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

Abstract

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

Preparation of new bicyclo[2.1.1]hexane compact modules: an opening towards novel sp3-rich chemical space

“…The latter was further monodeprotected, giving 31 as a TFA salt. These transformations highlight the versatility and modularity that this scaffold offers to construct valuable sp 3 -rich building blocks to be incorporated into drug-like compounds.…”

“…In the quest to further improve the physicochemical properties of lead compounds, medicinal chemists tend to prefer sp 3 -rich and strained bicyclic scaffolds as bio-isosteres. 1,2 Their intrinsic properties play a fundamental role in modulating and sometimes improving the solubility, activity, and conformational restriction of candidates, 3 while offering new vector's angle opportunities. The bicyclo [1.1.1]pentane motif remains to date the most renowned example of bicycles used.…”

Preparation of new bicyclo[2.1.1]hexane compact modules: an opening towards to novel sp3-rich chemical space

“…In the quest of further improving the physicochemical properties of lead compounds, medicinal chemists tend to favor sp 3 -rich and strained bicyclic scaffolds as bio-isosteres. 1,2 Their intrinsic properties are playing a fundamental role in modulating and sometimes improving solubility, activity, and conformational restriction of candidates, 3 while offering new vectors's angles opportunities. The bicyclo[1.1.1]pentane motif remains to date the most renowned example of bicycles used.…”