Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• using acyclic enones 14 [27]. Their tandem conjugate addition/Mannich reaction methodology offers access to various non-cyclic β-aminoketones 16 with multiple contiguous stereocenters in high diastereo- and enantioselectivity (Scheme 5a). Additionally, chiral isoindolinones 18 and 2,3,4-trisubstituted

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• cinchona alkaloid-derived quaternary ammonium salts (cat. 55) as the phase-transfer catalyst. The products were obtained in high yields (53–93%) with high enantioselectivities (40–76% ee) (Table 12) [46]. Lebrun et al. developed a new method to synthesize optically active isoindolinones via asymmetric

• by using different PTCs in order to improve yield and diastereomeric excess. They incorporated PTC and chiral auxiliary and reacted a variety of chiral phthalimidines 57 to obtain isoindolinones 59 in good yields (≈85%) with excellent de ranging 48–96% (Table 13) [48]. 1.5 Catalysis by chiral

• aza-Michael/alkylation reaction catalyzed by cinchona alkaloid-derived quaternary ammonium salts. Asymmetric aza-Michael synthesis of isoindolinones. Asymmetric aza-Michael addition reaction catalysed by chiral bifunctional thiourea. Enantioselective 1,6-aza-Michael addition of isoxazolin-5-ones to p

Bifurcated synthesis of methylene-lactone- and methylene-lactam-fused spirolactams via electrophilic amide allylation of γ-phenylthio-functionalized γ-lactams

• Tetsuya Sengoku,
• Koki Makino,
• Ayumi Iijima,
• Toshiyasu Inuzuka and
• Hidemi Yoda

Beilstein J. Org. Chem. 2020, 16, 2769–2775, doi:10.3762/bjoc.16.227

• obtained under the conditions depicted in Scheme 1b, seems to be accessible from the common precursor 3 prepared through the reaction between 1 and 3-heterosubstituted isoindolinones 2 followed by cyclization. Considering that 2 is estimated to be less reactive compared with the oxindole derivative D which

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• methods include the efficiency in saving raw materials and working time. However, there is still a need of new catalytic systems to allow the enantioselective preparation of these heterocycles by multicomponent reactions. Keywords: indolin-2-ones; isoindolinones; γ-lactams; multicomponent reactions; 2

• -oxindoles; Introduction Pyrrolidin-2-ones (I, Figure 1) are heterocycles that contain a γ-lactam ring that can be found in many biologically active compounds with natural or synthetic origin [1]. When an aryl group is fused to the 3- and 4-positions of the five-membered heterocycle, isoindolinones (II

• from Phalaris coerulescens (Figure 3). Likewise, maremycins [13] and spirotryprostatin B [14] have been isolated from marine Streptomyces and from the fermentation broth of Aspergillus fumigatus. Among benzo-fused γ-lactam chemical entities, natural and synthetic isoindolinones are a prominent class of

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,
• Stéphane Lebrun,
• Frédéric Capet,
• Francine Agbossou-Niedercorn,
• Christophe Michon and
• Eric Deniau

Beilstein J. Org. Chem. 2018, 14, 593–602, doi:10.3762/bjoc.14.46

• 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. Keywords: asymmetric organocatalysis; Aza-Michael reaction; phase

• -transfer catalyst; 3-substituted isoindolinones; Introduction Isoindolinones I (Figure 1), e.g., 2,3-dihydro-1H-isoindol-1-ones, also 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

Synthesis of spiro[isoindole-1,5’-isoxazolidin]-3(2H)-ones as potential inhibitors of the MDM2-p53 interaction

• Salvatore V. Giofrè,
• Santa Cirmi,
• Raffaella Mancuso,
• Francesco Nicolò,
• Giuseppe Lanza,
• Laura Legnani,
• Agata Campisi,
• Maria A. Chiacchio,
• Michele Navarra,
• Bartolo Gabriele and
• Roberto Romeo

Beilstein J. Org. Chem. 2016, 12, 2793–2807, doi:10.3762/bjoc.12.278

• example MI-63 and MI-219, [15][16][17][18] have demonstrated cellular activity consistent with inhibition of MDM2-p53 binding and have shown in vivo antitumor activity [15][19] (Figure 1). Isoindolinones, belonging to the alkaloids family, are found in many natural products such as vitedoamine A

• –protein p53-MDM2 interaction. Results and Discussion Chemistry The synthetic scheme towards the construction of the spiro[isoxazolidin-isoindolinone] system 3 starts from isoindolinones 2 which have been synthesized, as reported [35], by Pd-catalyzed aminocarbonylation-N-heterocyclization of 2

• -dipolar cycloaddition in toluene at 110 °C for 4 h, under microwave irradiation: cycloadducts 6a–e have been isolated in 38–60% yield, as major isomers, together with isomers 7 as minor adducts and unreacted isoindolinones 2a–e mainly in E configuration (Scheme 2, Table 1). The cycloaddition reaction of

Copper-mediated arylation with arylboronic acids: Facile and modular synthesis of triarylmethanes

• H. Surya Prakash Rao and
• A. Veera Bhadra Rao

Beilstein J. Org. Chem. 2016, 12, 496–504, doi:10.3762/bjoc.12.49

• . Recently, we reported a copper-catalyzed C–C bond formation by substitution of the labile C(4)SMe group in 4H-chromenes or C(3)–OH in isoindolinones with aryl/alkenyl groups by employing the corresponding boronic acids [51][52]. Continuing these efforts, we designed a copper-catalyzed synthesis of a

A quadruple cascade protocol for the one-pot synthesis of fully-substituted hexahydroisoindolinones from simple substrates

• Hong-Bo Zhang,
• Yong-Chun Luo,
• Xiu-Qin Hu,
• Yong-Min Liang and
• Peng-Fei Xu

Beilstein J. Org. Chem. 2016, 12, 253–259, doi:10.3762/bjoc.12.27

• isoindolinones have been developed. The first method was the synthesis of 3-substituted isoindolinones from the corresponding N-methylmaleimides by the Diels–Alder reaction with 1,3-butadiene followed by hydrogenation. The second and the third methods employed the corresponding dicarboxylic acids and the

Bifunctional phase-transfer catalysis in the asymmetric synthesis of biologically active isoindolinones

• Antonia Di Mola,
• Maximilian Tiffner,
• Francesco Scorzelli,
• Laura Palombi,
• Rosanna Filosa,
• Paolo De Caprariis,
• Mario Waser and
• Antonio Massa

Beilstein J. Org. Chem. 2015, 11, 2591–2599, doi:10.3762/bjoc.11.279

• salts were investigated in an asymmetric cascade synthesis of a key building block for a variety of biologically relevant isoindolinones. With this chiral compound in hand, the development of further transformations allowed for the synthesis of diverse derivatives of high pharmaceutical value, such as

• particularly promising for large scale applications. Keywords: asymmetric synthesis; Belliotti (S)-PD 172938; heterocycles; isoindolinones cascade reactions; phase transfer catalysts; Introduction Among the nitrogen heterocycles, the isoindolinone ring system is a favored scaffold, owing to the wide range of

• applications and pharmacological properties [1][2][3]. A relevant structural aspect is the presence of a substituent at the C3 position of the ring. A higher biological activity of the enantioenriched compounds with respect to racemic mixtures has been demonstrated for several 3-substituted isoindolinones

New depsidones and isoindolinones from the mangrove endophytic fungus Meyerozyma guilliermondii (HZ-Y₂) isolated from the South China Sea

• Senhua Chen,
• Zhaoming Liu,
• Yayue Liu,
• Yongjun Lu,
• Lei He and
• Zhigang She

Beilstein J. Org. Chem. 2015, 11, 1187–1193, doi:10.3762/bjoc.11.133

• -Sen University, 74 Zhongshan Road II, Guangzhou 510080, China School of Life Sciences and Biomedical Center, Sun Yat-Sen University, 135 Xin gang West Road, Guangzhou 510275, China 10.3762/bjoc.11.133 Abstract Three new depsidones, botryorhodines E–G (1–3), and two new isoindolinones, meyeroguillines

• . Bioassay-guided fractionation of the bioactive extract led to the isolation of three new depsidones belonging to the analogues of the botryorhodines A–D [6], botryorhodines E–G (1–3), and two new isoindolinones, meyeroguillines A and B (7 and 9), together with five known compounds (4–6, 8 and 10) (Figure 1

Aza-Diels–Alder reaction between N-aryl-1-oxo-1H-isoindolium ions and tert-enamides: Steric effects on reaction outcome

• Amitabh Jha,
• Ting-Yi Chou,
• Zainab ALJaroudi,
• Bobby D. Ellis and
• T. Stanley Cameron

Beilstein J. Org. Chem. 2014, 10, 848–857, doi:10.3762/bjoc.10.81

• -isoindolinones as the N-acyliminium ion source and performing [4 + 2] imino-Diels–Alder reactions with tert-enamides. Our literature search also infuses confidence in the proposed scheme because the synthesis of N-aryl-3-hydroxyisoindolinones is well studied and standardized [13][14][15] and the reactions

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• yielding synthesis, ample quantities could be obtained for a preliminary evaluation of the biological activity of 79. In a first screen against A2058 melanoma and DU145 prostate cancer cell lines, 79 showed to be inactive [73]. Isoindolinones derived from isoquinoline alkaloids: The aporhoeadane alkaloids

Synthesis of a library of tricyclic azepinoisoindolinones

• Bettina Miller,
• Shuli Mao,
• Kara M. George Rosenker,
• Joshua G. Pierce and
• Peter Wipf

Beilstein J. Org. Chem. 2012, 8, 1091–1097, doi:10.3762/bjoc.8.120

• ; epoxide aminolysis; hydrozirconation; isoindolinones; metathesis; N-acyliminium ion; Introduction Isoindolinones represent a common scaffold seen in naturally occurring compounds such as magallanesine [1], lennoxamine [2] and clitocybin A [3], or drug candidates such as pagoclone [4] (Figure 1). These

• heterocycles have demonstrated a variety of pharmacological activities, including anti-inflammatory [5], antihypertensive [6] and vasodilatory [7], antipsychotic [8][9], and anticancer effects [10]. Due to the broad biological properties and the general utility of isoindolinones in the preparation of other

• commercially available or easily prepared starting materials and creates many opportunities for further functionalization and chemical library synthesis. For example, a ring-closing metathesis of the alkene addition product affords structurally novel tricyclic isoindolinones with a newly formed seven-membered

A concise synthesis of 3-(1-alkenyl)isoindolin-1-ones and 5-(1-alkenyl)pyrrol-2-ones by the intermolecular coupling reactions of N-acyliminium ions with unactivated olefins

• Nianhong Lu,
• Lihong Wang,
• Zhanshan Li and
• Wei Zhang

Beilstein J. Org. Chem. 2012, 8, 192–200, doi:10.3762/bjoc.8.21

• -1-ones or 5-hydroxypyrrol-2-ones with unactivated olefins such as styrene (2a) (Scheme 1 and Scheme 2). Isoindolinones and pyrrolones are the core structures of numerous natural alkaloids [25][26][27] as well as many drug candidates [28][29][30]. Isoindolinones demonstrate a remarkably wide range of

• biological activities, including anti-inflammatory, antihypertensive, antipsychotic and antileukemic and antiviral effects [31][32][33]. Thus, many methods have been developed to synthesize 2- or 3-functionalized isoindolinones. Among them, only two reports dealt with the synthesis of 3-(1-alkenyl)isoindolin

A simple and convenient one-pot synthesis of substituted isoindolin-1-ones via lithiation, substitution and cyclization of N'-benzyl-N,N-dimethylureas

• Keith Smith,
• Gamal A. El-Hiti,
• Amany S. Hegazy and
• Benson Kariuki

Beilstein J. Org. Chem. 2011, 7, 1219–1227, doi:10.3762/bjoc.7.142

• ]. Also, some members that possess this moiety have shown interesting biological properties [9][10][11][12][13][14][15]. Several traditional methods are available for the synthesis of isoindolinones [16][17][18][19][20][21][22][23][24][25], based on the use of Grignard reagents [26], Diels–Alder reactions