α-Fluoroenamides, potent rigid fluorinated bioisosters of ureas, have been synthesized by a highly regio- and stereo-selective hydrofluorination of ynamides in anhydrous HF. This reaction provides the first general entry to α-fluoroenamides and can easily be applied to a wide range of substrates.

The broad application of well-defined synthetic oligosaccharides in glycobiology and glycobiotechnology is largely hampered by the lack of sufficient amounts of synthetic carbohydrate specimens. Insufficient knowledge of the glycosylation reaction mechanism thwarts the routine assembly of these materials. Glycosyl cations are key reactive intermediates in the glycosylation reaction, but their high reactivity and fleeting nature have precluded the determination of clear structure–reactivity-stereoselectivity principles for these species. We report a combined experimental and computational method that connects the stereoselectivity of oxocarbenium ions to the full ensemble of conformations these species can adopt, mapped in conformational energy landscapes (CEL), in a quantitative manner. The detailed description of stereoselective S_N1-type glycosylation reactions firmly establishes glycosyl cations as true reaction intermediates and will enable the generation of new stereoselective glycosylation methodology.

Carbohydrates (glycans, saccharides, and sugars) are essential molecules in all domains of life. Research on glycoscience spans from chemistry to biomedicine, including material science and biotechnology. Access to pure and well-defined complex glycans using synthetic methods depends on the success of the employed glycosylation reaction. In most cases, the mechanism of the glycosylation reaction is believed to involve the oxocarbenium ion. Understanding the structure, conformation, reactivity, and interactions of this glycosyl cation is essential to predict the outcome of the reaction. In this Account, building on our contributions on this topic, we discuss the theoretical and experimental approaches that have been employed to decipher the key features of glycosyl cations, from their structures to their interactions and reactivity. We also highlight that, from a chemical perspective, the glycosylation reaction can be described as a continuum, from unimolecular S_N1 with naked oxocarbenium cations as intermediates to bimolecular S_N2-type mechanisms, which involve the key role of counterions and donors. All these factors should be considered and are discussed herein. The importance of dissociative mechanisms (involving contact ion pairs, solvent-separated ion pairs, solvent-equilibrated ion pairs) with bimolecular features in most reactions is also highlighted. The role of theoretical calculations to predict the conformation, dynamics, and reactivity of the oxocarbenium ion is also discussed, highlighting the advances in this field that now allow access to the conformational preferences of a variety of oxocarbenium ions and their reactivities under S_N1-like conditions. Specifically, the ground-breaking use of superacids to generate these cations is emphasized, since it has permitted characterization of the structure and conformation of a variety of glycosyl oxocarbenium ions in superacid solution by NMR spectroscopy. We also pay special attention to the reactivity of these glycosyl ions, which depends on the conditions, including the counterions, the possible intra- or intermolecular participation of functional groups that may stabilize the cation and the chemical nature of the acceptor, either weak or strong nucleophile. We discuss recent investigations from different experimental perspectives, which identified the involved ionic intermediates, estimating their lifetimes and reactivities and studying their interactions with other molecules. In this context, we also emphasize the relationship between the chemical methods that can be employed to modulate the sensitivity of glycosyl cations and the way in which glycosyl modifying enzymes (glycosyl hydrolases and transferases) build and cleave glycosidic linkages in nature. This comparison provides inspiration on the use of molecules that regulate the stability and reactivity of glycosyl cations.

Due to their combined stability and peculiar reactivity, ynamides have emerged as remarkably useful building blocks for chemical synthesis. The development of general and robust methods for their preparation has resulted in a massive interest in their chemistry. This notably gave rise to the development of incredibly efficient processes starting from these building blocks, which also recently found various applications in medicinal chemistry and natural product synthesis. Our efforts and contributions to the chemistry of ynamides, for which we have developed several reactions both for their preparation and for their use in synthesis, are overviewed in this highlight review.