A Brønsted Acid‐Catalyzed Michael Addition/Cyclization Sequence for the Diastereoselective Assembly of Chroman‐Bridged Polycyclic Isoindolinones

Abstract

The first p-TSA-catalyzed highly diastereoselective Michael addition/cyclization of 3-carboxylate-substituted isoindolinones and ortho-hydroxychalcones was developed to access a wide range of chroman-bridged polycyclic isoindolinones. This reaction represents a novel and efficient method for the construction of complex bridged polycyclic isoindolinones. Moreover, several derivatizations were carried out to further highlight the synthetic value of this protocol.

Recent Advances in the Direct Functionalization of Isoindolinones for the Synthesis of 3,3‐Disubstituted Isoindolinones

“…Up to now, several electrophiles such as α,β-unsaturated aldehydes, α,β-unsaturated ketones, aldehydes and sulfur reagents have been investigated in this transformation for the assembly of 3,3-disubstituted isoindolinones. In the reported examples, the installation of an electron-withdrawing group such as ester, [33][34] and CN [35] is necessary for activating the benzylic carbon at the C3-position, thus facilitating the downstream Michael addition, [33][34] aldol reaction [35][36] sulfenylation reaction [37] and fluorination. [37]…”

“…In 2019, they successfully developed a p-TSA catalyzed highly diastereoselective Michael addition/cyclization of 3ester substituted isoindolinones 99 and ortho-hydroxychalcones 111 to access the chroman-bridged polycyclic isoindolinones 112 in good yield (Scheme 36). [34] The reaction initiated with the Michael addition of 99 a to 111 a to give intermediate 113 under the catalysis of p-TSA. An intramolecular hemi-ketalization/dehydration sequence took place to generate oxocarbenium ion intermediate 114, which was equivalent with intermediate 115.…”

“…In 2019, they successfully developed a p ‐TSA catalyzed highly diastereoselective Michael addition/cyclization of 3‐ester substituted isoindolinones 99 and ortho ‐hydroxychalcones 111 to access the chroman‐bridged polycyclic isoindolinones 112 in good yield (Scheme 36). [34] …”

Synthesis and Organocatalytic Asymmetric Nitro-aldol Initiated Cascade Reactions of 2-Acylbenzonitriles Leading to 3,3-Disubstituted Isoindolinones

“…In this way, a number of interesting 3,3-disubstituted isoindolinones were obtained as racemates via a carbonyl addition step followed by a Dimroth type rearrangement of the immediate intermediate (Scheme 2) [8]. It is worthy to note that the number of methodologies for the asymmetric synthesis of 3,3-disubstituted isoindolinones is limited [31][32][33] and the reported strategies are mainly based on racemate resolution [31][32][33] or on the use of chiral auxiliaries [31][32][33], while asymmetric catalytic procedures are relatively rare [34][35][36][37][38][39]. Therefore, we were interested to investigate the reactivity of 2-acylbenzonitriles with common nucleophiles employing chiral organocatalytic systems in order to achieve a direct construction of chiral 3,3-disubstituted isoindolinones.…”

“…The best results in terms of enantioselectivity were obtained in the presence of the bifunctional ammonium salt C1 derived from trans-1,2-cyclohexyldiamine recently developed by our group [41,42], which gave a quantitative yield and moderate enantioselectivity (41% ee). On the other hand, (di)azepino based PTC E1 (Maruoka's catalyst) [43] and E2 (Lygo's catalyst) [43] were not effective (Entries 5, 6), which highlights the importance to use bifunctional ammonium salts with an effective hydrogen donor It is worthy to note that the number of methodologies for the asymmetric synthesis of 3,3-disubstituted isoindolinones is limited [31][32][33] and the reported strategies are mainly based on racemate resolution [31][32][33] or on the use of chiral auxiliaries [31][32][33], while asymmetric catalytic procedures are relatively rare [34][35][36][37][38][39]. Therefore, we were interested to investigate the reactivity of 2-acylbenzonitriles with common nucleophiles employing chiral organocatalytic systems in order to achieve a direct construction of chiral 3,3-disubstituted isoindolinones.…”