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3,4-Dihydroquinoxalin-2-one privileged motif: A journey from classical chiral tools based synthesis to modern catalytic enantioselective strategies

  • Author Footnotes
    1 Professor Lattanzi, the corresponding author on this paper is a member of the advisory board but this author had no involvement in the peer review process used to assess this work submitted to Tetrahedron Chem. This paper was managed by Dr Meazza, a scientific editor working on Tetrahedron Chem.
    Alessandra Lattanzi
    Footnotes
    1 Professor Lattanzi, the corresponding author on this paper is a member of the advisory board but this author had no involvement in the peer review process used to assess this work submitted to Tetrahedron Chem. This paper was managed by Dr Meazza, a scientific editor working on Tetrahedron Chem.
    Affiliations
    Department of Chemistry and Biology “A. Zambelli”, University of Salerno, 84084, Fisciano, Italy
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  • Author Footnotes
    1 Professor Lattanzi, the corresponding author on this paper is a member of the advisory board but this author had no involvement in the peer review process used to assess this work submitted to Tetrahedron Chem. This paper was managed by Dr Meazza, a scientific editor working on Tetrahedron Chem.
Open AccessPublished:August 28, 2022DOI:https://doi.org/10.1016/j.tchem.2022.100027

      Abstract

      Optically pure 3,4-dihydroquinoxalin-2-ones, being members of the privileged quinoxaline family, received significant interest in organic synthesis, more particularly in medicinal chemistry, proving also to be useful building blocks for facile entry to a relevant bioactive pharmacophore, namely tetrahydroquinoxalines. The first asymmetric approaches to 3,4-dihydroquinoxalin-2-ones relied on classical use of chiral pool available reagents and auxiliares, such as α-amino acids and mandelates/tartaric acid derivatives, respectively. Over the years, more general and appealing enantioselective catalytic routes have been developed, mainly concerned with metal- and organocatalyzed reduction of quinoxalinones. Additionally, different organocatalytic cyclization strategies, including sustainable one-pot processes, have been added to the synthetic toolbox. This perspective aims to showcase the state of art of asymmetric approaches developed to prepare 3,4-dihydroquinoxalin-2-ones with a focus on catalytic routes, highlighting challenges and opportunities for future developments.

      Graphical abstract

      Keywords

      1. Introduction

      Biologically active compounds, drugs and natural products often include in their structures one or more nitrogen-based heterocycle. To exemplify, around 40% of the marketed drugs comprises optically active nitrogen heterocycles, whose pharmacokinetic and pharmacodynamic parameters need to be checked for both enantiomers, as most of them are marketed in homochiral form [
      • Calcaterra A.
      • D'Acquarica I.
      The market of chiral drugs: chiral switches versus de novo enantiomerically pure compounds.
      ]. It is therefore imperative the use of chiral phase chromatography and crystallization techniques, which enable the separation of enantiomers, especially at an industrial scale, where grams amount of enantiomers are required for bio-assay [
      • Leek H.
      • Thunberg L.
      • Jonson A.C.
      • Öhlén K.
      • Klarqvist M.
      Strategies for large-scale isolation of enantiomers in drug discovery.
      ]. Afterward, asymmetric synthesis enormously helps the preparation of the target molecule with the defined absolute configuration of the stereocenters [
      • Sharma S.K.
      • Paniraj A.S.R.
      • Tambe Y.B.
      Developments in the catalytic asymmetric synthesis of agrochemicals and their synthetic importance.
      ]. In the last decades, asymmetric catalysis played a central role to achieve the production of bioactive compounds, through chiral ligand/metal complexes [
      • Dybtsev D.N.
      • Bryliakov K.P.
      Asymmetric catalysis using metal-organic frameworks.
      ] and small organic molecules [
      • Han B.
      • He X.-H.
      • Liu Y.-Q.
      • He G.
      • Peng C.
      • Li J.-L.
      Asymmetric organocatalysis: an enabling technology for medicinal chemistry.
      ] activation strategies of the reagents. These tools of modern organic synthesis evolved over time, benefiting of continuous innovation in enabling technologies [
      • Fitzpatrick D.E.
      • Battilocchio C.
      • Ley S.V.
      Enabling technologies for the future of chemical synthesis.
      ,
      • Ötvös S.B.
      • Kappe C.O.
      Continuous flow asymmetric synthesis of chiral active pharmaceutical ingredients and their advanced intermediates.
      ] and green strategies leading to the development of complex processes with high productivity and selectivity as well as low environmental and energetic impacts. It is certainly important to add biocatalysis as the third pillar for the synthesis of optically pure compounds, a highly valuable tool to prepare focused targets with excellent control of the stereoselectivity, working under benign reaction conditions [
      • Alcántara A.R.
      • Domínguez de María P.
      • Littlechild J.A.
      • Schürmann M.
      • Sheldon R.A.
      • Wohlgemuth R.
      Biocatalysis as key to sustainable industrial chemistry.
      ].
      3,4-Dihydroquinoxalin-2-ones, i. e. benzene-fused ketopiperazines, are important members of the wider family of quinoxalines, considered privileged nitrogen-based motives in medicinal chemistry [
      • Borah B.
      • Chowhan L.R.
      Recent advances in the transition-metal-free synthesis of quinoxalines.
      ,
      • Montana M.
      • Mathias F.
      • Terme T.
      • Vanelle P.
      Antitumoral activity of quinoxaline derivatives: a systematic review.
      ]. Optically pure 3,4-dihydroquinoxalin-2-ones are endowed with different pharmacological activities, exemplified by GW420867X, a potent non-nucleoside HIV-1 reverse transcriptase inhibitor entered into clinical trials in 2001 [
      • Arasteh K.
      • Wood R.
      • Müller M.
      • Prince W.
      • Cass L.
      • Moore K.
      • Dallow N.
      • Jones A.
      • Klein A.
      • Burt V.
      • Kleim J.-P.
      GW420867X administered to HIV-1-infected patients alone and in combination with lamivudine and zidovudine.
      ], or the Bradykinin B1 receptor antagonist 1 [
      • Chen J.J.
      • Qian W.
      • Biswas K.
      • Viswanadhan V.N.
      • Askew B.C.
      • Hitchcock S.
      • Hungate R.W.
      • Arik L.
      • Johnson E.
      Discovery of dihydroquinoxalinone acetamides containing bicyclic amines as potent Bradykinin B1 receptor antagonists.
      ], an agent against inflammation, able to relieve pain in septicaemia and compound 2, a bromo domain protein 4 (BDR4) inhibitor [
      • Jung M.
      • Gelato K.A.
      • Fernández-Montalván A.
      • Siegel S.
      • Haendler B.
      Targeting BET bromodomains for cancer treatment.
      ,
      • Rooney T.P.C.
      • Filippakopoulos P.
      • Fedorov O.
      • Picaud S.
      • Cortopassi W.A.
      • Hay D.A.
      • Martin S.
      • Tumber A.
      • Rogers C.M.
      • Philpott M.
      • Wang M.
      • Thompson A.L.
      • Heightman T.D.
      • Pryde D.C.
      • Cook A.
      • Paton R.S.
      • Müller S.
      • Knapp S.
      • Brennan P.E.
      • Conway S.J.
      A series of potent CREBBP bromodomain ligands reveals an induced-fit pocket stabilized by a cation-π interaction.
      ], involved in clinical trials for cancer treatment (Fig. 1 A).
      Fig. 1
      Fig. 1Optically pure 3,4-dihydroquinoxalin-2-ones and synthetic strategies. (A) Examples of biologically active non racemic 3,4-dihydroquinoxalin-2-ones. (B) The classical stoichiometric chiral pool/auxiliary approaches from α-amino acid and mandelate/tartaric acid sources. Asymmetric catalysis provided new routes able to greatly expand the substrate scope and increase the sustainability of the synthesis.
      For the preparation of this class of compounds, different routes have been envisaged over the years, according to a pathway typically followed to address the synthesis of an optically enriched compound. The first step is to look to readily available reagents from the chiral pool, bearing well-established absolute configuration of the stereocenters, with α-amino acids, sugars and terpenes often representing the principal natural source. Alternatively, the chiral auxiliary approach, mostly developed in the 1970s and 1980s, often turns out to be the method of choice, which has found extensive application in total syntheses of complex natural compounds and bioactive products [
      • Diaz-Muñoz G.
      • Miranda I.L.
      • Sartori S.K.
      • de Rezende D.C.
      • Nogueira Diaz M.A.
      Use of chiral auxiliaries in the asymmetric synthesis of biologically active compounds: a review.
      ]. However, proceeding through a catalytic process has several advantages over the stoichiometric methods in terms of costs, environmental impact and suitability of large scale production. Moreover, substrate scope applicability may happen to be problematic when applying the chiral pool or auxiliary strategies. Specifically, to prepare the 3,4-dihydroquinoxalin-2-ones, the Cu(I)-catalysed coupling of ortho-nitroaryl- or ortho-aminoaryl halides with L-α-amino acids readily available from the chiral pool [
      • TenBrink R.E.
      • Im W.B.
      • Sethy V.H.
      • Tang A.H.
      • Carter D.B.
      Antagonist, partial agonist, and full agonist imidazo[ 1,5-a]quinoxaline amides and carbamates acting through the GABA/A benzodiazepine receptor.
      ] has been firstly reported, followed by the (S)-mandelate auxiliary protocol (Fig. 1B) [
      • Lee Y.M.
      • Park Y.S.
      (S)-Mandelate-mediated dynamic kinetic resolution of α-bromo esters for asymmetric syntheses of aminoflavones, dihydroquinoxalinones and dihydrobenzoxazinones.
      ]. The asymmetric hydrogenation of suitable heterocyclic precursors, such as quinoxalinones, has been conceived as the most popular catalytic strategy to access the 3,4-dihydroquinoxalin-2-one scaffold. This is not surprising, being metal-catalysed hydrogenation one of the well-studied and largely applied fundamental process in asymmetric catalysis, where a great variety of tunable metal/chiral ligand systems have been developed so far [
      • Kim A.M.
      • Stoltz B.M.
      Recent advances in homogeneous catalysts for the asymmetric hydrogenation of heteroarenes.
      ]. Unexpectedly, organocatalytic transfer hydrogenation methods of quinoxalinones have been firstly developed [
      • Rueping M.
      • Tato F.
      • Schoepke F.R.
      The first general, efficient and highly enantioselective reduction of quinoxalines and quinoxalinones.
      ]. Alternatively, the catalytic construction of this heterocycle has been designed by using bifunctional organocatalysts via enantioselective cycloaddition reactions from small preformed fragments [
      • Abraham C.J.
      • Paull D.H.
      • Scerba M.T.
      • Grebinski J.W.
      • Lectka T.
      Catalytic, enantioselective bifunctional inverse electron demand hetero-diels-alder reactions of ketene enolates and o-benzoquinone diimides.
      ] or by using commercially or readily available reagents in reaction sequences operating under one-pot conditions [
      • Shi F.
      • Tan W.
      • Zhang H.-H.
      • Li M.
      • Ye Q.
      • Ma G.-H.
      • Tu S.-J.
      • Li G.
      Asymmetric organocatalytic tandem cyclization/transfer hydrogenation: a synthetic strategy for enantioenriched nitrogen heterocycles.
      ,
      • Volpe C.
      • Meninno S.
      • Crescenzi C.
      • Mancinelli M.
      • Mazzanti A.
      • Lattanzi A.
      Catalytic enantioselective access to dihydroquinoxalinones via formal α-halo acyl halide synthon in one pot.
      ].
      In this perspective, the progress in the synthesis of optically enriched 3,4-dihydroquinoxalin-2-ones are illustrated. To the best of our knowledge, the topic has been not previously treated from this point of view. After having given an outline on the chiral pool and auxiliary tools, a focused selection of key catalytic methods is discussed, highlighting advantages, reaction scope and limitations. The author apologies for not illustrating all contributions on this research topic. The final aim is to give the reader a picture of the scaffolds currently approachable, stimulating future research to address unmet synthetic goals as well as improvements on efficiency of the existing panel of methodologies necessary for the discovery of new drugs, embedding the 3,4-dihydroquinoxalin-2-one core.

      2. Chiral pool and auxiliary approaches: the first choice

      The chiral pool approach has been developed in the 1990s by using readily available L-α-amino acids or their esters in stepwise procedures involving: i) base catalysed nucleophilic aromatic substitution of o-nitroaryl fluorides followed by ii) reduction of the nitro group by Pd/C mediated hydrogenation [
      • TenBrink R.E.
      • Im W.B.
      • Sethy V.H.
      • Tang A.H.
      • Carter D.B.
      Antagonist, partial agonist, and full agonist imidazo[ 1,5-a]quinoxaline amides and carbamates acting through the GABA/A benzodiazepine receptor.
      ,
      • Smil D.V.
      • Manku S.
      • Chantigny Y.A.
      • Leit S.
      • Wahhab A.
      • Yan T.P.
      • Fournel M.
      • Maroun C.
      • Li Z.
      • Lemieux A.-M.
      • Nicolescu A.
      • Rahil J.
      • Lefebvre S.
      • Panetta A.
      • Besterman J.M.
      • Déziel R.
      Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors.
      ] or under other metal catalysed reductive conditions (SnCl2 [
      • Neagoie C.
      • Krchňák V.
      Piperazine amide linker for cyclative cleavage from solid support: traceless synthesis of dihydroquinoxalin-2-ones.
      ], Na2S2O4 [
      • Yang Y.
      • Zhao L.
      • Xu B.
      • Yang L.
      • Zhang J.
      • Zhang H.
      • Zhou J.
      Design, synthesis and biological evaluation of dihydroquinoxalinone derivatives as BRD4 inhibitors.
      ], Zn [
      • Chanda K.
      • Kuo J.
      • Chen C.-H.
      • Sun C.-M.
      Enantioselective synthesis of benzimidazolyl quinoxalinones on soluble polymer support using focused microwave irradiation.
      ], Fe [
      • Xu B.
      • Sun Y.
      • Guo Y.
      • Cao Y.
      • Yu T.
      Synthesis and biological evaluation of N4-(hetero)arylsulfonylquinoxalinones as HIV-1 reverse transcriptase inhibitors.
      ]), the last step being necessary for the intramolecular amidation reaction to occur (Scheme 1A, Eq. 1).
      Scheme 1
      Scheme 1Chiral auxiliary and pool approaches to 3,4-dihydroquinoxalin-2-ones. (A) α-Amino acids as reagents in base or Cu-catalysed coupling and cyclization with ortho-halide-substituted nitrobenzenes or anilines. (B) (S)-Mandelate and L-tartrate based dynamic kinetic resolution of α-bromoesters with ortho-phenylendiamines in nucleophilic substitution and cyclization.
      A catalytic Cu-catalysed coupling/cyclization process of the α-amino acid with o-aminoaryl bromides, can be alternatively performed (Scheme 1A, Eq. 2) [
      • Tanimori S.
      • Kashiwagi H.
      • Nishimura T.
      • Kirihata M.
      A general and practical access to chiral quinoxalinones with low copper-catalyst loading.
      ]. A certain number of simple or functionalized aliphatic groups at the stereogenic center and differently mono-substituted aromatic portions in the final product, including the pyridine ring can be easily introduced. Nevertheless, the chiral pool approach prevents the installation of aromatic and heteroaromatic moieties at the stereogenic center. In both processes harsh reaction conditions are required, which might somehow affect the optical purity of the final 3,4-dihydroquinoxalin-2-ones [
      • Tung C.-L.
      • Sun C.-M.
      Liquid phase synthesis of chiral quinoxalinones by microwave irradiation.
      ]. Heterocycles of both absolute configurations can be prepared when the D-α-amino acid is accessible at reasonable costs and this is of fundamental importance as both enantiomeric products need to be available for bioassay tests. Protocol reported in Eq. 1 is likely the most applied and it has been modified by taking advantage of solid phase synthesis to render the procedure more flexible and amenable of different functionalizations in view of compound libraries access [
      • Lee J.
      • Murray W.V.
      • Rivero R.A.
      Solid phase synthesis of 3,4-disubstituted-7-carbamoyl-1,2,3,4-tetrahydroquinoxalin-2-ones.
      ]. However, optimization of this procedure at different stages was necessary in order to minimize side-reactions and racemization of the final product [
      • Morales G.A.
      • Corbett J.W.
      • DeGrado W.F.
      Solid-phase synthesis of benzopiperazinones.
      ]. More recently, process illustrated in Eq. 1 has been improved from the “greenness” point of view by using envinromentally convenient Fe or Zn reducing agents under milder reaction conditions [
      • Li D.
      • Ollevier T.
      Iron- or zinc-mediated synthetic approach to enantiopure dihydroquinoxalinones.
      ].
      In 2009, Park and coauthors illustrated an example of dynamic kinetic resolution (DKR) of (S)-mandelate-based α-bromo esters in nucleophilic displacement with ortho-phenylendiamines to prepare 3,4-dihydroquinoxalin-2-ones (Scheme 1B, Eq. 3) [
      • Lee Y.M.
      • Park Y.S.
      (S)-Mandelate-mediated dynamic kinetic resolution of α-bromo esters for asymmetric syntheses of aminoflavones, dihydroquinoxalinones and dihydrobenzoxazinones.
      ]. This process has been efficiently elaborated on the grounds of previously reported SN2 displacement of (R)-Pantolactone esters of racemic α-bromo acids with amines to give enantioenriched α-amino acid esters, pioneered by Durst and co-workers [
      • Koh K.
      • Ben R.N.
      • Durst T.
      Reaction of (R)-pantolactone esters of alpha-bromoacids with amines. A remarkable synthesis of optically active alpha-amino esters.
      ].
      DKR is a challenging but more appealing procedure for the synthesis of optically active compounds with respect to classical kinetic resolution. In a dynamic kinetic resolution, a combined process of equilibration or racemization of the enantiomers/diastereoisomers is introduced. In an ideal case, the slower reacting enantiomer/diastereoisomer is in situ rapidly converted into the most reactive one, thus providing the final optically active product in 100% yield, rather than with the maximum 50% yield [
      • Pellissier H.
      In Chirality from Dynamic Kinetic Resolution.
      ].
      (S)-mandelate-based α-bromo esters of different diastereoisomeric ratios afforded the final 3,4-dihydroquinoxalin-2-ones with the same diastereoselectivity. This analysis attested a fast epimerization at the carbon-bromine under the reaction conditions employed and a selective displacement of only one diastereoisomer by the bis-nucleophilic diamine attack. An intramolecular amidation to 3,4-dihydroquinoxalin-2-ones then occurred under the same conditions, which also represents an easy removal of the mandelate auxiliary. High ee values were observed when using α-phenyl α-bromo ester with some bis-symmetrically disubstituted ortho-phenylendiamines, although only a few simple alkyl sustituted heterocycles have been isolated in good enantioselectivity. The use of (R)-mandelate based starting reagent is a viable option to obtain the heterocycle with opposite absolute configuration. To this end, the same group briefly showed the utility of inexpensive L-tartaric acid-mediated dynamic kinetic resolution of the corresponding α-bromo ester diastereisomeric mixtures (Scheme 1B, Eq. 4) [
      • Kim Y.
      • Park K.J.
      • Park Y.S.
      L-Tartaric acid as a new chiral auxiliary for asymmetric synthesis of piperazinones, morpholinones, dihydroquinoxalinones and dihydrobenzoxazinones.
      ]. The most attractive features of processes reported in Eqs. 3 and 4 are the ready availability, modest cost of the chiral auxiliaries and mild reaction conditions required for the displacement and cyclization. However, the substrate scope appears limited and the synthesis of α-substituted α-bromo esters involves at least a two stepwise sequence, which in addition to the auxiliary cleavage step, affect the step-economy of the procedure.

      3. Catalytic enantioselective reduction of quinoxalinones

      3.1 Reduction mediated by organocatalytic systems

      A straightforward transformation to prepare this and other related classes of heterocycles is the catalytic reduction of suitable heterocyclic precursors. In 2010, Rueping and co-workers reported a proof of concept organocatalytic transfer hydrogenation of quinoxalinones using the Hantzsch dihydropyridine ester as hydride source in the presence of 10 ​mol% of a sterically encumbered (R)-BINOL-derived phosphoric acid (Scheme 2A, Eq. 1) [
      • Rueping M.
      • Tato F.
      • Schoepke F.R.
      The first general, efficient and highly enantioselective reduction of quinoxalines and quinoxalinones.
      ]. This hydride source was inspired by well-known activity of natural redox coenzyme cofactor nicotinamide adenine dinucleotide phosphate (NADPH) in cells. A limited number of aryl-substituted at the stereocenter 3,4-dihydroquinoxalin-2-ones were prepared in moderate yields, but excellent level of enantioselectivity. The principal route to prepare quinoxalinones concerns the condensation of α-keto acids or esters with ortho-phenylendiamines [
      • Huang J.
      • Chen W.
      • Liang J.
      • Yang Q.
      • Fan Y.
      • Chen M.-W.
      • Peng Y.
      α-Keto acids as triggers and partners for the synthesis of quinazolinones, quinoxalinones, benzooxazinones, and benzothiazoles in water.
      ,
      • Ebersol C.
      • Rocha N.
      • Penteado F.
      • Silva M.S.
      • Hartwig D.
      • Lenardão E.J.
      • Jacob R.G.
      A niobium-catalyzed coupling reaction of α-ketoa with ortho-phenylenediamines: synthesis of 3-arylquinoxalin-2(1H)-ones.
      ]. Shi, Tu and co-workers designed a convenient one-pot process, where the same organic promoter assisted, at reduced loading, the condensation reaction of α-ketosters and bis-symmetrically substituted ortho-phenylendiamines to quinoxalinone en route to the following asymmetric transfer hydrogenation occurring under the same reaction conditions [
      • Shi F.
      • Tan W.
      • Zhang H.-H.
      • Li M.
      • Ye Q.
      • Ma G.-H.
      • Tu S.-J.
      • Li G.
      Asymmetric organocatalytic tandem cyclization/transfer hydrogenation: a synthetic strategy for enantioenriched nitrogen heterocycles.
      ]. The substrate scope was partially expanded to heterocycles bearing electron-withdrawing groups in the aromatic moiety (R1 group), observing excellent ee values. This multicomponent step-economic procedure elegantly overcomes the shortcoming to prepare in advance the quinoxalinones, thus significantly increasing the sustainability of the reductive catalytic route. Privileged (S)- and (R)-BINOL ligands, being available at reasonable price, secure the synthesis of both enantiopure phosphoric acid catalysts, some of them being commercially sold, but at high costs.
      Scheme 2
      Scheme 2Catalytic enantioselective reduction of quinoxalinones mediated by BINOL-derived phosphoric acid, Lewis base and metal/ligand systems. (A) Catalytic enantioselective transfer hydrogenation of quinoxalinones mediated by (R)-BINOL derived phosphoric acid with Hantzsch ester. (B) Lewis base catalysed enantioselective transfer hydrogenation of quinoxalinones. (C) Catalytic enantioselective hydrogenation of quinoxalinones mediated by metal/ligand complexes.
      In 2010, Zhang and co-workers extended a successful and general metal-free strategy known for the hydrosilylation of ketimines [
      • Malkov A.V.
      • Mariani A.
      • MacDougall K.N.
      • Kočovský P.
      Role of noncovalent interactions in the enantioselective reduction of aromatic ketimines with trichlorosilane.
      ] to quinoxalinones [
      • Xue Z.-Y.
      • Jiang Y.
      • Peng X.-Z.
      • Yuan W.-C.
      • Zhang X.-M.
      The first general, highly enantioselective lewis base organocatalyzed hydrosilylation of benzoxazinones and quinoxalinones.
      ]. The reaction was catalysed by (+)-ephedrine-derived picolamide organocatalyst and trichlorosilane as the reducing agent (Scheme 2B, Eq. 2). The activation of trichlorosilane in a hypervalent chiral complex with the Lewis base occurs, where the control of face-selectivity in the reduction would be steered by H-bonding as well as π-π interactions [
      • Denmark S.E.
      • Beutner G.L.
      Lewis base catalysis in organic synthesis.
      ]. A variety of mono N1-alkylated 3,4-dihydroquinoxalin-2-ones 3-aryl substituted at para and meta positions or bearing a heteroaromatic group were obtained in good to high yield and ee values. Being (−)-ephedrine commercially available, both enantioenriched benzene-fused ketopiperazines are obtainable. Sterically encumbered 1-naphthyl or ortho-phenyl substituted reagents did not provide the final product or this was isolated with low enantioselectivity, attesting the susceptibility of this system to steric effects. Symmetrically substituted ortho-phenylendiamines are employable in the synthesis of the heterocyclic precursors, to avoid regioselectitity problems, which represents a limitation in structural diversity and further post-functionalization in the aromatic portion of the product.

      3.2 Reduction mediated by metal-based systems

      In 2013, Vidal-Ferran and co-workers reported a first catalytic metal-based hydrogenation of quinoxalinones (Scheme 2C, Eq. 3) [
      • Núñez-Rico J.L.
      • Vidal-Ferran A.
      [Ir(P-OP)]-catalyzed asymmetric hydrogenation of diversely substituted C=N-containing heterocycles.
      ]. An iridium(I) complex of enantiopure phosphine-phosphite ligand proved to be active at very low loading (0.05–0.5 ​mol%) providing a limited number of NH free or mono N1-alkylated 3,4-dihydroquinoxalin-2-ones, bearing a phenyl or tolyl group at 3-position and bis-symmetrical substitution in the aromatic condensed portion. The conversion were almost quantitative and excellent ee values were observed. A first effective catalytic synthesis of an alkyl (3-methyl) substituted 3,4-dihydroquinoxalin-2-one has been reported with 90% ee. By using the diastereiosomeric ligand embedding the (S)-BINOL fragment, the opposite enantiomer of the final heterocycle has been formed in two representative examples with the same level of enantioselectivity. This is an interesting feature of the catalytic system, which showed the impact of the axially chiral fragment over the centrally chiral one to impart the stereocontrol.
      Recently, the group of Peng focused the attention on fluorine containing 3,4-dihydroquinoxalin-2-ones, taking into account the great importance of trifluoromethyl and more in general fluorine-containing moieties group in improving lipophilicity and kinetic stability when present in pharmaceutically active compounds. A commercially available well-established Pd(OCOCF3)2/(R)-SegPhos system efficiently catalysed, at 3 ​mol% loading, a highly enantioselective hydrogenation of a variety of mono- or bis-symmetrically substituted on the aromatic condensed ring quinoxalinones (Scheme 2C, Eq. 4) [
      • Chen M.-W.
      • Deng Z.
      • Yang Q.
      • Huang J.
      • Peng Y.
      Enantioselective synthesis of trifluoromethylated dihydroquinoxalinones via palladium-catalyzed hydrogenation.
      ]. The same system is likewise useful to access products methylated and benzylated at N (1)-position and the applicability of the process has been assessed at gram scale. Unfortunately, no other fluorinated groups at the chiral center were studied to prove the access to a wider panel of fluorine containing 3,4-dihydroquinoxalin-2-ones. Further reduction of the carbonyl group by diborane enabled the preparation of biologically active tetrahydroquinoxalines without loss of optical purity.
      A Ru-based system has been recently developed under biomimetic hydrogenation conditions and H-bonding activation with diarylurea as valuable protocol (Scheme 2C, Eq. 5) [
      • Zhao Z.-B.
      • Li X.
      • Chen M.-W.
      • Zhao Z.K.
      • Zhou Y.-G.
      Biomimetic asymmetric reduction of benzoxazinones and quinoxalinones using ureas as transfer catalysts.
      ]. The authors cleverly combined the biomimetic idea to use a hydride source as stoichiometrically introduced in (Eq. 1) with the Hantzsch dihydropyridine esters, in a catalytic and optically active ferrocene-derived regenerable NAD(P)H model. In this case, the chiral catalyst and hydride source precursor have been embedded in the same structure and its regeneration occurs under molecular hydrogen atmosphere. Comparatively, the Ru-based system is more sustainable, thanks to higher atom-economy than the approach based on Hantzsch dihydropyridine esters. Interestingly, the presence of the diaryl urea as additive was found to be necessary for the reaction to proceed, suggesting a crucial role in H-bonding activation of the starting quinaxolinone, likely through nitrogen atom at the C N group. Some heterocycles methylated and allylated at N (1)-position and bearing an aromatic group at stereogenic center, were synthesized in high yields and ee values. A key precursor for the synthesis of a BRD4 inhibitor has been obtained in 92% yield and 94% ee. Additionally, very recently, a more general system consisting of Ru (diamine) complex at 1 ​mol% has been reported in the asymmetric hydrogenation of 3-aryl and linear or cyclic 3-alkyl substituted quinoxalinones. The reaction proved to be effective at room temperature, leading to the heterocycles in high to excellent yields and ee values [
      • Li C.
      • Zhang S.
      • Li S.
      • Feng Y.
      • Fan Q.-H.
      Ruthenium-catalyzed enantioselective hydrogenation of quinoxalinones and quinazolinones.
      ].

      4. Organocatalytic enantioselective synthesis of 3,4-dihydroquinoxalin-2-ones

      4.1 Cycloaddition reactions

      In 2006, Lectka and co-workers pioneered the construction of 3,4-dihydroquinoxalin-2-ones via an inverse electron demand hetero Diels-Alder reaction of ortho-benzoquinone diimides, a four-atom partner, and differently substituted aliphatic acyl chlorides (Scheme 3, Eq. 1) [
      • Abraham C.J.
      • Paull D.H.
      • Scerba M.T.
      • Grebinski J.W.
      • Lectka T.
      Catalytic, enantioselective bifunctional inverse electron demand hetero-diels-alder reactions of ketene enolates and o-benzoquinone diimides.
      ]. The cooperative activation of ortho-benzoquinone diimide and aliphatic acyl chloride has been envisaged using 10 ​mol% of Lewis acid zinc triflate and 10 ​mol% of benzoyl quinidine, respectively. The presence of stoichiometric diisopropyl ethyl amine (DIPEA) was necessary to in situ generate the ketene which then reacted with the organocatalyst to give a covalent species, i.e. the enolate, during a slow addition of the acyl chloride at −78 ​°C. The cycloaddition reaction enabled the preparation of bis-N-benzoylated heterocycles, bearing a variety of common and functionalized alkyl groups at the chiral center, in good to high yields and excellent control of the enantioselectivity. Mono- and symmetrically substituted condensed aromatic rings can be installed in the heterocyclic core. A stepwise mechanism has been proposed, supported by the attack of the optically pure enolate at the more electrophilic nitrogen atom, observed when using ortho-benzoquinone diimides mono-substituted with electron-withdrawing groups. The pseudo-enantiomeric quinine derived catalyst worked with comparable efficiency, thus securing the synthesis of both enantiopure isomers of the product. The most attractive features of this system are i) a good substrate scope, with the exception of aryl and heteroaryl substitution, ii) control of the regioselectivity when using differently EWG-substituted ortho-benzoquinone diimides, iii) the impressive level of enantioselectivity achievable by popular and readily available Cinchona alkaloids derived organocatalysts.
      Scheme 3
      Scheme 3Organocatalyzed enantioselective cycloaddition to 3,4-dihydroquinoxalin-2-ones.
      However, strictly controlled reaction conditions and deprotection steps to obtain NH-free heterocycles useful for further manipulation, are required.
      A similar approach based on optically pure N-heterocyclic carbene (NHC)-catalysed reaction of α-chloro aldehydes and ortho-benzoquinone diimides has been more recently developed by Chi and coworkes (Scheme 3, Eq. 2) [
      • Huang R.
      • Chen X.
      • Mou C.
      • Luo G.
      • Li Y.
      • Li X.
      • Xue W.
      • Jin Z.
      • Chi Y.R.
      Carbene-catalyzed α-carbon amination of chloroaldehydes for enantioselective access to dihydroquinoxaline derivatives.
      ]. In this protocol a different covalent species, i. e. an acylazolium enolate, is generated from aldehydes under NHC catalysis, able to react with the ortho-benzoquinone diimides. The reaction scope has been focused on 2-chloro-3-aryl propionaldehydes, although 2-chloro buryraldehyde and 2-chloro octylaldehyde can be successfully converted to the heterocycles in very high ee values working at room temperature. Installation of an aromatic group (R1 ​= ​Ph) was not effective in terms of conversion, but still high enantioselectivity was observed. A good control of the regioselectivity has been demonstrated using a mono-substituted ortho-benzoquinone diimide, while mantaining excellent ee values. To improve the sustainability of the cycloaddition, the same reaction was investigated using simple and readily available aldehydes under oxidative conditions to give the azolium enolate or under one-pot fashion, generating the ortho-benzoquinone diimide via oxidation of the diamide precursor, followed by NHC catalysis. However, modest yield of the 3,4-dihydroquinoxalin-2-ones was observed in both cases, indicating that further investigations are necessary to replace the stepwise process.

      4.2 Epoxide ring-opening/cyclization in one-pot and stepwise sequence

      Epoxides behave as highly useful intermediates involved in natural and biologically active compounds preparation, but also in the production of small building-blocks, where two vicinal carbon centers need to be created with a defined stereochemistry [
      • Schneider C.
      Synthesis of 1,2-difunctionalized Fine Chemicals through Catalytic, Enantioselective Ring-Opening Reactions of Epoxides.
      ]. Moreover, when two identical electron-withdrawing and leaving groups (EWG ​= ​Cl, CN, SO2R) are positioned at the same carbon atom, they mask a α-halo acyl halide synthon. In this context, Corey pioneered a stepwise asymmetric synthesis of α-amino acids using optically enriched gem-dichloro epoxides as intermediates in situ generated from enantioenriched alcohols [
      • Corey E.J.
      • Link J.O.
      A general, catalytic, and enantioselective synthesis of α-amino acids.
      ]. With the view to obtain a convenient and more sustainable route to 3,4-dihydroquinoxalin-2-ones, Lattanzi and co-workers recently developed a one-pot protocol using 1-phenylsulfonyl-1-cyano epoxides as new α-halo acyl halide synthon (Scheme 4, Eq.1) [
      • Volpe C.
      • Meninno S.
      • Crescenzi C.
      • Mancinelli M.
      • Mazzanti A.
      • Lattanzi A.
      Catalytic enantioselective access to dihydroquinoxalinones via formal α-halo acyl halide synthon in one pot.
      ]. A streamlined catalytic asymmetric strategy involving Knoevenagel reaction/asymmetric epoxidation/domino ring-opening cyclization (DROC) has been developed in toluene as single solvent, where a popular quinine derived urea was able to stereoselectively catalyze two out of three steps. Commercially available aromatic aldehydes, (phenylsulfonyl)acetonitrile, cumyl hydroperoxide (CHP) and ortho-phenylendiamines were sequentially added in the reaction vessel to give the final heterocycles in good to high overall yield and generally high ee values. A lower level of enantioselectivity was detected with ortho-benzaldehydes as the reagent. The reaction accomodates a good range of mono- and bis-functionalized aromatic aldehydes and symmetrically substituted ortho-phenylendiamines. The process was scalable at 1 ​mmol of aldehyde and the organocatalyst proved robust enough to be recycled up to four one-pot runs without losing any activity, thus increasing the sustainability of the process. A variety of 3-alkyl substituted 3,4-dihydroquinoxalin-2-ones, embedding C–C double or triple bonds, were also achievable with comparable efficiency, through a one-pot process starting from the corresponding alkenes. Key to the success of the process was a (E)-selective Knoevenagel reaction and highly enantioselective epoxidation both steered by crucial H-bonding interactions between reagents and the bifunctional organocatalyst, as attested by DFT study. An important class of bioactive nitrogen-based heterocycles, such as enantioenriched tetrahydroquinoxalines could be readily obtained via diborane reduction of the corresponding 3,4-dihydroquinoxalin-2-ones. Current limitations of the procedure concern the poor regioselectivity achieved when using mono-substituted ortho-phenylendiamines and the preparation of the opposite enantiomer of the heterocycles achieved with lower level of stereocontrol.
      Scheme 4
      Scheme 4Enantioselective strategies to 3,4-dihydroquinoxalin-2-ones involving epoxide ring-opening/cyclization or photo-redox catalysis. (A) Organocatalysed epoxide-ring opening/cyclization in one pot and stepwise fashion. (B) Merged visible-light photoredox catalysis and aminocatalysis for the functionalization of 3,4-dihydroquinoxalin-2-ones with ketones.
      Concurrently, Arai and co-workers illustrated an asymmetric epoxidation of alkylidenemalononitriles using 2.5 ​mol% of C2-symmetric 3,3′-bis((R,R)-2-naphthylethylaminomethyl)-(R)-binaphtholorganocatalyst, CHP as the oxidant in trifluorotoluene at −30 ​°C (Scheme 4, Eq. 2) [
      • Ogino E.
      • Nakamura A.
      • Kuwano S.
      • Arai T.
      Chiral C2-symmetric aminomethylbinaphthol as synergistic catalyst for asymmetric epoxidation of alkylidenemalononitriles: easy access to chiral spirooxindoles.
      ]. A variety of simple alkenes afforded the epoxides in generally fairly good yield and good to high enantioselectivity with the exception of the aliphatic alkene. Interestingly, when starting with isatilidenemalononitriles, the same reaction provided the spiro-epoxides in high yield and good to high ee values.
      Spiro-heterocycles are endowed with several biological activities and are present as structural core in many natural products. Hence, research on the challenging task of their asymmetric synthesis has become a key topic in the last decades [
      • Rios R.
      Enantioselective methodologies for the synthesis of spiro compounds.
      ,
      • Wang Y.
      • Angel A.
      • Cobo
      • Franz A.K.
      Recent advances in organocatalytic asymmetric multicomponent cascade reactions for enantioselective synthesis of spirooxindoles.
      ]. On the grounds of the susceptibility demonstrated by this class of epoxides to serve as α-halo acyl halide synthons [
      • Meninno S.
      • Vidal-Albalat A.
      • Lattanzi A.
      Asymmetric epoxidation of alkylidenemalononitriles: key step for one-pot approach to enantioenriched 3-substituted piperazin-2-ones.
      ], ortho-phenylendiamine was reacted with a limited number of enantioenriched epoxides to satisfactorily provide the 3-aryl substituted 3,4-dihydroquinoxalin-2-ones with maintained level of ee values. Two new dihydroquinoxalinyl spiro-oxindoles were also obtained, representing a first example of optically active spiro 3,4-dihydroquinoxalin-2-ones. Mechanistic studies suggested a synergistic activation provided by the organocatalyst of the alkylidenemalononitrile by the phenolic protons and the oxidant by the secondary basic group. The preparation of the opposite enantiomer of the heterocycle appears difficult and further investigation is required. It is worth noting that this class of organocatalysts easily derives from chiral ligands used in metal catalysis. Accordingly, the chance to revisit the well-known libraries of chiral ligands with a view to explore their potential as organocatalysts, is a useful hint coming from this study.

      4.3 Combined with photoredox catalysis

      Visible-light photoredox catalysis has become a hot topic in organic synthesis over the last decade, given the significant advantages relying on its abundance, easy applicability, cheap cost and environmental friendliness [
      • Xuan J.
      • Xiao W.-J.
      Visible-light photoredox catalysis.
      ]. Merging photoredox catalysis with organocatalysis has been a facile step to shape new reactivity and functionalization through different activation modes of the reagents, especially in the asymmetric α- and β-functionalization of carbonyl compounds [
      • Zou Y.-Q.
      • Hörmann F.M.
      • Bach T.
      Iminium and enamine catalysis in enantioselective photochemical reactions.
      ].
      Recently, Vila, Pedro and coauthors illustrated a mild and cheap system, combining visible-light photoredox catalysis and asymmetric organocatalysis to accomplish an oxidative Mannich reaction of 3,4-dihydroquinoxalin-2-ones with ketones [
      • Rostoll-Berenguer J.
      • Blay G.
      • Muñoz M.C.
      • Pedro J.R.
      • Vila C.
      A combination of visible-light organophotoredox catalysis and asymmetric organocatalysis for the enantioselective Mannich reaction of dihydroquinoxalinones with ketones.
      ]. They envisaged Eosin-mediated photo-oxidation of 3,4-dihydroquinoxalin-2-ones to form the electrophilic quinoxalinone partner, and the use of L-proline to generate the enamine reagent from ketone (Scheme 4, Eq. 3).
      To minimize side-products, the quinoxalinone was firstly formed under photoredox conditions at room temperature in DMF, then L-proline and the ketone were subsequently added under darkness. A variety of linear, branched, functionalized and cyclic ketones were tolerated and the formation of a single regioisomer of the final heterocycle in moderate to high yield, low diastereoselectivity, but generally high ee value, was observed. Mono- or symmetrically substituted in the aromatic fused ring and differently protected at the N1 atom products, were obtained. The practicality of reaction was successfully demonstrated scaling to 5 ​mmol the reagents under sun light source at 0.5 ​mol% loading of Eosin. The involvement of a radical mechanism in the photo-oxidation has been experimentally supported. Although the 3-alkyl-3,4-dihydroquinoxalin-2-ones illustrated in Scheme 4, Eq. 3 represent a highly focused library of products, the introduction of a keto group in the alkyl side chain expands the structural diversity, offering a site for further functionalization of the scaffold. The methodology requires the construction of the heterocyclic precursor, likewise those reported in Scheme 2, but in this case a complementary strategy has been adopted.

      5. Conclusion and outlook

      The optically enriched 3,4-dihydroquinoxalin-2-one core has been significantly targeted over the last decades, due to the diversified bioactivities shown, of interest in drug discovery and being a molecular platform useful to access relevant pharmacophores. A typical evolution in the asymmetric synthesis of this scaffold can be traced back from the 1990s up to now. In the early stages, the stoichiometric methods based on the chiral pool and auxiliaries have been developed, taking advantage of the broadly available L-α-aminoacids and mandelates or tartrates auxiliaries. The protocols starting from L-α-aminoacids are likely the most versatile and cost-convenient and are those ones which experienced improvements over the years from the sustainability point of view, exploiting solid-phase synthesis application or greener reaction conditions. Although a restriction is imposed on the nature of the substituents to install at the chiral center, the regioselectivity issue in mono-substitution of the condensed aromatic portion is controllable and can be a priori designed. Indeed, this synthetic problem represents one major limitation observed in the other methodologies, including the catalytic ones, where the symmetrical substitution pattern is mostly achievable.
      In a catalytic context, asymmetric hydrogenation or transfer hydrogenation have been actively investigated, under low loading of precious metal/ligand systems or employing organic promoters. The metal-based system showed significantly higher atom economy when compared to the organocatalytic counterpart. The metal-catalysed hydrogenation is far from having demonstrated its full potential. Hence, new and more affordable and abundant metals are expected to work under milder reductive reaction conditions, while offering wider substrate applicability.
      The organocatalytic cyclization strategies based on Diels-Alder reaction or ring-opening/cyclization of epoxides showed to be susceptible to proceed using readily available organic promoters and reagents under one-pot conditions, thus minimizing waste, working times and costs for the isolation of intermediates. Interestingly, the preparation of spirocyclic 3,4-dihydroquinoxalin-2-ones has been preliminarly demonstrated. Given the relevance in medicinal chemistry of optically pure spiro-heterocycles, the epoxides ring-opening/cyclization approach should deserve further investigation in the future.
      At present, photocatalysis has been only marginally applied in combination with organocatalysis, proving to be a viable route to prepare enantioenriched 3,4-dihydroquinoxalin-2-ones. Additional strategies of this type, including photo- and metal based systems are certainly awaited to supply efficient alternatives able to broaden the structural diversity. As a general consideration, a good variety of simple alkyl, cycloalkyl, functionalized aliphatic and aromatic groups can be installed at the chiral center, in contrast to seldom reported heteroaromatic groups. Hence, improved methodologies should fill this gap, including the use of more environmentally friendly solvents and reduced amount of catalyst loading, to become of interest for industrial application.
      Lastly, asymmetric tools that assure the installation of a quaternary sterocenter are lagging behind and efforts will be necessary to unlock this very challenging goal. Cyclization routes or ring-opening/cyclization of epoxides would appear suitable to address this issue, but other reaction pathways should be devised to open the access to missing enantioenriched 3,4-dihydroquinoxalin-2-ones, bearing a quaternary stereocenter.

      The bigger picture

      Challenges/opportunities.
      • Today, the continuous development of new catalytic and selective processes has become a pressing need to achieve sustainable chemical productions. Asymmetric catalysis is often required for the synthesis of drugs and biologically active compounds, which significantly populate the pharmaceutical and agrochemical markets. In this context, asymmetric catalysis demonstrated to be a powerful and effective tool to expand the classical stoichiometric chiral pool and auxiliary based approaches to medicinally and synthetically important 3,4-dihydroquinoxalin-2-ones.
      • Catalysis provided by metal/ligand complexes and small organic molecules followed complementary pathways to access the 3,4-dihydroquinoxalin-2-one scaffold. The construction of the prochiral quinoxalinone precursor, in the most recurrent chiral ligand-Ir, Pd, Ru-catalysed hydrogenation reaction, is required. Conversely, the organocatalytic protocols, occasionally performable under more appealing one-pot conditions, involve cycloaddition or ring-opening/cyclization of readily available reagents and intermediates.
      • However, there is the need for further improvements in terms of more sustainable reaction conditions, substrate scope and most of all the development of enantioselective catalytic methods to hitherto hardly accessible 3,4-dihydroquinoxalin-2-ones, featuring quaternary stereocenters.

      Declaration of competing interest

      The author declares no competing interests.

      Acknowledgements

      Ministero dell'Università e Ricerca (MUR) and University of Salerno are acknowledged for financial support.

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