NFSI mediated C3-ether oxidation of glycals for the synthesis of hex-3-enuloses.

Hex-3-enuloses constitute a vital carbohydrate synthetic intermediate that provide access to wide range of chiral molecules through diverse derivatizations. Herein we report synthesis of these fascinating scaffolds by oxidation of C3-ether protections on glycals in presence of N-fluorobenzenesulfonimide (NFSI) under Cu(I) catalysed conditions. Benzyl, methyl and silyl ethers have been efficiently oxidized to the carbonyl group. The oxidation has been found to be highly regioselective where an array of protecting groups were tolerant to the reaction conditions. Pyranosyl glycals from various commercially available sugars have been studied in this work to evaluate the broad substrate scope.

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 ß-directing leaving groups on glycal substrates. The directing groups facilitate ß-selective Ferrier rearrangements for hard alcohol nucleophiles by following the Pd(0)-catalyzed Tsuji-Trost inner sphere pathway.

Cyanomethyl (CNMe) ether: an orthogonal protecting group for saccharides.

Logical manipulation of protecting groups is one of the vital strategies involved in the synthesis of complex oligosachharides. As opposed to the robust permanent protecting groups, the chemoselective protection-deprotection processes on orthogonal protecting groups have facilitated the synthesis of the target molecules with higher effeciency. While the derivatives of benzyl ethers are the most popular orthogonal ether based protecting groups for hydroxyls, the exploration of methyl ethers for similar synthetic application is much limited. We herein report cyanomethyl (CNMe) ether as a readily synthesized orthogonal protecting group for saccharides. The ether moiety was rapidly removed under Na-naphthalenide conditions in good to excellent yields and was found to be compatible with other well-known benzyl/methyl/silyl ether and acetal protecting groups. Additionally, the CNMe group was observed to be tolerant to standard reagents used for the deprotection of ether, ester and acetal protecting groups. The protection and deprotection steps remained unaffected by the position of hydroxyl, the configuration of monosaccharides or the presence of olefins in the skeleton.

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

Inner sphere Tsuji-Trost reaction has found recent application for ß-selective Ferrier rearrangement of glycal substrates with alcohol nucleophiles. Herein, we report an efficient and stereoselective synthesis of 2,3-dideoxy-ß-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 ß-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.

Cyanomethyl Ether as an Orthogonal Participating Group for Stereoselective Synthesis of 1,2-trans-ß-O-Glycosides.

Stereoselective formation of glycosidic linkages has been the prime focus for contemporary carbohydrate chemistry. Herein, we report cyanomethyl (CNMe) ether as an efficient and effective participating orthogonal protecting group for the stereoselective synthesis of 1,2-trans-ß-O-glycosides. The participating group facilitated good to high ß-selective glycosylation with a broad range of electron-rich and electron-deficient glycosyl acceptors. Detailed experimental and theoretical studies reveal the involvement of CNMe ether in the formation of a six-membered imine-type cyclic intermediate for the observed stereoselectivity. Rapid incorporation and selective removal of the CNMe ether group in the presence of benzyl ether and isopropylidene acetal protection have also been reported here. The nitrile group provided an opportunity for the glycodiversification through further derivatizations.

Imidates: an emerging synthon for N-heterocycles.

The unique electronic reactivity of imidates has been recently exploited for the syntheses of diverse classes of N-heterocycles via C-N annulation reactions under acid/base/metal-catalyzed/radical-mediated reaction conditions. As opposed to amides, the imidate functionality provides both electrophilic and nucleophilic centers and eventually enhances its versatility as an organic synthon. In general, imidate motifs act as the soft nucleophiles that coordinate with transition metals to form stable 5-membered metallacycles to activate the proximal C-H bonds followed by annulation reactions to afford the desired N-heterocycles. The imidate precursor also generates in situ nitrogen radicals under suitable conditions to form C-N bonds via 1,5-HAT. This review highlights the recent application of imidates as building blocks for the synthesis of saturated and un-saturated N-heterocycles like oxazolines, oxazines, quinazolines, isoquinolines, imidazoles, and triazoles among others. Different reaction conditions, coupling partners, and imidate substrates reported in the literature have been addressed herein for the nitrogen-containing mono-, bi- and tricyclic ring systems.

Gold(III)-Catalyzed Glycosylation using Phenylpropiolate Glycosides: Phenylpropiolic Acid, An Easily Separable and Reusable Leaving Group.

An efficient and operationally simple gold(III)-catalyzed glycosylation protocol was developed using newly synthesized benchtop stable phenylpropiolate glycosyl (PPG) donors. Gold(III)-catalyzed activation of PPGs proceeds well with various carbohydrate and noncarbohydrate-based glycosyl acceptors and leads to their corresponding O/ N-glycosides in good to excellent yields with regeneration of reusable and easily separable phenylpropiolic acid. Differentially protected PPGs reacted well under the optimized reaction conditions. In particular, good anomeric selectivity was observed with mannosyl and rhamnosyl PPG donors. A preliminary mechanistic study reveals that the presence of a triple bond adjacent to the ester group is essential for activation, and PPG-based donor shows higher reactivity than analogous acetate and benzoate donors.

Electron-deficient pyridinium salts/thiourea cooperative catalyzed O-glycosylation via activation of O-glycosyl trichloroacetimidate donors.

The glycosylation of O-glycosyl trichloroacetimidate donors using a synergistic catalytic system of electron-deficient pyridinium salts/aryl thiourea derivatives at room temperature is demonstrated. The acidity of the adduct formed by the 1,2-addition of alcohol to the electron-deficient pyridinium salt is increased in the presence of an aryl thiourea derivative as an hydrogen-bonding cocatalyst. This transformation occurs under mild reaction conditions with a wide range of O-glycosyl trichloroacetimidate donors and glycosyl acceptors to afford the corresponding O-glycosides in moderate to good yields with predictable selectivity. In addition, the optimized method is also utilized for the regioselective O-glycosylation by using a partially protected acceptor.

Primary Amide Directed Regioselective ortho-C-H-Arylation of (Aryl)Acetamides.

An efficient and regioselective palladium(II)-catalyzed primary acetamide assisted ortho arylation of arylacetamide has been discovered. This is the first report where functionalizable primary acetamide (-CH2CONH2) is used as a directing group for C(sp2)-H activation/cross-coupling reactions, circumventing the extra steps of installation and subsequent removal of the directing groups. The synthetic utility of this transformation is demonstrated through the scale-up synthesis. In addition, the primary acetamide can be manipulated into synthetically important derivatives such as nitriles and carboxylic acids.

Copper(II)-Mediated Aerobic Oxidation of Benzylimidates: Synthesis of Primary α-Ketoamides.

A simple and straightforward method for the synthesis of primary α-ketoamides has been discovered. The reaction represents the first example of benzylimidates directly converting to primary α-ketoamides by using sustainable molecular oxygen as an oxidant. This reaction proceeds in the presence of copper(II) salt via cleavage of benzylic C-H and C-O bonds of the benzylimidates with liberation of alcohols as the only byproduct. A wide substrate scope, operationally mild conditions, the use of single substrates, and a reaction scaled up to grams make this strategy very attractive and practical. Furthermore, mechanistic studies illustrate that the imidate group adjacent to the benzylic position plays crucial role in facilitating this chemical process.