Synthesis of Novel Crown Ether-Squaramides and Their Application as Phase-Transfer Catalysts.

Zsuzsanna Fehér,Sándor Nagy,Dóra Richter,Zsolt Rapi,Péter Bagi,Péter Huszthy,László Drahos,József Kupai,Péter Bakó,András Simon

doi:10.3390/molecules26216542

Abstract

This work presents the synthesis of six new phase-transfer organocatalysts in which the squaramide unit is directly linked to the nitrogen atom of an aza-crown ether. Four chiral skeletons, namely hydroquinine, quinine, cinchonine (cinchonas), and α-d-glucopyranoside were responsible for the asymmetric construction of an all-carbon quaternary stereogenic center in α-alkylation and Michael addition reactions of malonic esters. We investigated the effects of these different chiral units and that of crown ethers with different sizes on catalytic activity and enantioselectivity. During extensive parameter investigations, both conventional and emerging green solvents were screened, providing valuable α,α-disubstituted malonic ester derivatives with excellent yields (up to 98%).

Highlights

Investigating the creation of quaternary stereogenic centers is essential in organic synthesis as it poses a challenge to organic chemists due to the possible steric repulsion between the groups around the stereocenter
We have prepared a series of crown ethers with a squaramide hydrogen bond donor unit (Scheme 1) for catalyzing the α-alkylation reaction of malonates, which may be an important method for obtaining α,α-disubstituted α-amino acid intermediates
We have shown that the substituent on the nitrogen atom of glucose-based aza-crown ether G influences the catalytic effect [30]

Summary

Introduction

Investigating the creation of quaternary stereogenic centers is essential in organic synthesis as it poses a challenge to organic chemists due to the possible steric repulsion between the groups around the stereocenter. A decade ago, a new method involving enantioselective phase-transfer catalytic double α-alkylation of malonates was developed for the construction of chiral quaternary carbon centers, applying tert-butyl diphenylmethyl α-alkylmalonates as starting materials [1]. This method was later extended in numerous publications by examining a broad substrate scope [3,4,5,6]. Similar phase-transfer catalytic reactions, such as the α-benzoyloxylation of tert-butyl methyl α-alkylmalonates [7] and the Michael addition reaction of tert-butyl methyl α-benzylmalonate to acrylates, have been elaborated [2] In all of these papers, quaternary ammonium salts were applied as phase-transfer catalysts (PTCs) in the enantioselective α-alkylation of malonates, while chiral macrocycle PTCs remain a rather neglected tool for these asymmetric reactions

Methods

Results

Conclusion