TY  - JOUR
AB  - 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 C2- or C3-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, hydroboration and oxidation of piperazine-2,6-diones led to 3-(3,5-dioxopiperazin-2-yl)propionaldehydes. Whereas reaction of such an aldehyde with base provided the bicyclic alcohol 9-benzyl-6-hydroxy-3-(4-methoxybenzyl)-3,9-diazabicyclo[3.3.1]nonane-2,4-dione in only 10 % yield, the corresponding sulfinylimines reacted with base to give N-(2,4-dioxo-3,9-diazabicyclo[3.3.1]nonan-6-yl)-2-methylpropane-2-sulfinamides in >66 % yield. 3. Transformation of a piperazine-2,6-dione with 1,4-dibromobut-2-ene and 3-halo-2-halomethylprop-1-enes provided 3,8-diazabicyclo[3.2.1]octane-2,4-dione and 3,9-diazabicyclo[3.3.1]nonane-2,4-dione with a vinyl group at the C2- or a methylene group at the C3-bridge, respectively. Since bridging via sulfinylimines and the one-pot bridging with 3-bromo-2-bromomethylprop-1-ene gave promising yields, these strategies will be exploited for the synthesis of novel receptor ligands bearing various substituents in a defined orientation at the carbon bridge
AU  - Gao, Donglin
AU  - Penno, Christian
AU  - Wünsch, Bernhard
DA  - 2020-08-27
DO  - 10.17879/33069568582
KW  - bridged piperazines
KW  - rigid scaffolds
KW  - Dieckmann cyclization
KW  - aldol reactions
KW  - medicinal chemistry
LA  - eng
N1  - Chemistry Open 9 (2020) 8, 874-889
N1  - Finanziert über die DEAL-Vereinbarung mit Wiley 2019-2022.
N1  - Förderer: Deutsche Forschungsgemeinschaft / Projektnummer: 194347757
N1  - Funding organisation: Deutsche Forschungsgemeinschaft / Project number: 194347757
PY  - 2020-08-27
TI  - Rigid Scaffolds: Synthesis of 2,6-Bridged Piperazines with Functional Groups in all three Bridges
UR  - https://nbn-resolving.org/urn:nbn:de:hbz:6-43059505713
Y2  - 2024-11-22T09:17:45
ER  -