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

• electrophilic allylation. We initially chose N-phenyl-3-(acetoxy)isoindolinone (2a) as a reactant. However, 2a showed no reactivity under the reaction conditions determined for the palladium-catalyzed allylation in our previous work and was recovered in 98% yield [17] (Table 1, entry 1). The use of strong bases

• an amide side chain [14]. Therefore, we here examined reactions using N-alkyl derivatives in order to gain the structural diversity. Reactions of 3-(phenylthio)isoindolinone derivatives bearing an N-benzyl (2c), N-methyl (2d), and N-(n-pentyl) group (2d) with 1a readily proceeded under the optimized

• applicability to other substrates. Reactions of isoindolinone derivatives 3c–h under the comparable conditions used for 3b were successful, furnishing the corresponding N-alkyl and N-phenyl bislactams 4b–g in 79–91% two-step yields. Similarly, non-aromatic substrates 3i–o were also converted into 4h–n in 84–94

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

• , Figure 1) are generated, while if such fusion takes place between the 4- and 5-positions of the γ-lactam ring, 2-oxindoles (also named as indolin-2-ones III, Figure 1) are formed. The isoindolinone structural motif is a part of the core of many natural products [2]. To cite some examples, cichorine [3

• ] and zinnimidine [4] (Figure 2) are simple isoindolinone alkaloids, for which total syntheses have been reported [5], and nuevamine (Figure 2) is an isoindoloisoquinoline alkaloid [6][7]. Moreover, in this last decade, new compounds such as impatien A [8] (Figure 2) or daldinans B and C [9] have been

• compounds. Molecules containing the isoindolinone moiety are of pharmaceutical interest as anxiolytic (pazinaclone [15], pagoclone [16], and JM1232 [17]), anticancer (lenalidomide) [18], anti-inflammatory (indoprofen) [19] and antibiotic agents (lactonamycin) [20] (Figure 4). In addition, some isoindolinone

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

• diastereoselectivity could not be obtained and we looked for improvements through the use of an appropriate chiral organocatalyst [63][64][65]. Indeed, within the same reaction conditions, the use of cinchoninium catalyst 18a afforded isoindolinone (S)-3a with higher de (54%), (Table 1, entry 5). We assumed such de

• bearing an array of acrylamide groups (Scheme 3). Substrate 6a bearing a (R)-α-methylbenzyl chiral auxiliary led to isoindolinone 3a in 80% de and a pure diastereoisomer was recovered after chromatography on silica gel (EtOAc/hexanes 3:7) and crystallization from hexanes/toluene. Reactions of substrates

• intramolecular aza-Michael reaction of acrylamide (R)-24 was then performed using the best phase-transfer catalyst 18c and the optimized experimental conditions to give isoindolinone (2R,3S)-25 as a mixture of diastereoisomers (82% yield, 71% de) which were separated by chromatography and purified by

The photodecarboxylative addition of carboxylates to phthalimides as a key-step in the synthesis of biologically active 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones

• Ommid Anamimoghadam,
• Saira Mumtaz,
• Anke Nietsch,
• Gaetano Saya,
• Cherie A. Motti,
• Jun Wang,
• Peter C. Junk,
• Ashfaq Mahmood Qureshi and
• Michael Oelgemöller

Beilstein J. Org. Chem. 2017, 13, 2833–2841, doi:10.3762/bjoc.13.275

• structure of the dehydration product (E)-7a was furthermore confirmed by X-ray crystallographic analysis (Figure 3). Remarkably, the phenyl group of the arylmethylene unit is positioned almost perpendicular to the isoindolinone ring. Compound (E)-7a forms dimers through CH–π interactions between the phenyl

• -isomers was again observed (Table 4, entries 26 and 27). The solid state structure of the amination product (Z)-8a was furthermore established by X-ray crystal structure analysis (Figure 4). The phenyl group of the arylmethylene unit is positioned almost perpendicular to the isoindolinone ring on top of

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

• inhibitory [32] and cytotoxic activity. Recently, MDM2-p53 inhibitors based on an isoindolinone scaffold [33][34] have been reported. These latter results demonstrate the versatility of the isoindolinone scaffold as MDM2-p53 inhibitor and show that significant improvements in potency may be gained by modest

• structural modifications. Introducing structural diversity into the isoindolinone scaffold can represent an important approach towards the design of new chemotherapeutics. On the basis of these considerations, we have designed a route towards a new class of potential MDM2-p53 inhibitors 3, through the

• construction of the spiro[isoxazolidin-isoindolinone] system. The synthetic scheme (Figure 2) exploits the strategy of the 1,3-dipolar cycloaddition of nitrones on the substrate isoindolin-3-methylene-1-one 2, obtained by a recent methodology of a PdI2 catalyzed aminocarbonylation-N-heterocyclization of 2

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

• , this method is fast and easy to implement, and it is suitable for large-scale synthesis (Scheme 1). Many isoindolinone skeletons show high biological potential as antihypertensives, anesthetics, etc. [66][67][68]. The useful hydrolyzed product rac-4a was obtained in 80% yield by treating rac-3a with

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

• 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

• -cyanobenzaldehydes [29]. Then we decided to address the asymmetric synthesis of bioactive isoindolinones, identifying the chiral isoindolinone 9 as a very useful, key building block, as shown in Scheme 1. Results and Discussion Asymmetric cascade reaction of 2-cyanobenzaldehyde under phase-transfer conditions As

• spectroscopic data are in agreement with that reported in literature [21][22]. Chiralpack AD column, hexane/iPrOH 8:2, 0.8 mL/min, λ = 254 nm, t = 19.4 min, t = 29.3 min. (S)-2-(1-Oxoisoindolin-3-yl)acetic acid (9) from 7. A flask containing a solution of isoindolinone 7 (320 mg, 1.20 mmol) and HCl 6 M (2 mL

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

• exhibited strong α-glucosidase inhibitory activity with IC50 values ranging from 2.1 to 13.3 μM. Moreover, kinetic studies of compounds 2 and 6 showed that both of them were noncompetitive inhibitors of α-glucosidase. Keywords: endophytic fungus; depsidone; α-glucosidase inhibitory activity; isoindolinone

• , compound 7 contained a bicyclic aromatic lactam fragment. Further detailed analysis of the 1H and 13C NMR spectra suggested that 7 is an isoindolinone derivative [18]. Analysis of the 1H,1H COSY spectrum suggested the presence of one spin system, which included H-8/H-9/H-10/H-11 (Figure 3). In the HMBC

• spectrum (Figure 3), the correlations of H-10 and H-11 to C-12 (carbonyl), H-8 to C-10, and H-11 to C-9, established a valeric acid moiety. The linkage of valeric acid moiety to N-2 of the isoindolinone was assigned by HMBC correlations from H-8 to C-1 and C-3. The two aromatic hydroxy groups were

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

• ; isoindolinone; isoindolone; natural products; Introduction Isoindole (2H-isoindole, 1), known since more than a century, consists of a fused benzopyrrole ring system and constitutes the regioisomer of the abundant 1H-indole heterocycle. The fully reduced member of the isoindole family is termed isoindoline

• (2,3-dihydro-1H-isoindole, 2). Formal oxidation to the 10π-system leads to isoindole (1), which is usually only stable when the labile ortho-quinoid structure is embedded in a π-system [1]. Incorporation of additional oxygen gives the isoindolinone (1,3-dihydro-2H-isoindole-1-one, 3) and phthalimide

• selenide. Oxidation and elimination of the corresponding selenoxide at elevated temperature generated the necessary dienophile, which directly underwent an intramolecular endo-Diels–Alder reaction to give the isoindolinone 68. For the synthesis of 69 another ten steps were necessary to discriminate between

Synthesis of conformationally restricted glutamate and glutamine derivatives from carbonylation of orthopalladated phenylglycine derivatives

• Esteban P. Urriolabeitia,
• Eduardo Laga and
• Carlos Cativiela

Beilstein J. Org. Chem. 2012, 8, 1569–1575, doi:10.3762/bjoc.8.179

• results, however, in the formation of the cyclic isoindolinone or the open 2-carboxyphenylglycine methyl esters, with the reaction outcome being driven by the choice of the solvent. Keywords: C–H functionalization; carbonylation; glutamic acid; glutamide; palladium; phenylglycine; Introduction The

• . In spite of the presence of an intramolecular nucleophile (the N atom of the NR2 group), the formation of the cyclic isoindolinone derivatives has been observed only in one case. This means that the nitrogen atoms of the NMe2 or the NHTf groups behave as weaker nucleophiles than the oxygen or

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

• , the addition to in situ prepared N-acyliminium species, and ring-closing metathesis (RCM) were key steps in the preparation of a tricyclic isoindolinone scaffold. An unusual alkene isomerization process during the RCM was identified and studied in some detail. Chemical diversification for library

• ring [19]. We have now developed this concept further toward a library synthesis of functionalized azepino-isoindolinone derivatives. Results and Discussion N-Alkylation of phthalimide with 4-penten-1-ol under Mitsunobu conditions, followed by NaBH4 reduction and pivaloate protection of the

• ]. Conclusion A library of novel tricyclic isoindolinone amino alcohols was prepared in seven steps from commercially available starting materials. Key transformations include the addition of in situ generated alkenylalanes to an N-acyliminium ion derived from pivaloate 1, a tandem ring-closing metathesis

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

• ; isoindolin-1-ones; directed lithiation; electrophiles; substitution; synthesis; Introduction In recent years there has been a great deal of interest in compounds possessing an isoindolinone ring system since it represents the core unit of numerous naturally occurring substances [1][2][3][4][5][6][7][8