Making Analogues of Tröger's Base – Fused oligomers, endo/exo isomers and twisted amides

Sammanfattning: The centenarian Tröger’s base (TB) was envisaged as scaffold for the construction of tubular-shaped cleft molecules due to its the remarkable structural properties. This endeavor started with the synthesis of the three possible diastereomers of a linear symmetrically fused tris-TB analogue, the anti-anti, the syn-syn, and the syn-anti. All three diastereomers showed unprecedented stability to acid isomerization. The desymmetrization protocol presented, established the foundations for the synthesis of higher generations of fused analogues of TB. Following this, new methodologies for the functionalization of both the aromatic and the methanodiazocine ring of TB were introduced. The development of a palladium-catalyzed amination conditions converted 2,8-dihalo analogues of TB to their corresponding mono- and diamino analogues. Regarding the diazocine ring, the benzylic methylenes of TB were oxidized to give the first example of a twisted bis-amide. Its unconventional amide reactivity allowed the development of the first rational synthesis of 6,12-endo,endo-substituted analogues of TB. Alternatively, endo and exo functionalization of the benzylic methylenes was also achieved via metalation followed by electrophilic quenching. All the knowledge acquired was ultimately used in the synthesis of the first fused heptakis-TB analogue. The functionalization at the benzylic positions of TB with (R)-menthyl ester groups allowed the diastereomeric resolution of the TB analogue. Each diastereomer was used to independently build two differently substituted fused heptakis-TB analogue. Our developed synthetic strategy, involving the sequential condensation, hydrolysis, desymmetrization, and condensation, together with a remarkable solubility in organic solvents observed for the heptakis-TB’s, sets the stage to build even higher generations of fused oligo-TB.