Versatile approach towards fully desymmetrized trehalose with a novel set of orthogonal protecting groups.

Trehalose-containing glycans play an essential role in bacterial pathogenesis, host-pathogen interaction, and cell signaling. The investigation of trehalose uptake and metabolism in Mycobacteria using synthetic desymmetrized trehalose probes is an important approach for the development of diagnostic tools and potential therapeutics for tuberculosis. Trehalose-derived mycobacterial glycolipids activate the innate immune response through recognition by the C-type lectin Mincle, justifying efforts to develop novel trehalose-based Mincle-dependent adjuvants. The chemical synthesis of trehalose-based glycoconjugates, glycolipids, and small-molecule trehalose probes requires the challenging chemical desymmetrization of eight hydroxyl groups in a C 2-symmetric disaccharide αGlc(1↔1)αGlc. Using a novel set of orthogonal protecting groups, we developed a flexible multiscale synthetic approach to a collection of differently and variably protected fully desymmetrized trehalose derivatives, ready for final chemical modification with relevant functional or reporter groups. Using a regioselective and site-specific protecting group strategy, we performed multiple symmetry-breaking operations, resulting in a library of trehalose-derived orthogonally protected building blocks as a versatile source for the synthesis of complex trehalose-containing glycans.

Regioselective 3-O-Substitution of Unprotected Thiodigalactosides: Direct Route to Galectin Inhibitors.

The synthesis of tailored bioactive carbohydrates usually comprises challenging (de)protection steps, which lowers synthetic yields and increases time demands. We present here a regioselective single-step introduction of benzylic substituents at 3-hydroxy groups of ß-d-galactopyranosyl-(1→1)-thio-ß-d-galactopyranoside (TDG) employing dibutyltin oxide in good yields. These glycomimetics act as inhibitors of galectins-human lectins, which are biomedically attractive targets for therapeutic inhibition in, for example, cancerogenesis. The affinity of the prepared glycomimetics to galectin-1 and galectin-3 was studied in enzyme-linked immunosorbent (ELISA)-type assays and their potential to inhibit galectin binding on the cell surface was shown. We used our original in vivo biotinylated galectin constructs for easy detection by flow cytometry. The results of the biological experiments were compared with data from molecular modeling with both galectins. The present work reveals a facile and elegant synthetic route for the preparation of TDG-derived glycomimetics that exhibit differing selectivity and affinity to galectins depending on the choice of 3-O-substitution.

Enantioselective Synthesis of All-Carbon Quaternary Centers Structurally Related to Amaryllidaceae Alkaloids.

Enantioselective synthesis of all-carbon quaternary centers remains a considerable challenge for synthetic organic chemists. Here, we report a two-step protocol to synthesize such centers including tandem cyclization/Suzuki cross-coupling followed by halocarbocyclization. During this process, two rings, three new C-C bonds and a stereochemically defined all-carbon quaternary center are formed. The absolute configuration of this center is controlled by the stereochemistry of the adjacent stereocenter, which derives from an appropriate enantioenriched starting material. Using this method, we synthesized polycyclic compounds structurally similar to Amaryllidaceae alkaloids in high enantiomeric excesses. Because these products resemble naturally occurring compounds, our protocol can be used to synthesize various potentially bioactive compounds.