influence the reactivity of the glycals. Two possible Ferrier rearrangement intermediates, dioxolenium and allyloxycarbenium ions, were hypothesized to exist in thermodynamic equilibrium that shifted toward the former. The allyloxycarbenium ion participates in the final rearrangement step and determines the reaction regioselectivity. Furthermore, the conformational stability of the 2,3-unsaturated pyranose ring determines the stereoselectivity of the reaction. Factors influencing this stability, as well as the NMR data enabling recognition of the 0H5 and 5H0 conformations, were identified. Chemoselective hydrogenation of 2,3-unsaturated diosgenyl glycosides provided a series of 2,3-dideoxy analogues. The anticancer, hemolytic, and antibacterial activities of the synthesized saponins are presented alongside a discussion of the structure-activity relationships.

Influence of C-4 Axial/Equatorial Configuration and Neighboring Group/Remote Group Participation (NGP/RGP) Driven Conformational Evidence in Chemoselective Activation of Glycals.

We herein reveal the possibility of the C-4 neighboring group/remote group participation (NGP/RGP) facilitating the stabilization of the anomeric center via dioxolenium intermediates in the chemoselective activation of glycal donors. We further realized that the axial/equatorial configuration of the C-4 group in the galacto- and gluco-glycal series enables diverse pathways to give direct 1,2-addition or Ferrier rearrangement, respectively. A proof-of-principle for stereoselective glycosylation was amply illustrated by employing carbohydrates, amino acids, natural products, and bioactive molecules to develop 2-deoxy-glycan analogs.

Ferrier Glycosylation Mediated by the TEMPO Oxoammonium Cation.

The TEMPO oxoammonium cation has been proven to be both an efficient oxidizing reagent and an electrophilic substrate frequently found in organic reactions. Here, we report that this versatile chemical reagent can also be used as an efficient promoter for C- and N-glycosylation reactions through a Ferrier rearrangement with moderate to high yields. This unprecedented reactivity is explained in terms of a Lewis acid activation of glycal by TEMPO+ forming a type of glycal-TEMPO+ mesomeric structure, which occurs through an extended vinylogous hyperconjugation toward the π*(O═N+) orbital [LP(O1) → π*(C1═C2), π*(C1═C2) → σ*(C3-O3), and LP(O6) → π*(O═N+)]. This enables the formation of the respective Ferrier glycosyl cation, which is trapped by various nucleophiles. The extended hyperconjugation (or double hyperconjugation) toward the π*(O═N+) orbital, which confers the Lewis acid character of the TEMPO cation, was supported by natural bond orbital analysis at the M06-2X/6-311+G** level of theory.

Recent Advances of 2‐Nitroglycals as Powerful Glycosyl Donors

Abstract2‐Nitroglycals are important synthons for biological active 2‐aminoglycosides, glycoconjugates and natural products synthesis. Herein, we summarized the recent advances of 2‐nitroglycals including its synthetic methods and its applications. Using 2‐nitroglycals, 2‐aminoglycosides, nitro‐polyol derivatives, sugar‐furan derivatives, sugar‐pyrrole molecules, 2,3‐diaminoglycosides and 2‐amino‐1,3‐dithioglycosides were obtained via Michael–type addition, retro‐Henry‐type reaction, C1/C3‐Ferrier rearrangement and [3+2] N‐heterocyclic addition. Most of these conversions are achieved via mild organo‐catalysis glycosylation methods.

Microwave-induced ferrier rearrangement of hyroxy beta-lactams with glycals

Microwave-induced organic methods are extremely useful in synthetic organic chemistry for the preparation of molecules. A combination of irradiation and high temperature is probably responsible to obtain the final product in an accelerated process. This review focuses on a crucial nucleophilic reaction using hydroxy beta-lactams as the starting compounds. Specifically, the reaction of cis- and trans-hydroxy beta-lactams with different types of glycals under microwave irradiation using iodine as the catalyst is explored. This reaction produces unstaturated glycosides through Ferrier Rearrangement.

Stereoselective strain-release Ferrier rearrangement: the dual role of catalysts

ACu(OTf)2/Fe(OTf)3-promoted facile and stereoselective synthesis of 2,3-unsaturated glycosides through Ferrier rearrangement of rationally designed glycals with C3-CCBz. The dual roles of the metal catalysts in the reaction are explored with DFT.

Reinvestigation of SnCl4 catalyzed efficient synthesis of 2,3-unsaturated glycopyranosides

The Ferrier rearrangement is a powerful tool to prepare 2,3-unsaturated glycopyranosides. We have reinvestigated SnCl4 catalyzed Ferrier rearrangements through direct allylic substitution of the hydroxyl group at the C-3 position of glycals, resulting in the formation of stereoselective 2,3-unsaturated glycosides at 0 °C. The catalytic amount of SnCl4 (0.1 equiv.) was successfully used to promote this transformation on 3,4,6-tri-O-acetyl-D-glucal, 3,4,6-tri-O-acetyl-D-galactal and 3,4-di-O-acetyl-D-arabinal using various nucleophiles viz alcohols, azide and thiols to form a variety of 2,3-unsaturated glycopyranosides (pseudoglycals). This straightforward process is notable for its strong anomeric selectivity, excellent yields and shorter reaction time.

Amino-Acid-Derived Amides as Stereodirecting Leaving Groups for Ferrier Rearrangement via Pd(0)-Catalyzed Tsuji-Trost Reactions.

Ferrier rearrangement on glycals is an efficient tool to form 2,3-dideoxy glycosides that provide access to various sugar derivatives through olefin functionalization. The classical acid-mediated transformation delivers the α-O-glycosides selectively. In this protocol, amides obtained from amino acids, glycine and proline, have been utilized as sustainable β-directing leaving groups on glycal substrates. The directing groups facilitate β-selective Ferrier rearrangements for hard alcohol nucleophiles by following the Pd(0)-catalyzed Tsuji-Trost inner sphere pathway.

Cover Feature: Ferrier/Aza‐Wacker/Epoxidation/Glycosylation (FAWEG) Sequence to Access 1,2‐Trans 3‐Amino‐3‐deoxyglycosides (Chem. Eur. J. 17/2023)

Travelling without moving. A Ferrier rearrangement on commercial glycals brings the double bond from position 1,2 to 2,3. Subsequent Aza-Wacker reaction allows both a 3,4-cis amination at position 3 and movement of the double bond restoring the glycal. These motions, reminiscent of a swing, enable the synthesis of 3-amino-3-deoxyglycals. Epoxidation/Glycosylation of 3-amino-3-deoxygalactal derivative provide a disaccharide with high yield, defining “FAWEG” as a new sequence to access 1,2-trans 3-amino-3-deoxyglycosides. More information can be found in the Research Article by A. Joosten and co-workers (DOI: 10.1002/chem.202203987).

Ferrier/Aza-Wacker/Epoxidation/Glycosylation (FAWEG) Sequence to Access 1,2-Trans 3-Amino-3-deoxyglycosides.

3-Amino-3-deoxyglycosides constitute an essential class of nitrogen-containing sugars. Among them, many important 3-amino-3-deoxyglycosides possess a 1,2-trans relationship. In view of their numerous biological applications, the synthesis of 3-amino-3-deoxyglycosyl donors giving rise to a 1,2-trans glycosidic linkage is thus an important challenge. Even though glycals are highly polyvalent donors, the synthesis and reactivity of 3-amino-3-deoxyglycals have been little studied. In this work, we describe a new sequence, involving a Ferrier rearrangement and subsequent aza-Wacker cyclization that allows the rapid synthesis of orthogonally protected 3-amino-3-deoxyglycals. Finally a 3-amino-3-deoxygalactal derivative was submitted for the first time to an epoxidation/glycosylation with high yield and great diastereoselectivity, highlighting FAWEG (Ferrier/Aza-Wacker/Epoxidation/Glycosylation) as a new approach to access 1,2-trans 3-amino-3-deoxyglycosides.

Acid Catalyzed Stereocontrolled Ferrier-Type Glycosylation Assisted by Perfluorinated Solvent.

Described herein is the first application of perfluorinated solvent in the stereoselective formation of O-/S-glycosidic linkages that occurs via a Ferrier rearrangement of acetylated glycals. In this system, the weak interactions between perfluoro-n-hexane and substrates could augment the reactivity and stereocontrol. The initiation of transformation requires only an extremely low loading of resin-H+ and the mild conditions enable the accommodation of a broad spectrum of glycal donors and acceptors. The 'green' feature of this chemistry is demonstrated by low toxicity and easy recovery of the medium, as well as operational simplicity in product isolation.

Reactions of 1-C-acceptor-substituted glycals with nucleophiles under acid promoted (Ferrier-rearrangement) conditions

The reactivity of O-peracetylated and O-perbenzoylated 1-COOMe, 1-CONH2 and 1-CN-substituted glycals was studied against O-, S-, N- and C-nucleophiles in the presence of Lewis acids. Allylic substituted products with exclusive axial stereoselectivity were formed with simple alcohols, N3−, and Cl− ions, but with benzyl thiol the Ferrier rearrangement took place and thioglycosides were obtained. The use of a sugar derived thiol resulted in the formation of both the allylic substituted and the rearranged products.

Citric acid mediated simple and stereoselective synthesis of o-linked glycosides by Ferrier rearrangement

A simple and environment-friendly citric acid-mediated synthesis of glycosides has been reported using Ferrier-rearrangement. Using this protocol, synthesis of several glycosides including pseudo disaccharides was prepared. Citric acid was successfully employed for the synthesis of glycosides from D-glucal, L-rhamnal, D-xylal and D-galactal with various alcohols to give a broad range of glycosides in up to 80% yields with α-isomer as major product under mild reaction conditions.

Antimicrobial and anticancer activities of copolymers of tri-O-acetyl-D-glucal and itaconic anhydride

This paper reports the synthesis and characterization of monomers itaconic anhydride (IA) and tri-O-acetyl-D-glucal (TAG) as well as 4,6-di-O- -acetyl-D-glucal (PSG). The homopolymers and copolymers of IA and TAG were synthesized via free radical copolymerization in bulk, using azobisisobutyronitrile as an initiator with different feed ratios of monomers. Their structural, molecular and thermal characterization was done using 1H-NMR spectroscopy, gel permeation chromatography and differential scanning calorimetry, respectively. The glass transition temperature (Tg) of copolymers was found in the range of 139?145 ?C. The highest Tg was found for IA?TAG2 copolymers, whereas IA?TAG4 copolymer showed lowest Tg. The molecular weight of the copolymers was in the range 5157?5499 g mol-1. The monomer TAG undergoes Ferrier rearrangement in water to give PSG. The antimicrobial activity of IA, TAG, PSG and IA?TAG copolymers was studied using the minimum microbicidal concentration-broth dilution method. TAG, IA and PSG, as well as homopolymer and copolymers of IA and TAG are excellent antimicrobial agents.

O-Cyanobenzoate: A Recyclable and Reusable Stereo-directing Group for β-O-Glycosylation via Pd(0)-catalyzed Ferrier Rearrangement.

Inner sphere Tsuji-Trost reaction has found recent application for β-selective Ferrier rearrangement of glycal substrates with alcohol nucleophiles. Herein, we report an efficient and stereoselective synthesis of 2,3-dideoxy-β-O-glycosides from C3-(o-cyanobenzoate) ester protected glycal donors via Ferrier rearrangement under Pd(0)-catalyzed Tsuji-Trost conditions. The synthesized donors indeed reacted with a variety of acceptors to afford the corresponding glycosides in good yields and excellent β-stereoselectivity. The stereochemical outcome of the reactions has been found to be independent of the nature of protecting groups or conformational flexibility of the glycal donors. Furthermore, regeneration of ortho-cyanobenzoic acid post rearrangement makes it a recyclable and reusable stereodirecting group. A preliminary mechanistic study demonstrates the importance of cyano-group for the observed rearrangement and stereoselectivity. Incorporation of the directing group on the benzoate ester has altered the reactivity of the ester group as a leaving group for Tsuji-Trost as well as Ferrier Rearrangement pathway.

Electrochemical Bromination of Glycals.

Herein, the convenient one-step electrochemical bromination of glycals using Bu4NBr as the brominating source under metal-catalyst-free and oxidant-free reaction conditions was described. A series of 2-bromoglycals bearing different electron-withdrawing or electron-donating protective groups were successfully synthesized in moderate to excellent yields. The coupling of tri-O-benzyl-2-bromogalactal with phenylacetylene, potassium phenyltrifluoroborate, or a 6-OH acceptor was achieved to afford 2C-branched carbohydrates and disaccharides via Sonogashira coupling, Suzuki coupling, and Ferrier rearrangement reactions with high efficiency. The radical trapping and cyclic voltammetry experiments indicated that bromine radicals may be involved in the reaction process.

New insights into the reactivity of 2-halo-glycals: Synthesis of novel iodinated O- and S-glycosides

We present the selective synthesis of new 2-iodo-2,3-unsaturated O- and S-glycosides. This is the first report on the Ferrier rearrangement of 2-halo-glycals with S-nucleophiles. We obtained α-glycosides in good yields and with high anomeric selectivity. We also describe the particular behavior of heteroaromatic thio sugar derivatives, where the C3 addition was performed in an alternative mechanism. We present a complete structure and conformation analysis by NMR.

From Glycals to Nitrogen Heterocycles and Carbocycles via "Cleavage-Intramolecular Recombination Strategy".

Glycals (carbohydrate enol-ethers) have enjoyed profound applications in organic synthesis for more than a century. They not only serve as versatile glycosyl donors or as substrates for Ferrier rearrangement, but also find extensive synthetic applications especially as a "chiral pool" for accomplishing the synthesis of a variety of natural and biologically important compounds. As cyclic enol ethers, they demonstrate high reactivity and are among the most and variously transformable monosaccharide derivatives. The uniqueness of the reactivity of glycals is that they can be synthetically tuned to get a library of derivatives through stereo- and regioselective introduction of a variety of functional groups at C1, C2, C3 as well as C4 carbons of the sugar. We have developed a practical approach for stereoselective mono- and diamination of glycals and over the years utilized these scaffolds for the synthesis of a variety of biologically important nitrogen heterocycles and carbocycles through a "Diversity Oriented Approach". Our synthetic strategy in this direction mainly relied on the cleavage of ring O-C bond of the sugar followed by an "intramolecular recombination" reaction. Utilizing this strategy, we have accomplished the synthesis of several biologically important natural products, their analogues and related unnatural derivatives. Examples of such compounds reported from our group include polyhydroxypyrrolidines, DMDP, anisomycin, steviamine, pochonicine, conduramines, bulgecinine, aminocyclitols, azepanes, 4-hydroxy-D-proline, azanucleosides and their analogues. A personal account highlighting these syntheses is presented here.