Supramolecular organogelators based on Janus type AT nucleosides

Tetrahedron 69 (2013) 9245e9251

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Supramolecular organogelators based on Janus type AT nucleosides Shiliang He a, y, Hang Zhao a, b, y, Xiurong Guo a, y, Guang Xin a, Baozhan Huang a, Limei Ma a, Xinglong Zhou a, Rui Zhang a, Dan Du a, Xiaohua Wu a, Zhihua Xing a, Wen Huang a, *, Qianming Chen b, *, Yang He a, * a

Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China b State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renminnan Road, Chengdu, Sichuan 610041, China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 17 May 2013 Received in revised form 3 August 2013 Accepted 20 August 2013 Available online 27 August 2013

J-AT nucleoside-based organogelators 1a and 1b were designed and synthesized. They were endowed with unparalleled superiority to natural nucleobase analogues 2e6 to gelate aromatic solvents due to their excellent self-assembly properties. The J-AT nucleoside-based organogelators showed a specific self-complementary base pair recognition characteristic. The gel stabilities of 1a and 1b were drastically influenced by adenine analogue 2, hardly affected by thymine analogue 3, uracil analogue 4, cytosine analogue 5, and mildly interrupted by guanine analogue 6. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Modified nucleosides Supramolecular gelators Pyrimido[4,5-d]pyrimidine Base pair recognition

1. Introduction Supramolecular gelators based on reversible non-covalent interactions have recently attracted considerable interest for the development of stimuli-responsive materials, the nano-scale inorganic materials employing organgels as templates, new drug delivery systems, and many other potential applications.1 Various kinds of molecules, such as steroidal derivatives,2 fatty acid derivatives,3 condensed aromatic steroids,4 anthryl derivatives,5 carbohydrate derivatives,6 and amino acid-type compounds7 have been utilized as scaffolds to design supramolecular gels. Nucleosides, an important molecular class, which hardly offer the possibility to gelate any solution by themselves, are able to become gelators as well when the base moiety and/or the sugar residues are modified. The modifications provide suitable components and balance the hydrophilicehydrophobic forces, which are necessary for gel formation. Of the five natural nucleobases, generally speaking, guanine-based gelators8 have received the most investigations due to their unique self-assembly proprieties. Besides, there are a number of efforts have been made to

* Corresponding authors. Tel./fax: þ86 288 516 4075; e-mail addresses: [email protected] (S. He), [email protected] (W. Huang), [email protected] (Q. Chen), [email protected] (Y. He). y Authors contributed equally to this work. 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.08.058

develop modified thymidine-based organogelators9 and hydrogelators,10 deoxyadenosine-based hydrogelators11 and uridinebased hydrogelators.12 Over the years, the native heterocycles found in DNA and RNA are reported to serve as structural elements to the self-assembly of higher aggregates including G-quadruplexes,13 T/U-quintets14 and T/U-quartets.15 In addition to these canonical purine and pyrimidine derivatives with highly specific Watson-Crick base pairs in the classic double-helix, other heterocyclic systems with diverse base pair patterns are capable of self-assembling into various higher architectures,16 such as cyclic trimeric guanosine-cytidine dinucleosides,16c G^C quartet,16d pentamers of isoguanine16e and the hexameric Lehn-Mascal guanosine-cytosine (GC) base.16f However, few of them have been fabricated into organogelators. Recently our group17 shown that excellent self-assembly properties were exhibited by Janus type pyrimido[4,5-d]pyrimidine nucleosides, particularly, the bidentate Janus-type AT (J-AT) nucleosides can form an unique flower-like superstructure in aqueous solution.17c Besides, single crystal structure of 2,3,5-tri-O-benzoyl-b-D-ribofuranosyl J-AT nucleoside17d showed that J-AT adopted the reverse Watson-Crick base pairs, leading to the formation of an infinite linear tape structure (Scheme 1), which indicates that J-AT might have a potential to act as a gelator. However, J-AT nucleosides were sparsely dissolved in organic solvents. In order to investigate if they can also form special supramolecular architectures in organic media, we have designed and synthesized 1a and 1b (Scheme 2) by

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choosing 50 -O-t-butyldimethylsilyl and 20 ,30 -O-isopropylidene as the modifying group for its sugar residue. Interestingly, we found 1a and 1b were endowed with unparalleled gelation proprieties compared with normal nucleobase analogues 2e6 (Scheme 2) due to their self-complementary base pair properties, which offer a new class of chemical entities in the area of supramolecular organogelators. Moreover the molecular recognition18 of nucleosides/ nucleobases based on their specific hydrogen bond motifs usually occurs in aqueous environment. Only few attempts to combine nucleoside/nucleobase derivatives with their complementary analogues in organic media have been reported.19,9b Therefore, we assessed the influences of natural nucleoside derivatives 2e6 on the gel formation of 1a and 1b, and found the gel stabilities of 1a and 1b were indeed affected in varying degrees due to the base pair recognitions.

in organic solvents resulting from its strong self-assembly capability. To overcome this problem, we chose a sugar component 1-Oacetyl-5-O-tert-butyldimethylsilyl-2, 3-O-isopropylidene-b-D-ribofuranose21 (9) to carry out the direct Vorbrueggen glycosylation reaction22 (Scheme 4). To our best knowledge, this is the first report investigating the feasibility of using compound 9 to synthesis the pyrimido[4,5-d]pyrimidine nucleosides. By treating silylated J-AT base moiety 8 with compound 9 with the presence of Lewis acid catalyst Trimethylsilyl triflate (TMSOTf), a 1:1 mixture of a:b anomers was formed. The anomeric configurations of the resulting compounds 1a and 1b were firstly determined by the difference in 1 H chemical shifts between the two methyl signals of the isopropylidene group, Dd. According to Imbach’s rules:23 when 0
Scheme 1. Linear tape structure of J-AT based on reverse Watson-Crick base pair motifs (R represents sugar moieties).

Scheme 2. The molecular structures of 50 -O-(tert-butyldimethylsilyl)-20 ,30 -O-isopropylidene J-AT nucleosides 1a, 1b and nucleosides with canonical bases (2e6). The arrows of D represent the hydrogen donors; the arrows of A represent the hydrogen acceptors.

Scheme 4. Synthesis of the 50 -O-(tert-butyldimethylsilyl)-20 ,30 -O-isopropylidene J-AT nucleosides 1a and 1b: R¼TMS; (i) HMDS, TMSCl, reflux; (ii) Dry acetonitrile: Dry 1,2dichloroethane¼1:1, TMSOTf, 80  C, 3 h.

2. Results and discussion

2.2. Gelation behaviours of compounds 1e6

2.1. Synthesis and characterization of 1e6

Next, the gelation behaviours of compounds 1e6 were investigated in 20 organic solvents and the results are summarized in Table S1. In general, compound 1a and 1b were solvent selectivity gelators for aromatic solvents, such as 1,2,3,4-tetrahydronaphthalene (THN), benzene and toluene (Table 1), but they could not form robust gels in other organic solvents including dipolar aprotic solvents (DMSO and DMF) and more polar solvents (methanol, ethanol, isopropanol and tert-butanol). In the case of natural nucleobase analogues 2e6, generally, they could not effectively form gels in the investigated solvents, except for guanine derivative 6, which showed relatively broader gel formation abilities in different organic solvents

Generally the ribose-modified nucleoside derivatives 2e6 could be prepared by first protecting 50 -OH with tert-butyldimethylsilyl chloride in DMF or CH2Cl2, followed by introducing 20 ,30 -O-isopropylidene in acid condition, or vice versa (Scheme 3).20

Table 1 Gelation behaviours of compounds 1e6 at room temperaturea

Scheme 3. General routes for the synthesis of ribose-modified nucleoside derivatives 2e6: (a) tert-butyldimethylsilyl chloride, DMF or CH2Cl2; (b) p-TsOH/perchloric acid, 2,2-dimethoxypropane, acetone.

However, both routes turned out to be infeasible for the synthesis of 50 -O-(tert-butyldimethylsilyl)-20 ,30 -O-isopropylidene J-AT nucleosides, because of the poor solubilities of free J-AT nucleoside

a

Solvent

1a

1b

2

3

4

5

6

Benzene Toluene Dimethylbenzene THN CCl4

Gb (0.9)c G (0.5) G (0.5) G (0.4) G (0.6)

G (0.9) G (0.9) G (4.1) G (2.7) PG

S I S S S

S S S S S

S S S S S

S S S S S

I G (2.6) I G (2.4) G (2.6)

The maximum concentration tested for all of the samples are 5.0 wt %. G: gel, PG: partial gel, S: soluble, I: insoluble when heated. c The critical gelation concentrations [wt %] of gelators are shown in the parentheses. b

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in line with guanine’s well documented self-assembly property. But the critical gelation concentration of 6 was much higher when compared with that of 1a and 1b. Since the critical concentration of 1a and 1b was observed to be very low, for example, in toluene the gelation took place at a critical concentration of 0.5 wt % and 0.9 wt % for 1a and 1b, respectively, they can be taken as super-gelator24 and consequently have a superior gelation ability compared with the natural nucleoside derivatives 2e6. It is worth mentioning that 1a was a more robust gelator compared with 1b. Firstly, the critical gelation concentration of 1a in aromatic solvents was generally much lower than that of 1b (Table 1). Second, in toluene, the sol-gel phase transition temperature (Tgel) of 1a at a concentration of 1 wt % was measured to be 80  C, however even at a higher concentration of 2 wt %, the Tgel for compound 1b was measured to be only 46  C. Thirdly, at room temperature, 1a/toluene gel (1%) is stable for longer than half a year, while 1b/toluene gel (2%) is stable for just a week. Furthermore, rheological measurements were conducted to explore the mechanical properties of the gels in detail (Fig. 1). The linear viscoelastic regions (LVR) of gels 1a and 1b were determined by strain amplitudes ranging from 0.01 to 10% at 6.28 rad s1. Both

Fig. 1. Dynamic oscillatory data for 1a/toluene gel (1 wt %) and 1b/toluene gel (2 wt %) at 20  C. (a) Strain sweep of gels at a frequency of 6.28 rad s1. (b) Frequency sweep of gels at a strain of 0.1%.

the storage modulus (G0 ) and loss modulus (G00 ) values remained approximately independent of the applied strain up to 0.5%. The typical elastic natures of both gels were clearly displayed from the fact that G0 >G00 (solid-like behaviour) at low strain values. A gradually crossover to G0
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over the entire applied frequency range. The G0 values showed a substantial elastic response, which was uniformly found to be of greater magnitude than the associated G0 , either in the case of 1a or 1b, thereby indicating the predominantly viscoelastic nature of the gels. The 1a/toluene gel (1 wt %) (G0 z121,000 Pa) showed greater viscoelasticity compared with the 1b/toluene gel (2 wt %) (G0 z67,000 Pa), which confirmed the rigidities of the two gels observed by the Tgel experiments mentioned above. To obtain micro-structures of the organogel formed by 1a and 1b, we prepared xerogels for scanning electron microscope (SEM) observations and found the two gel systems of 1a/toluene and 1b/ toluene formed different microscopic morphologies (Fig. 2). The SEM images of 1a/toluene xerogel reveal a rectangular bars-like microstructure. These bars are approximately 200e800 nm in width and several mm long. Whereas, 1b/toluene xerogel shows quite a different network structure consisting of many entangled flaky aggregates of widths about 1 mm and lengths of nearly 10 mm. 2.3. Influences of natural nucleoside derivatives 2e6 on the gel formation of compounds 1a and 1b As we designed, the base moiety of J-AT ribonucleoside derivatives has one face with a WatsoneCrick acceptor-donor (AD) hydrogen-bond array of adenine and the other with a donoreacceptor (DA) hydrogen-bond array of thymine. That means, apart from the self-complementary base pair, J-AT can be competitively base paired with either adenine or thymine/uracil derivatives. Inspired by this consideration, we examined the influence of addition of the complementary or non-complementary natural nucleoside derivatives 2e6 into 1a/1b organogels. For this purpose, 1a/toluene system (1 wt %) and 1b/toluene system (2 wt %) were chosen as the standard substrates. The gelation abilities of mixtures were tested and the results are summarized in Table 2. Initially, we supposed that both adenine derivative 2 and thymine/uracil derivative 3/4 may interrupt the gel formation of 1a/1b because the elongation of the J-AT linear tape structure (Scheme 1) based on reverse Watson-Crick self-complementary base pairs will be terminated by J-AT-A or J-AT-T/U base pairs (Scheme 5). Indeed, we can see that adenine derivative 2 with a mole ratio up to 0.4 equiv already completely destroyed both of the gel systems of 1a and 1b (Table 2 and Fig. 3). However, contrary to our anticipation, thymine/uracil derivative 3/4 does not affect the gelation stabilities of 1a and 1b. Adding T/U up to 1.0 equiv the gel system remained intact. In addition, we measured the Tgel values of 1a and 1b as a function of additive concentrations (Fig. 4). It is shown that the Tgel values of 1a and 1b were hardly influenced by the addition of 3 and 4 up to the molar ratio of 1.0 (Fig. 4aed). According to these phenomena, adenine derivative 2 can form competitive hydrogen-bonds with J-AT nucleoside to destroy the gel formation of compounds 1a and 1b; on the other hand, no competitive hydrogen-bonds were formed in the case of thymine/uracil derivatives 3/4. This assumption was confirmed by the 1H NMR titration experiment of 1a with 2 (Fig. 5) and 3 (Fig. S5) in CDCl3. In the case of 1aþ2, the proton signals related to the hydrogen-bond formation groups had apparent downfield shifting by increasing the concentration of 2 relative to the fixed concentration of compound 1a (1.3102 mol/L). However, in the case of 1aþ3, no apparent downfield shifts were observed under the same condition (Fig. S5). This selective base pair formation could be explained by the rotation barrier of the glycosyl bond. J-AT (1a/1b) can pair with adenine derivatives (2) only when the glycosyl bond adopts anti conformation and pair with thymine/uracil derivatives (3/4) only when it adopts syn conformation (Scheme 5). According to these experimental results, obviously the glycosyl bond of 1a/1b could

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Fig. 2. SEM images of the xerogels prepared from 1a (a) and 1b (b) in toluene.

Table 2 Gelation tests for mixtures of 1aþadditive and 1bþadditive Molar ratio [additive]/[1]

Additive

0.1

0.2

0.3

0.4

0.5e1.0

1a/toluene system (1 wt %)

2 3e5 6 2 3e6

G G G G G

PG G G G G

PG G G PG G

S G PG S G

S G S S G

1b/toluene system (2 wt %)

Results: G: gel, PG: partial gel, S: solution.

R= 5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene- -D-ribofuranosyl; R’=CH3 (3) or H (4); Scheme 5. The possible process of 1a (syn/anti) base pairing with 2 and 3/4.

not rotate freely due to the additional steric hindrance of the bulky 50 -O-tert-butyldimethylsilyl group. So, the preferred conformation adopted by J-AT must be in anti conformation (the thymine ring of the J-AT base moiety is located outside the sugar plane). Actually, the anti conformation has been previously confirmed by the single crystal structures of 2,3,5-tri-O-benzoyl-b-D-ribofuranosyl J-AT nucleoside and 2-deoxy-3,5-di-O-(p-toluoyl)-a-D-pentofuranosyl JAT nucleoside.17d When cytosine derivative 5 was added to 1a/toluene system (1 wt %) and 1b/toluene system (2 wt %), no change was observed, upon increasing the concentration of the additive, for both the gel stability (Table 2) and Tgel (Fig. 4e and f). Though there were some reports that cytosine has certain chances to pair with adenine or thymine when the adenine was either protonated or in a rare tautomeric form;25 or in the case of C-U base pair, a bridging water molecule is present26 linking the hydrogen bond between the hydrogen-bond donor of U and hydrogen-bond acceptor of C, but both cases are very unlikely under current circumstances. Therefore our experiment was in accordance with that cytosine derivative 5 pairs with neither the adenine face nor the thymine face of compound 1a/1b under such conditions.

Fig. 3. (a) Phase transition of 1a/toluene system (1 wt %) after adding 0.4 equiv of adenine derivative 2; (b) Phase transition of 1b/toluene system (2 wt %) after adding 0.4 equiv of adenine derivative 2.

Finally, guanine derivative 6 showed a partial destabilization effect to 1a/toluene system (1 wt %) (Table 2 and Fig. 4g), and mildly destabilized 1b/toluene system (2 wt %) as the addition of 6 induced a gentle decrease in the Tgel values of 1b (Fig. 4h). This phenomenon was actually in accordance with the well documented G-A, G-T and G-U mismatches27 due to the guanine’s multiple hydrogen-bonding sites. The larger p-area of guanine derivative 6 than that of 3/4/5 is an additional factor accounting for the disrupting effect on the p-p stacking interaction of 1a/1b. 3. Conclusion In summary, we have synthesized for the first time the J-AT nucleoside-based organogelators 1a/1b and demonstrated their

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4. Experimental section 4.1. General materials and methods All chemicals were commercially available. The solvents and reagents were analytic pure. Solvents 1,2-dichloroethane and acetonitrile were purified by distilling from P2O5. Thin-layer chromatography (TLC) was performed on aluminium sheet covered with silica gel 60 F254 (0.2 mm, Merck, Germany). Flash column chromatography (FC): silica gel 60 (Haiyang chemical company, PR China) at 0.4 bar. NMR spectra were recorded on a AV II (Bruker, Germany) spectrometer at 400 MHz and 600 MHz, the d values in ppm are relative to Me4Si as internal standard; High resolution mass spectra were measured with mass analyzer (Q-TOF, Bruker, Germany). SEM was observed by JSM-7500F. The UV absorption spectra were recorded on a DU-800 spectrophotometer (Beckman, US), lmax in nm, ε in dm3 mol1 cm1. Fig. 4. Tgel of 1a/toluene system (1 wt %) and 1b/toluene system (2 wt %) plotted against additive concentrations: (a) (1aþ3), (b) (1bþ3), (c) (1aþ4), (d) (1bþ4), (e) (1aþ5), (f) (1bþ5), (g) (1aþ6) and (h) (1bþ6).

Fig. 5. 1H NMR titration spectra of compound 1a with 2 in CDCl3 at room temperature (the molar ratios of 2/1a were shown in the figure). The concentration of compound 1a was kept constant (1.3102 mol/L). The downfield shifts of the proton signals of all the active hydrogen atoms were highlighted in different colour.

unparalleled superiority to natural nucleobase analogues to gelate aromatic solvents, which offered a new chemical entities for the design of nucleobase/nucleoside-based gelators by selfassembly through non-covalent bonds. Moreover, the J-AT nucleoside-based organogelators showed a specific base pair recognition characteristic. The gel stabilities of 1a and 1b were drastically influenced by adenine analogue 2, hardly affected by thymine analogue 3, uracil analogue 4, cytosine analogue 5, and mildly interrupted by guanine analogue 6. The fact that adenine derivative 2 did but thymine/uracil derivatives 3/4 did not destabilize the gel of 1a and 1b was ascribed to that the glycosyl bond of J-AT could not rotate freely and adopted the anti conformation; So J-AT could easily pair with adenine, but not with thymine/uracil. With its excellent self-assembly capability, J-AT are expected to be fabricated into diverse supramolecular gelators by further structural modification on the side chains of sugar components, such as combining them with steroidal or amino acid derivatives. Other efforts to develop stimuliresponsive materials based on J-AT organogelators have also been made and these experiments will be reported in the near future.

4.1.1. 5-Amino-8-(5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-

b- D-ribofuranoside)pyrimido[4,5-d]pyrimidine-2,4(3H,8H)-dione (1a); 5-Amino-8-(5-O-tert-butyldimethylsilyl-2,3-O-isopropylidenea-D-ribofuranoside)pyrimido[4,5-d]pyrimidine-2,4(3H,8H)-dione (1b). Compound 7 (1 g, 5.6 mmol) was suspended in Hexamethyldisilazane (HMDS) (50 ml) and stirred at 140  C for about 3 min, then trimethylsilyl chloride (TMSCl) (1 ml, 7.9 mmol) was added, the reaction was stirred at reflux until the mixture was clear, then the solution was evaporated to remove excess of HMDS, the silylated base 5 was obtained, which was immediately used in next step without further purification. Dry 1,2-dichloroethane (30 ml) was added in the pot containing silylated base 8 and stirred. 1-OAcetyl-5-O-tert-butyldimethylsilyl-2, 3-O-isopropylidene-b-Dribofuranose (1 g, 2.9 mmol) dissolved in dry acetonitrile (30 ml) was added in the above solution. Trimethylsilyl triflate (TMSOTf) (0.5 ml, 2.8 mmol) was added as catalyst at 0  C. After the mist vanished, the reaction mixture was moved to an oil bath and stirred at 80  C with exclusion of moisture. 3 h later, saturated NaHCO3 aqueous solution (60 ml) was added at 0  C to quench the reaction; CH2Cl2 (360 ml) was used to extract the organic phase. After dried with anhydrous Na2SO4, the organic phase was evaporated. The residue was applied to F.C. (CH2Cl2/methanol¼98:2), furnishing compound 1a (650 mg, 25%) and 1b (617 mg, 24%). Compound 1a: UV (MeOH): 251 (14,946), 277 (3702). 1H NMR (400 MHz, DMSO-d6) d (ppm): 0.00 (6H, d, J¼2.2 Hz, Si(CH3)2), 0.81 (9H, s, t-Bu), 1.27 (3H, s, CH3), 1.48 (3H, s, CH3), 3.79e3.93 (2H, m, 50 H2), 4.18e4.21 (1H, m, 40 -H), 4.82e4.84 (1H, m, 30 -H), 5.04e5.06 (1H, dd, J1¼6.2 Hz, J2¼1.4 Hz, 20 -H), 6.16 (1H, d, J¼1.3 Hz, 10 -H), 8.52 (1H, s, CH), 8.97e9.00 (2H, d, J¼12.2 Hz, NH2), 10.79 (1H, s, NH). 13C NMR (150 MHz, DMSO-d6) d (ppm): 5.04, 5.00, 18.46, 25.76, 25.95, 26.25, 27.53, 63.60, 80.88, 85.29, 87.50, 88.72, 93.32, 113.30, 152.67, 156.77, 157.64, 162.11, 165.35. HRMS (ESIþ) m/z: Calcd for C20H31N5O6Si: 488.1942 [MþNa]þ; Found 488.1942 [MþNa]þ. Compound 1b: UV (MeOH): 250 (24,935), 276 (6048). 1H NMR (400 MHz, DMSO-d6) d (ppm): 0.00 (6H, s, Si(CH3)2), 0.82 (9H, s, tBu), 1.16 (3H, s, CH3), 1.19 (3H, s, CH3), 3.66e3.73 (2H, m, 50 -H2), 4.44 (1H, t, J¼2.8 Hz, 30 -H), 4.76e4.82 (2H, m, 40 -H and 20 -H), 6.42 (1H, d, J¼4.2 Hz, 10 -H), 8.23 (1H, s, CH), 8.87e8.88 (2H, d, J¼7.1 Hz, NH2), 10.67 (1H, s, NH). 13C NMR (150 MHz, DMSO-d6) d (ppm): 5.16, 5.08, 18.34, 24.34, 25.77, 25.95, 26.31, 64.88, 79.33, 82.10, 83.78, 87.06, 87.64, 112.75, 151.46, 156.81, 157.39, 161.95, 165.31. HRMS (ESIþ) m/z: Calcd for C20H31N5O6Si: 488.1942 [MþNa]þ; Found 488.1945 [MþNa]þ. uridine 4.1.2. 50 -O-(tert-Butyldimethylsilyl)-20 ,30 -O-isopropylidene (4). A stirred solution of 50 -O-tert-butyldimethylsilyl uridine20a (1.4 g, 4 mmol) in acetone (20 ml) was treated with 2,2dimethoxypropane (9.8 ml, 80 mmol) and p-TsOH (69 mg,

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0.4 mmol). After stirring at room temperature for 3 h, the mixture was neutralized with saturated solution of NaHCO3 and concentrated. The residue was taken up in EtOAc (80 ml), washed with water (50 ml), brine (50 ml), dried with anhydrous Na2SO4 and concentrated. Purification by F.C. (CH2Cl2/methanol¼9:1) afforded a white solid 4 (1.4 g, 88%). UV (EtOH): 259 (14,172). 1H NMR (400 MHz, DMSO-d6) d (ppm): 0.00 (6H, s, Si(CH3)2), 0.82 (9H, s, tBu), 1.25 (3H, s, CH3), 1.44 (3H, s, CH3), 3.73 (2H, m, 50 -H2), 4.07 (1H, d, J¼3.5 Hz, 40 -H), 4.66 (1H, s, 30 -H), 4.87 (1H, d, J¼6.2 Hz, 20 -H), 5.54 (1H, d, J¼8.0 Hz, 5-H), 5.76 (1H, s, 10 -H), 7.66 (1H, d, J¼8.0 Hz, 6-H), 11.35 (1H, s, NH). 13C NMR (100 MHz, DMSO-d6) d (ppm): 5.51, 17.96, 25.14, 25.71, 26.98, 63.11, 80.36, 83.96, 86.67, 91.79, 101.50, 112.86, 141.91, 150.25, 163.12. HRMS (ESIþ) m/z: Calcd for C18H31N3O5Si: 399.1952 [MþH]þ; Found 399.1951 [MþH]þ. 4.1.3. 50 -O-(tert-Butyldimethylsilyl)-20 ,30 -O-isopropylidene cytidine (5). To a solution of 50 -O-tert-butyldimethylsilyl cytidine28 (1.7 g, 4.8 mmol) in acetone (40 ml) was added 2,2-dimethoxypropane (29 ml, 240 mmol). p-TsOH (1.6 g, 9.6 mmol) was then added at room temperature and soon a precipitate formed. The reaction mixture was stirred for an additional 20 min, after which it was neutralized by addition of aqueous ammonia (26%). Then the solvent was removed under reduced pressure. The residue was taken up in CH2Cl2 (100 ml), washed with brine (100 ml), dried with anhydrous Na2SO4 and concentrated. Purification by F.C. (CH2Cl2/ methanol¼9:1) afforded a white solid 5 (1.6 g, 84%). UV (EtOH): 272 (6873). 1H NMR (400 MHz, DMSO-d6) d (ppm): 0.00 (6H, s, Si(CH3)2), 0.82 (9H, s, t-Bu), 1.24 (3H, s, CH3), 1.43 (3H, s, CH3), 3.68e3.80 (2H, m, 50 -H2), 4.02e4.05 (1H, dd, J1¼8.6 Hz, J2¼4.2 Hz, 40 -H), 4.66e4.68 (1H, dd, J1¼6.2 Hz, J2¼3.7 Hz, 30 -H), 4.78e4.80 (1H, dd, J1¼6.3 Hz, J2¼1.9 Hz, 20 -H), 5.65 (1H, d, J¼7.4 Hz, 5-H), 5.74 (1H, d, J¼1.9 Hz, 10 -H), 7.18 (2H, s, NH2), 7.61e7.63 (1H, d, J¼7.4 Hz, 6-H). 13 C NMR (100 MHz, DMSO-d6) d (ppm): 5.49, 17.94, 25.16, 25.73, 27.03, 63.22, 80.50, 84.52, 86.80, 92.65, 93.87, 112.56, 142.64, 154.78, 165.83. HRMS (ESIþ) m/z: Calcd for C18H31N3O5Si: 398.2112 [MþH]þ; Found 398.2108 [MþH]þ. 4.2. Gelation test of compounds 1e6 5 mg of compounds 1e6 was added to a glass sampler vial, to which 100 ml solvent was added one by time. The vial was heated to promote the dissolution of the mixture. Then the solution was gradually allowed to cool to room temperature. When the sample was insoluble at boiling point of the solvent, added solvent until 1000 ml. Gelation was considered to have occurred when a homogeneous substance was obtained, which exhibited no gravitational flow. Partial gelation was considered to have occurred when the formed gel flows neither freely like clear solution nor selfsupporting. 4.3. Measurements of sol-gel transition temperatures The sealed tube containing the gel was immersed inversely in a thermostated oil bath. The temperature was raised at a rate of 1  C min1. Here, the Tgel was defined as the temperature at which the gel turned into the sol phase. 4.4. Rheological studies Rheological studies were carried out with a stress-controlled rheometer (TA Instruments, AR 2000ex) equipped with steel parallel-plate geometry (40 mm diameter). The gap distance was fixed at 0.031 mm the gel was scooped on the plate of the rheometer. Strain sweep at a constant frequency (6.28 rad s1) was performed in the 0.01e10% range to determine the linear viscoelastic region (LVR) of the gel sample. Oscillatory frequency sweep

was obtained from 0.1 to 100 rad s1 at a constant strain of 0.1%, well within the linear regime determined by the strain sweep, to ensure the calculated parameters corresponded to an intact network structure. All measurements were carried out at a constant temperature (20  C). The rheometer had a built-in computer, which converted the torque measurements into G0 (the storage modulus) and G00 (the loss modulus). 4.5. Test of compounds 2e6 on the gel formation of compounds 1a and 1b 500 ml of 1a/toluene gel (1 wt %) and 1b/toluene gel (2 wt %) were prepared beforehand in glass sampler vials, to which 0.1 equiv compounds 2e6 was added, respectively (the mole ratio of the additives was based on that of compounds 1a/1b). Then the mixtures were heated and vortexed to disperse the additives and homogenize the mixtures. The vials then standed at room temperature. After a while, if the gel reformed, the mixture with the certain mole ratio was noted down as gel. If the mixture remained in solution after 12 h, the mixture with the certain mole ratio was noted down as solution. If the mixture formed no gel, but turned into partial gel after 12 h, the mixture with the certain mole ratio was noted down as partial gel. The same procedure was carried out until the total amount of the additives added into the vials was up to 1.0 equiv. Acknowledgements We thank the National Natural Science Foundations of China (document no: 20772087, 81061120531, 30930100), ISTCPC (2012DFA31370) and the Open Foundation (SKLODSCUKF2012-03, SKLODSCUKF2012-04) from the State Key Laboratory of Oral Diseases Sichuan University for the financial support. Supplementary data 1 H NMR spectra and NOE NMR spectra for compound 1a and 1b (Figs. S1eS4). Gelation behaviours of compounds 1e6 in 20 organic solvents (Table S1). 1H NMR titration experiment of compound 1a with 3 (Fig. S5). Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.tet.2013.08.058.

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