Rigid Scaffolds: Synthesis of 2,6‐Bridged Piperazines with Functional Groups in all three Bridges

• Published in: ChemistryOpen (Weinheim) Vol. 9; no. 8; pp. 874 - 889
• Main Authors: Gao, Donglin, Penno, Christian, Wünsch, Bernhard
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.08.2020; John Wiley and Sons Inc; Wiley-VCH
• Subjects: Acetates; Aldehydes; aldol reactions; Allyl compounds; Azabicyclo Compounds - chemical synthesis; bridged piperazines; Bridges; Bridging; Carbon; Chemical reactions; Cyclization; Dieckmann cyclization; Diketopiperazines - chemical synthesis; Functional groups; Hydroboration; medicinal chemistry; Molecular Structure; Oxidation; Reagents; rigid scaffolds; Scaffolds; Synthesis; Dieckmann cyclization; aldol reactions; rigid scaffolds; medicinal chemistry; bridged piperazines
• ISSN: 2191-1363; 2191-1363
• DOI: 10.1002/open.202000188

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 Creating a bridge: Reduction of conformational flexibility can be considered as a strategy to increase free binding energy of ligands towards a target protein. A method was developed to reproducibly obtain piperazine‐2,6‐diones (cyclic imides) in high yields. Various approaches were pursued to bridge these piperazine‐2,6‐diones. This bridge is bearing various functional groups.