Synthesis of conformation-restricted tripodal ligands for molecular recognition

Abstract

1,3,5-Triacetyl-2,4,6-trialkoxybenzenes are the derivatives of hexasubstituted benzene with fully alternated up-down arrangements of the binding arms to be exploited as the tripodal ligands. The precursor, 1,3,5-triacetyl-2,4,6-trihydroxybenzene (53), was synthesized from acetylations of phloroglucinol in one-pot process with 91% yield. Alkylations on the phenolic hydroxyl groups provided the scaffold 70-72 in the range of 72-93% yields, displaying ababab facial segregation of the respective substituents around the phenyl plane. Triple O-alkylations of the core structure 53 by 1,5-dibromopentane generated the symmetric intermediate 72 and subsequent substitutions with azide followed by reduction achieved the tris-amine ligand 86 in overall 59% yield. Chiral tripodal ligand 94 could also be obtained in overall 34% yield from the substitutions of intermediate 72 with (R)-(+)-1-phenylethylamine. The methylated product 70 was condensed with hydroxylamine to generate compound 75, which was substituted with protected L-proline derivatives. Chiral tripodal ligand 100 was obtained in overall 18% yield.