Metal-Catalyzed and Metal-Mediated Approaches to the Synthesis and Functionalization of Tetramic Acids Metal ‐ Catalyzed and Metal ‐ Mediated Approaches to the Synthesis and Functionalization of Tetramic Acids

: The heterocyclic ring of tetramic acids is found in naturally occurred biologically active products isolated from fungi, bacteria, molds, and sponges. Thus, these molecules have attracted signiﬁcant attention as synthetic targets, and various synthetic paths have been developed. Over recent years, a growing number of catalytic approaches toward functionalized products have been established in order to overcome the limitations of the conventional methods. The present review describes the strategies for the metal-catalyzed and metal-promoted synthesis and further derivatization of tetramic acids, with emphasis on recent examples from the literature. Abstract: The heterocyclic ring of tetramic acids is found in naturally occurred biologically active products isolated from fungi, bacteria, molds, and sponges. Thus, these molecules have attracted significant attention as synthetic targets, and various synthetic paths have been developed. Over recent years, a growing number of catalytic approaches toward functionalized products have been established in order to overcome the limitations of the conventional methods. The present review describes the strategies for the metal ‐ catalyzed and metal ‐ promoted synthesis and further derivatization of tetramic acids, with emphasis on recent examples from the literature.


Introduction
Natural and synthetic products incorporating the tetramic acid nucleus (pyrrolidine-2,4-dione) [1,2] have been identified as potent antibacterial [3][4][5], antifungal [6], antiviral [7], and anticancer agents [8]. In addition, these molecules exhibit agricultural bioactivities, such as being fungicidal [9][10][11], herbicidal [12,13] and nematicidal [14]. Reutericyclin, tenuazonic acid, streptolydigin, and equisetin are representative examples of biologically active natural products, whereas the most wellknown commercial product is the insecticidal spirocyclic tetramic acid spirotetramat [15] (Figure 1).  Tetramic acids possessing a 3-acyl group have the ability to chelate divalent or trivalent metal ions ( Figure 2) [19,20]. Metal chelation by tetramic acid nucleus seems to be important for transport across membranes in biological tissues [2]. Janda et al. [21], in a great research article that boosted the synthetic interest in tetramic acids during the last decade, reported a novel tetramic acid degradation product from the quorum-sensing N-acetyl homoserine lactone as a potent antibacterial agent and its complex with Fe(III). Schobert et al. [22] prepared complexes of natural melophlins A and C with Mg(II), Zn(II), Ga(III), La(III), and Ru(II), and found that the lanthanum and ruthenium complexes exhibit enhanced cytotoxic activities. Some of the tetramic acid-copper(II) complexes have shown higher antimicrobial activity than their parent compounds [23]. Markopoulou et al. have reported many synthetic and structural studies on tetramic acid complexes [24][25][26]. Recently, we found that the cadmium(II) complex of the N-acetyl-3-acetyl-5-benzylidenetetramic acid inhibits most of the tested bacterial and fungal strains more effectively than the ligand, and it is particularly potent against Cryptococcus neoformans (MIC = 8 μg/mL) [27]. Apart from the above, a number of platinum or palladium containing 3-acyl tetramic acids with potential antitumor activities have been reported [28][29][30].

Scheme 1. Tautomeric forms of 3-acetyl tetramic acids.
Tetramic acids possessing a 3-acyl group have the ability to chelate divalent or trivalent metal ions ( Figure 2) [19,20]. Metal chelation by tetramic acid nucleus seems to be important for transport across membranes in biological tissues [2]. Janda et al. [21], in a great research article that boosted the synthetic interest in tetramic acids during the last decade, reported a novel tetramic acid degradation product from the quorum-sensing N-acetyl homoserine lactone as a potent antibacterial agent and its complex with Fe(III). Schobert et al. [22] prepared complexes of natural melophlins A and C with Mg(II), Zn(II), Ga(III), La(III), and Ru(II), and found that the lanthanum and ruthenium complexes exhibit enhanced cytotoxic activities. Some of the tetramic acid-copper(II) complexes have shown higher antimicrobial activity than their parent compounds [23]. Markopoulou et al. have reported many synthetic and structural studies on tetramic acid complexes [24][25][26]. Recently, we found that the cadmium(II) complex of the N-acetyl-3-acetyl-5-benzylidenetetramic acid inhibits most of the tested bacterial and fungal strains more effectively than the ligand, and it is particularly potent against Cryptococcus neoformans (MIC = 8 µg/mL) [27]. Apart from the above, a number of platinum or palladium containing 3-acyl tetramic acids with potential antitumor activities have been reported [28][29][30].
Noteworthy, Hosseini et al. have prepared N-tetramic acid dipeptide analogues (Figure 3; Part A) [31], 3-amino-pyrrolidinone dipeptides [32], and tripeptides [33] that contributed to the research of peptidomimetics bearing tetramate analogues [34,35]. More recently, Lee et al. prepared ampicillin, cephalosporin, cephamycin, and other β-lactam-tetramic acid hybrids, and evaluated their antimicrobial activity (Figure 3; Part B) [36,37]. Even though tetramic acid was firstly synthesized in 1972 [38], preparations of 3-acetyl and other substituted tetramic acids have been available since the middle of 20th century [39]. Over the years, numerous papers have improved the established methodologies in terms of yield, purity, enantiopurity, and functionalization. Given the products' great biological activities, more and more functionalized and complex molecules are needed. However, the conventional synthetic strategies, often require highly functionalized and difficult to prepare starting materials or high temperatures in alkaline conditions. As the development of improved strategies toward these five-membered heterocycles is still in demand, a number of catalytic approaches have been developed as a tool to overcome the limitations of the traditional methods.
In this review, after an overview of the well-established conventional methodologies, we will present the catalytic protocols for the synthesis of tetramic acids and their analogues in a critical way one by one, mentioning the advantages and the limitations of each method. Moreover, the methodologies involving the use of a catalyst toward the further functionalization of the ring will be reported.

Conventional Synthetic Methods
Until now, over 300 research articles have been published concerning the synthesis of tetramic acids. Up to 2008, this topic has been covered extensively by reviews on the chemistry, synthesis and biosynthesis of tetramic acids [2,40,41]. Since then, most of the synthetic papers involve modifications, further optimization on novel derivatives, and some sophisticated novel methods, some of which are catalytic.
Before we overview the methodologies for the preparation of the most important 3-acyl and 3-alkoxycarbonyl tetramic acids, we will briefly mention the synthesis of 3-unsubstituted tetramic acid. The tetramic acid was prepared decades after the 3-substituted analogues [38]. In fact, it derived from decarboxylation of the 3-ethoxycarbonyltetramic acid. Earlier approaches [42,43] were proven to lead to the isomeric 2-iminotetronic acid. In most circumstances, the 3-unsubstituted tetramic acid is used as a starting material toward 3-acylated derivatives [44][45][46][47].

Lacey-Dieckmann Cyclization
In 1954, Lacey published a two-step synthetic route to 3-acyltetramic acids 1 starting from α-aminoesters 2 and diketene 3 (Scheme 2; Part A) [39]. This method is similar to the biosynthesis of these molecules. Lacey's strategy is flexible, and can be used in the preparation of many 3-acyltetramic acid derivatives. It has been used in a plethora of syntheses of compounds, even natural products [48]. Many modifications of this method have been published, the most important being the ones by i. Isowa and Ohta [49], in which an ethoxycarbonylacetyl chloride was used instead of the diketene; ii. Mulholland et al. [38], which used malonic ester chlorides; iii. Boeckmann [50] and Paquette [51] in ikarugamycin synthesis; and iv. Schlessinger via activated phosphonate intermediates [52,53]. Recently, the latter method was applied in the total synthesis of macrocidin A [54] and cylindramine A [55]. Lacey's method has been adapted successfully in solid-phase synthesis as well [56] (Scheme 2; Part B).

From Meldrum's Acid
According to Jouin's method [60] a C-acylation reaction between the appropriate α-aminoacid 5 and Meldrum's acid 6 using ICPF (isopropenyl chloroformate) as the acylating agent and DMAP (4-(dimethylamino)pyridine) as the catalyst, gives 3-unsubstituted tetramic acids 7 in two steps (Scheme 3; Part A). This protocol is ideal for the synthesis of these tetramic acids, due to the relatively mild conditions (neutral pH and refluxing the intermediate products in acetonitrile or ethyl acetate for 15-30 min). The yields are very high (up to 94% for the L-phenylalanine derivative), and the reaction proceeds without racemization. The scope of this method is limited to 3-unsubstituted compounds.
Earlier, the synthesis of tetramates (and tetronates/thiotetronates) [80] incorporating the ylide Ph3PCCO 17 was published following the first paper on this methodology on tetronates in 1995 [81]. As reported by the same group, since tetramic and tetronic acids have acidic hydrogens at C-3, they This protocol has been adapted successfully in the solid-phase synthesis of tetramic acids 13 using a p-nitrophenyl carbonate linker on Wang resin 14 (Scheme 4; Part C) [75].

Involving Activated Cyclic Starting Materials or Intermediates
DeShong et al. developed a method based in Lacey's protocol, according to which the alkylation of a substituted isoxazole 20 followed by fragmentation of the resulting isoxazolium salt 21 leads to a β-ketoamide 22 [86,87]. Next, this intermediate undergoes base-catalyzed cyclization under Lacey's conditions to afford 3-acyltetramic acid 23 (Scheme 6; Part A).
Markopoulou et al. have reported two protocols involving cyclic starting materials for activation and/or protection. The first involved (S)-N-acetylaspartic acid anhydride [88]. Optically active 3-acyl-5-carboxymethyl tetramic acids were prepared with this route. An interesting feature of this study is the incorporation of 3-alkyl and 3-aryl substituents using LDA at −78 °C, without racemization. A similar starting material, O-protected hydroxyl succinic anhydride (malic acid anhydride), has been used from the same group [89] for the synthesis of chiral tetronic acids. In the second, 2-methyl-4benzylidene-5(4H)-oxazolone 24 was found to serve successfully as both a protected and an activated α-amino acid. Therefore, the desired 5-benzylidene tetramic acid 25 was prepared in just one step (Scheme 6; Part B), without the removal of the N-acetyl group, which is considered crucial for the biological activities and the natural product synthesis [26]. Stachel has prepared a library of Nbenzoyl or N-unsubstituted 5-arylidenetetramic acids [90] starting from a similar 2-phenyl oxazolone. Earlier, the synthesis of tetramates (and tetronates/thiotetronates) [80] incorporating the ylide Ph 3 PCCO 17 was published following the first paper on this methodology on tetronates in 1995 [81]. As reported by the same group, since tetramic and tetronic acids have acidic hydrogens at C-3, they can react with the same ylide 17 to give the corresponding 3-(triphenylphosphoranylidene) acetyl derivatives 18 [82], which were used toward the synthesis of ravenic acid 19 in 2010 (Scheme 5; Part B) [47].

Involving Activated Cyclic Starting Materials or Intermediates
DeShong et al. developed a method based in Lacey's protocol, according to which the alkylation of a substituted isoxazole 20 followed by fragmentation of the resulting isoxazolium salt 21 leads to a β-ketoamide 22 [86,87]. Next, this intermediate undergoes base-catalyzed cyclization under Lacey's conditions to afford 3-acyltetramic acid 23 (Scheme 6; Part A).
Markopoulou et al. have reported two protocols involving cyclic starting materials for activation and/or protection. The first involved (S)-N-acetylaspartic acid anhydride [88]. Optically active 3-acyl-5-carboxymethyl tetramic acids were prepared with this route. An interesting feature of this study is the incorporation of 3-alkyl and 3-aryl substituents using LDA at −78 • C, without racemization. A similar starting material, O-protected hydroxyl succinic anhydride (malic acid anhydride), has been used from the same group [89] for the synthesis of chiral tetronic acids. In the second, 2-methyl-4-benzylidene-5(4H)-oxazolone 24 was found to serve successfully as both a protected and an activated α-amino acid. Therefore, the desired 5-benzylidene tetramic acid 25 was prepared in just one step (Scheme 6; Part B), without the removal of the N-acetyl group, which is considered crucial for the biological activities and the natural product synthesis [26]. Stachel has prepared a library of N-benzoyl or N-unsubstituted 5-arylidenetetramic acids [90] starting from a similar 2-phenyl oxazolone. Martinez used protected (Fmoc, Boc or Z) urethane-N-carboxyanhydride 26 to prepare Nprotected 3-unsubstituted chiral tetramic acid 27 under mild conditions (Scheme 7; Part A) [91]. This synthesis is an interesting modification of Jouin's method. Two synthetic methods developed by Jones are using cyclic starting materials or active intermediates as precursors to 3-acyltetramic acids. The first involves the conversion of a pyrone (δ-lactone) to 3-acyltetramic acid [92], and the second is a cycloaddition approach via active isoxazolecarboxylic esters [93].
One of the most interesting and well-established methods for the preparation of chiral tetramic acids is Moloney's method. Regioselective Dieckmann cyclization using an N-acyloxazolidine 28 derived from serine [94,95], and later α-methyl serine [96] and threonine 29 (Scheme 7; Part B) [97,98] gives functionalized monocyclic 30 or bicyclic tetramic acid 31 in high yield and enantioselectivity. Moloney's group has studied in detail the antibacterial activity of many modified tetramic acid libraries using this method [4,[99][100][101]. Martinez used protected (Fmoc, Boc or Z) urethane-N-carboxyanhydride 26 to prepare N-protected 3-unsubstituted chiral tetramic acid 27 under mild conditions (Scheme 7; Part A) [91]. This synthesis is an interesting modification of Jouin's method. Two synthetic methods developed by Jones are using cyclic starting materials or active intermediates as precursors to 3-acyltetramic acids. The first involves the conversion of a pyrone (δ-lactone) to 3-acyltetramic acid [92], and the second is a cycloaddition approach via active isoxazolecarboxylic esters [93].

Silver-Catalyzed CO2 Incorporation to Propargylic Amines
A novel methodology toward tetramic acids has been developed by Yamada et al. involving silver-catalyzed carbon dioxide incorporation into propargylic amine 32 forming a substituted oxazolidinone 33 [102]. This intermediate undergoes an intramolecular rearrangement under mild conditions (DBU-1,8-diazabicyclo [5.4.0]undec-7-ene, 60 °C) to yield the corresponding tetramic acid 34 (Scheme 8). The group reported a one-pot reaction as well, to solve the problem of the 5unsubstituted tetramic acid, which was not able to be prepared in the initial conditions. So far, the reported compounds are limited to 3-aryl (except one unsubstituted derivative), and most of them are 5-disubstituted with the same substituents or 5-hexyl. In the case of 5-monosubstituted (5-ethyl or 5-phenyl) compounds, they appear to be racemic. The authors' hypothesis for the reaction mechanism involved the formation of a cyclic intermediate through silver catalyzed alkyne activation, followed by intramolecular cyclization triggered by deprotonation of the amide from the base (DBU).

Silver-Catalyzed CO 2 Incorporation to Propargylic Amines
A novel methodology toward tetramic acids has been developed by Yamada et al. involving silver-catalyzed carbon dioxide incorporation into propargylic amine 32 forming a substituted oxazolidinone 33 [102]. This intermediate undergoes an intramolecular rearrangement under mild conditions (DBU-1,8-diazabicyclo [5.4.0]undec-7-ene, 60 • C) to yield the corresponding tetramic acid 34 (Scheme 8). The group reported a one-pot reaction as well, to solve the problem of the 5-unsubstituted tetramic acid, which was not able to be prepared in the initial conditions. So far, the reported compounds are limited to 3-aryl (except one unsubstituted derivative), and most of them are 5-disubstituted with the same substituents or 5-hexyl. In the case of 5-monosubstituted (5-ethyl or 5-phenyl) compounds, they appear to be racemic. The authors' hypothesis for the reaction mechanism involved the formation of a cyclic intermediate through silver catalyzed alkyne activation, followed by intramolecular cyclization triggered by deprotonation of the amide from the base (DBU). Catalysts 2019, 9,  This method is presented as an application of that previously reported by the same group transformations using similar starting materials for the CO2 incorporation. In one of them, the authors described the synthesis of benzoxazine-2-ones with the same silver catalytic system [103]. Yamada et al. have prepared as well, a number of biologically interesting 4-hydroxyquinolin-2(1H)-ones 35 under mild conditions in the presence of catalytic AgNO3 (Scheme 9; Part A). Isotopic labeling experiments revealed that the quinolinone contained the carbon dioxide atoms [104]. Earlier, in 2009, in the presence of silver acetate oxazolidinones were prepared under mild conditions without any base [105]. Since then, many heterocyclic compounds such as cyclic carbonate 36 (Scheme 9; Part B) [106] and numerous 2-oxazolidinone derivatives [107] have been prepared by a metal catalyzed reaction of CO2 with propargylic amine or alcohol 37 and even the metal-free synthesis of substituted oxazolones [108].

SmI2-Mediated Cyclizations
Recently, Huang and Py developed a method for the synthesis of chiral tetramic acids 38 involving SmI2-mediated reducting coupling via β-methylenyl-γ-amino esters 39. This mild reducting agent was used to produce the above intermediate esters from nitrones or tertbutanesulfinyl imines 40 (Scheme 10; Part A). The esters 39 were cyclized to the corresponding βmethylenyl-γ-lactams 41 with zinc under ultrasound activation, or by acid hydrolysis (HCl in MeOH). The produced lactams can be easily converted to tetramic acids 38 by ozonolysis (Scheme 10; Part B). The final tetramic acid 38 was found to be optically active, and its chirality was determined by comparison of the αD with literature data; however, no enantiomeric excess was reported [109]. This method is presented as an application of that previously reported by the same group transformations using similar starting materials for the CO 2 incorporation. In one of them, the authors described the synthesis of benzoxazine-2-ones with the same silver catalytic system [103]. Yamada et al. have prepared as well, a number of biologically interesting 4-hydroxyquinolin-2(1H)-ones 35 under mild conditions in the presence of catalytic AgNO 3 (Scheme 9; Part A). Isotopic labeling experiments revealed that the quinolinone contained the carbon dioxide atoms [104]. Earlier, in 2009, in the presence of silver acetate oxazolidinones were prepared under mild conditions without any base [105]. Since then, many heterocyclic compounds such as cyclic carbonate 36 (Scheme 9; Part B) [106] and numerous 2-oxazolidinone derivatives [107] have been prepared by a metal catalyzed reaction of CO 2 with propargylic amine or alcohol 37 and even the metal-free synthesis of substituted oxazolones [108]. This method is presented as an application of that previously reported by the same group transformations using similar starting materials for the CO2 incorporation. In one of them, the authors described the synthesis of benzoxazine-2-ones with the same silver catalytic system [103]. Yamada et al. have prepared as well, a number of biologically interesting 4-hydroxyquinolin-2(1H)-ones 35 under mild conditions in the presence of catalytic AgNO3 (Scheme 9; Part A). Isotopic labeling experiments revealed that the quinolinone contained the carbon dioxide atoms [104]. Earlier, in 2009, in the presence of silver acetate oxazolidinones were prepared under mild conditions without any base [105]. Since then, many heterocyclic compounds such as cyclic carbonate 36 (Scheme 9; Part B) [106] and numerous 2-oxazolidinone derivatives [107] have been prepared by a metal catalyzed reaction of CO2 with propargylic amine or alcohol 37 and even the metal-free synthesis of substituted oxazolones [108].

SmI2-Mediated Cyclizations
Recently, Huang and Py developed a method for the synthesis of chiral tetramic acids 38 involving SmI2-mediated reducting coupling via β-methylenyl-γ-amino esters 39. This mild reducting agent was used to produce the above intermediate esters from nitrones or tertbutanesulfinyl imines 40 (Scheme 10; Part A). The esters 39 were cyclized to the corresponding βmethylenyl-γ-lactams 41 with zinc under ultrasound activation, or by acid hydrolysis (HCl in MeOH). The produced lactams can be easily converted to tetramic acids 38 by ozonolysis (Scheme 10; Part B). The final tetramic acid 38 was found to be optically active, and its chirality was determined by comparison of the αD with literature data; however, no enantiomeric excess was reported [109].

SmI 2 -Mediated Cyclizations
Recently, Huang and Py developed a method for the synthesis of chiral tetramic acids 38 involving SmI 2 -mediated reducting coupling via β-methylenyl-γ-amino esters 39. This mild reducting agent was used to produce the above intermediate esters from nitrones or tert-butanesulfinyl imines 40 (Scheme 10; Part A). The esters 39 were cyclized to the corresponding β-methylenyl-γ-lactams 41 with zinc under ultrasound activation, or by acid hydrolysis (HCl in MeOH). The produced lactams can be easily converted to tetramic acids 38 by ozonolysis (Scheme 10; Part B). The final tetramic acid 38 was found to be optically active, and its chirality was determined by comparison of the α D with literature data; however, no enantiomeric excess was reported [109].
The same year, Pettus et al. reported the synthesis of chiral 3-methyl tetramic acids 42 under mild conditions, using SmI 2 -mediated cyclization (Scheme 11). In the same work, the application of the protocol to the total synthesis of the cytotoxic 3-methyl tetramate natural product palau'imide was presented. The paper demonstrates the synthesis of seven derivatives with high yields and good to exceptional enantiomeric ratios (84:16 to >99:1, determined by HPLC) [110]. The same year, Pettus et al. reported the synthesis of chiral 3-methyl tetramic acids 42 under mild conditions, using SmI2-mediated cyclization (Scheme 11). In the same work, the application of the protocol to the total synthesis of the cytotoxic 3-methyl tetramate natural product palau'imide was presented. The paper demonstrates the synthesis of seven derivatives with high yields and good to exceptional enantiomeric ratios (84:16 to >99:1, determined by HPLC) [110]. Similarly to Py's method, intermediate lactams have previously been prepared by indiumcatalyzed Conia-ene reactions [111], by the selective ring expansion of secondary methylenecyclopropyl amides using catalytic MgI2 at high dilution [112]. Pattenden's work on the radical cyclizations of propargyl bromoamides 43 [113] found application to the synthesis of lactams similar to tetramates [114], to the synthesis of γ-lactams [115], and ultimately to the synthesis of 3methyl-5,5-disubstituted tetramic acids 44 via ozonolysis of the corresponding γ-lactam 45 (Scheme 12) [116]. These protocols involve the cyclization of the enantiopure α-ethynyl substituted serine derivatives using Bu3SnH and AIBN (azobisisobutyronitrile).  The same year, Pettus et al. reported the synthesis of chiral 3-methyl tetramic acids 42 under mild conditions, using SmI2-mediated cyclization (Scheme 11). In the same work, the application of the protocol to the total synthesis of the cytotoxic 3-methyl tetramate natural product palau'imide was presented. The paper demonstrates the synthesis of seven derivatives with high yields and good to exceptional enantiomeric ratios (84:16 to >99:1, determined by HPLC) [110]. Similarly to Py's method, intermediate lactams have previously been prepared by indiumcatalyzed Conia-ene reactions [111], by the selective ring expansion of secondary methylenecyclopropyl amides using catalytic MgI2 at high dilution [112]. Pattenden's work on the radical cyclizations of propargyl bromoamides 43 [113] found application to the synthesis of lactams similar to tetramates [114], to the synthesis of γ-lactams [115], and ultimately to the synthesis of 3methyl-5,5-disubstituted tetramic acids 44 via ozonolysis of the corresponding γ-lactam 45 (Scheme 12) [116]. These protocols involve the cyclization of the enantiopure α-ethynyl substituted serine derivatives using Bu3SnH and AIBN (azobisisobutyronitrile).

Scheme 12.
Pattenden's radical approach to 3-methyl tetramic acids 44. Similarly to Py's method, intermediate lactams have previously been prepared by indium-catalyzed Conia-ene reactions [111], by the selective ring expansion of secondary methylenecyclopropyl amides using catalytic MgI 2 at high dilution [112]. Pattenden's work on the radical cyclizations of propargyl bromoamides 43 [113] found application to the synthesis of lactams similar to tetramates [114], to the synthesis of γ-lactams [115], and ultimately to the synthesis of 3-methyl-5,5-disubstituted tetramic acids 44 via ozonolysis of the corresponding γ-lactam 45 (Scheme 12) [116]. These protocols involve the cyclization of the enantiopure α-ethynyl substituted serine derivatives using Bu 3 SnH and AIBN (azobisisobutyronitrile). The same year, Pettus et al. reported the synthesis of chiral 3-methyl tetramic acids 42 under mild conditions, using SmI2-mediated cyclization (Scheme 11). In the same work, the application of the protocol to the total synthesis of the cytotoxic 3-methyl tetramate natural product palau'imide was presented. The paper demonstrates the synthesis of seven derivatives with high yields and good to exceptional enantiomeric ratios (84:16 to >99:1, determined by HPLC) [110]. Similarly to Py's method, intermediate lactams have previously been prepared by indiumcatalyzed Conia-ene reactions [111], by the selective ring expansion of secondary methylenecyclopropyl amides using catalytic MgI2 at high dilution [112]. Pattenden's work on the radical cyclizations of propargyl bromoamides 43 [113] found application to the synthesis of lactams similar to tetramates [114], to the synthesis of γ-lactams [115], and ultimately to the synthesis of 3methyl-5,5-disubstituted tetramic acids 44 via ozonolysis of the corresponding γ-lactam 45 (Scheme 12) [116]. These protocols involve the cyclization of the enantiopure α-ethynyl substituted serine derivatives using Bu3SnH and AIBN (azobisisobutyronitrile).
Nevertheless, the samarium diiodide, which was first used in organic synthesis by Kagan et al. [117], has been used for the development of various transformations and cyclization reactions under mild conditions [118].

Pd-Catalyzed Oxidative Aminocarbonylation of 2-Ynylamines
An interesting novel synthesis of 4-dialkylamino-5,5-disubstituted-γ-lactam 46 by PdI 2 -catalyzed oxidative carbonylation of the appropriate 2-ynylamine 47 was reported in 2004 by Gabriele et al. [119]. The method is an expansion of the previously published method by the same group for similar γ-lactones [120]. The γ-lactams can easily be transformed to tetramic acid 48 by acid hydrolysis at room temperature. The reaction toward lactam 46 proceeds in one step. 2-Ynylamines are directly carbonylated using the appropriate amine in the presence of palladium diiodide and a mixture of CO-air at 20 atm and at 25 to 100 • C (Scheme 13). The starting 2-ynylamines can easily be prepared from 2-yn-1-olacetates according to the literature method [121]. The derivatives presented in this publication are limited to 3-unsubstituted lactams with no reference to enantiomeric excess at C-5. Nevertheless, the samarium diiodide, which was first used in organic synthesis by Kagan et al. [117], has been used for the development of various transformations and cyclization reactions under mild conditions [118].

Pd-Catalyzed Oxidative Aminocarbonylation of 2-Ynylamines
An interesting novel synthesis of 4-dialkylamino-5,5-disubstituted-γ-lactam 46 by PdI2catalyzed oxidative carbonylation of the appropriate 2-ynylamine 47 was reported in 2004 by Gabriele et al. [119]. The method is an expansion of the previously published method by the same group for similar γ-lactones [120]. The γ-lactams can easily be transformed to tetramic acid 48 by acid hydrolysis at room temperature. The reaction toward lactam 46 proceeds in one step. 2-Ynylamines are directly carbonylated using the appropriate amine in the presence of palladium diiodide and a mixture of CO-air at 20 atm and at 25 to 100 °C (Scheme 13). The starting 2-ynylamines can easily be prepared from 2-yn-1-olacetates according to the literature method [121]. The derivatives presented in this publication are limited to 3-unsubstituted lactams with no reference to enantiomeric excess at C-5.

Lithium Telluride-Triggered Synthesis of Tetramic Acids
An alternative approach to the synthesis of 3-unsubstituted, 3-methyl, and 3,3-dimethyl tetramic acid 49 and tetramates by Dieckmann cyclization promoted by Li2Te has been reported by Dittmer et al. (Scheme 14; Part A) [122]. The reaction undergoes in mild conditions with no strong base involved, thus reducing the formed side products. On the other side, racemization occurs with the addition of the silyl ether. The authors noticed that greater excess of the t-butyldiphenylsilyl chloride reagent increases the yield to be almost quantitative, but produces racemic products. In some cases, such as the 3,3-dimethyl 50 or the 3-unsubstituted derivative 51, the target molecule can be prepared without the addition of a base (Scheme 14; Part B, C). Schobert et al. applied this reaction to the synthesis of the natural product rigidiusculamide B using only 1.15 equivalents of the silyl reagent, reducing the racemization to a minimum of 6:1 (diastereomeric ratio) [123]. The lithium telluride reagent is prepared by known literature methods [124], as this reagent has been used in numerous syntheses of heterocycles [125][126][127]. In general, this less known reaction is a good alternative for the synthesis of 3-methyl tetramic acids, which are not readily produced from conventional methodologies. Scheme 13. Gabriele's Pd-catalyzed method to γ-lactam 46, which can easily be converted to tetramic acid 48.

Lithium Telluride-Triggered Synthesis of Tetramic Acids
An alternative approach to the synthesis of 3-unsubstituted, 3-methyl, and 3,3-dimethyl tetramic acid 49 and tetramates by Dieckmann cyclization promoted by Li 2 Te has been reported by Dittmer et al. (Scheme 14; Part A) [122]. The reaction undergoes in mild conditions with no strong base involved, thus reducing the formed side products. On the other side, racemization occurs with the addition of the silyl ether. The authors noticed that greater excess of the t-butyldiphenylsilyl chloride reagent increases the yield to be almost quantitative, but produces racemic products. In some cases, such as the 3,3-dimethyl 50 or the 3-unsubstituted derivative 51, the target molecule can be prepared without the addition of a base (Scheme 14; Part B, C). Schobert et al. applied this reaction to the synthesis of the natural product rigidiusculamide B using only 1.15 equivalents of the silyl reagent, reducing the racemization to a minimum of 6:1 (diastereomeric ratio) [123]. The lithium telluride reagent is prepared by known literature methods [124], as this reagent has been used in numerous syntheses of heterocycles [125][126][127]. In general, this less known reaction is a good alternative for the synthesis of 3-methyl tetramic acids, which are not readily produced from conventional methodologies. Catalysts 2019, 9, x FOR PEER REVIEW 15 of 28 Scheme 14. General protocol for the synthesis of tetramic acid 49 using lithium telluride (A); 3disubstituted derivative 50 without the addition of base (B) and 3-unsubstituted tetramic acid 51 without base; but using crown ether and the similar sodium telluride (C).

ZrCl4-Catalyzed Synthesis of β-Ketoamides
β-Ketoamides are versatile intermediates in the synthesis of many heterocyclic compounds, for example lactams [128], isoquinolines [129], and naphthyridines [130]. Apparently, they are used for the synthesis of 3-acyltetramic acids via Dieckmann cyclization. However, in the established conventional methods, there is a limitation in the group that can be incorporated at C-3 of the ring. This problem has been solved to an extent by the catalytic or non-catalytic 3-acylation of 3unsubstituted tetramic acids. Yet again, these methodologies are often unable to provide solutions to chemoselectively acylate a 3,5-unsubstituted tetramic acid at position C-3 of the heterocycle.
Yoshii et al. have developed a method for the Zr(IV) chloride-catalyzed C-H insertion reaction of aldehyde 52 with the diazoacetamide of N-protected glycinate 53 (Scheme 15). This protocol is compatible with the Dieckmann cyclization to afford the desired 3-acylated 5-unsubstituted tetramic acid 54. According to the literature, two equivalents of the catalyst are used, and the reaction is quite effective for sterically hindered aldehydes [131]. Scheme 15. ZrCl4 catalyzed synthesis of β-acetamide 53 toward tetramic acid 54 with bulky 3-acyl groups.

Scheme 14.
General protocol for the synthesis of tetramic acid 49 using lithium telluride (A); 3-disubstituted derivative 50 without the addition of base (B) and 3-unsubstituted tetramic acid 51 without base; but using crown ether and the similar sodium telluride (C).

ZrCl 4 -Catalyzed Synthesis of β-Ketoamides
β-Ketoamides are versatile intermediates in the synthesis of many heterocyclic compounds, for example lactams [128], isoquinolines [129], and naphthyridines [130]. Apparently, they are used for the synthesis of 3-acyltetramic acids via Dieckmann cyclization. However, in the established conventional methods, there is a limitation in the group that can be incorporated at C-3 of the ring. This problem has been solved to an extent by the catalytic or non-catalytic 3-acylation of 3-unsubstituted tetramic acids. Yet again, these methodologies are often unable to provide solutions to chemoselectively acylate a 3,5-unsubstituted tetramic acid at position C-3 of the heterocycle.
Yoshii et al. have developed a method for the Zr(IV) chloride-catalyzed C-H insertion reaction of aldehyde 52 with the diazoacetamide of N-protected glycinate 53 (Scheme 15). This protocol is compatible with the Dieckmann cyclization to afford the desired 3-acylated 5-unsubstituted tetramic acid 54. According to the literature, two equivalents of the catalyst are used, and the reaction is quite effective for sterically hindered aldehydes [131].

ZrCl4-Catalyzed Synthesis of β-Ketoamides
β-Ketoamides are versatile intermediates in the synthesis of many heterocyclic compounds, for example lactams [128], isoquinolines [129], and naphthyridines [130]. Apparently, they are used for the synthesis of 3-acyltetramic acids via Dieckmann cyclization. However, in the established conventional methods, there is a limitation in the group that can be incorporated at C-3 of the ring. This problem has been solved to an extent by the catalytic or non-catalytic 3-acylation of 3unsubstituted tetramic acids. Yet again, these methodologies are often unable to provide solutions to chemoselectively acylate a 3,5-unsubstituted tetramic acid at position C-3 of the heterocycle.
Yoshii et al. have developed a method for the Zr(IV) chloride-catalyzed C-H insertion reaction of aldehyde 52 with the diazoacetamide of N-protected glycinate 53 (Scheme 15). This protocol is compatible with the Dieckmann cyclization to afford the desired 3-acylated 5-unsubstituted tetramic acid 54. According to the literature, two equivalents of the catalyst are used, and the reaction is quite effective for sterically hindered aldehydes [131].

CuI-Catalyzed Synthesis from β-Ketoesters
An unexpected simple and practical one-step synthetic method toward 1-benzyloxycarbonyl-3, 5-disubstituted tetramic acid 55 has been reported recently by González-Muñiz et al. (Scheme 16; Part A) [132]. Studying the applications of the known CuI/L-proline catalytic system for coupling reactions of aryl halides with active methylene compounds to 2-aryl-1,3-dicarbonyl molecules [133], they developed and optimized a method for the synthesis of tetramic acid 55. Controlling the reaction conditions, it is possible to obtain the intermediate dicarbonyl derivative 56 (Scheme 16; Part B). Chiral HPLC experiments for the determination of the optical purity is reported only for the indole analogues, and indicate almost complete racemization.

CuI-Catalyzed Synthesis from β-Ketoesters
An unexpected simple and practical one-step synthetic method toward 1-benzyloxycarbonyl-3,5-disubstituted tetramic acid 55 has been reported recently by González-Muñiz et al. (Scheme 16; Part A) [132]. Studying the applications of the known CuI/L-proline catalytic system for coupling reactions of aryl halides with active methylene compounds to 2-aryl-1,3-dicarbonyl molecules [133], they developed and optimized a method for the synthesis of tetramic acid 55. Controlling the reaction conditions, it is possible to obtain the intermediate dicarbonyl derivative 56 (Scheme 16; Part B). Chiral HPLC experiments for the determination of the optical purity is reported only for the indole analogues, and indicate almost complete racemization.

Pd-Catalyzed α-Arylation of Tetramic Acids
In 2009, Tanner et al. published an interesting research article [134] on the Pd-catalyzed αarylation of tetramic acids 57. The few methods described in the literature [94,135] until then were not general, and required the use of a strong base. Even though many existing methods of the αarylation of similar systems (1,3-dicarbonyl compounds) led to non-chiral products, the authors performed extended optimization of the reaction conditions, and they concluded to high yielded conversion under mild conditions for most of the substrate 58 with enantiomeric excess up to 97% (Scheme 17). Specifically, it was found that the ideal results can be obtained using 2% Pd(OAc)2, 4% of 2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl as the phosphine ligand, and the weak inorganic base K3PO4. The reaction was held in THF at 80 °C for one hour. Most of the substrate 58 that was tested gave identical results e.g., protected amines, nitro groups alcohols, ketones, ethers, esters, and others, except heterocycles and unprotected imines, which were found to be noncompatible. Meta-substituted and para-substituted aryl halides worked, whereas ortho-substituted compounds did not react due to steric hindrance.

Pd-Catalyzed α-Arylation of Tetramic Acids
In 2009, Tanner et al. published an interesting research article [134] on the Pd-catalyzed α-arylation of tetramic acids 57. The few methods described in the literature [94,135] until then were not general, and required the use of a strong base. Even though many existing methods of the α-arylation of similar systems (1,3-dicarbonyl compounds) led to non-chiral products, the authors performed extended optimization of the reaction conditions, and they concluded to high yielded conversion under mild conditions for most of the substrate 58 with enantiomeric excess up to 97% (Scheme 17). Specifically, it was found that the ideal results can be obtained using 2% Pd(OAc) 2 , 4% of 2-di-tert-butylphosphino-2 ,4 ,6 -triisopropyl-1,1 -biphenyl as the phosphine ligand, and the weak inorganic base K 3 PO 4 . The reaction was held in THF at 80 • C for one hour. Most of the substrate 58 that was tested gave identical results e.g., protected amines, nitro groups alcohols, ketones, ethers, esters, and others, except heterocycles and unprotected imines, which were found to be non-compatible. Meta-substituted and para-substituted aryl halides worked, whereas ortho-substituted compounds did not react due to steric hindrance. Catalysts 2019, 9,

Metal-Catalyzed 3-Acylation of Tetramic Acids
One of the most common catalytic reactions on the tetramic acid ring is undoubtedly the Lewis acid acylation on C-3 with acyl chlorides. While boron trifluoride-diethyl ether has been used for acylations [136], titanium(IV) chloride is used universally in nitromethane or dichloromethane under mild heating (Scheme 18) [44,137].

Chemoselective Ru-Catalyzed Hydrogenation of Exocyclic C=C Bonds
In 2011, Karaiskos et al. reported a pioneering method for the chemoselective catalytic hydrogenation of exocyclic double carbon bonds in 3,5-bisarylidene tetramic acid 59 [74]. According to this method, the exocyclic double carbon bonds are preferentially hydrogenated over other reducing functions (endocyclic C3-C4 double bond and carbonyls). Moreover, by carefully selecting the conditions, the reduction of the double bond at C-5 or both C-3 and C-5 is achievable. The chemoselectivity depends on the Ru complex ligands, substrate, solvent, and temperature. The reaction conditions were, as expected, harsher than those for the non-conjugated systems reported in the literature. Depending on the substrate, the yield of the hydrogenation process can reach up to 95% (Scheme 19). The variation of the applied hydrogen pressure is less effective compared to the temperature; however, higher pressure favors the formation of the more saturated molecule.

Metal-Catalyzed 3-Acylation of Tetramic Acids
One of the most common catalytic reactions on the tetramic acid ring is undoubtedly the Lewis acid acylation on C-3 with acyl chlorides. While boron trifluoride-diethyl ether has been used for acylations [136], titanium(IV) chloride is used universally in nitromethane or dichloromethane under mild heating (Scheme 18) [44,137].

Metal-Catalyzed 3-Acylation of Tetramic Acids
One of the most common catalytic reactions on the tetramic acid ring is undoubtedly the Lewis acid acylation on C-3 with acyl chlorides. While boron trifluoride-diethyl ether has been used for acylations [136], titanium(IV) chloride is used universally in nitromethane or dichloromethane under mild heating (Scheme 18) [44,137].

Chemoselective Ru-Catalyzed Hydrogenation of Exocyclic C=C Bonds
In 2011, Karaiskos et al. reported a pioneering method for the chemoselective catalytic hydrogenation of exocyclic double carbon bonds in 3,5-bisarylidene tetramic acid 59 [74]. According to this method, the exocyclic double carbon bonds are preferentially hydrogenated over other reducing functions (endocyclic C3-C4 double bond and carbonyls). Moreover, by carefully selecting the conditions, the reduction of the double bond at C-5 or both C-3 and C-5 is achievable. The chemoselectivity depends on the Ru complex ligands, substrate, solvent, and temperature. The reaction conditions were, as expected, harsher than those for the non-conjugated systems reported in the literature. Depending on the substrate, the yield of the hydrogenation process can reach up to 95% (Scheme 19). The variation of the applied hydrogen pressure is less effective compared to the temperature; however, higher pressure favors the formation of the more saturated molecule.

Chemoselective Ru-Catalyzed Hydrogenation of Exocyclic C=C Bonds
In 2011, Karaiskos et al. reported a pioneering method for the chemoselective catalytic hydrogenation of exocyclic double carbon bonds in 3,5-bisarylidene tetramic acid 59 [74]. According to this method, the exocyclic double carbon bonds are preferentially hydrogenated over other reducing functions (endocyclic C3-C4 double bond and carbonyls). Moreover, by carefully selecting the conditions, the reduction of the double bond at C-5 or both C-3 and C-5 is achievable. The chemoselectivity depends on the Ru complex ligands, substrate, solvent, and temperature. The reaction conditions were, as expected, harsher than those for the non-conjugated systems reported in the literature. Depending on the substrate, the yield of the hydrogenation process can reach up to 95% (Scheme 19). The variation of the applied hydrogen pressure is less effective compared to the temperature; however, higher pressure favors the formation of the more saturated molecule.
Three years later, the same group reported a Cu(I)-catalyzed (2 + 3) annulation reaction of tetramic acids 69 with 2H-azirine 70 toward hexahydropyrrolo [3,4-b]pyrrole 71 [144]. The reaction is catalyzed by Cu(II) as well, but the best results were obtained with the use of the N-heterocyclic carbene-copper(I) complex IPrCuCl (Scheme 22). Inevitably, bis(pyrrolidinedione) was formed as a side product, although the ratio of product to by-product reached 12:1 after optimization. Since then, manganese(II) acetate has been used as a catalyst for the domino annulation reaction of vinyl azide 72 and 4-hydroxycoumarin 73 toward tetramic acid analogue spirofuranone-lactam 74 (Scheme 23) [145].

Sn(IV)-Catalyzed Diastereoselective Aldol Reaction via Siloxy Pyrroles
A general diastereoselective aldol method leading to the synthesis of compounds that are commonly found in natural products (e.g., paecilosetin, cylindramide A, and tetrapetalone B) tetramic acid aldolate adduct 75 has been reported by Pettus et al. [146]. The protocol proceeds via C-2 O-silylated pyrrole 76. Tin tetrachloride (SnCl4) was found to be the optimal choice among the examined Lewis acids, and the reaction proved to be catalytic (Scheme 24). The authors have

Sn(IV)-Catalyzed Diastereoselective Aldol Reaction via Siloxy Pyrroles
A general diastereoselective aldol method leading to the synthesis of compounds that are commonly found in natural products (e.g., paecilosetin, cylindramide A, and tetrapetalone B) tetramic acid aldolate adduct 75 has been reported by Pettus et al. [146]. The protocol proceeds via C-2 O-silylated pyrrole 76. Tin tetrachloride (SnCl 4 ) was found to be the optimal choice among the examined Lewis acids, and the reaction proved to be catalytic (Scheme 24). The authors have examined the incorporation of many aldehydes on 3-methyl, 3-bromo, or 3-unsubstituted tetramic acid 77.
However, there are no indications of synthesis of 3-acetyl/acyl tetramic acids, or tetramic acids with different substituent on nitrogen.
Catalysts 2019, 9, x FOR PEER REVIEW 21 of 28 examined the incorporation of many aldehydes on 3-methyl, 3-bromo, or 3-unsubstituted tetramic acid 77. However, there are no indications of synthesis of 3-acetyl/acyl tetramic acids, or tetramic acids with different substituent on nitrogen.

Conclusions
The work described in this review represents an effort and advancement in the metal-catalyzed synthesis of tetramic acids. Many reports with new or modified catalytic and other alternative routes have been published recently. Nevertheless, additional work and the development of catalytic systems are needed in order to overcome the conventional methods' drawbacks: harsh conditions and limitations in functionalization.
While application of the developed methods to the total synthesis of natural products is important, the contribution of these methods to the medicinal chemistry is invaluable. Tetramic acids consist of a heterocyclic ring with known antimicrobial, anticancer, and pesticidal activities, and the novel methodologies will give access to more complex or previously inaccessible bioactive structures.
Funding: This work received no external funding.