Synthesis of molecular frameworks containing two distinct heterocycles connected in a single molecule with enhanced three-dimensional shape diversity.

ABSTRACT

Herein, we report the synthesis of fused-triazole scaffolds that are connected by pyrimidines, pyrazoles, or pyrazolopyrimidines through carbohydrate-derived stereodivergent linkers. Pyrimidine-, pyrazole-, or pyrazolopyrimidine-based carbohybrids were constructed through condensations of the key intermediates, 2-C-formyl glycals, with various dinucleophiles. Fused-triazole scaffolds were obtained through intramolecular 1,3-dipolar cycloadditions after selective functionalization of the carbohybrid polyol moieties with azide and alkyne functionalities using SN 2-type alkylations or Mitsunobu reactions. Overall, this synthetic method affords two distinct privileged substructures in a single molecule, connected by stereodivergent diol linkers derived from abundant natural chiral sources, namely, carbohydrates. The resulting vicinal diols in the linker were further modified to achieve unique connectivities between the two privileged structures for maximized three-dimensional shape diversity, which we called the linker diversification strategy.