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A Review of the Synthetic Strategies Toward Dihydropyrrolo[1,2-A]Pyrazinones

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A Review of the Synthetic Strategies Toward Dihydropyrrolo[1,2-A]Pyrazinones Review A Review of the Synthetic Strategies toward Dihydropyrrolo[1,2-a]Pyrazinones Pieterjan Winant 1,† , Tomas Horsten 1,† , Shaiani Maria Gil de Melo 2, Flavio Emery 2,* and Wim Dehaen 1,* 1 Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium; [email protected] (P.W.); [email protected] (T.H.) 2 Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences at Ribeirao Preto of the University of Sao Paulo, Ribeirao Preto 14040903, SP, Brazil; [email protected] * Correspondence: fl[email protected] (F.E.); [email protected] (W.D.) † Both authors contributed equally to this work. Abstract: Dihydropyrrolo[1,2-a]pyrazinone rings are a class of heterocycles present in a wide range of bioactive natural products and analogues thereof. As a direct result of their bioactivity, the synthesis of this privileged class of compounds has been extensively studied. This review provides an overview of these synthetic pathways. The literature is covered up until 2020 and is organized according to the specific strategies used to construct the scaffold: fusing a pyrazinone to an existing pyrrole, employing a pyrazinone-first strategy, an array of multicomponent reactions and some miscellaneous reactions. Keywords: pyrrole; pyrazinone; heterocycle; natural product; cycloaddition; multicomponent reaction 1. Introduction Citation: Winant, P.; Horsten, T.; Gil de Melo, S.M.; Emery,F.; Dehaen, W.A Nitrogen-containing heteroaromatic rings are valuable motifs in bioactive molecules Review of the Synthetic Strategies toward and recurrent scaffolds present in drugs [1,2]. The application of nitrogen ring systems Dihydropyrrolo[1,2-a]Pyrazinones. in drug development is related to their diverse properties, including relatively small con- Organics 2021, 2, 118–141. https:// formational freedom, while retaining some polarity, compared to aromatic hydrocarbons. doi.org/10.3390/org2020011 Additionally, commercial availability, synthetic tractability, chemical diversity and the tendency for functionalization should also be highlighted [3]. However, the wide chem- Academic Editor: David StC Black ical space of nitrogen heterocycles is not yet fully explored in the attempt to find new drug candidates. Received: 11 May 2021 Dihydropyrrolo[1,2-a]pyrazinone rings are found in the structure of a number of Accepted: 2 June 2021 bioactive compounds, including synthetic and natural products isolated from various Published: 4 June 2021 sources like fungi, plants or sponges. These natural products (some structures are shown in Figure1 ) often contain one or two bromine substituents on the pyrrole ring. The sim- Publisher’s Note: MDPI stays neutral plest congeners are longamide A [4] and its nonbrominated analog mukanadin C [5] with regard to jurisdictional claims in (not shown), longamide B [6], hanishin [7], stylisine D [8], cyclooroidin [9], and age- published maps and institutional affil- samide [10]. More complicated tetracyclic analogs include dibromophakellstatin, dibro- iations. mophakellin [11] and the different agelastatins A-F [12,13]. One of the most complicated pyrrolopyrazinone natural products is palau’amine [14], and its structure has been seen as a challenge for total synthesis. Some related natural products are the higher oxidation state analogs peramine [15] and nannozinone B [16], containing the pseudoaromatic pyrazi- Copyright: © 2021 by the authors. none ring, the pyrrolodiketopiperazines brevianamide T [17] and macrophominol [18], Licensee MDPI, Basel, Switzerland. and the oxopyrrole derivative oxocyclostylidol [19] (Figure1). This article is an open access article Several bioactivities have been found for these pyrrolopyrazinone natural products. distributed under the terms and Hanishin shows cytotoxicity against non-small cell lung carcinoma [7], and agelastatin A conditions of the Creative Commons and D display significant activity against different cell lines [20]. Longamide B was found to Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ have antiprotozoal [21] and antibacterial [6] properties, with good potency against African 4.0/). Organics 2021, 2, 118–141. https://doi.org/10.3390/org2020011 https://www.mdpi.com/journal/organics Organics 2021, 2, FOR PEER REVIEW 2 Organics 2021, 2 119 to have antiprotozoal [21] and antibacterial [6] properties, with good potency against Af- rican trypanosome. Palau’amine and the similar dibromophakellin and dibromo- trypanosome. Palau’amine and the similar dibromophakellin and dibromophakellstatin phakellstatin inhibit the human 20S proteasome [22]. Peramine is an insect feeding deter- inhibit the humanrent 20S [23]. proteasome [22]. Peramine is an insect feeding deterrent [23]. Figure 1. PyrrolopyrazinoneFigure natural 1. Pyrrolopyrazinone products. natural products. In view of theseIn bioactivities, view of these there bioactivities, has been there a keen has been interest a keen in syntheticinterest in synthetic analogs, analogs, and and pyrrolopyrazine is now recognized as a privileged scaffold. The best known example is pyrrolopyrazine is now recognized as a privileged scaffold. The best known example is AS-3201 (ranirestat), a potent aldose reductase inhibitor [24] that has been granted orphan AS-3201 (ranirestat), a potent aldose reductase inhibitor [24] that has been granted orphan drug status for the treatment of diabetic neuropathy. Pyrrolopyrazines 1 have also been drug status for thedescribed treatment as melanin-concentrating of diabetic neuropathy. hormone Pyrrolopyrazines (MCH-R1) antagonists1 have alsoof interest been in anti- described as melanin-concentratingobesity therapy [25]. hormoneOther notable (MCH-R1) bioactiv antagonistse derivatives ofare interest the HIV-1 in antiobe- integrase com- sity therapy [25].pounds Other 2 notable [26], the bioactive potent and derivatives noncompetitive are the mGluR1 HIV-1 antagonists integrase compounds3 [27], the kinase in- 2 [26], the potenthibitors and noncompetitive 4 [28] and 5 [29] mGluR1and the immunosuppressive antagonists 3 [27 ],response the kinase indoleamine-2,3-dioxy- inhibitors 4 [28] and 5 [29]genase and the 1 (IDO-1) immunosuppressive inhibitors 6 [30] (Figure response 2). indoleamine-2,3-dioxygenase 1 (IDO-1) inhibitors 6 [30] (Figure2). In this review, we will cover the different synthetic strategies leading to the dihy- dropyrrolopyrazinone scaffold. These include (1) the fusion of a pyrazinone to a pyrrole derivative, (2) the fusion of a pyrrole to a pyrazinone, (3) multicomponent reactions and (4) miscellaneous strategies. The literature will be covered until the end of 2020, and the focus is indeed on ring formation rather than an elaboration of substituents during the multistep total syntheses of complicated natural product analogs or the details of their biological properties. Also, we will not cover any examples that have indoles or other fused pyrrole rings in the structure, neither quinoxalines nor other fused pyrazines, since their chemistry is in most cases rather different. This review has a focus on the dihydropyrrolo[1,2-a]pyrazinones, in comparison to a recent general overview of the eight different pyrrololactam isomers [31]. Organics 2021, 2 120 Organics 2021, 2, FOR PEER REVIEW 3 FigureFigure 2. 2.Synthetic Synthetic bioactive bioactive dihydropyrrolopyrazinones. dihydropyrrolopyrazinones. 2. Fusion of a Pyrazinone to a Pyrrole Derivative In this review, we will cover the different synthetic strategies leading to the dihydro- 2.1. Starting from 2-Monosubstituted Pyrroles pyrrolopyrazinone scaffold. These include (1) the fusion of a pyrazinone to a pyrrole de- rivative,The most (2) the common fusion way of a toward pyrrole pyrrolopyrazinones to a pyrazinone, (3) is multicomponent fusing a pyrazinone reactions to a pyrrole. and (4) Onemiscellaneous way to realize strategies. this is starting The literature from 1H will-pyrrole-2-carboxamide be covered until the end bearing of 2020, electrophilic and the focus groupsis indeed on the on amidering formation that react rather in an than intramolecular an elaboration fashion of substituents with the nucleophilic during the pyrrolemultistep nitrogen.total syntheses Several of electrophilic complicated groups natural are product possible. analogs Electron-poor or the details alkenes of their can undergo biological aza-Michael addition, as in the base-catalyzed formation of N-benzyl longamide B deriva- properties. Also, we will not cover any examples that have indoles or other fused pyrrole tive 8 from the corresponding open chain pyrrole-2-amide 7 after potassium carbonate rings in the structure, neither quinoxalines nor other fused pyrazines, since their chemis- (K CO )-catalyzed cyclization, bromination with N-bromosuccinimide (NBS) and saponifi- try2 is3 in most cases rather different. This review has a focus on the dihydropyrrolo[1,2- cation (Scheme1)[ 32]. A similar aza-Michael cyclization was reported in the total synthesis a]pyrazinones, in comparison to a recent general overview of the eight different pyrrolo- of longamide B and cyclooroidin via the Wadsworth–Horner–Emmons olefination of lactam isomers [31]. longamide A [33,34] or in the 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU)-catalyzed cycliza- tion of precursors to kinase inhibitors 5 [29]. An enantioselective aza-Michael cyclization Organics 2021, 2, FOR PEER REVIEW 2. Fusion of a Pyrazinone to a Pyrrole Derivative 4 (up to 56%ee) was realized with compounds analogous to 7 in the presence of a chiral
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