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.

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

doi:10.3762/bjoc.14.46

Romain Sallio, Francine Agbossou-Niedercorn + Show 4 more

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https://doi.org/10.3762/bjoc.14.46

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Journal: Beilstein journal of organic chemistry	Publication Date: Mar 9, 2018
Citations: 12	License type: CC BY 4.0

Abstract

A new asymmetric organocatalyzed intramolecular aza-Michael reaction by means of both a chiral auxiliary and a catalyst for 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-1ones, 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]
Substituted 3-isoindolinones, such as JM-1232 (II) [12,13,14] and pazinaclone (III) [15,16] (Figure 1), have shown sedative-hypnotic activities used for the treatment of anxiety by acting as partial agonists at GABAA (γ-aminobutyric acid type A) benzodiazepine receptors [17]
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-catalyzed 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-1ones, 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]. Diastereoselective reactions implying the use of a chiral auxiliary resulted effectively in various optically pure compounds [10,18,19,20]. We noticed along our studies some intramolecular azaMichael reactions were effectively catalysed by cinchoninium phase-transfer catalysts (PCT) affording the targeted 3-substituted isoindolinones with promising enantioselectivities (up to 91%) [20].

Results

Conclusion