Rigid Scaffolds: Synthesis of 26‐Bridged Piperazines with Functional Groups in all three Bridges

摘要

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 ‐ or C ‐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 ‐(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 C ‐ or a methylene group at the C ‐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