biostudies-literatureUnknown9(8)Gao DDeutsche ForschungsgemeinschaftThe activity of pharmacologically active compounds can be increased by presenting a drug in a defined conformation, which fits exactly into the binding pocket of its target. Herein, the piperazine scaffold was conformationally restricted by substituted C<sub>2</sub>- or C<sub>3</sub>-bridges across the 2- and 6-position. At first, a three-step, one-pot procedure was developed to obtain reproducibly piperazine-2,6-diones with various substituents at the N-atoms in high yields. Three strategies for bridging of piperazine-2,6-diones were pursued: 1. The bicyclic mixed ketals 8-benzyl-6-ethoxy-3-(4-methoxybenzyl)-6-(trimethylsilyloxy)-3,8-diazabicyclo[3.2.1]octane-2,4-diones were prepared by Dieckmann analogous cyclization of 2-(3,5-dioxopiperazin-2-yl)acetates. 2. Stepwise allylation, hydroboChemistryOpen874-889https://www.ebi.ac.uk/biostudies/studies/S-EPMC7450790biostudies-literatureRigid Scaffolds: Synthesis of 2,6-Bridged Piperazines with Functional Groups in all three Bridges.PMC7450790Penno CWunsch BGao DfalseRigid Scaffolds: Synthesis of 2,6-Bridged Piperazines with Functional Groups in all three Bridges.The activity of pharmacologically active compounds can be increased by presenting a drug in a defined conformation, which fits exactly into the binding pocket of its target. Herein, the piperazine scaffold was conformationally restricted by substituted C<sub>2</sub>- or C<sub>3</sub>-bridges across the 2- and 6-position. At first, a three-step, one-pot procedure was developed to obtain reproducibly piperazine-2,6-diones with various substituents at the N-atoms in high yields. Three strategies for bridging of piperazine-2,6-diones were pursued: 1. The bicyclic mixed ketals 8-benzyl-6-ethoxy-3-(4-methoxybenzyl)-6-(trimethylsilyloxy)-3,8-diazabicyclo[3.2.1]octane-2,4-diones were prepared by Dieckmann analogous cyclization of 2-(3,5-dioxopiperazin-2-yl)acetates. 2. Stepwise allylation, hydrobo2020-01-01T00:00:00Z2020 Aug2026-07-15T20:40:44.104Z2025-05-29T21:27:31.479ZS-EPMC74507903288488310.1002/open.202000188