Chiral Phase Transfer Catalysis in the Asymmetric Synthesis of a 3,3-Disubstituted Isoindolinone and Determination of Its Absolute Configuration by VCD Spectroscopy.

Guglielmo Monaco,Maximilian Tiffner,Mario Waser,Antonio Massa,Antonia Mola,Wouter Herrebout

doi:10.3390/molecules25102272

Abstract

In this work we report our endeavors toward the development of an asymmetric synthesis of a 3,3-disubstituted isoindolinone, dimethyl 2-(1-methyl-3-oxoisoindolin-1-yl)malonate, via asymmetric cascade reaction of 2-acetylbenzonitrile with dimethylmalonate and the determination of its absolute configuration (AC) by vibrational circular dichroism (VCD). Bifunctional ammonium salts, derived from trans-1,2-cyclohexanediamine in combination with inorganic bases under phase transfer conditions, were the most effective catalytic systems, leading to the target in high yields and moderate enantioselectivity. An efficient process of heterochiral crystallization allowed the increase of the enantiopurity up to 96% ee and in an acceptable overall yield. An important aim of the present work is the comparison of different VCD methodologies for AC determination of the target compound.

Highlights

Isoindolinones are privileged heterocycles with a wide range of biological activities and applications (Figure 1) [1,2,3]
In the course of our recent research activity, we have developed a straightforward approach to racemic 3,3-disubstituted isoindolinones via K2 CO3 catalyzed cascade reactions of
All the reactions were monitored by thin layer chromatography (TLC) on precoated silica gel plates procedures [12]

Summary

Introduction

Isoindolinones are privileged heterocycles with a wide range of biological activities and applications (Figure 1) [1,2,3]. These compounds are characterized by a γ-lactam fused with a benzene ring, which can be either unsubstituted, mono- or di-substituted in 3 position (Figure 1). Despite the great number of articles describing synthesis and properties of unsubstituted or 3-mono substituted isoindolinones, asymmetric synthesis of 3,3-disubstituted derivatives has received relatively little attention [2,3,4,5,6,7,8,9,10], because of the well-known difficulties in the asymmetric construction of quaternary stereocenters [11]. (trans)-PD172938 a representative known derivative; bioactive from natural sources; is a representative knownisbioactive In the course of our recent research activity, we have developed a straightforward approach to racemic 3,3-disubstituted isoindolinones via K2 CO3 catalyzed cascade reactions of

Methods

Results

Conclusion