Synthesis and reactivity of olefinic, carbohydrate-derived natural product analogs

Date of Completion

January 2009


Chemistry, Organic




Due to the ubiquity of carbohydrates in nature, the potential applications of carbohydrate mimics are far-reaching. Although formally part of the carbohydrate class of biomolecules, septanosides (representing a ring motif not observed in nature) are expected to mimic natural pyranose systems. Analogous to glycal chemistry, seven-membered cyclic enol ethers ( oxepines) were prepared as septanoside precursors. A novel three-step protocol was used in the preparation of these carbohydrate-derived oxepines from pyranose lactols. Functionalization of the oxepine olefin afforded a variety of septanosides. This method of pyranose homologation provides an extension from the anomeric position, offering an alternative to the C6-cyclization approach typical of septanoside preparation from aldohexose sugars. ^ In efforts toward determining conditions for the stereoselective preparation of septanoside sugars from oxepines, an analogy was drawn to conventional pyranose chemistry. The reactivity of a D-xylose-derived oxepine (ring-expanded glycal) was described and the corresponding iodonium and 1,2-anhydrosugar electrophilic intermediates were assessed for utility in preparing septanosides. Resultant from the 1,2-anhydrosugar pathway, a thiophenyl septanosyl donor was found to be useful in the unprecedented preparation of a diseptanoside. ^ Synthetic efforts were then focused on the preparation of rationally designed septanose analogs that were assessed for interactions with plant lectin concanavalin A. Despite the larger molecular volume and extra hydroxyl group, the unnatural septanoside ligands were found to bind to concanavalin A in competition with pyranosides. Such recognition events from a natural system lends support to the argument that septanosides may serve as useful pyranoside mimics. Further characterization of this interaction via the analysis of designed septanoside probes remains ongoing. ^ Emergent from studies investigating the ability of septanoside derivatives to serve as agents of biological activity, a series of unsaturated, carbohydrate-fused [13]-macrodiolides were prepared. Under thermodynamic cyclization conditions the facial presentation of the embedded olefin within this rigidified ring system was found to be dictated by the configuration of a stereocenter located five atoms/bonds away. The expected generality of this toggling mechanism among other rigidified macrocycles is put in context with examples from the literature. Preliminary results have shown some carbohydrate-fused [13]-macrodiolides to be active as inhibitors of cancer cell migration. ^