Combinatorial Chemistry Online Volume 16, Issue 7

Combinatorial Chemistry - An Online Journal 16 (2014) 25–28

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Combinatorial Chemistry - An Online Journal journal homepage: www.elsevier.com/locate/comche

Combinatorial Chemistry Online Volume 16, Issue 7, July 2014 N.K. Terrett Ensemble Therapeutics Corp., Cambridge, MA 02139, USA

O

1. Current literature highlights 1.1. Parallel solution phase synthesis of uridine antibiotic analogues Natural products offer a range of three-dimensional structural complexity that makes them highly informative when designing new compound libraries. In particular, structural variation around nucleoside structures have resulted in a range of biological properties including anticancer, antiviral and antifungal activities. A goal of a recent study has been to prepare a library of compounds based on nucleoside templates through the NIH Roadmap Program and the Molecular Libraries Probe Production Centers Network (MLPCN) [1]. Regular nucleosides that retain a 50 -hydroxyl group can generate problems however, as they can enter nucleoside metabolic pathways, as well as causing general toxicity through inhibition of DNA and RNA metabolism. Consequently, a goal of this current study was to use the 50 -subsituent to introduce new chemical functionality to replace the hydroxyl and thus avoid these pitfalls. The 50 -position can be used to introduce other groups following oxidation of the hydroxyl in the starting material (1) by reaction with TEMPO-iodobenzene diacetate to a carboxylic acid (2). Alternatively, the hydroxyl can be converted to an amine (3) by conversion to a tosylate, displacement with azide and reduction by transfer hydrogenation over palladium catalyst.

NH HO

http://dx.doi.org/10.1016/j.comche.2014.06.001

O

O

O

O

1

O

O NH HOOC

N

NH O

H2N

N

O

O

O

O

E-mail: [email protected]

N

O

2

O

O

3

Compounds 2 and 3 provide the starting points for further derivatisation to the library components. For example, the carboxylic acid in compound 2 was coupled with phenylalanine methyl ester to provide amino acid functionality in the 50 -postion. The 50 -carboxylic acid (2), the 50 -amino (3), and the carboxylic acid of the phenylalanine derivative (4) provided three sites for diversification through reductive amination, sulphonylation and peptide coupling chemistry. Following derivatisation, the acetonide protecting group was removed by treatment with 50% aqueous formic acid.

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N.K. Terrett / Combinatorial Chemistry - An Online Journal 16 (2014) 25–28

O NH HOOC

N

O

O

O

O

2

O

HOOC

H N

NH O

N

O

O Ph O

O

4

To generate a library of 94 analogues, these reactions were undertaken using solution phase techniques, on a sufficiently large scale to target 50–100 mg of product. Reductive amination of the amine (3) was achieved by imine formation with a range of aldehydes followed by sodium borohydride reduction. Reactions were carried out on a Radleys 12-place carousel reaction station at ambient temperature. Other chemistries were undertaken on a 24-position MiniBlock XT solution phase vessel positioned on a Tecan automated liquid sample handler. The compounds prepared have been screened against a number of disease-relevant targets, and activity for some compounds has been noted, such as antagonism of the D3 dopamine receptor, and inhibition of hepatitis C virus and dengue virus type 2. All of the prepared compounds have been submitted to the MLPCN. 2. A summary of the papers in this month’s issue

1-(2-aminophenyl)pyrroles, aldehydes, and isonitriles, the target heterocyclic scaffold was assembled in a one-pot, operationally friendly process. With three points of diversity and formation of three chemical bonds in one step, this strategy proves to be very general, and it is envisioned that access to larger libraries of diverse analogues will be feasible [3]. A concise method has been developed for the synthesis of caroverine and its derivatives. The quinoxalinone scaffold of these compounds was constructed via the tandem nitrosation/ aerobic oxidative carbon–nitrogen bond formation reaction of N-(2-chloroethyl)-2-cyano-N-phenylacetamide, followed by sequential Grignard, Finkelstein and nucleophilic substitution reactions. The paper describes the development of this strategy, the optimisation of each step and the effect of different additives on the individual reactions [4]. A unique, user-friendly, concise two-step, one-pot protocol for the synthesis of highly substituted quinoxalines has been described. Conducting the Ugi reaction with appropriately functionalised classical reagents with subsequent acid treatment of the adduct affords collections of diversified quinoxalines in good to excellent yields. The methodology exploits what may be viewed as a ‘convertible carboxylic acid’, which in addition may be captured in an intramolecular sense to generate structurally complex 2-benzimidazolylquinoxalines in just two steps [5]. A simple and facile approach to highly functionalised pyrimidone derivatives and indole fused pyrimidones has been developed. The synthesis of substituted pyrimidone derivatives in moderate to good yields involves the[4+2] cycloaddition of 1,4-dipoles generated from a,b-unsaturated imines and dimethyl acetylenedicarboxylate with isocyanates as dipolarophiles. Furthermore, the pyrimidones resulted from 2-bromophenyl isocyanate could be transformed into various indole fused pyrimidones via intramolecular palladium-catalysed Heck reaction under different conditions. All these approaches offer potential utility for library synthesis [6]. An operationally simple and facile synthesis of a-hydroxyimino-b-oxodithioesters has been achieved by nitrosation of a-enolicdithioesters. These products were further treated with internal alkynes to afford diverse 1,4-thiazin-3-ones via a domino reduction/annulation strategy under mild reaction conditions [7]. A new Staudinger/aza Wittig/Strecker multicomponent reaction sequence to give C-1-cyano iminoalditols has been developed. When applied to 5-azidodeoxy-D-xylose and -D-glucose as substrates, the method leads smoothly in good yield and with excellent stereoselectivity to respectively, 1,5-dideoxy-1,5-iminoD-idurono nitrile and 2,6-didesoxy-2,6-imino-D-glycero-D-ido-heptononitrile. Implementation of this MCR route to alternative azidodeoxy sugar substrates is expected to provide a variety of alternative analogues, and these promise to provide a number of interesting focussed compound libraries [8].

2.1. Polymer supported synthesis 2.3. Scaffolds and synthons for combinatorial libraries An azido-Ugi reaction involving cyclic ketones, primary amines, isonitriles, and azides has been used to give substituted tetrazole derivatives. These intermediates were then hydrolysed to the corresponding acid derivatives. Amide bond formation of this product gave fused tetrazolo[1,5-a][1,4]benzodiazepines in high yield and good diversity. Current efforts are seeking a solid supported protocol to close the ring to rapidly access large libraries of tricyclic tetrazole derivatives [2].

In the field of medicinal chemistry, the intriguing and challenging molecular architectures of nitrogen-containing heterocycles with potential bioactive properties have received significant attention from researchers engaged in the areas of natural product synthesis and heterocyclic methodology. In a recent review article, recent developments in the environmentally benign synthetic methods providing access to quinazoline and quinazolinone scaffolds with promising biological potential has been summarised [9].

2.2. Solution-phase synthesis 2.4. Solid-phase supported reagents An isocyanide-based multicomponent reaction applied to the rapid assembly of novel, biologically relevant dihydropyrrolo [1,2-a]quinoxalines-amidines has been presented. Starting from

A solid-supported rhodium(0) catalyst has been developed and applied to the chemo- and regio-selective reduction of nitroarenes

N.K. Terrett / Combinatorial Chemistry - An Online Journal 16 (2014) 25–28

to their corresponding amines using hydrazine hydrate as a reducing source under mild microwave irradiation conditions. This methodology also shows excellent compatibility with a broad range of other structurally diverse reducible functional groups. The catalyst can be recovered by simple filtration and reused for 13 cycles with consistent activity [10]. A silica supported palladium catalyst has been shown to have excellent activity and reusability for the selective oxidation of alcohols to corresponding carbonyl compounds. Hydrogen peroxide was used as the oxidant in a base-free environment, and a wide range of alcohols including aliphatic alcohols were tolerated as substrates using a 0.1% loading of palladium [11]. 2.5. Novel resins, linkers and techniques No papers this month. 2.6. Library applications By considering published structural information, high throughput biaryl lipophilic acid arrays have been designed leveraging facile chemistry to permit their synthesis. Multiple hits were rapidly identified which were of suitable prostaglandin I2 receptor agonist potency [12]. A diverse library of bis[1,2]dithiolo[1,4]thiazines and bis[1,2]dithiolopyrrole derivatives has been prepared for evaluation of activity against the nucleocapsid protein of the Feline Immunodeficiency Virus (FIV). Using this target as a model for HIV, an in vitro cell culture approach has yielded nanomolar active compounds with low toxicity [13]. A library of Schiff bases has been synthesised by condensation of aromatic amines incorporating sulphonamide, carboxylic acid or carboxymethyl functionalities as zinc2+-binding groups, with aromatic aldehydes incorporating tert-butyl, hydroxy and/or methoxy groups. The corresponding amines were thereafter obtained by reduction of the imines. These compounds were assayed for the inhibition of two cytosolic human carbonic anhydrase isoenzymes, hCA I and II. The reduced Schiff bases are stable to hydrolysis and several low-nanomolar inhibitors were detected, most of them incorporating sulphonamide groups [14]. A 47-membered library of novel long-chain arylpiperazines, which contain cyclic amino acid amides in the terminal fragment have been synthesised on Rink-amide resin and evaluated for binding affinity to 5-HT7 and 5-HT1A receptors. Representative compounds from the library displayed high-to-low affinity for 5-HT7 and 5-HT1A sites. The possible interactions implicated in binding of the studied compounds to the 5-HT7 receptor were supported by molecular modelling [15]. a7 Nicotinic acetylcholine receptor agonists are promising therapeutic candidates for the treatment of cognitive impairment. A novel series of a7 nAChR agonists have been investigated and results described in a recent publication. Starting from molecular docking studies on two series of molecules, an alternative scaffold was designed attempting to combine the optimal features of these previously identified urea and pyrazole compounds. A small library was synthesised in a parallel manner, affording compounds with excellent a7 nAChR activity, selectivity and a preliminary ADME profile was obtained [16]. References [1] Moukha-chafiq O, Reynolds RC. Parallel solution-phase synthesis and general biological activity of a uridine antibiotic analog library. ACS Comb Sci 2014;16(5):232–7. [2] Yerande SG, Newase KM, Singh B, Boltjes A, Dömling A. Application of cyclic ketones in MCR: Ugi/amide coupling based synthesis of fused tetrazolo[1,5a][1,4]benzodiazepines. Tetrahedron Lett 2014;55(21):3263–6.

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[3] Medda F, Hulme C. Exploiting the divalent nature of isonitriles: a novel Pictet-Spengler amidination process. Tetrahedron Lett 2014;55(22): 3328–31. [4] Kobayashi Y, Suzuki Y, Ogata T, Kimachi T, Takemoto Y. A diversity-oriented synthesis of caroverine derivatives via TEMPO-promoted aerobic oxidative CN bond formation. Tetrahedron Lett 2014;55(22):3299–301. [5] Ayaz M, Xu Z, Hulme C. Novel succinct routes to quinoxalines and 2benzimidazolylquinoxalines via the Ugi reaction. Tetrahedron Lett 2014;55(23):3406–9. [6] Lei M, Tian W, Li W, Lu P, Wang Y. One-pot, three-component synthesis of highly functionalized pyrimidone derivatives and access to indole fused pyrimidones via palladium-catalyzed intramolecular Heck reaction. Tetrahedron 2014;70(23):3665–74. [7] Nagaraju A, Shukla G, Srivastava A, Ramulu BJ, Verma GK, Raghuvanshi K, et al. Easy access to a-hydroxyimino-b-oxodithioesters and application towards the synthesis of diverse 1,4-thiazine-3-ones via reduction/annulation cascade. Tetrahedron 2014;70(23):3740–6. [8] Zoidl M, Müller B, Torvisco A, Tysoe C, Benazza M, Siriwardena A, et al. Concise synthesis of C-1-cyano-iminosugars via a new Staudinger/aza Wittig/ Strecker multicomponent reaction strategy. Bioorg Med Chem Lett 2014;24(12):2777–80. [9] Khan I, Ibrar A, Abbas N, Saeed A. Recent advances in the structural library of functionalized quinazoline and quinazolinone scaolds: synthetic approaches and multifarious applications. Eur J Med Chem 2014;76:193–244. [10] Guha NR, Bhattacherjee D, Das P. Solid supported rhodium(0) nanoparticles: an efficient catalyst for chemo- and regio-selective transfer hydrogenation of nitroarenes to anilines under microwave irradiation. Tetrahedron Lett 2014;55(18):2912–6. [11] Sahu D, Sarmah C, Das P. A highly efficient and recyclable silica-supported palladium catalyst for alcohol oxidation reaction. Tetrahedron Lett 2014;55(23):3422–5. [12] McKeown SC, Charlton SJ, Cox B, Fitch H, Howson CD, Leblanc C, et al. Emily Stanley Identification of novel IP receptor agonists using historical ligand biased chemical arrays. Bioorg Med Chem Lett 2014;24(10):2247–50. [13] Asquith CRM, Meli ML, Konstantinova LS, Laitinen T, Peräkylä M, Poso A, et al. Evaluation of the antiviral efficacy of bis[1,2]dithiolo[1,4]thiazines and bis[1,2]dithiolopyrrole derivatives against the nucelocapsid protein of the Feline Immunodeficiency Virus (FIV) as a model for HIV infection. Bioorg Med Chem Lett 2014;24(12):2640–4. [14] Nasr G, Cristian A, Barboiu M, Vullo D, Winum J-Y, Supuran CT. Carbonic anhydrase inhibitors. Inhibition of human cytosolic isoforms I and II with (reduced) Schi’s bases incorporating sulfonamide, carboxylate and carboxymethyl moieties. Bioorg Med Chem 2014;22(10):2867–74. [15] Canale V, Guzik P, Kurczab R, Verdie P, Satała G, Kubica B, et al. Solid-supported synthesis, molecular modeling, and biological activity of long-chain arylpiperazine derivatives with cyclic amino acid amide fragments as 5-HT7 and 5-HT1A receptor ligands. Eur J Med Chem 2014;78:10–22. [16] Nencini A, Castaldo C, Comery TA, Dunlop J, Genesio E, Ghiron C, et al. Design and synthesis of a hybrid series of potent and selective agonists of a7 nicotinic acetylcholine receptor. Eur J Med Chem 2014;78:401–18.

Further reading Papers on combinatorial chemistry or solid-phase synthesis from other journals Traficante CI, Delpiccolo CML, Mata EG. Palladium-catalyzed cross-coupling reactions of arylsiloxanes with aryl halides: application to solid-supported organic synthesis. ACS Comb Sci 2014;16(5):211–4. Arisawa M, Sato T, Hoshiya N, Al-Amin M, Kogami Y, Shuto S. Ligand-free SuzukiMiyaura coupling with sulfur-modified gold-supported palladium in the synthesis of a conformationally-restricted cyclopropane compound library with three-dimensional diversity. ACS Comb Sci 2014;16(5):215–20. McMaster C, Fulopova V, Popa I, Grepl M, Soural M. Solid-phase synthesis of anagrelide sulfonyl analogues. ACS Comb Sci 2014;16(5):221–4. Kim W-K, Jang J-H, Jo H, Park K. Parallel and combinatorial liquid-phase synthesis of alkylbiphenyls using pentaerythritol support. ACS Comb Sci 2014; 16(5):225–31. Bonache MA, Balsera B, Lopez-Mendez B, Millet O, Brancaccio D, Gomez-Monterrey I, et al. De novo designed library of linear helical peptides: an exploratory tool in the discovery of protein-protein interaction modulators. ACS Comb Sci 2014;16(5): 250–8. Laraia L, Stokes J, Emery A, McKenzie GJ, Venkitaraman AR, Spring DR. High content screening of diverse compound libraries identifies potent modulators of tubulin dynamics. ACS Med Chem Lett 2014;5(5):598–603. Zhou Q-Q, Xiao Y-C, Yuan X, Chen Y-C. Asymmetric Diels-Alder reactions of 2,4,6trienals via tetraenamine catalysis. Asian J Org Chem 2014;3(4):545–9. Sola J, Lafuente M, Atcher J, Alfonso I. Constitutional self-selection from dynamic combinatorial libraries in aqueous solution through supramolecular interactions. Chem Commun (Cambridge, UK) 2014;50(35):4564–6. Wu H, Li Y, Bai G, Niu Y, Qiao Q, Tipton JD, et al. C-AApeptide-based small-molecule ligands that inhibit Ab aggregation. Chem Commun (Cambridge, UK) 2014; 50(40):5206–8.

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Ulrich S, Dumy P. Probing secondary interactions in biomolecular recognition by dynamic combinatorial chemistry. Chem Commun (Camb) 2014;50(44):5810–25. Zeglis BM, Emmetiere F, Pillarsetty N, Weissleder R, Lewis JS, Reiner T. Building blocks for the construction of bioorthogonally reactive peptides via solid-phase peptide synthesis. ChemistryOpen 2014;3(2):48–53. Brust A, Schroeder CI, Alewood PF. High-throughput synthesis of peptide athioesters: a safety catch linker approach enabling parallel hydrogen fluoride cleavage. ChemMedChem 2014;9(5):1038–46. Mei X, Huang G. The construction strategies of mono- and oligosaccharide microarrays. Curr Org Chem 2014;18(5):615–9. Wu H, Teng P, Cai J. Rapid access to multiple classes of peptidomimetics from common c-AA peptide building blocks. Eur J Org Chem 2014;8:1760–5.

Chang Y-P, Banerjee J, Dowell C, Wu J, Gyanda R, Houghten RA, et al. Discovery of a potent and selective a3b4 nicotinic acetylcholine receptor antagonist from an a-conotoxin synthetic combinatorial library. J Med Chem 2014;57(8):3511–21. Samaritoni JG, Copes AT, Crews DK, Glos C, Thompson AL, Wilson C, et al. Unexpected hydrolytic instability of N-acylated amino acid amides and peptides. J Org Chem 2014;79(7):3140–51. Zohrabi-Kalantari V, Wilde F, Gruenert R, Bednarski PJ, Link A. 4-Aminocyclopentane1,3-diols as platforms for diversity: synthesis of a screening library. MedChemComm 2014;5(2):203–13. Brieke C, Cryle MJ. A Facile Fmoc Solid phase synthesis strategy to access epimerization-prone biosynthetic intermediates of glycopeptide antibiotics. Org Lett 2014;16(9):2454–7.