Introduction 2643 2. Nucleophilic Addition of Organometallic Reagents to N-Acyl Pyridinium Salts 2644 2.1. Regioselective Additions to N-Acyl Pyridinium Species and Their Derivatives 2644 2.1.1. Influence of Pyridine Ring Substituents on Regioselectivity of Addition 2646 2.1.2. Control of Regio-and Diastereoselectivity by the Introduction of Removable Blocking Groups 2648 2.2. Synthesis of 4-Pyridones: 1,2-Addition to 4-Methoxypyridines 2649 2.2.1. Diastereoselective Addition to 3-Trialkylsilyl-4-methoxypyridines 2651 2.2.2. Application in the Synthesis of Natural Products Containing Chiral Piperidine Units 2652 2.3. Diastereoselective 1,2-Addition to N-Imidoyl Pyridinium Salts 2652 2.4. Enantioselective 1,2-Addition Controlled by a Chiral Catalyst 2657 2.5. Diastereoselective 1,4-Addition Controlled by Pyridine 3-Substituents 2657 3. Nucleophilic Addition to N-Alkyl Pyridinium Salts and Their Derivatives 2659 3.1. Regioselective Additions to N-Alkyl Pyridinium SaltsNature of the Nucleophile 2659 3.1.1. Organometallic Reagents as Nucleophiles 2659 3.1.2. Cyanide as Nucleophile 2663 3.2. Diastereoselective Additions of Organometallic Reagents to N-Alkyl Pyridinium Salts 2663 3.3. Regioselective Additions of Enolates to N-Alkyl Pyridinium Salts 2666 3.3.1. Wenkert Procedure: Seminal Work 2667 3.3.2. Wenkert Procedure: Addition of Nucleophiles Positioned at the Nitrogen of Indole Derivatives 2670 3.3.3. Wenkert Procedure: Addition of Enolates Located at the C-2/C-3 Position of Indoles 2671 3.3.4. Addition of Miscellaneous Nucleophiles to N-Alkyl Pyridinium Species 2674 4. Nucleophilic Additions to N-Heteroatom Pyridinium Species 2676 4.1. Nucleophilic Additions to Pyridine N-Oxides and N−O Salts 4.1.1. Properties, Synthesis, and Deprotection of Pyridine N-Oxides 4.1.2. Addition of Grignard Reagents to Pyridine N-Oxides 4.1.3. Addition of Cyanide Nucleophiles via Reissert-Type Reactions 4.1.4. Addition of Hetero Nucleophiles to Pyridine N-Oxides and N−O Salts 4.

This communication describes a metal-free methodology involving an efficient and controlled reduction of secondary amides to imines, aldehydes, and amines in good to excellent yields under ambient pressure and temperature. The process includes a chemoselective activation of a secondary amide with triflic anhydride in the presence of 2-fluoropyridine. The electrophilic activated amide can then be reduced to the corresponding iminium using triethylsilane, a cheap, rather inert, and commercially available reagent. Imines can be isolated after a basic workup or readily transformed to the aldehydes following an acidic workup. The amine moiety can be accessed via a sequential reductive amination by the addition of silane and Hantzsch ester hydride in a one-pot reaction. Moreover, this reduction tolerates various functional groups that are usually reactive under reductive conditions and is very selective to secondary amides.

Glycosylated natural products and synthetic glycopeptides represent a significant and growing source of biochemical probes and therapeutic agents. However, methods that enable the aqueous glycosylation of endogenous amino acid functionality in peptides without the use of protecting groups are scarce. Here, we report a transformation that facilitates the efficient aqueous O-glycosylation of phenolic functionality in a wide range of small molecules, unprotected tyrosine, and tyrosine residues embedded within a range of complex, fully unprotected peptides. The transformation, which uses glycosyl fluoride donors and is promoted by Ca(OH), proceeds rapidly at room temperature in water, with good yields and selective formation of unique anomeric products depending on the stereochemistry of the glycosyl donor. High functional group tolerance is observed, and the phenol glycosylation occurs selectively in the presence of virtually all side chains of the proteinogenic amino acids with the singular exception of Cys. This method offers a highly selective, efficient, and operationally simple approach for the protecting-group-free synthesis of O-aryl glycosides and Tyr-O-glycosylated peptides in water.

The development of efficient and selective transformations is crucial in synthetic chemistry as it opens new possibilities in the total synthesis of complex molecules. Applying such reactions to the synthesis of ketones is of great importance, as this motif serves as a synthetic handle for the elaboration of numerous organic functionalities. In this context, we report a general and chemoselective method based on an activation/addition sequence on secondary amides allowing the controlled isolation of structurally diverse ketones and ketimines. The generation of a highly electrophilic imidoyl triflate intermediate was found to be pivotal in the observed exceptional functional group tolerance, allowing the facile addition of readily available Grignard and diorganozinc reagents to amides, and avoiding commonly observed over-addition or reduction side reactions. The methodology has been applied to the formal synthesis of analogues of the antineoplastic agent Bexarotene and to the rapid and efficient synthesis of unsymmetrical diketones in a one-pot procedure.

We report a synthetic glycosylation reaction between sucrosyl acceptors and glycosyl fluoride donors to yield the derived trisaccharides. This reaction proceeds at room temperature in an aqueous solvent mixture. Calcium salts and a tertiary amine base promote the reaction with high site-selectivity for either the 3′-position or 1′-position of the fructofuranoside unit. Because non-enzymatic aqueous oligosaccharide syntheses are underdeveloped, mechanistic studies were carried out in order to identify the origin of the selectivity, which we hypothesized was related to the structure of hydroxyl group array in sucrose. The solution conformation of various mono-deoxysucrose analogs revealed the cooperative nature of the hydroxyl group in mediating both this aqueous glycosyl bond-forming reaction and the site-selectivity at the same time.