Novel rigid 8-biaryl-2'-deoxyadenosines with tuneable fluorescent properties can be accessed by an efficient sequential catalytic Pd-0-coupling approach

Baumann, C.G.

Fairlamb, I.J.S.

Storr, T.E.

Strohmeier, J.A.

English

Thomas E. Storr

Johanna A. Strohmeier

Christoph G. Baumann

Ian J. S. Fairlamb

Crossref

Chemical Communications

A sequential direct arylation/Suzuki–Miyaura cross-coupling transformation of unprotected 2′-deoxyadenosine affords a novel class of fluorescent analogues

White Rose Research Online

This is a repository copy of A sequential direct arylation/Suzuki-Miyaura cross-coupling transformation of unprotected 2 '-deoxyadenosine affords a novel class of fluorescent analogues.White Rose Research Online URL for this paper:https://eprints.whiterose.ac.uk/19794/Article:Storr, T.E., Strohmeier, J.A., Baumann, C.G. orcid.org/0000-0002-8818-972X et al. (1 moreauthor) (2010) A sequential direct arylation/Suzuki-Miyaura cross-coupling transformation of unprotected 2 '-deoxyadenosine affords a novel class of fluorescent analogues. Chemical Communications. pp. 6470-6472. ISSN 1364-548X https://doi.org/10.1039/c0cc02043eeprints@whiterose.ac.ukhttps://eprints.whiterose.ac.uk/Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. 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S (2010) A sequential direct arylation/Suzuki-Miyaura cross-coupling transformation of unprotected 2 '-deoxyadenosine affords a novel class of fluorescent analogues Chemical Communications  46  (35) 6470- 6472 http://dx.doi.org/10.1039/c0cc02043e  A sequentialQ1 direct arylation/Suzuki–Miyaura cross-couplingtransformation of unprotected 20-deoxyadenosine affords a novelclass of fluorescent analogueswThomas E. Storr,ab Johanna A. Strohmeier,b Christoph G. Baumann*b andIan J. S. Fairlamb*aReceived 23rd June 2010, Accepted 22nd July 2010DOI: 10.1039/c0cc02043eNovel rigid 8-biaryl-20-deoxyadenosines with tuneable fluorescentproperties can be accessed by an efficient sequential catalyticPd0-coupling approach.Fluorescent nucleosides are used widely as probes of enzy-matic turnover and biomolecular structure, and as labels inhigh-throughput biotechnologies.1 Common organic, e.g. pyrenylor fluorescein, and inorganic metal-containing extrinsic fluoro-phores can be attached to either sugar2 or nucleobase.3 Directcoupling of a conjugated aromatic group yields a more com-pact fluorescent analogue. Examples include aryl,4 heteroaryl5or arylalkynyl6 nucleosides, but also modified nucleobasemimetics exhibiting unique fluorescent properties (Fig. 1).7This communication describes the synthesis of novel 8-biaryl-20-deoxyadenosines (e.g. II, Scheme 1) which function as RigidOrgano-fluorescent Nucleosides (RONs). These p-conjugatedsystems are accessible using our recently developed directarylation methodology for unprotected adenine nucleosides,which facilitates the chemoselective installation of an arylgroup at the 8-position.8 The use of a dihaloaromatic couplingpartner would provide a secondary handle for further chemicalmanipulation, allowing addition of aryl groups via a classicalcross-coupling (hereafter ‘coupling’) approach. Suzuki–Miyaura coupling has been used effectively with unprotectednucleosides9 and nucleotides,10 therefore it should be applicableto these substrates. This sequential coupling approach wouldprovide a divergent synthetic route to differently substituted8-biaryl-20-deoxyadenosines (via I).For the synthesis of target I, the use of diiodobenzene wasdismissed as our prior findings indicated that double C–Harylation occurs.8a However, we rationalised that an aromaticcoupling partner possessing two sites with different chemicalreactivity towards Pd0 might provide an elegant solution.Therefore, as a first step towards the selective synthesis ofthe intermediate compounds, we evaluated iodobromo-benzenes and iodochlorobenzenes as direct arylation substrates(Scheme 2). Using our established direct arylation conditions,8bboth 4-bromo and 4-chloro-iodobenzene reacted with 20-deoxy-adenosine to give compounds 1 and 2 in 54% and 97% yields,respectively.15101520253035404550551510152025303540455055Fig. 1 Fluorescent nucleosides.Scheme 1 Proposed targets and sequential direct arylation/Suzuki–Miyaura approach (R = 20-deoxyribose).Scheme 2 Direct arylation of 20-deoxyadenosine. Reagents andconditions: (i) ArI (2.0 eq.), Pd(OAc)2 (5.0 mol%), CuI (3.0 eq.),piperidine (0.4 eq.), Cs2CO3 (2.5 eq.), DMF, 80 1C, 15 h (R =20-deoxyribose; Z = H or F).aDepartment of Chemistry, University of York, York YO10 5DD, UK.E-mail: ijsf1@york.ac.ukbDepartment of Biology, University of York, York YO10 5YW, UK.E-mail: cb17@york.ac.ukw Electronic supplementary information (ESI) available: Experimentaldetails (including characterisation data for all compounds) and X-raydata for 5d and 5i, including cif files. CCDC [CCDC NUMBER(S)].For ESI and crystallographic data in CIF or other electronic formatsee DOI: 10.1039/c0cc02043eThis journal is !c The Royal Society of Chemistry 2010 Chem. Commun., 2010, 46, 1–3 | 1COMMUNICATION www.rsc.org/chemcomm | ChemComm3-Fluoro-4-bromoiodobenzene was a robust substrategiving 3 in 53% yield, whilst 3-chloro-iodobenzene provided4 in 87% yield.With the 8-haloaryl-20-deoxyadenosines (1–4) in hand wefocussed on the Suzuki–Miyaura coupling methodology. Weemployed a Pd : TPPTS (tris-(3-sulfophenyl)phosphine tri-sodium salt = TPPTS) water soluble catalyst system. A slightlymodified version of Shaughnessy’s protocol was employed, speci-fically Pd(OAc)2 (1.25 mol%), TPPTS (2.5 mol%), Na2CO3(2.0 eq.), MeCN : H2O (2 : 1), 80 1C, 1.5 h (hereafterConditions A).9a,b Interestingly, the employment of a catalystpreformation/preactivation step {Pd(OAc)2, ligand, solventand heating} led to a poor catalyst system resulting inincomplete reaction (Table 1; numbers in parentheses). Thishas implications for product isolation as it has a similarpolarity to the starting material. The addition of the pre-catalyst and ligand with the solid reagents to a dry vessel(under an argon atmosphere) prior to addition of the solventmixture worked most effectively (Table 1, all other yields).The coupling of arylboronic acids with bromo analogue 1using Conditions A proceeded well. Both electron-rich andelectron-deficient arylboronic acids were efficient couplingpartners (entries 1, 3, 5–7 and 9, Table 1). It is not surprisingthat chloro analogue 2 failed to serve as a substrate usingConditions A. Indeed, the difference in reactivity of C–Cland C–Br bonds is apparent in the high yield observed for 5e(81%, entry 5). We identified Buchwald’s bulky electron-rich phosphine Xphos (2-dicyclohexylphosphino-20,40,60-triisopropylbiphenyl = Xphos) as an enhancing ligand.Reactions were conducted using standard ‘in-house’ condi-tions, namely Pd(OAc)2 (5 mol%), XPhos (10 mol%), aq.Na2CO3 (2 M), 80 1C, 3.5 h (hereafter Conditions B). Ninesubstituted biphen-4-yl-2 0-deoxyadenosines were generated ingood yields (entries 1–4, 6–10, Table 1) and three heteroaro-matics were also coupled successfully (entries 11–13, Table 1).Using PhBF3K as a substitute for PhB(OH)2, a slightly loweryield of 5c (entry 3, Table 1) was obtained with Conditions B.The structures of compounds 5d and 5i were determined bysingle crystal X-ray diffraction; 5d is shown as a representativeexample in Fig. 2.The crystal structure of 5d shows that this nucleoside adoptsa syn-C20-endo conformation and exhibits an intramolecularH-bond, consistent with related 8-aryl-20-deoxyadenosines.8bThe Suzuki–Miyaura couplings using 3 (Conditions A)provided the 8-(2-fluoro-biphen-4-yl)-20-deoxyadenosines 6aand 6b in good yields (Table 2, entries 1 and 2). 8-(Biphen-3-yl)-20-deoxyadenosines 7a–c were accessible from 4 and ArB(OH)2using Conditions B (Table 2, entries 3–5). Finally, the chloro-substituted analogue 5e was subjected to Conditions B to giveterphenyl analogue 8 in 76% yield (Scheme 3).15101520253035404550551510152025303540455055Table 1 Suzuki–Miyaura couplings of 1 and 2 with arylboronic acids(R = 20-deoxyribose)Entry Ar CpdYield/%ConditionsA (from 1)ConditionsB (from 2)1 4-MeOC6H4 5a 71 (38)a 882 4-MeC6H4 5b — 723 C6H5 5c 89 (74)a 91 [81]b4 4-FC6H4 5d — 925 4-ClC6H4 5e 81c,d —6 3,5-F2C6H3 5f 82 94e7 4-CF3C6H4 5g 77 888 3-CF3C6H4 5h — 799 4-AcC6H4 5i 89c 7610 4-CHOC6H4 5j — 8411 2-Furyl 5k — 7112 2-Thienyl 5l — 52f13 3-Thienyl 5m — 63a Using a preformed catalyst (see main text for details). b UsingPhBF3K as a substitute for PhB(OH)2.c 3 h reaction time. d Residualboronic acid starting material remaining. e 2 h reaction time. f 18 hreaction time.Fig. 2 Crystal structure of compound 5d (using arbitrarynumbering).Table 2 Suzuki–Miyaura couplings of 3 and 4 with arylboronic acidsEntry Substrate Conditions R0 Cpd Yield/%1 3 A 40-MeO 6a 652 3 A H 6b 933 4 B 40-MeO 7a 884 4 B H 7b 875 4 B 30,50-F 7c 872 | Chem. Commun., 2010, 46, 1–3 This journal is !c The Royal Society of Chemistry 2010The photophysical properties of all RONs (5a–j, 6a, 6b,7a–c, 8 and 9) were determined (lmax, e, lem and F are listed inTable 3). A sequential increase in the UV lmax and decrease influorescence lifetime is observed as the p-system is extended:phenyl (289 nm, 2.6 ns, 9), biphen-4-yl (304 nm, 1.9 ns, 5c) andterphenyl (315 nm, 1.7 ns, 8). The biphen-3-yl derivatives(7a–c) possess unfavourable lmax values which overlap withbiomolecular absorption bands.11 In the 5a–m series the lmaxvalues are either similar to 5c or shifted to longer wavelengths.The 8-aryl-20-deoxyadenosines (5a–h, 5k–m, 6a, b, 8 and 9)have excellent fluorescence quantum yields (0.59–0.81).In summary, a library of novel RONs has been synthesisedusing an efficient sequential direct arylation/Suzuki–Miyauracoupling approach. The spectroscopic properties of RONs canbe tuned by changing the terminal aryl group, in most caseswithout adversely affecting the quantum yield. Once incorpo-rated into oligonucleotides using solid-phase synthesis, the RONscould be exploited as thymine specific base-discriminatingfluorescent probes.10aEPSRC, BBSRC and Royal Society are acknowledged forfunding this work. Dr A. C. Whitwood and R. J. Thatcher(York) are thanked for single crystal X-ray structural analysis.Dr A. Beeby and G. A. Rosser (Durham) are thanked forassistance with fluorescence lifetime measurements.Notes and references1 (a) M. J. Rist and J. P. Marino, Curr. Org. Chem., 2002, 9, 775;(b) D. M. Jameson and J. F. Eccleston, Methods Enzymol., 1997,278, 363; P. Herdewijn, Modified Nucleosides: in Biochemistry,Biotechnology and Medicine Q2, 2008, ISBN: 978-3-527-31820-9;(c) Y. Tor, Tetrahedron, 2007, 63, 3415.2 (a) W. Zhang, Y. Wang, Y. Xu and X. Qian, Monatsh. Chem.,2003, 134, 393; (b) K. Yamana, R. Iwase, S. 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Chem., 2008, 6, 2233.11 Absorption bands at 260 and 280 nm for nucleic acids andproteins, respectively.15101520253035404550551510152025303540455055Scheme 3 Synthesis of terphenyl derivative 8.Table 3 Photophysical properties of 8-substituted-20-deoxyadenosinesin DMSO at 25 1CCpd lmax/nme "104/M#1 cm#1 lem/nmStokesshift/cm#1 F5a 309 3.13 400 7362 0.655b 305 2.26 409 8337 0.685c 304 2.07 414 8740 0.695d 304 2.30 412 8623 0.695f 307 1.71 434 9532 0.725g 307 1.75 440 9846 0.755h 304 1.76 427 9475 0.775i 314 2.02 491 11 481 0.275j 318 2.53 399 6384 0.105k 320 2.71 407 6680 0.705l 322 2.25 419 7190 0.595m 307 2.14 403 7759 0.646a 310 2.21 408 7748 0.606b 304 1.89 420 9085 0.697aa 275 3.30 393 10 918 —7ba 261 1.93 380 11 278 —7ca 260 1.98 383 12 352 —8 315 3.14 424 8161 0.779b 289 1.29 384 8560 0.81a Measurements determined using methanol solutions. b Compound 9is 8-phenyl-20-deoxyadenosine.8bThis journal is !c The Royal Society of Chemistry 2010 Chem. Commun., 2010, 46, 1–3 | 3

A sequential direct arylation/Suzuki-Miyaura cross-coupling transformation of unprotected 2 '-deoxyadenosine affords a novel class of fluorescent analogues

Novel rigid 8-biaryl-2′-deoxyadenosines with tuneable fluorescent properties can be accessed by an efficient sequential catalytic Pd0-coupling approach

A sequential direct arylation/Suzuki-Miyaura cross-coupling transformation of unprotected 2 '-deoxyadenosine affords a novel class of fluorescent analogues

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