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Synthesis 2010(17): 2859-2883  
DOI: 10.1055/s-0030-1257906
REVIEW
© Georg Thieme Verlag Stuttgart ˙ New York

Piperazine Scaffolds via Isocyanide-Based Multicomponent Reactions

Alexander Dömling*, Yijun Huang
University of Pittsburgh, Drug Discovery Institute, Pittsburgh, PA 15261, USA
Fax: +1(412)3835298; e-Mail: asd30@pitt.edu;

Dedicated to Ivar Ugi who invented his ingenious reaction 50 years ago


Further Information

Publication History

Received 25 March 2010
Publication Date:
30 July 2010 (online)

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Biographical Sketches

Alexander Dömling (left), Associate Professor at the University of Pittsburgh, studied chemistry at the Technical University Munich and performed his Ph.D. work under the late Ivar Ugi. Under a Feodor Lynen stipendship of the Alexander von Humboldt Society, he spent his postdoctoral year at the Scripps Research Institute in San Diego in the laboratory of Nobel Laureate Barry Sharpless. Back in Germany he founded the Biotechnology Company Morphochem, which focused on the preclinical and clinical discovery and development of novel drugs for unmet medical needs using MCR-based technologies. After he performed his Habilitation in 2003 he accepted a position at the University of Pittsburgh in the Drug Discovery Institute in 2006. Here he is teaching and researching at the Departments of Pharmacy, Chemistry (sec. appointment) and Computational Biology (sec. appointment). His research interests are new MCR-related methodologies and their application in drug discovery, specifically protein-protein interaction. His therapeutic interests include cancer, neglected tropical diseases and CNS-related disorders. He is author of more than 100 research articles, reviews, book contributions and patents.
Yijun Huang (right) was born in Jiangsu, China in 1981. He graduated from Nanjing University (Nanjing, China) with a B.Sc. in chemistry and M.Sc. in organic chemistry. In 2006, he continued his studies of organic synthesis at Texas Christian University (Fort Worth, TX, USA), where he obtained his M.Sc. in chemistry. Currently he is a Ph.D. student in the Department of Pharmaceutical Sciences at the School of Pharmacy, University of Pittsburgh (Pittsburgh, PA, USA). He is currently conducting research under the guidance of Professor ­Alexander Dömling focusing on the development of new MCR methodologies and their applications for drug discovery, such as p53-Mdm2/Mdm4 protein-protein interaction antagonists.

Abstract

Piperazine scaffolds are amongst the most extensively used backbones in medicinal chemistry and many bioactive compounds are built upon this template. The physicochemical properties and the three-dimensional structures of the different piperazine chemotypes are of utmost importance to understanding its biological activities. Knowing the synthetic access to this chemical space of piperazines is of great importance to designing compounds with better properties. Isocyanide-based multicomponent reactions (IMCRs) allow for the truly convergent and efficient access to not less than 35 different piperazine derived scaffolds. These are reviewed, and their scopes and limitations are discussed.

1 Piperazine Scaffolds in Chemistry and Medicine

2 Chemical Space of Piperazines via Isocyanide-Based ­Multicomponent Reactions

3 Monocyclic Piperazines

3.1 Piperazine

3.2 Ketopiperazine

3.3 2,5-Diketopiperazine

3.4 2,6-Diketopiperazine

4 Bicyclic Fused Piperazines

5 Polycyclic Fused Piperazines

6 Introduction of the Piperazine Moiety via a Starting ­Material

7 Conclusions and Outlook

Key words

piperazine - diketopiperazine - heterocycles - multicomponent reaction - isocyanide

1 Piperazine Scaffolds in Chemistry and ­Medicine

Piperazine is a chemical motif that consists of a six-membered ring containing two opposing nitrogen atoms. 73 Drug entries of piperazine derivatives are deposited in the Drug Bank. [¹] The parent compound piperazine (1) was first introduced as an antihelmintic in 1953, and was especially useful in the treatment of partial intestinal obstruction. [²] Representative structures of drug entities containing piperazine scaffolds are cyclizine (2), flunarizine (3), and olanzapine (4), shown in Figure  [¹] . The unusual properties of some piperazines are exemplified in GSK221149A (5), a potent, selective and orally available oxytocin antagonist which is currently undergoing advanced clinical testing for the treatment of preterm labor. Preterm labor occurs in 10% of all births worldwide and is the single largest cause of neonatal morbidity and death. Several peptidic oxytocin antagonists are currently used to treat preterm labor, which by their nature have to be given intravenously. Interestingly the small molecule GSK221149A is not only more potent but also more selective against the related vasopressin receptors than the peptide drugs, despite its much lower molecular weight. Praziquantel (6) is a very important piperazine-substructure-containing drug used to treat the neglected tropical disease schistosomiasis, which affects more than 200 million people worldwide. [³]

Figure 1 Representative structures of marketed and experimental drug entities containing piperazine scaffolds

In addition to the piperazine ring as a privileged structure shown in a number of drugs, ketopiperazines and piperazine scaffolds fused with bi- and tricyclic ring systems also exist in drug entities, such as piperacillin and praziquantel (6). Piperazines are also abundant in natural products and the diketopiperazines can be regarded as the smallest cyclized peptides. Due to the borderline nature of piperazine derivatives between small molecules and peptides, they can be used as a step in the logic pathway for the process of depeptidisation: peptide = > peptidomimetic = > small molecule drug. In the following, we define the expression scaffold as the smallest atomic denominator and its connectivity as resulting from a reaction or reaction sequence using starting materials with common functional groups. The scaffold, together with its ligands, defines important physicochemical properties of the compounds such as the three-dimensional shape, number, quality and directionality of hydrogen-bond donors and acceptors, polar surface area, and lipophilicity. These properties, in contrast, are correlated to the biological activity of the compounds, including target affinity and specificity, water solubility, ability to penetrate lipid bilayers, oral bioavailability, protein binding, metabolism, toxicity and distribution. Therefore the informed chemist must know the synthesis, shape and properties of the different piperazines in order to invent new matter with useful properties. [4]

2 Chemical Space of Piperazines via Isocyanide-Based Multicomponent Reactions

Conceptually, piperazine-containing compounds can be assembled in two ways using isocyanide-based multicomponent reactions (IMCR; Scheme  [¹] ). The in situ assembly of the piperazine or derivative scaffold during the reaction comprises the first strategy. This is exemplified by the synthesis of polycyclic natural product alkaloid-like structure 10 from an isocyanide 7, orthogonally protected aminoacetaldehyde dimethyl acetal (8) and bifunctional ketocarboxylic acid 9. The two-step sequence comprises an initial Ugi reaction followed by a Pictet-Spengler ring closure and was recently introduced by Wang et al. [5] In this strategy, the piperazine substructure of 10 is assembled from three different starting materials. In the second strategy, piperazines and derivatives are introduced as a side chain of a starting material. For example, the otherwise difficult to access polyamine 14 was synthesized concisely by Pirali et al. [6] This two-step sequence comprises an interesting variation of the Ugi four-component reaction (Ugi-4CR), the so-called split-Ugi modification using piperazine (1) as a bifunctional bis-secondary amine, isocyanide 11, glycine derivative 12, and paraformaldehyde (13), followed by exhaustive reduction. This sequence facilitates the entry into a large and important group of natural products exemplified by spermidine. The approach is limited by the availability or easy accessibility and appropriate reactivity of the corresponding building blocks. In fact, many isocyanides derived from amino acids can be easily converted into piperazine-comprising building blocks 15 as recently shown by Dömling et al. (Scheme  [²] ). [7] Some of these isocyanides have been prepared on a kilogram scale for the synthesis of active ­pharmaceutical ingredients. Both strategies are complementary and very valuable for the synthesis of piperazines and derivatives, as we demonstrate in this review.

Scheme 1 Two conceptually different IMCR approaches towards piperazine-comprising compounds

Scheme 2 Piperazino isocyanide building block synthesis by simple solventless mixing of amino acid derived isocyanides with suitable piperazines. The synthesis is very convenient since the odorless (!) isocyanide precipitates and can be easily isolated and purified by filtration and washing.

Figure 2 Some topologically possible piperazines based on the classical Ugi-4CR of isocyanides (CNC), oxo component (C), primary amine (N) and carboxylic acid (C) and a subsequent ring formation

Scheme 3 Simplified mechanisms of Ugi-type reactions yielding some exemplary scaffolds

In the following we first showcase the in situ assembling strategy by discussing the different scaffolds and then representative examples of the second strategy. Since most of the transformations are of the Ugi type, a short review of the mechanism is given in Scheme  [³] , [8] which is helpful to better understand the following transformations. As generally assumed, during the Ugi reaction a Schiff base C or an enamine is formed first from their oxo B and amine components A. Under Lewis or Brønsted acid conditions of the Ugi reaction, the nucleophilic isocyanide reacts next to form a reactive cationic nitrilium species D which eagerly adds onto a suitable anionic nucleophile, forming the key α-adduct F. Depending on the nature of the nucleophile, many different rearrangements to the final Ugi scaffold are possible, e.g. G-J. Suitable acid components are thus carboxylic acid, carbonic acid, thiocarboxylic ­acid, hydrazoic acid, cyanuric acid, thiocyanuric acid, water, hydrogen sulfide, hydrogen selenide, cyanamide and, as recently discovered, phenols. [9] The scaffold diversity of IMCRs is a result of the different acid components and the many secondary transformations. The mild reaction conditions of MCRs in general, and IMCR specifically, allow the incorporation of most orthogonal functional groups thus rendering this chemistry ideal for building up complex scaffolds in only few steps.

The atom connectivity of an Ugi product is CNCCNC, starting with the isocyanide CNC, followed by the oxo component C, an amine N and an acid component C. Clearly, the basic Ugi backbone allows for many topologically possible piperazine formations (Figure  [²] ). The currently described piperazine backbones synthesized via IMCRs are summarized in Figure  [³] .

The reader is also referred to the excellent recent reviews focusing more on classical multi-step synthetic approaches towards piperazines and derivatives thereof published by Fischer, [¹0] Horton, [¹¹] Martins, [¹²] and Dinsmore. [¹³]

3 Monocyclic Piperazines

3.1 Piperazine

Rossen et al. developed an efficient and versatile method for the synthesis of piperazine-2-carboxamides 16 via a one-pot, four-component Ugi condensation with a carboxylic acid, an N-alkylethylenediamine, chloroacetaldehyde, and an isocyanide in 34-66% isolated yields (Scheme  [4] ). [¹4] Selective N1 (formation of 17) and N4 (formation of 18) deprotections were achieved by acid hydrolysis of the formamide and hydrogenolysis of the benzyl derivative, respectively. The well-known poor diastereo­induction of chiral acids (e.g., gulonic, camphanoic, mandelic acid, and a serine derivative) in Ugi reactions each yielded a 1:1 mixture, which can be readily separated by flash chromatography. A similar methodology was applied to efficiently prepare chiral piperazine 20 as a key intermediate of the HIV protease inhibitor indinavir (Scheme  [4] ). [¹5] The vinyl chloride 19 was synthesized by the Merck process research group via the Ugi reaction with dichloroacetaldehyde, N-Boc ethylenediamine, formic acid, and tert-butyl isocyanide followed by subsequent elimination with triethylamine in quantitative yield. Catalytic asymmetric hydrogenation and deprotection of 19 yielded the piperazine 20 in good yields and without concomitant racemization. This short sequence compares favorably with the currently used technical route. The shortage of technical-scale syntheses of HIV drugs and the associated reduction of cost-of-goods is a timely topic, due to the unaffordability of many drugs to patients in third world countries.

Cyclic α-amino amidines have been made via a multi-component reaction using different catalysts. Keung, [¹6] Shaabani, [¹7] and Kysil et al. [¹8] described the use of scandium triflate, p-toluenesulfonic acid and chlorotrimethylsilane, respectively. α-Amino amidine 21 was obtained by the scandium(III) triflate catalyzed Ugi three-component reaction involving 2-methylpropanal, p-methoxyaniline, and cyclohexyl isocyanide (Scheme  [5] ). [¹6] The chemistry of the α-amino amidine product was elaborated further for the synthesis of hydantoin imide 22 and imidopyrazine derivative 23.

Shaabani et al. reported the synthesis of highly substituted dihydropyrazine derivatives 24 via isocyanide-base three-component reactions (Scheme  [6] ). [¹7] The reaction of a ketone, 2,3-diaminomaleonitrile (DAMN) and an isocyanide in the presence of p-toluenesulfonic acid provided products 24 in good to excellent yields at ambient temperature. The formed 1,2-dicyanodihydropyrazines provide starting materials for a variety of further heterocycle syntheses.

Kysil et al. developed the chlorotrimethylsilane-promoted three-component reaction of ethylenediamine, diverse carbonyl compounds, and isocyanides for the synthesis of tetrahydro-2-aminopiperazines of general structure 25. [¹8] The utility of this IMCR was examined using a variety of isocyanides and carbonyl compounds including ketones, aliphatic, aromatic, and heteroaromatic aldehydes (Scheme  [7] ). Recently, the detailed scope and limitations of the reactions with regard to each of the components were investigated in connection with their use in direct and convenient routes to dozens of 2-aminopyrazine derivatives. [¹9]

3.2 Ketopiperazine

An elegant and efficient procedure to produce arrays of N-sulfonylpiperazine-2-acylamides 26 was described by Ilyin et al. (Scheme  [8] ). [²0] The one-step combinatorial preparation of piperazinone derivatives was achieved by a convenient U-4CR protocol that utilizes readily available amines, isocyanides, and easily synthesized keto acids. This process has proven to be suitable for parallel liquid-phase synthesis of a high-quality 218-member library, with no chromatographic purification required, as the product precipitates in most cases.

Figure 3 Chemical space of piperazine scaffolds via isocyanide-based multicomponent reactions (red: isocyanide component, blue: amine component, black: acid component, purple: oxo component)

Scheme 4 One-pot synthesis of piperazine scaffold and shortcut to the HIV protease inhibitor drug indinavir using convergent IMCR; BINAP = 2,2′-bis(diphenylphosphino)-1,10-binapthyl, cod = cyclo-octadiene

Scheme 5 Scandium(III) triflate mediated U-3CR

Cheng et al. developed the one-pot preparation of the Δ5-2-oxopiperazine ring system in high yields both in solution phase and on a solid support. [²¹] The Ugi four-component condensation of benzoic acid, 2-methylpropanal, aminoacetaldehyde diethyl acetal and isocyanide 27 yielded the intermediate product 28, which underwent an N-acyliminium ion cyclization to produce 29 (Scheme  [9] ). This strategy was used for library synthesis involving immobilization of isocyanides on solid support and gave high-quality products. Note that the secondary amide in 28 stemming from the isocyanide is hidden in the product, incorporated into a piperazine ring comprising a tertiary amide. Methods to reduce the number of amide bonds in IMCR products are of particular interest due to the known issues of unbalanced numbers of amides for oral bioavailability and many other drug-like properties.

Scheme 6 The synthesis of dihydropyrazines via isocyanide-based three-component reactions

Scheme 7 Tetrahydro-2-aminopiperazines by chlorotrimethylsilane-promoted IMCR of ethylenediamine

Scheme 8 Parallel liquid-phase synthesis of 5-carbamoyl-4-sulfonyl-2-piperazinones

Faggi et al. reported the synthesis of 1,6-dihydrooxopyrazine-2-carboxylic acid derivatives via the Ugi four-component reaction (Scheme  [¹0] ). [²²] U-4CR of arylglyoxal 30, amines, benzoylformic acids and isocyanides afforded the Ugi products, which were cyclized in a [5+1] fashion with ammonium acetate to give products with general structure 31 in good yields.

Tetrahydropyrazine derivatives 33 were synthesized by Illgen et al. via a three-component, one-pot condensation from aldehydes, amines, and 3-dimethylamino-2-isocyanoacrylic acid methyl ester (32; Schöllkopf’s isocyanide). [²³] Without catalyst, this reaction proceeds poorly; however, catalyst screening showed ytterbium(III) triflate to be optimal (Scheme  [¹¹] ). Another noteworthy transformation involves the reaction of unprotected phenylalanine as amine component leading to bis(methyl ester) 34. This reaction involves a so-called U-5C-4CR (Ugi five-center four-component reaction) variant. In the U-5C-4CR, an α-amino acid (two functional and participating groups in one molecule: -NH2, -CO2H) reacts with an oxo component, an isocyanide and one equivalent of alcoholic solvent to form the final product.

Scheme 9 The one-pot synthesis of Δ5-2-oxopiperazine ring system

Scheme 10 Synthesis of 1,6-dihydro-6-oxopyrazine-2-carboxylic acid derivatives

Scheme 11 Above: 3-CR, involving Schöllkopf’s isocyanide, towards ketopiperazines. Below: combinatorial 96-well reaction optimization using a sterically and electronically representative set of aldehydes and primary amines. First plate without catalyst, second plate with optimized Yb(OTf)3 catalyst (color code corresponds to LC-UV-ELSD-MS determined reaction performance: green = good, >50%; yellow = product present, <50%; red = product not present).

The convertible isonitrile 35 was used by Hulme et al. for the solution-phase generation of ketopiperazine libraries. [²4] Use of mono-N-Boc diamines in the Ugi multicomponent reaction, followed by deprotection and cyclization, afforded ketopiperazines 36 in good yield (Scheme  [¹²] ). This process is amenable to both scale-up and solution-phase library synthesis in a 96-well plate format. The process sequence of an Ugi reaction with suitably and orthogonally protected starting materials followed by a deprotection and a subsequent (spontaneous) cyclization has been termed ‘UDC’. UDC is a very powerful synthetic strategy to access many different heterocyclic and drug-like scaffolds with a large diversity.

In another UDC variation, Hulme and Cherrier developed the reaction of mono-N-protected ethylenediamine with isocyanides, carboxylic acids, and ethyl glyoxalate to yield 3-amido-4-acyl-2-ketopiperazines 37 (Scheme  [¹³] ). [²5] This methodology employs the Ugi-4CR followed by Boc-deprotection and cyclization in a one-pot procedure. Cyclic ethylenediamines, including phenylenediamine and cyclohexyl-1,2-diamine, yielded the corresponding condensed bicyclic ketopiperazines.

3.3 2,5-Diketopiperazine

Several orthogonal MCR pathways to access the 2,5-diketopiperazine backbone have been described. All differ in details of the achievable backbone and in the used starting materials, as well as in their incorporation in the structure of the scaffold. 2-Aminocarboxy-2,5-diketopiperazines, for example, can be assembled by two different strategies. Szardenings et al. first reacted N- and C-protected amino acids 38 and 39 as carboxy and amino components together with oxo and isocyanide components to yield the Ugi reaction product with two more protected functional groups (Boc-amine and carboxylmethyl ester). Upon deprotection of the amino group, the intermediate either spontaneously, or upon basification, cyclizes to yield the highly substituted 2,5-diketopiperazine 40 (Scheme  [¹4] ). [²6] [²7] The initially published diketopiperazine libraries were focused on cysteine and showed strong and selective inhibition of the metalloprotease collagenase-1. The Ugi reaction is usually performed in methanol at ambient temperature. The subsequent ring closure proceeds under acidic conditions either spontaneously or upon addition of an external base (Et3N) to render the amine sufficiently basic for cyclization.

Scheme 12 Ketopiperazine synthesis involving convertible cyclohexenyl isocyanide and mono-protected ethylenediamines

Scheme 13 Highly substituted ketopiperazines by a two-step UDC procedure

Scheme 14 MCR synthesis of 2,5-diketopiperazines according to Szardenings et al.

Exactly the same scaffold can be synthesized by the reaction of C- and N-terminal unprotected dipeptides 41 with oxo and isocyanide components as elaborated by Cho et al. (Scheme  [¹5] ). [²8] Therein, the not-isolated α-adduct intermediate F (Scheme  [³] ) comprises a nine-membered cycle which collapses to form the preferred six-membered diketopiperazine via transacylation. Note that the former access to the same scaffold involved a linear α-adduct. This reaction was performed either in lipophilic protic trifluoroethyl alcohol or in the ionic liquid [Bmim]PF6, or in mixtures thereof, best utilizing microwave to increase reaction speed. The MCR access to one scaffold by two different reaction pathways (Schemes  [¹4] and  [¹5] ) is meaningful and might have consequences for the stereoselectivity, accessibility of the starting materials and the size and shape of the resulting chemical space.

Scheme 15 MCR synthesis of 2,5-diketopiperazines according to Cho et al.

The IMCR-derived 2,5-diketopiperazine scaffold has recently gained a lot of attention due to the discovery of GSK221149A (5), an oxytocin antagonist currently in advanced clinical trials. GSK221149A was developed from a low-potency high-throughput screening hit by extensive medicinal chemistry optimizations that endowed the compound with optimal target affinity and selectivity and solubility, stability, protein binding, half-life time and metabolism (Scheme  [¹6] ). [²9] Recently, ligand efficiency has crystallized as an important parameter to determine successful pathways of drug discovery projects. Ligand efficiency (Δg) is defined as the binding energy of the ligand per atom (Δg = ΔG/Nnon-hydrogen atoms). [²9b] In the current case, ligand efficiency of clinical candidate 5 (Δg = -0.35 kcal/mol per non-H atom) is improved over that of the initial hit 42 (Δg = -0.25 kcal/mol per non-H atom). The peptide derivative atosiban is the current preterm-treatment paradigm. Interestingly, GSK221149A is not only more potent and selective against related receptors as compared to atosiban, but also orally bioavailable. The ligand efficiency of atosiban (Δg = -0.16 kcal/mol per non-H atom) is comparably low due to the lower affinity and, at the same time, higher molecular weight.

Scheme 16 Discovery of GSK221149A, an orally bioavailable oxytocin receptor antagonist for the prevention of preterm birth, and atosiban, the current treatment

In the early optimization phase, the optimal stereochemistry was established. This backbone comprises three stereo-centers and therefore eight stereoisomers are possible. Two stereocenters can be controlled by the precursor amino acid, and the third results from the aldehyde component. Sollis stereoselectively synthesized all eight stereoisomers of the model compound 43 using different types of strategies, all based on Ugi reactions (Scheme  [¹7] ). [³0] Route 1 accessed the diketopiperazine scaffold from N- and C-protected amino acid precursors, benzaldehyde, and tert-butyl isocyanide in a UDC sequence. Route 2 involved a U-5C-4CR of leucine, benzaldehyde, and tert-butyl isocyanide in methanol to yield a linear precursor of the diketopiperazine scaffold. Upon hydrolysis of the methyl ester and coupling of the constrained phenylalanine, the final diketopiperazine was obtained by N-deprotection and cyclization. It is worth mentioning that the secondary amine of 45 could only be coupled with 47 when it was in the form of its free carboxylic acid 46: attempts to form the amide bond in the presence of the methyl ester failed. It was proposed that the difference in reactivity is due to the formation of a mixed anhydride followed by an intramolecular transacylation. Interestingly, several alternative sequential syntheses of diketopiperazine 43 were considered in an attempt to prepare the required stereoisomers in a selective manner; however none were efficient or sufficiently selective.

Scheme 17 Establishment of the optimal stereochemistry of oxytocin antagonists by stereoselective synthesis of all stereoisomers using different Ugi MCR strategies

Scheme 18 MCR synthesis of investigational drug GSK221149A (5)

The synthesis of the clinical candidate GSK221149A (5) is shown in Scheme  [¹8] and used the aforementioned U-4CR, followed by deprotection and cylization, to give the diketopiperazine 45. [³¹] At this stage, the two stereoisomers were separated and the benzyl group of the major isomer was hydrogenated, followed by carbonyl diimidazole mediated N-acyl carbamate formation and subsequent mild hydrolysis. The 2-O-protected 1-isocyanophenols used here were first introduced by Ugi et al. as a so-called convertible isocyanide to mildly cleave the amide bond in the presence of labile strained β-lactam ring systems. [³¹d] Final coupling of the carboxylic acid with morpholine yielded 5. Overall, the highly complex product 5 was synthesized in a short, stereoselective and high-yielding route thanks to the convergent character of MCR.

The same reaction sequence has been described for many amino acids, and can be also performed with side-chain-functionalized amino acids by using appropriate protecting groups. For example, Rhoden et al. recently documented the use of tryptophan as a suitable amino acid for application in combinatorial chemistry (Scheme  [¹9] ). [³²] The reactions of N-amino-protected tryptophans 48 with different combinations of amines, isocyanides, and aldehydes afforded the corresponding diketopiperazines 49.

As a second example of Ugi-type MCR chemistry with high relevance to the discovery and synthesis of pharmacologically active compounds, aplaviroc is mentioned here. Aplaviroc is a CCR5 receptor antagonist and an investigational drug for HIV treatment. [³³] Habashita et al. described the anti-HIV activity of a series of diketopiperazines synthesized by Ugi MCR (Scheme  [²0] ). [³4] Both ­solid- and liquid-phase syntheses have been disclosed in great detail. [³5]

Scheme 19 One-pot multicomponent synthesis of N-substituted tryptophan-derived diketopiperazines

Scheme 20 MCR approach to CCR5 receptor antagonist aplaviroc

Blackwell and Campbell used the macroarray synthesis technology originally developed by Frank to prepare arrays of diketopiperazines on simple filter paper. [³6] Libraries of diketopiperazines have been generated in high purity using the small molecule macroarray synthesis platform (Scheme  [²¹] ). [³7]

Scheme 21 Rapid synthesis of diketopiperazine macroarrays on planar solid supports

Marcaccini et al. described a facile entry into 2,5-diketopiperazine by the reaction of a primary amine, an aromatic aldehyde, an isocyanide, and chloroacetic acid, followed by a ring closure involving a nucleophilic substitution reaction (Scheme  [²²] ). [³8] The initial Ugi reaction is performed in good to high yields. The ring closure is described under ultrasound conditions with potassium hydroxide as a base in ethanol, again in good to excellent yields. Although this method suffers from limitations due to the nature of the aldehyde (as aliphatic aldehydes are not well tolerated during the cyclization), it was noted that a wide variety in the substitution pattern of the intermediate product, and subsequently in the diketopiperazines, can be easily achieved by changing the components in the Ugi reaction. Bruttomesso et al. used this methodology to synthesize the novel steroid derivative 50 (Scheme  [²²] ). [³9] The 2,5-diketopiperazine was attached to the C-17 of the steroidal nucleus and high stereoselectivity was observed during the Ugi reaction. In fact, many compounds based on this diketopiperazine scaffold are commercially available as screening compounds.

Scheme 22 Diketopiperazine synthesis according to Marcaccini et al.

The Ugi MCR followed by Boc deprotection and cyclization was used to generate diketopiperazine libraries. ­Armstrong’s convertible isonitrile 35 was used in the Ugi reaction utilising an ‘internal nucleophile’ approach for diketopiperazine (Scheme  [²³] ). [40] In each case, the Ugi reaction proceeded in good yield (72-92%). The diketopiperazine library was generated via a three-step, one-pot procedure.

Scheme 23 Solution-phase synthesis of diketopiperazine libraries

Hulme et al. recently introduced n-butylisonitrile as an ­alternative to ‘designer convertible isonitriles’ (Scheme  [²4] ). [4¹] This is significant, since n-butylisonitrile is commercially available, shelf-stable, cost-effective and more atom-economic than the more complex alternatives. In analogy to Scheme  [²5] , the amine comprises the leaving group under the herein-used microwave conditions and a diversity of 2,5-diketopiperazines was obtained.

Rhoden et al. described the use of the recently discovered 1-isocyano-2-(2,2-dimethoxyethyl)benzene 51 as a mild C-1 synthon to access 2,5-diketopiperazines under very mild conditions (Scheme  [²5] ). [4²] This isocyanide was independently introduced by the Wessjohann and Kobayashi groups. [4³] The reaction of Boc-protected α-amino acids, with oxo components, primary amines, and the isocyanide 51, gave the Ugi product. Under the mild acidic conditions, the acetal and the Boc group are cleaved and an indole serves as leaving group during the diketopiperazine formation. Seven examples were described in good yields and with stereochemical retention of the α-amino acid center. The advantages of this route are the stability, easy accessability and versatility of isocyanide 51, Gratifyingly, 51 is also devoid of the usual characteristic isocyanide odor. The intermediate Ugi product can be cleaved with several kinds of nucleophiles under very mild conditions. This is significant as it can support stereochemically sensitive reactions.

Scheme 24 Use of n-butyl isocyanide as efficient convertible isocyanide according to Hulme et al.

Scheme 25 Mild diketopiperazine synthesis using an elaborated designer convertible isocyanide

3.4 2,6-Diketopiperazine

Ugi et al. describe the MCR synthesis of the rare 2,6-diketopiperazine 52 (Scheme  [²6] ). [44] This reaction involves the union of two U-MCR reactions, the U-5C4CR and the tetrazole variant. Likely glycine reacts first to form the iminodicarboxylic acid monomethyl ester 53. The secondary amine component then reacts with additional isocyanide, propanal, and hydrazoic acid (formed in situ from sodium azide) to yield the bis-Ugi product 54. Upon acid Dowex catalysis, the 2,6-diketopiperazine is formed.

Scheme 26 The union of two Ugi MCRs yields a complex 2,6-diketopiperazine

Scheme 27 MCR synthesis of pyrrazolopyrazine-carboxamides

4 Bicyclic Fused Piperazines

Multiple synthetic pathways towards bicyclic piperazines involving MCRs have been disclosed. Ilyn et al. described the preparation of different heterocycle-fused pyrazinones as a little-explored scaffold group using Ugi MCRs (Scheme  [²7] ). [45] Thus pyrazolopyrazine-carboxamides 56 have been obtained from several differently substituted pyrazole-5-carboxylates 55, by first alkylating the pyrazole with chloroacetone under phase-transfer conditions in the presence of potassium carbonate and 18-crown-6. The two formed regioisomers were subjected to mild hydrolysis and subsequent Ugi reaction. Only the N1-substituted derivatives reacted to form the corresponding heterocycles. The desired products mostly precipitated from the reaction media, thus allowing for easy separation by filtration of the reaction mixtures. Similarly, the same research group reported on the synthesis of the corresponding indolo-ketopiperazines. [46] [47] The described methodology is suitable for rapid, parallel, automated synthesis of the corresponding combinatorial libraries of this interesting scaffold.

Akritopoulou-Zanze et al. used a secondary azide-alkyne [3+2] cycloaddition to prepare libraries of triazoloketopiperazines 57 comprising a wide variation of substituents (Scheme  [²8] ). [48] Alkynes and alkenes are orthogonal functional groups in Ugi-type reactions and do not interfere with the reaction and can consequently be used for further reaction. Thus, α-azidocarboxylic acids and the alkyne moiety introduced by propargylamine can be subsequently clicked. Employing other combinations of orthogonal bifunctional starting materials can lead to six topologically different scaffold groups to be explored in the future.

Scheme 28 Different bifunctional azide-incorporating starting materials allow for the sequential Ugi/alkyne-azide cycloaddition reactions of 12 topologically different product classes

Nixey et al. disclosed a novel application of the trimethylsilyl azide modified Ugi-4CR for the solution-phase ­synthesis of fused tetrazole-ketopiperazines 58 (Scheme  [²9] ). [49] Simple reflux of the three components in methanol produced the expected products in high yields. The reaction is suitable for high-throughput chemistry and was reported for the generation of libraries with three points of diversity in the 10,000 member range. In the high-throughput protocol, scavenger resins PS-NCO and PS-TsNHNH2 (functionalized polystyrene resins) were used to remove unreacted amine and oxo-component in order to substantially improve purities.

Scheme 29 High-throughput synthesis of tetrazoloketopiperazines

The Ugi-MCR of aldehydes, primary amines, trimethyl­silyl azide and 2-isocyanoethyl tosylate (59) yielding tetrazolopiperazine building blocks 60 was reported by Umkehrer et al. (Scheme  [³0] ). [50] The isocyanide 59 contains a second orthogonal leaving group and can be advantageously synthesized in only two steps from ethanolamine. Clearly this and similar isocyanides could be of use for other creative secondary transformations as well.

Scheme 30 Tetrazolopiperazines via Ugi-4CR and in situ S N2 reaction using the building-block isocyanide 59

Bienaymé et al. described the reaction of readily available methyl 1-(N,N-dimethylamino)-2-isocyanoacrylate 32 (Schöllkopf’s isocyanide [5¹a] ) with an aldehyde, a primary amine, and trimethylsilyl azide to form bicyclic tetrazoles 61 (Scheme  [³¹] ). [5¹b] During this variation, the intermediate secondary amine formed in the Ugi reaction cyclizes in situ via a Michael addition and subsequent dimethylamine elimination. The methyl ester could be used for further functionalization, such as amidation, and chemically distinct reactants are tolerated: aliphatic, aromatic and heteroaromatic aldehydes and even ketones react. Both aliphatic and aromatic amines are also good partners. A workup protocol has been described for high-throughput extractive purification.

Scheme 31 Synthesis of tetrazolopiperazines according to Bienaymé et al.

Nikulnikov et al. described the microwave-assisted preparation of fused pyrazolo-diketopiperazines 63 via an initial Ugi-4CR using 3-carboxypyrazoles 62. Microwave treatment in acetic acid yielded the fused product in medium to good overall yields (38-70%, 11 examples). This reaction is a remarkable case of neighboring-group-assisted cleavage of tert-butyl amides and demonstrates the utility of tert-butyl isocyanide as a convertible isocyanide (Scheme  [³²] ). [5²] The advantage of this procedure is that tert-butyl isocyanide is commercially available, indefinitely shelf-stable and very reactive in IMCRs, often giving high yields of products.

Scheme 32 Pyrazolo-diketopiperazines via a Ugi-4CR and subsequent ring closure to eliminate the tert-butylamine side chain of the isocyanide

The solution-phase synthesis of an array of biologically relevant quinoxalinones in a simple two-step procedure was revealed by Nixey et al. Transformations were carried out in excellent yield by condensation of mono-Boc-protected o-phenylenediamines, glyoxylic acids, and supporting Ugi reagents (Scheme  [³³] ). Subsequent acid treatment and evaporation afforded quinoxalinones 64 in good to excellent yields. [5³] The efficiency of a UDC strategy for the construction of heterocyclic compounds has been improved through the incorporation of microwave and fluorous technologies (Scheme  [³³] ). [54]

Neochoritis et al. found that o-phenylenediamines, TOSMIC (65), and aldehydes react in the presence of a base to form quinoxalines 66 in good yields (Scheme  [³4] ). The reaction mechanism likely involves a primary Schiff base formation, followed by TOSMIC addition, cyclization, elimination and oxidation. 2,3-Disubstituted quinoxalines have recently drawn attention as investigational drugs for diabetes treatment. [55] Additionally substituted quinoxalines are of high value in different areas of drug discovery.

Scheme 33 MCR synthesis of an array of biologically relevant quinoxalinones; F-Boc = CO2C(Me)2CH2CH2C8F17

Scheme 34 MCR synthesis of quinoxaline derivatives

Dihydroquinoxalinones 67 and 68 were synthesized by Oblé et al. using two different approaches. [56] El Kaïm discovered an interesting novel variation of the Ugi reaction whereby phenols react as acid components, and the rearrangement of the α-adduct involves a Smiles rearrangement. [9a] Thus, the first method uses a Smiles-Ugi variation and a secondary copper-catalyzed Ullmann-type ring closure (Scheme  [³5] ), whereas the second approach employs o-nitrophenols in the initial Smiles-Ugi reaction, and proceeds through reduction of the nitro group and acid-catalyzed cyclization. During this cylization, the amine portion of the isocyanide acts as leaving group and overall the isocyanide contributes only the carbonyl carbon to the dihydroquinoxalinone scaffold. Twelve different examples were described using a range of aliphatic primary amines, aliphatic isocyanides and aromatic and aliphatic oxo components, in medium to good yields.

Scheme 35 Highly substituted dihydroquinoxalinones by Smiles-Ugi reaction and ring closure

Other 1,2-diaminoethanes, in the presence of scandium(III) triflate, chlorotrimethylsilane, cerium(IV) ammonium nitrate or p-toluenesulfonic acid, reacted accordingly to yield 3,4-dihydroquinoxalin-2-amine derivatives 69 (Scheme  [³6] ). [¹8] [57] [58] This backbone is of considerable interest since it incorporates an amidine functionality which is known to form charge-charge interactions with carboxylic acids and phenols in protein targets. Aliphatic isocyanides, however, react with o-aminobenzophenones in dichloromethane under Lewis acid catalysis at ambient temperature to give, unexpectedly, 4-aryl-4-hydroxy-3,4-dihydroquinazolines in good to excellent yields. The outcome of the reaction is rationalized by a skeletal rearrangement of the initially formed ‘intramolecular Passerini’ reaction products, 2-amino-3-hydroxy-3-aryl-3H-indoles.

Scheme 36 MCR synthesis of 3,4-dihydroquinoxalin-2-amines using different catalysts

Hili et al. recently described an interesting intermolecular variation of the U-5C-3CR leading to 2,5-diketopiperazines using two bifunctional and unprotected starting materials - an α-amino acid and an aziridine aldehyde - and an isocyanide in trifluoroethanol (Scheme  [³7] ). [59] A range of amino acids were subjected to this reaction, and in all cases the corresponding piperazinone products 70 were obtained as single diastereoisomers without formation of linear peptides. The interesting stereochemical reaction outcome can be rationalized based on the assumption of a preformed a-amino acid Schiff base including a closely aligned zwitterion in the rather lipophilic solvent trifluoroethanol (aziridine-COOH), a subsequent isocyanide attack to form the nitrilium ion, and finally ring closure (Scheme  [³] ). Note that the stereochemistry-determining step is the addition of the isocyanide onto the Schiff base. From a practical point of view, this reaction is also interesting since analytically pure product can be isolated by precipitation from the reaction mixture.

Scheme 37 Stereoselective one-pot U-5C-3CR aziridino-diketo-piperazine formation

The solid-supported synthesis of a bicyclic diketopiperazine 71, a potential peptide β-turn mimetic, was reported (Scheme  [³8] ). The Ugi reaction between the resin ester of α-N-Boc-diaminopropionic acid (an amine input), α-bromo acid, aldehyde, and isocyanide is the key step in the protocol. [60] The final product was obtained in high yield and good purity.

Scheme 38 Solid-supported synthesis of a bicyclic diketopipera­zine

5 Polycyclic Fused Piperazines

El Kaïm et al. introduced a short and efficient sequence to form tricyclic 2,5-diketopiperazines in a two-step sequence of Ugi and Pictet-Spengler reactions (Scheme  [³9] ). [6¹] A bifunctional α-ketocarboxylic acid, a primary amine, an oxo component, and homoveratryl isocyanide (7) led to the formation of α-keto amides in a primary Ugi reaction. The keto group next reacted intramolecularly with the electron-rich phenol to give the tricyclic diketopiperazine 72 under Pictet-Spengler conditions.

Scheme 39 Synthesis of polycyclic diketopiperazines via a Ugi/­Pictet-Spengler sequence

A different twist on the Ugi and Pictet-Spengler combination was described by Liu et al. (Scheme  [40] ). [6²] They prepared polycyclic ring systems 74 by first reacting electron-rich isocyanides 73 with a carboxylic acid, an oxo component, and aminoacetaldehyde dimethylacetal (8). The intermediate Ugi products were cyclized via ­Pictet-Spengler reaction under strongly acidic conditions.

Scheme 40 Ugi/Pictet-Spengler multicomponent formation of tetrahydro-β-carboline scaffold

In an intramolecular variation, Wang et al. worked with oxocarboxylic acids 75 and were able to access even more complex polycyclic ring systems 76. [5] [6³] Significantly, aliphatic acyclic and cyclic as well as aromatic oxo acids were all found to be suitable substrates for this reaction sequence (Scheme  [4¹] ).

Scheme 41 Ugi/Pictet-Spengler multicomponent formation of polycyclic indole derivatives

A similar synthetic principle was applied by Cao et al. to yield the Schistosomiasis drug praziquantel (6) (Scheme  [4²] ). [64] This is by far the shortest synthesis of this drug that, according to WHO, is essential. The cost-of-goods for this active pharmaceutical ingredient synthesis is very important since Schistosomiasis is a poor-country disease and more than 200 million people in sub-Saharan Africa suffer from this highly debilitating disease. [³]

Scheme 42 Very short and convergent synthesis of praziquantel

Tsirulnikov et al. prepared tricyclic indolo-diketopiperazines 77 by reacting 1H-indole-2-carboxylic acids, ethyl pyruvate, isocyanides, and primary amines via a one-pot, two-step procedure involving Ugi reaction and microwave-assisted cyclization (Scheme  [4³] ). [46] This one-pot procedure is amenable to parallel synthesis owing to both its simplicity and the easy purification of the products.

Scheme 43 Synthesis of 2,3-dihydropyrazino[1,2-a]indole-1,4-di­ones

Franckevicius et al. reacted α-amino methyltetrazoles 78 as α-amino acid surrogates with oxo components and isocyanides to give tricyclic tetrazolopiperazines of general structure 79 (Scheme  [44] ). [65] In contrast to α-amino acids, α-amino methyltetrazoles cannot rearrange after the formation of the α-adduct, and the tetrahydrotetrazolopyrrolo­pyrazine is the stable final product. Two stereoisomers (syn and anti) of the exocyclic imine can be isolated. A range of aromatic as well as aliphatic isocyanides and aliphatic aldehydes reacted in generally good to excellent yields, resulting in a broad scope for this reaction. Several MCR approaches to unusually substituted α-amino methyltetrazoles have been described, thus potentially rendering the above reaction even more diverse in starting materials. [66]

Scheme 44 MCR synthesis of tricyclic tetrazolopiperazines

Kalinski et al. described the use of o-fluorophenyl isocyanide in the tetrazole Ugi variation and the subsequent ring closure took place under remarkably mild conditions (Scheme  [45] ). [67] The Ugi reaction of the isocyanide, tri­methylsilyl azide, the oxo component, and the primary amine yielded a secondary tetrazolomethylamine, which underwent an intramolecular nucleophilic aromatic substitution reaction in the presence of cesium carbonate to produce tricyclic tetrazolopiperazines 80.

Scheme 45 Tricyclic tetrazolopiperazines by an Ugi reaction fol­lowed by an intramolecular nucleophilic aromatic substitution

Aromatic ring incorporated five- and six-membered amidines are known to react with aldehydes and isocyanides in the so-called Groebcke-Blackburn-Bienaymé (GBB) 3CR to form fused 5-amino imidazoles. The GBB-3CR of 2-aminopyridine (80) with benzaldehyde and the Walborsky reagent (82) using chlorotrimethylsilane as a promoter yielded N-isooctyl imidazo[1,2-a]azin-3-amine 83 (Scheme  [46] ). After removal of the isooctyl group, 2-phenylimidazo[1,2-a]pyridin-3-amine (84) was isolated as the hydrochloride salt by filtration. [68] Subsequent ­Buchwald-Hartwig arylation of the latter with heteroaryl halide 85 using a palladium-catalyzed protocol produced the 3-arylaminoimidazo[1,2-a]azine derivative 86.

Scheme 46 Palladium-catalyzed arylation of the Groebke-­Blackburn-Bienaymé product

The Ugi reaction has been employed as a key step in the total synthesis of several natural products. Recently Takiguchi et al. disclosed the asymmetric total synthesis of two anticancer natural products employing a common tricyclic imine precursor 87 and an Ugi reaction (Scheme  [47] ). [69] Thus N-acetylardeemin was accessed by the U-3CR of 87 with anthranilic acid, isocyanide and N-protected d-Ala in toluene followed by deprotection and polycondensation, whereas fructigenine was synthesized by the U-3CR of 87 with p-methoxybenzyl isocyanide and Boc-Phe with subsequent deprotection and diketopiperazine ring closure under basic conditions. In both cases, the Ugi reaction was highly stereoselective and the isocyanide attack took place preferentially from the side opposite the bulky reverse-prenyl group of imine 87. Other natural products incorporating piperazine moieties that have been synthesizied by Ugi reactions are furanomycin (Joullié and co-workers), [70a] ecteinascidin 784, naphthyridinomycin and lemonomycin (Fukuyama and co-workers). [70b-d] Clearly, natural product synthesis is a highly promising and currently underdeveloped field with regard to the application of IMCRs.

Scheme 47 Ugi reaction as a key step in the asymmetric total syntheses of two pyrazino-pyrroloindole alkaloids, fructigenine A and 5-N-acetylardeemin

6 Introduction of the Piperazine Moiety via a Starting Material

The in situ generation of the piperazine moiety during the MCR is restricted to 35 methods that have been described so far and discussed in this review. However, based on the versatility of MCR reactions, many more piperazine-containing molecules can be accessed by introducing the six-membered-ring system via a starting material. Since a comprehensive discussion goes beyond the scope of this review, only a few examples are shown here in order to demonstrate the underlying principle.

The GBB-3CR of 2-aminopyrazine yielded bicyclic piperazine 88. [7¹] Kercher et al. from Array Biopharmaceuticals described the preparation of large arrays of bicyclic imidazo-piperazines by an initial GBB-3CR, followed by a selective reduction of the piperazine moiety (Scheme  [48] ). [7¹d]

Giovenzana et al. described a highly innovative variation of the Ugi-4CR of secondary amines which is now called the split-Ugi modification. [7²] The use of secondary amines in the Ugi reaction yields N,N-diacyl products due to the lack of a suitable trans-acylatable secondary amine in the α-adduct F (Scheme  [³] ). [8] If, however, a bis secondary amine is used in the Ugi reaction, then the second secondary amine in the α-adduct can be trans-acylated (Scheme  [49] ). For example, the use of piperazine as an amine component in the Ugi reaction yields N-acyl N′-aminoacylmethylpiperazines 89. This scaffold can be regarded as a chimera between the products of an Ugi-3CR and an Ugi-4CR. The reaction is quite versatile and a wide variety of isocyanides and aliphatic as well as aromatic oxo and acid components give the products in generally good to high yields. The scaffold comprises a tertiary amine in addition to a tertiary amide, both stemming from the piperazine. The tertiary amine provides considerable basicity to the scaffold, eventually resulting in preferred blood-brain penetration and preferential solubility properties. [7²] Moreover, this Ugi modification can be used to easily synthesize otherwise difficult-to-access polyamines such as 14 (Scheme  [¹] ) and related natural products. [6]

Scheme 48 MCR synthesis of tetrahydroimidazo[1,2-a]pyrazine

Scheme 49 Piperazine as a diamine component for the split-Ugi MCR

Isocyanides containing the piperazine substructure have also been used as MCR starting materials (Scheme  [50] ). [7³] The three-component reaction of l-valine, mercaptoacet­aldehyde, and isocyanide 90 smoothly and stereoselectively yielded 91. The unprotected α-amino acid contributed two of the required four functional groups. Here, the intermediate α-adduct F (Scheme  [³] ) is a six-membered ring and the side-chain nucleophile sulfhydryl induces the transacylation to form the thiolactone. This reaction is of great generality and many examples have been disclosed.

A sequential approach involving multiple multicomponent macrocyclizations including Ugi-4CR was developed by Rivera and Wessjohann. [74] Piperazine-derived diamine 92 was used as one of the bifunctional building blocks for the synthesis of impressively complex and architectural macromulticycles, such as 93 (Scheme  [5¹] ).

A multicomponent reaction of a piperazine derivative was used in an antimalarial drug discovery strategy by ­Musonda et al. [75] The reaction of 4-aminoquinoline 94, an aldehyde and the isocyanoacetamide 95 yielded aminoxazole derivatives 96 (Scheme  [5²] ). The antiplasmodial activity against chloroquine-sensitive strain 3D7 was impressive (96a, IC50 = 0.52 µM; 96b, IC50 = 0.14 µM).

Scheme 50 MCR synthesis of a Δ-thiolactone scaffold

Scheme 51 Sequential multiple multicomponent macrocyclizations

Adamantane 11-β-HSD-1 inhibitors were synthesized by Sörensen et al. via IMCR. [76] The reaction of isocyanide 97, cyclobutanone, and aryl piperazine 98 provided adamantane aminoamide 99 after ester hydrolysis (Scheme  [5³] ). The acid was then converted into the corresponding amide 100 by a standard coupling procedure. The potency of human 11-HSD1 inhibition was measured for both 99 (K i = 17 nM) and 100 (K i = 7 nM).

Akritopoulou-Zanze et al. from Abbott Laboratories applied a van Leusen-3CR in their synthesis of GSK-3 kinase inhibitors for the treatment of mood disorders. [77] The reaction of piperazine derivative 101 as the amine component, TOSMIC derivative 102 as the isocyanide component, and indazole derivative 103 as the aldehyde component yielded compound 104 (Scheme  [54] ).

Hulme et al. at Amgen prepared tetrazolylmethylpiperazines, using an Ugi-4CR, in their search for melanin concentrating hormone receptor antagonists with potential applications in diabetes. [78] Compound 106, for example, was synthesized by the Ugi reaction of Boc-piperazine, benzaldehyde, isocyanide 105 and trimethylsilyl azide, followed by deprotection (Scheme  [55] ).

Scheme 52 MCR synthesis of antimalarial agents

Scheme 53 MCR synthesis of adamantane HSD1 inhibitors

Scheme 54 Synthesis of a kinase inhibitor via vL-3CR

Scheme 55 Synthesis of tetrazolylmethylpiperazines via Ugi-4CR

7 Conclusion and Outlook

Isocyanide-based multicomponent reactions provide a large pool of elegant, short and versatile syntheses of different mono-, bi- and oligocyclic piperazines and oxidized versions thereof. Currently 35 different ways to access piperazines have been described and they are summarized in this review. Thus the IMCRs comprise a synthetic hub for piperazine syntheses (Figure  [³] ). The knowledge about the 3D structures, the scope and limitations of their syntheses and their scaffold-intrinsic physicochemical properties provides a competitive advantage in the never-ending hunt for new and improved medications for diseases and unmet medical needs.

Acknowledgment

Research in the Dömling laboratory in the area of this review has been generously supported by the NIH (1R21GM087617-01A1 and 1P41GM094055-01) and the University of Pittsburgh.

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Khoury, K.; Dömling, A.; ChemMedChem in press.

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Dömling, A.; Wang, K.; Wang, W. Chem. Rev. submitted for publication.

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Liu, H. X.; William, S.; Herdtweck, E; Botros, S.; Dömling, A. Bioorg. Med. Chem. submitted for publication.

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Cao, H.; Liu, H. X.; Dömling, A. Chem. Eur. J. in press

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Khoury, K.; Dömling, A.; ChemMedChem in press.

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Dömling, A.; Wang, K.; Wang, W. Chem. Rev. submitted for publication.

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Liu, H. X.; William, S.; Herdtweck, E; Botros, S.; Dömling, A. Bioorg. Med. Chem. submitted for publication.

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Cao, H.; Liu, H. X.; Dömling, A. Chem. Eur. J. in press

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Figure 1 Representative structures of marketed and experimental drug entities containing piperazine scaffolds

Scheme 1 Two conceptually different IMCR approaches towards piperazine-comprising compounds

Scheme 2 Piperazino isocyanide building block synthesis by simple solventless mixing of amino acid derived isocyanides with suitable piperazines. The synthesis is very convenient since the odorless (!) isocyanide precipitates and can be easily isolated and purified by filtration and washing.

Figure 2 Some topologically possible piperazines based on the classical Ugi-4CR of isocyanides (CNC), oxo component (C), primary amine (N) and carboxylic acid (C) and a subsequent ring formation

Scheme 3 Simplified mechanisms of Ugi-type reactions yielding some exemplary scaffolds

Figure 3 Chemical space of piperazine scaffolds via isocyanide-based multicomponent reactions (red: isocyanide component, blue: amine component, black: acid component, purple: oxo component)

Scheme 4 One-pot synthesis of piperazine scaffold and shortcut to the HIV protease inhibitor drug indinavir using convergent IMCR; BINAP = 2,2′-bis(diphenylphosphino)-1,10-binapthyl, cod = cyclo-octadiene

Scheme 5 Scandium(III) triflate mediated U-3CR

Scheme 6 The synthesis of dihydropyrazines via isocyanide-based three-component reactions

Scheme 7 Tetrahydro-2-aminopiperazines by chlorotrimethylsilane-promoted IMCR of ethylenediamine

Scheme 8 Parallel liquid-phase synthesis of 5-carbamoyl-4-sulfonyl-2-piperazinones

Scheme 9 The one-pot synthesis of Δ5-2-oxopiperazine ring system

Scheme 10 Synthesis of 1,6-dihydro-6-oxopyrazine-2-carboxylic acid derivatives

Scheme 11 Above: 3-CR, involving Schöllkopf’s isocyanide, towards ketopiperazines. Below: combinatorial 96-well reaction optimization using a sterically and electronically representative set of aldehydes and primary amines. First plate without catalyst, second plate with optimized Yb(OTf)3 catalyst (color code corresponds to LC-UV-ELSD-MS determined reaction performance: green = good, >50%; yellow = product present, <50%; red = product not present).

Scheme 12 Ketopiperazine synthesis involving convertible cyclohexenyl isocyanide and mono-protected ethylenediamines

Scheme 13 Highly substituted ketopiperazines by a two-step UDC procedure

Scheme 14 MCR synthesis of 2,5-diketopiperazines according to Szardenings et al.

Scheme 15 MCR synthesis of 2,5-diketopiperazines according to Cho et al.

Scheme 16 Discovery of GSK221149A, an orally bioavailable oxytocin receptor antagonist for the prevention of preterm birth, and atosiban, the current treatment

Scheme 17 Establishment of the optimal stereochemistry of oxytocin antagonists by stereoselective synthesis of all stereoisomers using different Ugi MCR strategies

Scheme 18 MCR synthesis of investigational drug GSK221149A (5)

Scheme 19 One-pot multicomponent synthesis of N-substituted tryptophan-derived diketopiperazines

Scheme 20 MCR approach to CCR5 receptor antagonist aplaviroc

Scheme 21 Rapid synthesis of diketopiperazine macroarrays on planar solid supports

Scheme 22 Diketopiperazine synthesis according to Marcaccini et al.

Scheme 23 Solution-phase synthesis of diketopiperazine libraries

Scheme 24 Use of n-butyl isocyanide as efficient convertible isocyanide according to Hulme et al.

Scheme 25 Mild diketopiperazine synthesis using an elaborated designer convertible isocyanide

Scheme 26 The union of two Ugi MCRs yields a complex 2,6-diketopiperazine

Scheme 27 MCR synthesis of pyrrazolopyrazine-carboxamides

Scheme 28 Different bifunctional azide-incorporating starting materials allow for the sequential Ugi/alkyne-azide cycloaddition reactions of 12 topologically different product classes

Scheme 29 High-throughput synthesis of tetrazoloketopiperazines

Scheme 30 Tetrazolopiperazines via Ugi-4CR and in situ S N2 reaction using the building-block isocyanide 59

Scheme 31 Synthesis of tetrazolopiperazines according to Bienaymé et al.

Scheme 32 Pyrazolo-diketopiperazines via a Ugi-4CR and subsequent ring closure to eliminate the tert-butylamine side chain of the isocyanide

Scheme 33 MCR synthesis of an array of biologically relevant quinoxalinones; F-Boc = CO2C(Me)2CH2CH2C8F17

Scheme 34 MCR synthesis of quinoxaline derivatives

Scheme 35 Highly substituted dihydroquinoxalinones by Smiles-Ugi reaction and ring closure

Scheme 36 MCR synthesis of 3,4-dihydroquinoxalin-2-amines using different catalysts

Scheme 37 Stereoselective one-pot U-5C-3CR aziridino-diketo-piperazine formation

Scheme 38 Solid-supported synthesis of a bicyclic diketopipera­zine

Scheme 39 Synthesis of polycyclic diketopiperazines via a Ugi/­Pictet-Spengler sequence

Scheme 40 Ugi/Pictet-Spengler multicomponent formation of tetrahydro-β-carboline scaffold

Scheme 41 Ugi/Pictet-Spengler multicomponent formation of polycyclic indole derivatives

Scheme 42 Very short and convergent synthesis of praziquantel

Scheme 43 Synthesis of 2,3-dihydropyrazino[1,2-a]indole-1,4-di­ones

Scheme 44 MCR synthesis of tricyclic tetrazolopiperazines

Scheme 45 Tricyclic tetrazolopiperazines by an Ugi reaction fol­lowed by an intramolecular nucleophilic aromatic substitution

Scheme 46 Palladium-catalyzed arylation of the Groebke-­Blackburn-Bienaymé product

Scheme 47 Ugi reaction as a key step in the asymmetric total syntheses of two pyrazino-pyrroloindole alkaloids, fructigenine A and 5-N-acetylardeemin

Scheme 48 MCR synthesis of tetrahydroimidazo[1,2-a]pyrazine

Scheme 49 Piperazine as a diamine component for the split-Ugi MCR

Scheme 50 MCR synthesis of a Δ-thiolactone scaffold

Scheme 51 Sequential multiple multicomponent macrocyclizations

Scheme 52 MCR synthesis of antimalarial agents

Scheme 53 MCR synthesis of adamantane HSD1 inhibitors

Scheme 54 Synthesis of a kinase inhibitor via vL-3CR

Scheme 55 Synthesis of tetrazolylmethylpiperazines via Ugi-4CR