A dense hydrogen‐bond network is responsible for the mechanical and structural properties of polysaccharides. Random derivatization alters the properties of the bulk material by disrupting the hydrogen bonds, but obstructs detailed structure–function correlations. We have prepared well‐defined unnatural oligosaccharides including methylated, deoxygenated, deoxyfluorinated, as well as carboxymethylated cellulose and chitin analogues with full control over the degree and pattern of substitution. Molecular dynamics simulations and crystallographic analysis show how distinct hydrogen‐bond modifications drastically affect the solubility, aggregation behavior, and crystallinity of carbohydrate materials. This systematic approach to establishing detailed structure–property correlations will guide the synthesis of novel, tailor‐made carbohydrate materials.

Biopolymers, like DNA and proteins, fold in specific conformations in order to exert complex biological functions. Synthetic modifications are commonly used to alter those conformations and create engineered biomaterials. In stark contrast, the chemical complexity and dynamic nature of polysaccharides have hampered a detailed structural characterization and structure−function correlations are still incomplete. Many synthetic strategies have been developed to access complex unnatural oligosaccharides, capable of mimicking or even improving the properties of the natural counterpart. However, the structural features behind these results are often neglected. This perspective highlights the approaches adopted to develop unnatural glycans, with a particular focus on how the insertion of specific modifications results in more flexible or more constrained structures. Synthetic analogues of natural oligosaccharides could shine light on fundamental structural features. The combination of modern synthetic, computational, and analytical methods will result in novel carbohydrate based foldamers, with defined shape and aggregation behavior. Multiple applications in biology, material science, and nanotechnology can be envisioned.

Cellulose is a polysaccharide that displays chirality across different scales, from the molecular to the supramolecular level. This feature has been exploited to generate chiral materials. To date, the mechanism of chirality transfer from the molecular level to higher-order assemblies has remained elusive, partially due to the heterogeneity of cellulose samples obtained via top-down approaches. Here, we present a bottom-up approach that uses well-defined cellulose oligomers as tools to understand the transfer of chirality from the single oligomer to supramolecular assemblies beyond the single cellulose crystal. Synthetic cellulose oligomers with defined sequences self-assembled into thin micrometer-sized platelets with controllable thicknesses. These platelets further assembled into bundles displaying intrinsic chiral features, directly correlated to the monosaccharide chirality. Altering the stereochemistry of the oligomer termini impacted the chirality of the self-assembled bundles and thus allowed for the manipulation of the cellulose assemblies at the molecular level. The molecular description of cellulose assemblies and their chirality will improve our ability to control and tune cellulose materials. The bottom-up approach could be expanded to other polysaccharides whose supramolecular chirality is less understood.