&lt;span&gt;Diastereoselective auxiliary- and catalyst-controlled intramolecular aza-Michael reaction for the elaboration of enantioenriched 3-substituted isoindolinones. Application to the synthesis of a new pazinaclone analogue.&lt;/span&gt;&lt;span&gt;&lt;/span&gt;

Eric Deniau,Stéphane Lebrun,Christophe Michon,Frédéric Capet,Francine Agbossou-Niedercorn,Romain Sallio

doi:10.3390/ecsoc-22-05784

Abstract

A new asymmetric organocatalyzed intramolecular aza-Michael reaction under a double auxiliary and catalyst stereocontrol is reported for the synthesis of optically active isoindolinones. A selected cinchoninium salt was used as phase-transfer catalyst in combination with a chiral nucleophile, a Michael acceptor and a base to provide 3-substituted isoindolinones in good yields and diastereomeric excesses. This methodology was applied to the asymmetric synthesis of a new pazinaclone analogue which is of interest in the field of benzodiazepine-receptor agonists.

Highlights

Isoindolinones I (Figure 1), e.g. 2,3-Dihydro-1H-isoindol-1-ones, called phthalimidines are bicyclic lactams whose molecular structure is the basis of a wide range of alkaloids and biologically active compounds [1,2,3,4,5,6,7,8,9,10,11]
We noticed along our studies some intramolecular aza-Michael reactions were effectively catalysed by cinchoninium phase-transfer catalysts (PCT) affording the targeted 3-substituted isoindolinones with promising enantioselectivities
From a retrosynthetic point of view, (3S)-NH free 3-substituted isoindolinones 1 and 2 could be obtained in high enantioselectivities from the intermediates (2R,3S)-3-5 after removal of the chiral auxiliary (Scheme 1). (2R,3S)-bicyclic lactams 3-5 could be prepared by the asymmetric intramolecular organo-catalysed aza-Michael reaction of (R)-benzamides 6-8 bearing an acrylamide group at the ortho position of the benzene ring

Summary

Introduction

Isoindolinones I (Figure 1), e.g. 2,3-Dihydro-1H-isoindol-1-ones, called phthalimidines are bicyclic lactams whose molecular structure is the basis of a wide range of alkaloids and biologically active compounds [1,2,3,4,5,6,7,8,9,10,11]. Though various metal or organic catalysts were used to promote the aza-Michael reaction in different syntheses for the creation of nitrogen-carbon bonds, phase-transfer catalysts were less studied [see reviews 35-38] in intermolecular [39,40,41,42,43] and intramolecular [44,45,46] sequences. Among the latter, a short regio- and stereoselective organo-catalyzed intramolecular aza-Michael reaction was reported by us for the asymmetric synthesis of several isoindolinones [20,34]. To the best of our knowledge such approach involving a double auxiliary and catalyst stereocontrol was never applied before to asymmetric synthesis of enantioenriched isoindolinones

Retrosynthetic analysis

Synthesis of parent chiral benzamides 6-8

Conclusion