Ketopiperazines

Bond formation 7 to the ring junction nitrogen took place in the synthesis of 168 by a one-pot method from functionalized ketopiperazine and carbonyldiimidazole, via intermediate 167 (Scheme 22) <1999TL1159>. 

A library of l,3,7-substituted-perhydropyrazino[l,2-f]pyrimidine-2,6,8-triones was built by preparation of functionalized ketopiperazines on the solid phase, followed by N-acylation with 2-bromoacetic acid, reaction with isocyanate and with concomitant cyclization using trifluoroacetic acid (TFA) <2003W02003/013740>. 

The second mode of toxicity is postulated to involve the direct interaction of the epidithiodiketopiperazine motif with target proteins, forming mixed disulfides with cysteine residues in various proteins. Gliotoxin, for example, has been demonstrated to form a 1 1 covalent complex with alcohol dehydrogenase [13b, 17]. Epidithiodi-ketopiperazines can also catalyze the formation of disulfide bonds between proxi-mally located cysteine residues in proteins such as in creatine kinase [18]. Recently, epidithiodiketopiperazines have also been implicated in a zinc ejection mechanism, whereby the epidisulfide can shuffle disulfide bonds in the CHI domain of proteins, coordinate to the zinc atoms that are essential to the tertiary structure of that domain, and remove the metal cation [12d, 19],... 

Other approaches to tetrazoles were also recently published. Primary and secondary amines 195 were reacted with isothiocyanates to afford thioureas 196, which underwent mercury(II)-promoted attack of azide anion, to provide 5-aminotetrazoles 197 . A modified Ugi reaction of substituted methylisocyanoacetates 198, ketones, primary amines, and trimethylsilyldiazomethane afforded the one-pot solution phase preparation of fused tetrazole-ketopiperazines 200 via intermediate 199 <00TL8729>. Microwave-assisted preparation of aryl cyanides, prepared from aryl bromides 201, with sodium azide afforded aryl tetrazoles 202 . 

Maignan, S., Guilloteau, J.-P., Choi-Sledeski, Y.M., Becker, M.R., and Ewing, W.R. Molecular stmctures of human factor xa complexed with ketopiperazine inhibitors preference for a neutral group in the SI pocket./. Med. Chem. 2003, 46, 685-690. 

This general strategy has been employed for the synthesis of several types of heterocycles, including diketopiperazines [29-32], ketopiperazines [29, 33], pyrro-lidinones [34], 1,4-benzodiazepines [29, 32, 35-37], dihydroquinoxalinones [29], hexahydropyrrolodiazepines [38], and oxetanones [27]. Figure 4 shows some selected examples. 

Diketopiperazines 17 and ketopiperazines 19, which are important privileged structures, have been obtained by using various convertible isocyanides and by introducing the additional amino function, respectively, on the carboxylic [39] or amine component [33]. 

The use of convertible isocyanides is not always necessary in particular cases, also normal alkyl [32,40] or aryl [30] isocyanides have been employed for this task. For example, microwave irradiation of the Ugi adduct 16 (R = uBu) at 120°C in the presence of 10% CF3CO2H gave the desired diketopiperazines 17 in good yield, without the need to use more complex convertible isocyanides. However, for the synthesis of ketopiperazines 19, butyl isocyanide was found to be unsuitable. 

Introduction of a halogen atom into the amine component is not possible, but an alternative solution is represented by the use of ethanolamines 26, performing the cyclization under Mitsunobu or Mitsunobu-like conditions to give ketopiperazines. These compounds have been observed as side products in reactions promoted by... 

Although diketo- and ketopiperazines can be formed by coupling the Ugi reaction with an intramolecular acylation using convertible isocyanides, as described earlier, the approach that involves Sn2 reactions enables the introduction of an additional substituent R avoiding the loss of the diversity carried by the isocyanide. 

Gilley CB, Kobayashi Y (2008) 2-nitrophenyl isocyanide as a versatile convertible isocyanide rapid access to a fused y-lactam (3-lactone bicycle. J Org Chem 73 4198 204 Chen JJ, Golebiowski A, Klopfenstein SR, West L (2002) The universal Rink-isonitrile resin applications in Ugi reactions. Tetrahedron Lett 43 4083 085 Hulme C, Peng J, Morton G, Salvino JM, Herpin T, Labaudiniere R (1998) Novel safety-catch linker and its application with a Ugi/De-BOC/Cyclization (UDC) strategy to access carboxylic acids, 1, 4-benzodiazepines, diketopiperazines, ketopiperazines and dihydroqui-noxalinones. Tetrahedron Lett 39 7227-7230... 

Hulme C, Ma L, Kumar NV, Krolikowski PH, Allen AC, Labaudiniere R (2000) Novel applications of resin bound a-amino acids for the synthesis of benzodiazepines (via Wang resin) and ketopiperazines (via hydroxymethyl resin). Tetrahedron Lett 41 1509-1514... 

Fig. 1 Basic piperazine and ketopiperazine scaffolds and the number of commercial available derivatives according to substructure search from eMolecules [1]...

Scheme 10 Use of a bi-functional W-sulfonyl-iV-(2-oxoproply) glycines for the SCR synthesis of ketopiperazines and two representative 3D conformations of 59A (cyan) and 59B (Mm)...

Hulme et al. describes the novel use of ethyl glyoxalate in the Ugi-4CR to create ketopiperazines [31]. iV-alkylated/Boc-protected ethylene diamines 60 reacted with an isocyanide 61, a carboxylic acid 62, and ethyl 2-oxoacetate 63 in stoichiometric ratio of 1/1/1/1.25 in methanol. Deprotection and cyclization is completed using TFA and MP-carbonate (a macroporous polystyrene... 

Scheme 11 3-CR synthesis of ketopiperazines using ethyl glyoxalate and two representative 3D conformations of 65A (cyan) and 65B (blue). Yield shown represents yield over all steps...

Hulme et al. describes the use of a convertible isonitrile for the generation of a ketopiperazine library (Scheme 12) [32]. Using a mono-A -Boc diamine 68 in the classical Ugi reaction followed by Boc deprotection and base-facilitated cyclization (3 steps, 1 pot) afforded the ketopiperazine 72 in relatively high yields. 

Scheme 33 Synthesis of fused tetrazole-ketopiperazines 187 and two representative 3D conformations of 187A (blue) and 187B (cyan)...

A library of fused tetrazole-ketopiperazines 187 was obtained by Nixey et al. via Ugi four-component reaction in the solution phase [56]. The reaction of an oxo component 188, primary amine 189, methyl isocyanoacetate 190, and trimethylsi-lylazide 181 in methanol at reflux affords bicyclic tetrazole-ketopiperazines 187 in good yield (Scheme 33). The cyclization to afford the tetrazole-ketopiperazines is performed spontaneously under the reaction conditions. 

Piperazine fused polycyclic ring systems are unique in terms of structures and properties. Praziquantel 211 is the primary medication for human schistosomiasis, for which it is usually effective in a single dose treatment. As shown in Fig. 10, praziquantel consists of a ketopiperazine fused ring system. A co-crystal of praziquantel and glutathione-5-peroxidase of the helminth Schistosoma japonica was known [63]. Praziquantel binds in a channel joining the two xenobiotic substrate... 

A general strategy towards praziquantel derivatives 217 was developed by Liu et al. based on an Ugi four-component condensation (Ugi-4CR) followed by a Pictet-Spengler cyclization (PS-2CR) [66]. The variations of the groups and sub-stitutents in these scaffolds arise from the four starting materials isocyanide 218, aldehyde 219, amine 214, and carboxylic acid 220 (Scheme 39). This process produces ketopiperazine fused ring systems that mimic the scaffold of praziquantel. 

Combination of MCR with the Pictet-Spengler cyclization also leads to different types of scaffolds with ketopiperazine fused ring systems. Tetrahydro-jS-carboline scaffold 221 was prepared in a convergent, two-step procedure [67]. An array of indole derivatives was prepared by the reaction of tryptophan derivative 222, aldehyde 223, carboxylic acid 224, and bifunctional amine 214 (Scheme 40). 

Moreover, polycyclic indole alkaloid-type molecules 225 with a ketopiperazine were prepared by Wang et al. using Ugi-Pictet-Spengler process [68]. Ketocar-boxylic acids 227 were used as bifunctional substrates in Ugi reaction to yield lactams of varying ring sizes (Scheme 41). A diastereomer of hexacyclic indole derivative was crystallized and yielded X-ray diffraction suitable crystal to assign the stereochemistry. 

Hulme C, Peng J, Louridas B, Menard P, Krolikowski P, Kumar NV (1998) Applications of N-BOC-diamines for the solution phase synthesis of ketopiperazine libraries utilizing a Ugi/ De-BOC/Cyclization (UDC) strategy. Tetrahedron Lett 39(44) 8047-8050... 

Nixey T, Kelly M, Huhne C (2000) The one-pot solution phase preparation of fused tetrazole-ketopiperazines. Tetrahedron Lett 41(45) 8729-8733... 

The UDC concept can be further extended by application of ethyl glyoxylate (a convertible aldehyde ). Simple reaction of 48 in the Ugi MCR with /V-Boc anthranilic acids, /V-Boc-rt-amino acids, mono-A-Boc diamines, and niono-A-Boc phenylenediamines, followed by acid treatment and in some cases proton scavenging, affords 1,4-benzodiazepines 49, diketopiperazines 50, ketopiperazines 51, and dihydroquinoxalinones 52, respectively.25 Note that products differ from those obtained from convertible isocyanides in that they contain an additional exocyclic amide... 

Scheme 12. Synthetic routes to fused 6,5-ketopiperazine-tetrazoles and 7,5-azepine-tetrazoles. Reagents and conditions (i) R2R2C = O (1.5 equiv., 0.1 M in MeOH), TMSN3 (1 equiv., 0.1 M in MeOH), R3NH2 (1 equiv., 0.1 M in MeOH), 92 (1 equiv., 0.1 M in MeOH), 24 h, RT. (ii) 10% TFA in CH2C12. (iii) PS-DIEA, DMF/dioxane, 1 1, reflux, (iv) PS-NCO, PS-TsNHNH2 THF/DCE, 1 1. (v) Reflux, MeOH.

Workers at Amgen further exploited this reaction in an attempt to access 6,5-fused ketopiperazine-tetrazoles 96 and 7,5-fused azepine-tetrazoles 94, respectively (Scheme 12). Thus, reaction of methyl-isocyanoacetates 92,... 

Ketopiperazines, 2,5-Diketopiperazines and Quinoxalines by Ugi-4CR with N-Deprotection and Intramolecular Amide Bond Formation... 

---