combinatorial chemistry online volume 16 issue 3 march 2014

Combinatorial Chemistry - An Online Journal 16 (2014) 9–11 Contents lists available at ScienceDirect Combinatorial Chemistry - An Online Journal journal homepage: www.elsevier.com/locate/comche Combinatorial Chemistry Online Volume 16, Issue 3, March 2014 N.K Terrett Ensemble Therapeutics Corp., Cambridge, MA 02139, USA Current literature highlights 1.1 Combinatorial synthesis of oxazol–thiazole bis-heterocyclic compounds Amongst the diverse organic compounds found in nature a particular intriguing family of biologically active natural products, often derived from marine sources, contain bis-thiazoles, bis-oxazoles or bis-oxazol–thiazole systems Many thiazole/oxazole modified microcins have been discovered that present a range of biological activities including cytotoxicity, immunosuppression, antibacterial and antiviral properties Furthermore, the oxazole and thiazole ring motifs occur in a large number of synthetic drug molecules The frequency with which these structural groups occur has stimulated the design of a synthetic route to a library of bisheterocyclic compounds [1] In nature, the biosynthesis of oxazoles and thiazoles occurs by the cyclodehydration of b-hydroxy or thiopeptides followed by an oxidation reaction Using this approach as an impetus, numerous methods have been employed to synthesise these heterocycles The approach employed in this recent publication was to prepare oxazole amino acid building blocks in solution and then use them as components in the parallel solid-phase synthesis of oxazol–thiazole combinatorial libraries Additional reaction details include the use of Fmoc-isothiocyanate as a thioamide equivalent, and the incorporation of diverse haloketones into the thiazoles Boc-protected amino acids were selected for the solution-phase portion of this synthesis, and these were coupled with serine methyl ester to give the intermediate (1) Cyclization for the dipeptide was achieved by treatment with the fluorinating agent DAST, to give an oxazoline ester, followed by addition of BrCCl3 and DBU to effect oxidation to the oxazole ester (2) Hydrolysis of the ester provided the carboxylic acid (3) in an overall yield of 63% for the isoleucine derivative (R = iBu) LC–MS analysis of these products indicated very little racemisation had occurred during the synthesis This and other similar intermediates were then available for the combinatorial synthesis of the oxazol–thiazole bis-heterocycles R R H N BocHN COOMe O OH O N BocHN COOH O Using a solid phase synthetic approach, the oxazole amino acid building blocks were immobilised on p-methylbenzhydrylamine (MBHA) resin in ‘tea-bags’ using DIC and HOBt coupling conditions Boc groups were removed from by treatment with 55% TFA and reaction with Fmoc-isothiocyanate provided the substituted thioureas (5) Removal of the Fmoc protecting group with 20% piperidine, reaction with four different haloketones and thermal cyclisation gave the thiazoles (6) The final products were cleaved from the solid support and were isolated (7) in good yields and purities O H N NHBoc N O R O H N H N N O NHFmoc H N N O S R O H N S R N R' H2NOC H N N http://dx.doi.org/10.1016/j.comche.2014.02.001 COOMe R O E-mail: nterrett@ensemblediscovery.com N BocHN R S N R' 10 N.K Terrett / Combinatorial Chemistry - An Online Journal 16 (2014) 9–11 Overall, this is a concise approach to interesting and biologically precedented oxazol–thiazole bis-heterocyclic compounds The route is versatile and is currently being scaled up to generate a large library of similar compounds A summary of the papers in this month’s issue 2.1 Polymer supported synthesis No papers this month is promising for application to pharmaceutical study and production [6] The conversion of a commercially available polystyrene-supported phosphine oxide into synthetically useful polymeric halophosphonium salts using oxalyl chloride/bromide takes place at room temperature in five minutes and generates only CO and CO2 as by-products The polymeric halophosphonium salts so obtained have been shown to be useful reagents for Appel halogenations and other dehydrative coupling reactions This permits a simple three-step synthesis cycle for Appel and related reactions with very simple purification and no phosphorus waste.[7] 2.2 Solution-phase synthesis 2.5 Novel resins, linkers and techniques Indole-based novel small molecules have been designed as potential anticancer agents Multi step synthesis of these compounds was carried out by using Pd/C–Cu mediated coupling–cyclisation strategy as a key step Many of the compounds were evaluated for their anti-proliferative properties in vitro against six cancer cell lines as well as noncancerous cells The study suggests that the indole framework presented could be an attractive template for novel and potential anticancer agents and the synthetic strategy could be useful for generating a diversity based library of small molecules related to this scaffold [2] A two-step, one pot tandem microwave-assisted reaction of 3formylchromones with aminopyrazoles followed by a tin-free radical addition has been recently reported Using this new process, a library of forty-five substituted pyrazolo- and dihydropyrazolopyrimidines has been prepared Biological applications for these new dihydropyrazolopyrimidines have been investigated, and results suggest that this new class of compound presents cytotoxic properties [3] A silver(I)-catalysed reaction of 2-alkynylaryl aldimine with trimethyl(trifluoromethyl)silane has been reported The reaction proceeds efficiently under extremely mild conditions to generate 1(trifluoromethyl)-1,2-dihydroisoquinolines in good yields In a similar fashion, the three-component reaction of 2-alkynylbenzaldehyde and diverse amines with trimethyl(trifluoromethyl)silane has been reported As part of a program aiming to incorporate fluorine into natural product-like compounds containing privileged scaffolds, the synthesis of fluorinated isoquinolines such as these, permits the ready introduction of library diversity [4] 2.3 Scaffolds and synthons for combinatorial libraries No papers this month 2.4 Solid-phase supported reagents A clay-supported heteropolyacid catalyst has been prepared and investigated as a novel heterogeneous, reusable and efficient catalyst for the one-pot synthesis of b-phosphonomalononitriles under ultrasound irradiation at room temperature Compared with traditional methods, the present method is solvent-free, works under milder and cleaner conditions, furnishes products with higher purity and yields, needs shorter reaction time, easier work-up procedures, and generates less waste This procedure allows a series of b-phosphonomalononitriles to be synthesized from inexpensive and commercially available starting materials, and thus is a suitable candidate for combinatorial and parallel synthesis in drug discovery [5] A novel solid catalyst based on silica sulphuric acid (SSA) has been prepared When SSA was treated with Lewis acids, metal ions were easily immobilised on silica surface, which resulted in strengthened Lewis acidity The novel solid catalyst was demonstrated to be efficient in promoting the cyclocondensation of o-aminobenzonitriles with cycloketones in water, and thus A small family of P,P⁄-bidentate C1-symmetric ligands containing 1,3,2-diazaphospholidine rings with stereogenic phosphorus atoms has been prepared Palladium catalytic systems with these phosphine-diamidophosphites afforded good values of enantiomeric excess in asymmetric allylic substitution and desymmetrisation processes The influence of the nature of both the phosphine and diamidophosphite moieties of these compounds on the enantioselectivity is discussed and a ‘mixed-ligand approach’ in Pd-catalysed asymmetric allylation is proposed in the paper [8] Prior studies have shown an effective way to produce diverse ligand sets for catalyst discovery is by using mixtures of monodentate forms to generate catalysts A new paper illustrates that alkene-functionalised monodentate ligands could be used in this way and also could be cross metathesised in situ immediately before the catalysis step; a combination referred to as metacatalysis A library of quinidine and quinine alkaloid-derived phosphites were tested as mixtures of monomers and dimers formed via metathesis Metacatalysis is an option for expanding combinatorial methodology, and has the advantage of generating diverse, potentially chelating ligands [9] Merrifield resin has been modified by the introduction of an ortho-nitrophenylethanal group that served as a linker moiety to attach amines to resin by reductive amination Resin-bound tertiary amines were shown to be readily transferred into the respective liberated N-hydroxylated or N-methylated derivatives by either an oxidation/Cope elimination or a permethylation/Hofmann elimination protocol With these two divergent liberation/ derivatisation options, the resin offers new flexibility in the solid phase synthesis of N-modified secondary amines [10] 2.6 Library applications GluN2B subtype-selective NMDA antagonists represent promising therapeutic targets for the symptomatic treatment of multiple CNS pathologies A series of N-benzyl substituted benzamidines have been synthesised and the benzyl ring was further replaced with various polycyclic moieties A library of N-benzyl benzamidines was prepared from 4-(trifluoromethoxy)benzonitrile and variously substituted benzyl amines and these compounds were evaluated for activity at GluN2B containing NMDA receptors [11] A three-step synthetic pathway has been employed to synthesise a small library of 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethanone and 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethane-1, 2-dione derivatives that have been screened in a [3H] ifenprodil competition binding assay Some compounds exhibited significant binding affinity at nanomolar concentration One compound reduced NMDA-mediated excitatory post-synaptic currents recorded in mouse hippocampal slices indicating antagonistic effects In addition, the compound showed antioxidant effects in a preliminary screen, suggesting that it might be considered a prototype for future drug development of novel ‘dual target’ neuroprotective agents [12] N.K Terrett / Combinatorial Chemistry - An Online Journal 16 (2014) 9–11 References [1] Murru S, Nefzi A Combinatorial synthesis of oxazol–thiazole bis-heterocyclic compounds ACS Comb Sci 2014;16(1):39–45 [2] Dulla B, Sailaja E, Reddy U, Aeluri M, Kalle AM, Bhavani S, et al Synthesis of indole based novel small molecules and their in vitro anti-proliferative eects on various cancer cell lines Tetrahedron Lett 2014;55(4):921–6 [3] Zimmerman JR, Myers BJ, Bouhall S, McCarthy A, Johntony O, Manpadi M A twostep, single pot procedure for the synthesis of substituted dihydropyrazolopyrimidines Tetrahedron Lett 2014;55(4):936–40 [4] Wang X, Qiu G, Zhang L, Wu J Generation of 1-(trifluoromethyl)-1,2-dihydroisoquinolines via a silver(I)-catalyzed reaction of 2-alkynylaryl aldimine with trimethyl(trifluoromethyl)silane Tetrahedron Lett 2014;55(4):962–4 [5] Dar BA, Pandey N, Singh S, Bamezai RK, Sharma M, Vishwakarma RA, et al Heterogeneous reusable catalyst, ultrasound energy, and no solvent: a quick and green recipe for one-pot synthesis of b-phosphonomalononitriles at room temperature Tetrahedron Lett 2014;55(3):623–8 [6] Zhang LJ, Yu JL, Wang WL, Li H, Xu DD, Bi YD, et al Metal modified SSA as a heterogeneous catalyst to promote the cyclocondesation of o-aminobenzonitriles with cycloketones in water Tetrahedron Lett 2014;55(3):710–2 [7] Tang X, An J, Denton RM A procedure for Appel halogenations and dehydrations using a polystyrene supported phosphine oxide Tetrahedron Lett 2014;55(4):799–802 [8] Gavrilov KN, Shiryaev AA, Zheglov SV, Gavrilov VK, Groshkin NN, Maksimova MG, et al Nonsimple relationships between the P⁄-chiral diamidophosphite and the arylphosphine moieties in Pd-catalyzed asymmetric reactions:combinatorial approach and P, P⁄-bidentate phosphine-diamidophosphites Tetrahedron 2014;70(3):616–24 [9] Khumsubdee S, Burgess K Metathesis for catalyst design: metacatalysis Tetrahedron 2014;70(6):1326–35 [10] Pauli D, Bienz S Development of a new linker for the solid-phase synthesis of Nhydroxylated and N-methylated secondary amines Tetrahedron 2014;70(6):1348–56 [11] Beinat C, Banister SD, Hoban J, Tsanaktsidis J, Metaxas A, Windhorst AD, et al Structure–activity relationships of N-substituted 4-(trifluoromethoxy)benzamidines with affinity for GluN2B-containing NMDA receptors Bioorg Med Chem Lett 2014;24(3):828–30 [12] Gitto R, De Luca L, Ferro S, Russo E, De Sarro G, Chisari M, et al Synthesis, modelling and biological characterization of 3-substituted-1H-indoles as ligands of GluN2B-containing N-methyl-d-aspartate receptors Bioorg Med Chem 2014;22(3):1040–8 Further reading Papers on combinatorial chemistry or solid-phase synthesis from other journals Michaels HA, Velosa DC, Nefzi A Synthesis of trifunctional thiazolyl amino acids and their use for the solid-phase synthesis of small molecule compounds and cyclic peptidomimetics ACS Comb Sci 2014;16(1):1–4 Yu S-J, Zhu C, Bian Q, Cui C, Du X-J, Li Z-M, Zhao W-G Novel ultrasound-promoted parallel synthesis of trifluoroatrolactamide library via a one-pot Passerini/ hydrolysis reaction sequence and their fungicidal activities ACS Comb Sci 2014;16(1):17–23 11 Kim J, Lee WS, Koo J, Lee J, Park SB Synthesis and library construction of privileged tetra-substituted D5-2-oxopiperazine as b-turn structure mimetics ACS Comb Sci 2014;16(1):24–32 Messina I, Popa I, Maier V, Soural M Solid-phase synthesis of 5-noranagrelide derivatives ACS Comb Sci 2014;16(1):33–8 Brust A, Wang C-IA, Daly NL, Kennerly J, Sadeghi M, Christie MJ, et al Vicinal disulfide constrained cyclic peptidomimetics: A turn mimetic scaold targeting the norepinephrine transporter Angewandte Chemie, Int Ed 2013;52(46):12020–3 Kuchelmeister HY, Karczewski S, Gutschmidt A, Knauer S, Schmuck C Utilizing combinatorial chemistry and rational design: peptidic tweezers with nanomolar affinity to DNA can be transformed into efficient vectors for gene delivery by addition of a lipophilic tail Angewandte Chemie (International ed in English) 2013;52(52):14016–20 Reutlinger M, Rodrigues T, Schneider P, Schneider G Combining on-chip synthesis of a focused combinatorial library with computational target prediction reveals imidazopyridine GPCR ligands Angewandte Chemie International Edition 2014;53(2):582–5 Francis CL, Kenny PW, Dolezal O, Saubern S, Kruger M, Savage GP, et al Construction of the CSIRO fragment library Australian J Chem 2013;66(12):1473–82 Pathak S, Debnath K, Pramanik A Silica sulfuric acid: a reusable solid catalyst for one pot synthesis of densely substituted pyrrole-fused isocoumarins under solventfree conditions Beilstein J Org Chem 2013:92344–53 Wojcik F, Lel S, O’Brien AG, Seeberger PH, Hartmann L Synthesis of homo- and heteromultivalent carbohydrate-functionalized oligo(amidoamines) using novel glyco-building blocks Beilstein J Org Chem 2013:92395–403 Bode SA, Wallbrecher R, Brock R, van Hes JCM, Loewik DWPM Activation of cellpenetrating peptides by disulfide bridge formation of truncated precursors Chem Commun (Cambridge, United Kingdom) 2014;50(4):415–7 Wu J, An G, Lin S, Xie J, Zhou W, Sun H, et al Solution-phase-peptide synthesis via the group-assisted purification (GAP) chemistry without using chromatography and recrystallization Chem Commun (Cambridge, United Kingdom) 2014;50(10):1259–61 Sun S, Bai R, Gu Y Waste biomass to solid support: lignosulfonate as a cost-eective and renewable supporting material for catalysis Chem – A Eur J 2014;20(2):549–58 Iwai T, Tanaka R, Harada T, Sawamura M Tripod immobilization of triphenylphosphane on a silica-gel surface to enable selective mono-ligation to palladium: application to Suzuki-Miyaura cross-coupling reactions with chloroarenes Chem – A Eur J 2014;20(4):1057–65 Schuetznerova E, Oliver AG, Zajicek J, Krchnak V Polymer-supported stereoselective synthesis of (1S,5S)-6-oxa-3,8-diazabicyclo[3.2.1]octanes Eur J Org Chem 2013;15:3158–65 Costi R, Metifiot M, Esposito F, Cuzzucoli CG, Pescatori, Messore A, et al 6-(1-Benzyl1H-pyrrol-2-yl)-2,4-dioxo-5-hexenoic acids as dual inhibitors of recombinant HIV-1 integrase and ribonuclease H, synthesized by a parallel synthesis approach J Med Chem 2013;56(21):8588–98 Hibino H, Miki Y, Nishiuchi Y Evaluation of acid-labile S-protecting groups to prevent Cys racemization in Fmoc solid-phase peptide synthesis J Peptide Sci 2013;20(1):30–5 Zou Y, Spokoyny AM, Zhang C, Simon MD, Yu H, Lin Y-S, et al Convergent diversityoriented side-chain macrocyclization scan for unprotected polypeptides Org Biomol Chem 2014;12(4):566–73 Cergol KM, Thompson RE, Malins LR, Turner P, Payne RJ One-pot peptide ligationdesulfurization at glutamate Org Lett 2014;16(1):290–3 Zhang J, Proulx C, Tomberg A, Lubell WD Multicomponent diversity-oriented synthesis of aza-lysine-peptide mimics Org Lett 2014;16(1):298–301  ... Terrett / Combinatorial Chemistry - An Online Journal 16 (2014) 9–11 References [1] Murru S, Nefzi A Combinatorial synthesis of oxazol–thiazole bis-heterocyclic compounds ACS Comb Sci 2014 ;16( 1) :39 –45...10 N.K Terrett / Combinatorial Chemistry - An Online Journal 16 (2014) 9–11 Overall, this is a concise approach to interesting and biologically... reactions :combinatorial approach and P, P⁄-bidentate phosphine-diamidophosphites Tetrahedron 2014; 70 (3) : 616? ??24 [9] Khumsubdee S, Burgess K Metathesis for catalyst design: metacatalysis Tetrahedron 2014; 70(6): 132 6? ?35