The assembly of complex bacterial glycans presenting rare structural motifs and cis‐glycosidic linkages is significantly obstructed by the lack of knowledge of the reactivity of the constituting building blocks and the stereoselectivity of the reactions in which they partake. We here report a strategy to map the reactivity of carbohydrate building blocks and apply it to understand the reactivity of the bacterial sugar, caryophyllose, a rare C12‐monosaccharide, containing a characteristic tetrasubstituted stereocenter. We mapped reactivity–stereoselectivity relationships for caryophyllose donor and acceptor glycosides by a systematic series of glycosylations in combination with the detection and characterization of different reactive intermediates using experimental and computational techniques. The insights garnered from these studies enabled the rational design of building blocks with the required properties to assemble mycobacterial lipooligosaccharide fragments of M. marinum.

The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca 2+ -independent production of N -acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive N -acylethanolamines (NAEs) that are involved in various physiological processes such as food intake, pain, inflammation, stress, and anxiety. Recently, we identified α-ketoamides as the first pan-active PLAAT inhibitor scaffold that reduced arachidonic acid levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells. Here, we report the structure–activity relationships of the α-ketoamide series using activity-based protein profiling. This led to the identification of LEI-301 , a nanomolar potent inhibitor for the PLAAT family members. LEI-301 reduced the NAE levels, including anandamide, in cells overexpressing PLAAT2 or PLAAT5. Collectively, LEI-301 may help to dissect the physiological role of the PLAATs.

The assembly of complex bacterial glycans presenting rare structural motifs and cis-glycosidic linkages is significantly obstructed by the lack of knowledge of the reactivity of the constituting building blocks and the stereoselectivity of the reactions in which they partake. We here report a strategy to map the reactivity of carbohydrate building blocks and apply it to understand the reactivity of the bacterial sugars, caryophyllose, a rare C12-monosaccharide, containing a characteristic tetrasubstituted stereocenter. We mapped reactivity-stereoselectivity relationships for caryophyllose donor and acceptor glycosides, by a systematic series of glycosylations in combination with the detection and characterization of different reactive intermediates using experimental and computational techniques. The insights garnered from these studies enabled the rational design of building blocks with the required properties to assemble mycobacterial lipooligosaccharide fragments of M. marinum.

Cyclophellitols are potent inhibitors of exo- and endoglycosidases. Efficient synthetic methodologies are needed to fully capitalize on this intriguing class of mechanism-based enzyme deactivators. We report the synthesis of an orthogonally protected cyclitol from d -glucal (19% yield over 12 steps) and its use in the synthesis of α-(1,3)-linked di- and trisaccharide dextran mimetics. These new glycomimetics may find use as Dextranase inhibitors, and the developed chemistries in widening the palette of glycoprocessing enzyme-targeting glycomimetics.