combinatorial chemistry online volume 16 issue 3 march 2014

Combinatorial synthesis of oxazol–thiazole bis-heterocyclic compounds Amongst the diverse organic compounds found in nature a particular intriguing family of biologically active natural

Combinatorial Chemistry Online Volume 16, Issue 3, March 2014

N.K Terrett

Ensemble Therapeutics Corp., Cambridge, MA 02139, USA

1 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-oxaz-oles or bis-oxazol–thiazole systems Many thiazole/oxazole

modi-fied 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

bis-heterocyclic 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

het-erocycles 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

synthe-sis 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

dipep-tide 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

BocHN

H COOMe O

R

OH

R

O

R

O

3

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 4 by treatment with 55% TFA and reaction with Fmoc-isothiocyanate provided the substituted thio-ureas (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

NHBoc N

R

O H

H N

R

O H

S NHFmoc

H N

R

O H

S

R'

H N

H2NOC

R

O

S

R'

http://dx.doi.org/10.1016/j.comche.2014.02.001

E-mail: nterrett@ensemblediscovery.com

Contents lists available atScienceDirect

Combinatorial Chemistry - An Online Journal

j o u r n a l h o m e p a g e : w w w e l s e v i e r c o m / l o c a t e / c o m c h e

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

2 A summary of the papers in this month’s issue

2.1 Polymer supported synthesis

No papers this month

2.2 Solution-phase synthesis

Indole-based novel small molecules have been designed as

po-tential 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

in-dole framework presented could be an attractive template for

no-vel 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

3-formylchromones with aminopyrazoles followed by a tin-free

rad-ical addition has been recently reported Using this new process, a

library of forty-five substituted pyrazolo- and

dihydropyrazolopyr-imidines has been prepared Biological applications for these new

dihydropyrazolopyrimidines have been investigated, and results

suggest that this new class of compound presents cytotoxic

prop-erties[3]

A silver(I)-catalysed reaction of 2-alkynylaryl aldimine with

tri-methyl(trifluoromethyl)silane has been reported The reaction

pro-ceeds 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-alkynylbenzal-dehyde and diverse amines with trimethyl(trifluoromethyl)silane

has been reported As part of a program aiming to incorporate

fluo-rine 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

un-der milun-der and cleaner conditions, furnishes products with higher

purity and yields, needs shorter reaction time, easier work-up

pro-cedures, 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

suit-able candidate for combinatorial and parallel synthesis in drug

dis-covery[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

is promising for application to pharmaceutical study and production[6]

The conversion of a commercially available polystyrene-sup-ported phosphine oxide into synthetically useful polymeric halo-phosphonium salts using oxalyl chloride/bromide takes place at room temperature in five minutes and generates only CO and

CO2as by-products The polymeric halophosphonium salts so ob-tained have been shown to be useful reagents for Appel halogen-ations 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]

2.5 Novel resins, linkers and techniques

A small family of P,P⁄-bidentate C1-symmetric ligands contain-ing 1,3,2-diazaphospholidine rcontain-ings with stereogenic phosphorus atoms has been prepared Palladium catalytic systems with these phosphine-diamidophosphites afforded good values of enantio-meric excess in asymmetric allylic substitution and desymmetrisa-tion processes The influence of the nature of both the phosphine and diamidophosphite moieties of these compounds on the enanti-oselectivity is discussed and a ‘mixed-ligand approach’ in Pd-cata-lysed asymmetric allylation is proposed in the paper[8]

Prior studies have shown an effective way to produce diverse li-gand sets for catalyst discovery is by using mixtures of monoden-tate 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 metacataly-sis 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, poten-tially 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 ter-tiary amines were shown to be readily transferred into the respec-tive liberated N-hydroxylated or N-methylated derivarespec-tives by either an oxidation/Cope elimination or a permethylation/Hof-mann 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 promis-ing 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 benzami-dines 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)etha-none 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 re-duced NMDA-mediated excitatory post-synaptic currents recorded

in mouse hippocampal slices indicating antagonistic effects In addi-tion, 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]

[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

two-step, single pot procedure for the synthesis of substituted

dihydropyrazolo-pyrimidines Tetrahedron Lett 2014;55(4):936–40

[4] Wang X, Qiu G, Zhang L, Wu J Generation of

1-(trifluoromethyl)-1,2-dihydro-isoquinolines 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-aminobenzonitr-iles 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

N-hydroxylated 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)benzami-dines 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

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 norepi-nephrine 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 solvent-free 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 cell-penetrating 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 triphenylphos-phane 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-Benzyl-1H-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 diversity-oriented 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 ligation-desulfurization 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