Copper-Catalyzed Intramolecular Alkoxylation of Purine Nucleosides: One-Step Synthesis of 5′-O,8-Cyclopurine Nucleosides

Article abstract of DOI:10.1021/acs.joc.5b01360

A novel copper-catalyzed intramolecular dehydrogenative alkoxylation of purine nucleosides has been developed successfully, providing the 5′-O,8-cyclopurine nucleosides in one-step with a yield up to 90%. The method, which utilized an inexpensive CuCl catalyst and a di-tert-butyl peroxide (DTBP) oxidant was suitable in a broad substrate scope and proceeded well even in gram scale.

Full text of DOI:10.1021/acs.joc.5b01360

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Article
Copper-Catalyzed Intramolecular Alkoxylation of Purine Nucleosides:
One-Step Synthesis of 5’-O, 8 -Cyclopurine Nucleosides
Mingwu Yu, Zhiqian Wang, Junbin Hu, Shunlai Li, and Hongguang Du
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01360 • Publication Date (Web): 04 Sep 2015
Downloaded from http://pubs.acs.org on September 7, 2015
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CopperꢀCatalyzed Intramolecular Alkoxylation of Purine Nucleosides:
OneꢀStep Synthesis of 5’ꢀO, 8 ꢀCyclopurine Nucleosides
Mingwu Yu, Zhiqian Wang, Junbin Hu, Shunlai Li, Hongguang Du*
Faculty of Science, Beijing University of Chemical Technology, Beijing 100029, People’s
Republic of China
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*Eꢀmail: dhg@mail.buct.edu.cn
ABSTRACT: A novel copperꢀcatalyzed intramolecular dehydrogenative alkoxylation of
purine nucleosides has been developed successfully, providing the 5’ꢀO, 8ꢀcyclopurine
nucleosides in oneꢀstep with a yield up to 90%. The method that utilized an inexpensive
CuCl catalyst and a diꢀtertꢀbutyl peroxide (DTBP) oxidant was suitable in a broad
substrate scope and proceeded well even in gram scale.
INTRODUCTION
5’ꢀO, 8ꢀcyclopurine nucleosides with an additional large sevenꢀmembered ring
between the sugar ring and the purine base through a CꢀOꢀC bridge have attracted
increasing attention in medicinal and synthetic chemists for their varieties of potential
bioactivities, such as antiꢀplatelet aggregation1, rhodopsin kinase nucleoside inhibitor2,
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and equilibrative nucleoside transporter 1 (ENT1) inhibition3 (Figure 1). Due to their
unique molecular structure, these cyclopurine nucleosides were also an essential tool for
nucleosides conformational studies and key intermediates in the synthesis of the
heterocyclic moieties of nucleosides4.
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Figure 1. Selected examples of 5’ꢀO, 8ꢀcyclopurine nucleosides with bioactivities
Despite that 5’ꢀO, 8ꢀcyclopurine nucleosides play important roles in biological and
synthetic areas, the synthetic approaches are still limited to date. One of the most used
methods is intramolecular nucleophilic substitution of 8ꢀbromoꢀ2’, 3’ꢀOꢀisopropyliꢀ
denepurine nucleosides (Scheme 1, route A), but multiple steps were involved and strong
bases were required.5 The cyclization of 2’, 3’ꢀOꢀisopropylidenepurine nucleosides by
oxidation with I2ꢀNH3,6 NBSꢀAcOH,7 or stoichiometric amounts of Lewis acid, such as
lead tetraacetate8 and cupric chloride9 could be alternative ways for the synthesis of 5’ꢀO,
8ꢀcyclopurine nucleosides (Scheme 1, route B, aꢀd). Although the substrate scope was
very narrow, the photochemical oxidation of 2’, 3’ꢀOꢀisopropylidenepurine nucleosides
with pyrimido[5,4ꢀg]ꢀpteridinetetraone Nꢀoxide (PPO) could also lead to the
corresponding 5’ꢀO, 8ꢀcyclopurine nucleosides.10 (Scheme 1, route B, e) Thus, the
development of more efficient route to synthesize 5’ꢀO, 8ꢀcyclopurine nucleosides is
quite necessary but challenging.
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Till now, various transitionꢀmetalꢀcatalyzed CꢀH functionalization/CꢀO cyclizations
have been a powerful tool for constructing intramolecular CꢀO bonds in synthetic
chemistry11. To our best knowledge, transitionꢀmetalꢀcatalyzed intramolecular
alkoxylation is still unexplored for purine nucleosides. Herein, we will report a novel
copperꢀcatalyzed intramolecular alkoxylation of purine nucleosides to construct the
additional large sevenꢀmembered ring between 5’ꢀOH group and 8ꢀC atom, which
provides an efficient oneꢀstep method to synthesize 5’ꢀO, 8ꢀcyclopurine nucleosides
under neutral condition (Scheme 1, C).
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Scheme 1. Strategies for Synthesis of 5’ꢀO, 8ꢀcyclopurine Nucleosides
RESULTS AND DISCUSSION
The synthesis study was first carried out with 2’, 3’ꢀOꢀisopropylideneꢀ6ꢀ(2ꢀ
methoxyethyl)aminoadenosine 1a in the presence of CuCl2 (0.1 equiv) and DTBP (2
o
equiv) in CH3CN at 80 C (Table 1, entry 1). To our delight, the desired 5’ꢀO,
8ꢀcycloadenosine derivative 2a was successfully obtained in a yield of 41%. Then
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replacing the catalyst CuCl2 with other metal salts (Table 1, entries 2ꢀ6) shown that other
firstꢀrow transition metal chlorides (CoCl2, NiCl2) could not promote the alkoxylation
(Table 1, entries 2ꢀ3), but CuCl (Table 1, entry 4) was the most effective catalyst.
Because the oxidant was very important to the transitionꢀmetalꢀcatalyzed alkoxylation
reaction, we tried other various oxidants (THBP, BPO, K2S2O8, etc), and the results
indicated that DTBP was still the best oxidant (Table 1, entries 7ꢀ11). After getting the
catalyst and oxidant, the effect of solvents was next tested, and the results shown that
DMF was more effective than the other solvents including DCE, 1, 4ꢀdioxane, toluene,
and CH3CN (Table 1, entries 4, and 12ꢀ15). After screening the ration of DTBP and CuCl,
we successfully found that the best yield of 2a was obtained by employing of CuCl (0.5
equiv) and DTBP (3 equiv) in DMF at 80 oC (Table 1, entries 15ꢀ20). Moreover, when the
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temperature was reduced to 60 C, the yield would drop down to 79% from 95%, but a
higher temperature could not improve the yield any further (Table 1, entries 21ꢀ22).
Table 1. Optimization of the Reaction Conditions a
entry catalyst (equiv) oxidant (equiv) solvent yield (%)b
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CuCl2(0.1)
CoCl2 (0.1)
NiCl2 (0.1)
CuCl (0.1)
CuBr (0.1)
CuI (0.1)
DTBP (2)
DTBP (2)
DTBP (2)
DTBP (2)
DTBP (2)
DTBP (2)
THBP (2)
K2S2O8 (2)
DLP (2)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
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0c
0c
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46
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CuCl (0.1)
CuCl (0.1)
CuCl (0.1)
13
tracec
tracec
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CuCl (0.1)
CuCl (0.1)
CuCl (0.1)
CuCl (0.1)
CuCl (0.1)
CuCl (0.1)
CuCl (0.1)
CuCl (0.1)
CuCl (0.2)
CuCl (0.4)
CuCl (0.5)
CuCl (0.5)
CuCl (0.5)
BPO (2)
AgOAc(2)
DTBP (2)
CH3CN
CH3CN
DCE
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DTBP (2) 1,4ꢀdioxane
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DTBP (2)
DTBP (2)
DTBP (3)
DTBP (4)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
Toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
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95(86)d
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aReaction conditions: Unless otherwise noted, reactions were carried out with 1a (0.35 mmol) in solvent (3 mL) at
80 oC for 12 h. DTBP: Diꢀtertꢀbutyl peroxide; THBP: tertꢀbutyl hydroperoxide, 70% solution in water; DLP: Diꢀlauroyl
peroxide; BPO: Benzoyl peroxide. bYield was determined by 1H NMR. cYield was determined by TLC. dIsolated yield
based on 1a.eAt 60 oC. fAt 100 oC.
With the optimized reaction conditions in hand, a series of Cꢀ6ꢀsubstituted adenosines
were tested (Table 2). To our delight, the most products were obtained in moderate to
good isolated yields. Furthermore, various functional groups such as aryl halides (2h, 2i),
ether (2oꢀ2q), alkylamino (2cꢀ2n), arylamino (2j), amino (2b), and hydroxyl (2l)
survived under the oxidizing conditions. Notably, the results showed that substrate with
aliphatic cyclic amine substituted gave a slightly higher yield than those with aliphatic
amine groups substituted (2n vs 2cꢀ2l).The results also indicated that substrates with Cꢀ6
alkylamino groups were more reactive than those with Cꢀ6 alkyoxyl or alkythio groups
(2e vs 2p, 2q; 2c vs 2o). It was worth mentioning that 2’, 3’ꢀOꢀisopropylideneꢀ6ꢀ
(2ꢀhydroxyethyl)ꢀaminoadenosine (1l) was cyclized in DMF to give 2m but not 2l in 14%
yield possibly because of the esterification of hydroxyl group with DMF. After replacing
DMF with CH3CN, the desired product 2l was successfully synthesized only in a yield of
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22%, which might indicate that hydroxyl group was harmful to the catalystꢀoxidation
system. To our surprise, only trace or no products (2r, 2s, and 2t) were generated when
substrates (1r, 1s, and 1t) were applied to the experiments under standard condition, and
most raw materials were recovered. This result implied that the C6ꢀheteroatoms might
promote the reaction. Besides, the larger functional groups (Et or Ph) attached to Cꢀ6
maybe affect the coordination between the catalyst and 7ꢀN atom in purine structure,
which could lead to only trace products. It was worth to mention that there was still no
product for substrate 1t, although only one small hydrogen atom attached to the Cꢀ6. The
reason might be that the 1ꢀN atom was much easier to coordinate with the catalyst than
7ꢀN atom, which caused the deactivation of catalyst when there was no steric hindrance
in Cꢀ6 position in purine base.
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Table 2. Effect of Cꢀ6ꢀSubstituent in Purine Basea
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aUnless otherwise specified, all rections were carried out with purine nucleosides (1, 0.35 mmol), CuCl (0.5 equiv), and
b
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DTBP (3 equiv) at 80 oC in 3 mL DMF for 12 h. Isolated yields. The solvent was 6 mL CH3CN. The solvent was 3
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mL CH3CN. Recovery of staring material was 27%. fRecovery of staring material was 25%. gRecovery of staring
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material was 27%.hProducts 2rꢀ2t were detected by HPLCꢀMS. Recovery of staring material (2r) was 86%; Recovery
of staring material (2s) was 90%; Recovery of staring material (2t) was 91%.
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To explore the electronic and steric effects of Cꢀ2 substituents in the purine ring, a
further substrate scope study was performed, and the results were shown in Table 3. To
our delight, most of the substrates could afford the desired products in moderate to good
yields, even in presence of electron withdrawing halogen atoms (Cl, I) or electron
donating groups (SMe, SEt, OMe) on the 2ꢀposition of the purine ring. Notably, amino
group at Cꢀ2 position in purine ring led to an obvious decrease of the yield (4f, 17%),
possibly because the amino group coordinated with the copper catalyst and reduced the
activity. Meanwhile, the brief screening disclosed that the steric hindrance of Cꢀ2
substituents in the purine ring had no noticeable effect on the reaction.
On the other hand, 2’, 3’ꢀOꢀcyclohexylideneꢀ5’ꢀO, 8ꢀcyclopurine nucleosides (Table
3, 4iꢀ4k) were also successfully obtained under reaction conditions in good yields
(82ꢀ88%), which were similar to those of 2’, 3’ꢀOꢀisopropylidene protected products. It
was worth to mention that the unprotected nucleoside (3l) gave no product even after
prolonged reaction time under the standard conditions. This phenomenon also happened
when other methods and other substrates were used.6 The reason might be that the
isopropylidene group could force the furanose ring into a conformation that favored the
proximity of the hydroxyl group to the Cꢀ8 atom in purine base, which resulted in the
formation of an internal C(5’)ꢀOꢀC(8) linkage.12
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Table 3. Electronic and Steric Effects of Cꢀ2ꢀSubstitutent in Purine Base a
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aUnless otherwise specified, all rections were carried out with purine nucleosides (1, 0.35 mmol), CuCl (0.5 equiv), and
DTBP (3 equiv) at 80 oC in 3 mL DMF for 12 h. bIsolated yields. cThe solvent was 3 mL CH3CN.
To demonstrate the practicality of the present method, a scaleꢀup experiment was
conducted. To our delight, the corresponding product could be obtained in 73% yield in
gram scale (Scheme 2).
Scheme 2. Gramꢀscale for Synthesis of 2’, 3’ꢀOꢀisopropylideneꢀ6ꢀphenethylaminoꢀ
5’ꢀO, 8ꢀcycloadenosine (2g)
The optimized methodology was applied to the total synthesis of 5’ꢀO,
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8ꢀcycloadenosine, a rhodopsin kinase nucleoside inhibitor (Scheme 3). Protection of 2’,
3’ꢀhydroxyl groups of adenosine was achieved with SOCl2ꢀCH(OEt)3 in acetone.
Subsequently, a intramolecular cyclization of 2’, 3’ꢀOꢀisopropylideneadenosine (1b) in
the presence of CuCl (0.5 equiv) and DTBP (3 equiv) gave the intermediate (2b). Finally,
the deprotection of 2b promoted by CF3COOH afforded the 5’ꢀO, 8ꢀcycloadenosine in 67%
yield, of which the spectral data were identical with those reported in the literature.5b,13
Moreover, the present strategy was more efficient (three steps and 38% overall yield)
compared with the previous reported methods (four steps and 5% overall yield).13
Scheme 3. Synthesis of 5’ꢀO, 8ꢀcycloadenosine
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To gain some insights of the reaction mechanism, several control experiments were
carried out (Scheme 4). Firstly, radical trapping experiment was carried out in the
presence of a radical scavenger TEMPO (Scheme 4, a). As a result, only trace of 2c was
generated, and the major product was 2c’ in yield of 42%, which might be formed by
oxidation of 1c under TEMPOꢀCuCl system.14 The reaction with addition of another
radical inhibitor 2, 4, 6ꢀtriꢀtertꢀbutylphenol (TTBP) afforded no product (Scheme 4, b),
which implied that the reaction might include a radical process. To our surprise, the
reaction failed to give any desired product when substrate 1cꢀMe was applied to the
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standard conditions (Scheme 4, c). The reason might be that the methyl group prevented
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the catalyst from coordinating with 7ꢀN atom in purine structure. Subsequently, the H
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NMR study between 1a and CuClꢀDTBP was carried out and the downfield shift of the
resonance for the Cꢀ8ꢀH proton of 1a was observed. Meanwhile, the peak of Cꢀ8ꢀH
became very broad (see, Supporting Information).
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Scheme 4. Experiments for Preliminary Mechanistic Study
Base on the experimental results above and literatures,7ꢀ9,11fꢀg a proposed reaction
pathway was described in Scheme 5. Initially, the oxidation of CuCl with DTBP under
heating generated the copper species A and radical tꢀBuO·.15 After that, purine
nucleosides 1 coordinated with A and formed the 7ꢀNꢀcopper complex B.7ꢀ9,16
Subsequently, intramolecular nucleophilic addition of 5’ꢀOH to Cꢀ8 provided an
intermediate C with tꢀBuOH leaving assisted by tꢀBuO· radical.17 Finally, reductive
elimination of intermediate C afforded the desired products 2 and regenerated copper
catalyst with leaving of tꢀBuOH.
Scheme 5. Plausible Mechanism
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CONCLUSION
In summary, we have successfully developed an efficient oneꢀstep copperꢀcatalyzed
reaction for the synthesis of 5’ꢀO, 8ꢀcyclopurine nucleosides. This method could directly
construct the large sevenꢀmembered ring between the sugar ring and the purine base
through a CꢀOꢀC bridge, which avoided multiple steps. The cheap and readily available
catalystꢀoxidation (CuClꢀDTBP) system made this method very promising for the
synthesis of more 5’ꢀO, 8ꢀcyclopurine nucleosides. Notably, this protocol provided a
useful tool for convenient synthesis of rhodopsin kinase nucleoside inhibitor 5’ꢀO,
8ꢀcycloadenosine.
EXPERIMENTAL SECTION
General Information
Commercially available reagents were used without further purification. Melting
1
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points were determined on a hot stage melting point apparatus (uncorrected). H and C
NMR spectra were recorded in CDCl3 or DMSOꢀd6 with TMS as an internal standard,
and the chemical shifts (δ) are reported in parts per million (ppm). The obtained signal
multiplicities were distinguished with the common abbreviations s (singlet), d (doublet),
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dd (doublet of doublets), t (triplet), q (quartet), br s (broad singlet), quint (quintet), sex
(sextet), and m (multiplet). IR spectra were recorded on a FTꢀIR instrument. HRMS
measurements were carried out on an LC/MSD QTOF mass spectrometer.
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2’, 3’ꢀOꢀprotectedꢀ2, 6ꢀdisubtitued purine nucleosides 1a, 1cꢀ1t, 1cꢀMe, and 3aꢀ3k
were prepared according to the method in previous reports.18
General procedure for the copperꢀcatalyzed intramolecular alkoxylation of 2’,
3’ꢀOꢀprotectedꢀ2, 6ꢀdisubtitued purine nucleosides 2a – 2q and 4a – 4k.
Under ambient atmosphere, substrate 1 (0.35 mmol) and CuCl (0.175 mmol, 0.5
equiv) were suspended in DMF (3 mL) in a 15 mL vial. DTBP (1.05 mmol, 3 equiv) was
then added to the mixture. The vial was sealed with a Teflon lined cap, and the reaction
o
was heated at 80 C for 12 h. Then, the reaction mixture was diluted with ethyl
acetateꢀH2O (100ꢀ15 mL). A 1M HCl (0.1 mL) was added to the mixture. The organic
and the aqueous layers were separated and the organic layer was washed with brine (3×25
mL).The organic layer was dried over MgSO4, filtered, and concentrated. The resulting
oil was purified by chromatography on silica gel to afford products 2a – 2q and 4a – 4k.
as semisolid or colorless crystals.
2’, 3'-O-isopropylidene-6-(2-methoxyethyl)amino-5'-O, 8-cycloadenosine (2a).
Yield: 110 mg, 86%; white solid, mp: 82 – 84 oC; Rf = 0.16 (PE:EA = 1:2, v/v). 1H NMR
(400 MHz, CDCl3): δ 8.29 (s, 1H), 6.36 (s, 1H), 5.85 (br s, 1H), 5.06 (d, J = 5.6 Hz, 1H),
4.74 (d, J =5.6 Hz, 1H), 4.67 (s, 1H), 4.47 (d, J = 12.8 Hz, 1H), 4.17 (d, J = 12.8 Hz, 1H),
3.80 (br s, 2H), 3.57 (t, J = 4.6 Hz, 2H), 3.35 (s, 3H), 1.53 (s, 3H), 1.33 (s, 3H); 13C NMR
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(100 MHz, CDCl3): δ 153.6, 153.2, 152.6, 147.7, 115.4, 113.2, 86.6, 85.8, 85.7, 81.4,
74.4, 71.2, 58.8, 40.5, 26.1, 24.7; FTIR (film, cmꢀ1): 3310, 2985, 2935, 2870, 1625, 1583,
1560, 1501, 1382, 1350, 1277; ESIꢀHRMS [M+H]+ calcd for C16H22N5O5 m/z 364.1615,
found 364.1611.
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2’, 3'-O-isopropylidene-5'-O, 8-cycloadenosine (2b). Yield: 67 mg, 63%; white
solid, mp: 228 – 230 oC; Rf = 0.21 (EA). 1H NMR (400 MHz, DMSOꢀd6): δ 8.13 (s, 1H),
7.10 (br s, 2H), 6.04 (s, 1H), 5.11 (d, J = 5.6 Hz, 1H), 4.90 (d, J = 5.6 Hz, 1H), 4.75 (s,
1H), 4.64 (dd, J = 2.0, 12.8 Hz, 1H), 4.14 (d, J = 12.8 Hz, 1H), 1.47 (s, 3H), 1.31 (s, 3H);
13C NMR (100 MHz, DMSOꢀd6): δ 154.7, 153.1, 151.9, 147.6, 114.5, 111.9, 85.8, 85.2,
84.8, 80.9, 74.3, 25.9, 24.3; FTIR (neat, cmꢀ1):3425, 3178, 2990, 2930, 1641, 1608, 1578,
1550, 1451, 1382, 1091, 1066; ESIꢀHRMS [M+H]+ calcd for C13H16N5O4 m/z 306.1197,
found 306.1203.
2’, 3'-O-isopropylidene-6-methylamino-5'-O, 8-cycloadenosine (2c).Yield: 79 mg,
71%; white solid, mp: 205 – 206 oC; Rf = 0.20 (PE:EA = 1:2, v/v). 1H NMR (400 MHz,
CDCl3): δ 8.35 (s, 1H), 6.39 (s, 1H), 5.68 (br s, 1H), 5.09 (d, J = 5.6 Hz, 1H), 4.76 (d, J =
5.6 Hz, 1H), 4.70 (s, 1H), 4.50 (dd, J = 1.6, 12.8 Hz, 1H), 4.20 (d, J = 12.8 Hz, 1H), 3.18
(d, J = 4.4 Hz, 3H), 1.56 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 154.4,
153.2, 152.7, 147.4, 115.4, 113.3, 86.6, 85.8, 85.7, 81.4, 74.4, 27.8, 26.1, 24.7; FTIR
(film, cmꢀ1): 3297, 2989, 2940, 1630, 1583, 1562, 1508, 1378, 1321, 1278, 1094;
ESIꢀHRMS [M+H]+ calcd for C14H18N5O4 m/z 320.1353, found 320.1351.
2’, 3'-O-isopropylidene-6-ethylamino-5'-O, 8-cycloadenosine (2d).Yield: 87 mg,
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75%; white solid, mp:153 – 154 C. Rf = 0.36 (PE:EA = 1:2, v/v). H NMR (400 MHz,
CDCl3): δ 8.33 (s, 1H), 6.39 (s, 1H), 5.56 (br s, 1H), 5.09 (d, J = 5.6 Hz, 1H), 4.77 (d, J =
5.6 Hz, 1H), 4.70 (s, 1H), 4.49 (d, J = 12.8 Hz, 1H), 4.20 (d, J = 12.8 Hz, 1H), 3.67 (br s,
2H), 1.56 (s, 3H), 1.36 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
153.7, 153.2, 152.7, 147.5, 115.2, 113.3, 86.6, 85.8, 85.7, 81.3, 74.4, 35.9, 26.1, 24.7,
15.1; FTIR (film, cmꢀ1): 3297, 2989, 2940, 1630, 1583, 1562, 1508, 1378, 1321, 1278,
1094, 1039; ESIꢀHRMS [M+H]+ calcd for C15H20N5O4 m/z 334.1510, found 334.1512.
2’, 3'-O-isopropylidene-6-propylamino-5'-O, 8-cycloadenosine (2e).Yield: 97 mg,
80%; white solid, mp: 104 – 105 oC. Rf = 0.44 (PE:EA = 1:2, v/v). 1H NMR (400 MHz,
CDCl3): δ 8.33 (s, 1H), 6.39 (s, 1H), 5.50 (br s, 1H), 5.09 (d, J = 5.6 Hz, 1H), 4.76 (d, J =
5.6 Hz, 1H), 4.70 (s, 1H), 4.49 (dd, J = 2.0, 12.8 Hz, 1H), 4.19 (d, J = 12.8 Hz, 1H), 3.59
(br s, 2H), 1.69 (sext, J = 7.2 Hz, 2H), 1.56 (s, 3H), 1.36 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 153.9, 153.1, 152.7, 147.5, 115.2, 113.3, 86.6, 85.8, 85.7,
81.4, 74.4, 42.7, 26.1, 24.7, 23.1, 11.4; FTIR (film, cmꢀ1): 3285, 2960, 2934, 2872, 1624,
1583, 1559, 1500, 1379, 1322, 1277, 1065; ESIꢀHRMS [M+H]+ calcd for C16H22N5O4
m/z 348.1666, found 348.1664.
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2’, 3'-O-isopropylidene-6-hexylamino-5'-O, 8-cycloadenosine (2f).Yield: 107 mg,
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78%; white solid, mp: 76 – 78 C. Rf = 0.59 (PE:EA = 1:2, v/v). H NMR (400 MHz,
CDCl3): δ 8.35 (s, 1H), 6.40 (s, 1H), 5.53 (br s, 1H), 5.09 (d, J = 5.6 Hz, 1H), 4.76 (d, J =
5.6 Hz, 1H), 4.70 (s, 1H), 4.49 (d, J = 12.8 Hz, 1H), 4.18 (d, J = 12.8 Hz, 1H), 3.61 (br s,
2H), 1.63 (quint, J = 7.2 Hz, 2H), 1.56 (s, 3H), 1.40 – 1.25 (m, 11H), 0.88 (t, J = 7.0 Hz,
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3H); 13C NMR (100 MHz, CDCl3): δ 153.9, 153.3, 152.7, 148.0, 115.4, 113.3, 86.7, 85.8,
85.7, 81.4, 74.4, 41.0, 31.5, 29.8, 26.5, 26.1, 24.7, 22.6, 14.0; FTIR (film, cmꢀ1): 3295,
2960, 2930, 2857, 1624, 1583, 1560, 1501, 1381, 1322, 1277, 1065; ESIꢀHRMS [M+H]+
calcd for C19H28N5O4 m/z 390.2136, found 390.2131.
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2’, 3'-O-isopropylidene-6-phenethylamino-5'-O, 8-cycloadenosine (2g).Yield: 118
mg, 82%; white solid, mp: 73 – 74 oC. Rf = 0.50 (PE:EA = 1:2, v/v). 1H NMR (400 MHz,
CDCl3): δ 8.34 (s, 1H), 7.32 – 7.20 (m, 5H), 6.39 (s, 1H), 5.48 (br s, 1H), 5.08 (d, J = 5.6
Hz, 1H), 4.75 (d, J = 5.6 Hz, 1H), 4.69 (s, 1H), 4.47 (dd, J = 2.0, 12.8 Hz, 1H), 4.17 (d, J
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= 12.8 Hz, 1H), 3.92 (br s, 2H), 2.96 (t, J = 7.2 Hz, 2H), 1.56 (s, 3H), 1.36 (s, 3H); C
NMR (100 MHz, CDCl3): δ 153.6, 153.1, 152.7, 147.6, 138.9, 128.8, 128.6, 126.4, 115.3,
113.3, 86.6, 85.8, 85.7, 81.3, 74.4, 42.1, 36.0, 26.1, 24.7; FTIR (film, cmꢀ1): 3292, 3027,
2989, 2939, 2857, 1632, 1584, 1561, 1497, 1382, 1231, 1065; ESIꢀHRMS [M+H]+ calcd
for C21H24N5O4 m/z 410.1823, found 410.1827.
2’, 3'-O-isopropylidene-6-(4-fluorophenethyl)amino-5'-O, 8-cycloadenosine (2h).
Yield: 116 mg, 77%, white solid, mp: 82 – 84 oC. Rf = 0.45 (PE:EA = 1:2, v/v). 1H NMR
(400 MHz, CDCl3): δ 8.33 (s, 1H), 7.20 – 7.16 (m, 2H), 6.99 – 6.94 (m, 2H), 6.39 (s, 1H),
5.64 (br s, 1H), 5.08 (d, J = 5.6 Hz, 1H), 4.75 (d, J = 5.6 Hz, 1H), 4.69 (s, 1H), 4.48 (dd,
J = 2.0, 12.8 Hz, 1H), 4.18 (d, J = 12.8 Hz, 1H), 3.88 (br s, 2H), 2.93 (t, J = 7.0 Hz, 2H),
1.56 (s, 3H), 1.35 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.8, 160.3, 153.6, 153.2,
152.6, 147.7, 134.60, 134.57, 130.2, 130.1, 115.4, 115.2, 113.2, 86.6, 85.8, 85.7, 81.3,
74.4, 42.1, 35.2, 26.1, 24.6; FTIR (film, cmꢀ1): 3281, 2987, 2939, 2871, 1623, 1584, 1559,
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1508, 1382, 1220, 1065, 865; ESIꢀHRMS [M+H]+ calcd for C21H23FN5O4 m/z 428.1729,
found 428.1726.
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2’, 3'-O-isopropylidene-6-(3-chlorophenethyl)amino-5'-O, 8-cycloadenosine (2i).
Yield: 126 mg, 81%; white solid, mp: 85 – 86 oC. Rf = 0.44 (PE:EA = 1:2, v/v).1H NMR
(400 MHz, CDCl3): δ 8.32 (s, 1H), 7.21 – 7.08 (m, 4H), 6.39 (s, 1H), 5.96 (br s, 1H), 5.07
(d, J = 5.6 Hz, 1H), 4.75 (d, J = 5.6 Hz, 1H), 4.69 (s, 1H), 4.47 (d, J = 12.8 Hz, 1H), 4.18
(d, J = 12.8 Hz, 1H), 3.89 (br s, 2H), 2.93 (t, J = 6.8 Hz, 2H), 1.55 (s, 3H), 1.35 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 153.6, 153.2, 152.6, 147.7, 141.1, 134.2, 129.8, 128.9,
127.0, 126.6, 115.2, 113.3, 86.6, 85.8, 85.7, 81.3, 74.4, 41.8, 35.7, 26.1, 24.7; FTIR (film,
cmꢀ1): 3280, 3051, 2980, 2926, 2852, 1624, 1583, 1558, 1501, 1403, 1382, 1210, 1064,
865, 756; ESIꢀHRMS [M+H]+ calcd for C21H23ClN5O4 m/z 444.1433, found 444.1432.
2’, 3'-O-isopropylidene-6-(4-methylphenyl)amino-5'-O, 8-cycloadenosine (2j).
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Yield: 110 mg, 80%; white solid, mp: 105 – 108 C. Rf = 0.56 (PE:EA = 1:2, v/v). H
NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.37 (br s, 1H), 7.17 (d,
J = 8.0 Hz, 2H), 6.43 (s, 1H), 5.09 (d, J = 5.6 Hz, 1H), 4.78 (d, J = 5.6 Hz, 1H), 4.72 (s,
1H), 4.50 (dd, J = 2.0, 12.8 Hz, 1H), 4.20 (d, J = 12.8 Hz, 1H), 2.33 (s, 3H), 1.57 (s, 3H),
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1.36 (s, 3H); C NMR (100 MHz, CDCl3): δ 153.8, 152.3, 151.2, 147.8, 136.0, 133.1,
129.5, 120.8, 116.0, 113.3, 86.7, 85.8, 85.7, 81.3, 74.4, 26.1, 24.7, 20.9; FTIR (film, cmꢀ1):
3369, 3058, 2986, 2938, 2855, 1624, 1587, 1556, 1514, 1446, 1379, 1209, 1063;
ESIꢀHRMS [M+H]+ calcd for C20H22N5O4 m/z 396.1666, found 396.1666.
2’, 3'-O-isopropylidene-6-(furan-2-yl-methyl)amino-5'-O, 8-adenosine (2k).Yield:
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104 mg, 77%; white solid, mp: 74 – 76 C. Rf = 0.45 (PE:EA = 1:2, v/v). H NMR (400
MHz, CDCl3): δ 8.37 (s, 1H), 7.36 – 7.34 (m, 1H), 6.40 (s, 1H), 6.32 – 6.30 (m, 1H), 6.28
– 6.27 (m, 1H), 5.76 (t, J = 5.4 Hz, 1H), 5.08 (d, J = 5.6 Hz, 1H), 4.84 (m, 2H), 4.75 (d, J
= 5.6 Hz, 1H), 4.70 (m, 1H), 4.48 (dd, J = 2.5, 12.8 Hz, 1H), 4.18 (d, J = 12.8 Hz, 1H),
1.56 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 153.4, 153.2, 152.6, 151.8,
147.8, 142.1, 115.4, 113.3, 110.4, 107.3, 86.6, 85.8, 85.7, 81.3, 74.4, 37.8, 26.1, 24.7.
FTIR (film, cmꢀ1): 3289, 3021, 2986, 2929, 2872, 1622, 1558, 1503, 1445, 1379, 1209,
1063; ESIꢀHRMS [M+H]+ calcd for C18H20N5O5 m/z 386.1459, found 386.1462.
2’, 3'-O-isopropylidene-6-(2-hydroxyethyl)amino-5'-O, 8-cycloadenosine (2l).
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Yield: 27 mg, 22%; white solid, mp: 194 – 195 C. Rf = 0.05 (PE:EA = 1:2, v/v). H
NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 6.36 (s, 1H), 6.33 (br s, 1H), 5.07 (d, J = 5.6 Hz,
1H), 4.75 (d, J = 5.6 Hz, 1H), 4.71 (d, J = 0.8 Hz, 1H), 4.49 (dd, J = 2.0, 12.8 Hz, 1H),
4.26 (d, J = 12.8 Hz, 1H), 3.88 (br s, 2H), 3.76 (br s, 2H), 1.56 (s, 3H), 1.36 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 153.8, 153.2, 152.3, 147.3, 115.1, 113.3, 86.7, 85.7, 81.3,
74.5, 62.3, 44.1, 26.1, 24.7; FTIR (film, cmꢀ1): 3407, 3300, 2991, 2936, 2870, 1621, 1563,
1503, 1374, 1215, 1060; ESIꢀHRMS [M+H]+ calcd for C15H20N5O5 m/z 350.1459, found
350.1459.
2’, 3'-O-isopropylidene-6-(2-(formyloxy)ethyl)amino-5'-O, 8-cycloadenosine (2m).
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Yield: 19 mg, 14%; white solid, mp:86 – 88 C. Rf = 0.20 (PE:EA = 1:2, v/v). H NMR
(400 MHz, CDCl3): δ 8.33 (s, 1H), 8.07 (s, 1H), 6.40 (s, 1H), 5.85 (t, J = 5.6 Hz, 1H),
5.09 (d, J = 5.6 Hz, 1H), 4.76 (d, J = 5.6 Hz, 1H), 4.71(s, 1H), 4.51 (dd, J = 2.0, 12.8 Hz,
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1H), 4.40 (t, J = 5.6 Hz, 1H), 4.20 (d, J = 12.8 Hz, 1H), 3.97 (br s, 2H), 1.56 (s, 3H), 1.36
(s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.8, 153.5, 153.4, 152.5, 147.9, 115.4, 113.3,
86.7, 85.8, 85.7, 81.3, 74.5, 62.9, 39.6, 26.1, 24.7; FTIR (film, cmꢀ1): 3340, 2986, 2926,
2846, 1725, 1624, 1561, 1447, 1380, 1161, 1065; ESIꢀHRMS [M+H]+ calcd for
C16H20N5O6 m/z 378.1408, found 378.1406.
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2’, 3'-O-isopropylidene-6-cyclohexylamino-5'-O, 8-cycloadenosine (2n). Yield: 118
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mg, 87%. white solid, mp: 172 – 174 C. Rf = 0.52 (PE:EA = 1:2, v/v). H NMR (400
MHz, CDCl3): δ 8.32 (s, 1H), 6.38 (s, 1H), 5.39 (d, J = 8.0 Hz, 1H), 5.08 (d, J = 5.6 Hz,
1H), 4.76 (d, J = 5.6 Hz, 1H), 4.70 (s, 1H), 4.49 (d, J = 12.6 Hz, 1H), 4.18 (d, J = 12.6 Hz,
1H), 4.15 (m, 1H), 2.08 – 2.05 (m, 2H), 1.78 – 1.75 (m, 2H), 1.67 – 1.64 (m, 1H), 1.56 (s,
3H), 1.50 – 1.41 (m, 2H), 1.35 (s, 3H), 1.30 – 1.21 (m, 3H); 13C NMR (100 MHz, CDCl3):
δ 153.1, 153.0, 152.7, 147.5, 115.1, 113.2, 86.6, 85.8, 85.7, 81.3, 74.4, 49.2, 33.4, 26.1,
25.6, 24.8, 24.7; FTIR (film, cmꢀ1): 3416, 2989, 2930, 2855, 1619, 1582, 1493, 1381,
1161, 1066; ESIꢀHRMS [M+H]+ calcd for C19H26N5O4 m/z 388.1979, found 388.1980.
2’, 3'-O-isopropylidene-6-methoxyl-5'-O, 8-cycloinosine (2o).Yield: 70 mg, 62%;
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white solid, mp:184 – 185 C. Rf = 0.43 (PE:EA = 1:2, v/v). H NMR (400 MHz,
CDCl3): δ 8.47 (s, 1H), 6.45 (s, 1H), 5.11 (d, J = 5.6 Hz, 1H), 4.78 (d, J = 5.6 Hz, 1H),
4.73 (s, 1H), 4.55 (dd, J = 2.0, 13.2 Hz, 1H), 4.22 (d, J = 13.2 Hz, 1H), 4.15 (s, 3H), 1.57
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(s, 3H), 1.36 (s, 3H); C NMR (100 MHz, CDCl3): δ 159.7, 154.9, 151.6, 150.3, 117.6,
113.4, 86.9, 85.8, 85.7, 81.3, 74.5, 54.2, 26.1, 24.6; FTIR (film, cmꢀ1): 2989, 2942, 2867,
1610, 1580, 1548, 1481, 1452, 1376, 1199, 1062; ESIꢀHRMS [M+H]+ calcd for
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2’, 3'-O-isopropylidene-6-propoxyl-5'-O, 8-cycloinosine (2p).Yield: 75 mg, 61%;
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white solid, mp: 116 – 118 C. Rf = 0.69 (PE:EA = 1:2, v/v). H NMR (400 MHz,
CDCl3): δ 8.45 (s, 1H), 6.45 (s, 1H), 5.11 (d, J = 5.6 Hz, 1H), 4.78 (d, J = 5.6 Hz, 1H),
4.73 (s, 1H), 4.55 – 4.49 (m, 3H), 4.22 (d, J = 13.2 Hz, 1H), 1.89 (sext, J = 7.2 Hz, 2H),
1.57 (s, 3H), 1.36 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 159.7,
154.8, 151.6, 150.4, 117.5, 113.3, 86.9, 85.78, 85.76, 81.3, 74.5, 68.8, 26.1, 24.6, 22.2,
10.4; FTIR (film, cmꢀ1): 2969, 2938, 1608, 1579, 1547, 1376, 1318, 1187, 1061;
ESIꢀHRMS [M+H]+ calcd for C16H21N4O5 m/z 349.1506, found 349.1501.
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2’, 3'-O-isopropylidene-6-propylthio-5'-O, 8-cycloinosine (2q).Yield: 71 mg, 56%;
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white solid, mp: 140 – 141 C. Rf = 0.80 (PE:EA = 1:2, v/v). H NMR (400 MHz,
CDCl3): δ 8.63 (s, 1H), 6.44 (s, 1H), 5.10 (d, J = 5.6 Hz, 1H), 4.75 (d, J = 5.6 Hz, 1H),
4.73 (s, 1H), 4.55 (dd, J = 2.0, 13.2 Hz, 1H), 4.24 (d, J = 13.2 Hz, 1H), 3.35 (dt, J = 7.2,
13.2 Hz, 1H), 3.31 (dt, J = 7.2, 13.2 Hz, 1H), 1.79 (sext, J = 7.2 Hz, 2H), 1.56 (s, 3H),
1.35 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 159.1, 155.3, 151.5,
146.9, 128.1, 113.4, 86.7, 85.75, 85.73, 81.3, 74.7, 30.6, 26.1, 24.6, 22.9, 13.4; FTIR
(film, cmꢀ1): 2964, 2963, 2873, 1585, 1530, 1431, 1382, 1184, 1105; ESIꢀHRMS [M+H]+
calcd for C16H21N4O4S m/z 365.1278, found 365.1279.
2’, 3'-O-isopropylidene-2-methoxythio-6-(3-methoxyphenethyl)amino-5'-O, 8-cyclo
o
adenosine (4a). Yield: 121 mg, 79%; white solid, mp:73 – 74 C. Rf = 0.48 (PE:EA =
1
1:2, v/v). H NMR (400 MHz, CDCl3): δ 7.16 (t, J = 8.0 Hz, 1H), 6.79 – 6.70 (m, 3H),
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6.33 (s, 1H), 5.90 (br s, 1H), 5.04 (d, J = 5.6 Hz, 1H), 4.74 (d, J = 5.6 Hz, 1H), 4.65 (s,
1H), 4.43 (dd, J = 1.6, 13.2 Hz, 1H), 4.13 (d, J = 13.2 Hz, 1H), 3.86 (br s, 2H), 3.76 (s,
3H), 2.90 (t, J = 7.2 Hz, 2H), 2.57 (s, 3H), 1.55 (s, 3H), 1.34 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 163.9, 158.7, 152.0, 151.2, 147.1, 139.6, 128.5, 120.1, 113.5, 112.1,
111.3, 110.5, 85.4, 84.7, 84.6, 80.3, 73.3, 54.1, 40.8, 35.0, 25.1, 23.6, 13.5; FTIR (film,
cmꢀ1): 3294, 2989, 2935, 2825, 1619, 1584, 1561, 1443, 1382, 1220, 1064; ESIꢀHRMS
[M+H]+ calcd for C23H28N5O5S m/z 486.1806, found 486.1804.
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2’, 3'-O-isopropylidene-2-ethylthio-6-phenethylamino-5'-O, 8-cycloadenosine (4b).
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Yield: 134 mg, 82%; white solid, mp = 85 – 86 C; Rf = 0.55 (PE:EA = 1:2, v/v). H
NMR (400 MHz, CDCl3): δ 7.30 – 7.18 (m, 5H), 6.35 (s, 1H), 5.62 (br s, 1H), 5.05 (d, J
= 5.6 Hz, 1H), 4.73 (d, J = 5.6 Hz, 1H), 4.66 (s, 1H), 4.43 (d, J = 12.6 Hz, 1H), 4.13 (d, J
= 12.6 Hz, 1H), 3.87 (br s, 2H), 3.20 (dt, J = 7.2, 14.2 Hz, 1H), 3.15 (dt, J = 7.2, 14.2 Hz,
1H), 2.92 (t, J = 7.2 Hz, 2H), 1.56 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H), 1.35 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 164.6, 153.1, 152.3, 148.3, 139.0, 128.8, 128.6, 126.4, 113.1,
112.4, 86.4, 85.8, 85.7, 81.3, 74.4, 42.0, 36.0, 26.1, 25.6, 24.6, 15.0; FTIR (film, cmꢀ1):
3292, 3062, 2989, 2930, 2870, 1600, 1559, 1495, 1444, 1357, 1065; ESIꢀHRMS [M+H]+
calcd for C23H28N5O4S m/z 470.1857, found 470.1859.
2’, 3'-O-isopropylidene-2-ethylthio-6-(3-methoxybenzyl)amino-5'-O, 8-cycloadeno-
o
sine (4c). Yield: 131 mg, 77%; white solid, mp: 78 – 79 C; Rf = 0.54 (PE:EA = 1:2,
1
v/v). H NMR (400 MHz, CDCl3): δ 7.22 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H),
6.31 (s, 1H), 6.03 (br s, 1H), 5.02 (d, J = 5.6 Hz, 1H), 4.72 (m, 2H), 4.70 (d, J = 5.6 Hz,
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1H), 4.64 (s, 1H), 4.38 (d, J = 12.8 Hz, 1H), 4.09 (d, J = 12.8 Hz, 1H), 3.77 (s, 3H), 3.16
(dq, J = 7.2, 14.4 Hz, 1H), 3.10 (dq, J = 7.2, 14.4 Hz, 1H), 1.54 (s, 3H), 1.37 (t, J = 7.2
Hz, 3H), 1.34 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 164.6, 158.9, 152.9, 152.3, 148.4,
130.9, 128.9, 113.9, 113.1, 112.4, 86.4, 85.8, 85.7, 81.3, 74.4, 55.3, 44.0, 26.1, 25.5, 24.6,
14.9; FTIR (film, cmꢀ1): 3303, 2995, 2930, 2870, 1615, 1582, 1560, 1511, 1443, 1381,
1246, 1064; ESIꢀHRMS [M+H]+ calcd for C23H28N5O5S m/z 486.1806, found 486.1806.
2’, 3'-O-isopropylidene-2-ethylthio-6-hexylamino-5'-O, 8-cycloadenosine (4d).
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Yield: 122 mg, 77%; semisolid. Rf = 0.68 (PE:EA = 1:2, v/v). H NMR (400 MHz,
CDCl3): δ 6.33 (s, 1H), 5.44 (br s, 1H), 5.07 (d, J = 5.6 Hz, 1H), 4.75 (d, J = 5.6 Hz, 1H),
4.67 (s, 1H), 4.46 (dd, J = 2.0, 12.8 Hz, 1H), 3.59 (br s, 2H), 3.18 (dq, J = 7.2, 14.0 Hz,
1H), 3.12 (dq, J = 7.2, 14.0 Hz, 1H), 1.60 (quint, J = 7.2 Hz, 2H), 1.56 (s, 3H), 1.42 –
13
1.30 (m, 12H), 0.88 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 164.5, 153.3,
152.2, 148.2, 113.1, 112.3, 86.4, 85.8, 85.7, 81.3, 74.4, 40.8, 31.5, 29.8, 26.6, 26.1, 25.5,
24.6, 22.6, 14.9, 14.0; FTIR (film, cmꢀ1): 3305, 2962, 2929, 2857, 1619, 1584, 1562,
1497, 1444, 1374, 1221, 1065; ESIꢀHRMS [M+H]+ calcd for C21H32N5O4S m/z 450.2170,
found 450.2170.
2’, 3'-O-isopropylidene-2,6-dimethoxy-5'-O, 8-cycloguanosine (4e). Yield: 70 mg,
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57%; white solid, mp: 81 – 82 C; Rf = 0.40 (PE:EA = 1:2, v/v). H NMR (400 MHz,
CDCl3): δ 6.35 (s, 1H), 5.10 (d, J = 5.6 Hz, 1H), 4.80 (d, J = 5.6 Hz, 1H), 4.70 (s, 1H),
4.49 (dd, J = 2.0, 12.8 Hz, 1H), 4.18 (d, J = 12.8 Hz, 1H), 4.12 (s, 3H), 4.02 (s, 3H), 1.58
13
(s, 3H), 1.37 (s, 3H); C NMR (100 MHz, CDCl3): δ 161.2, 161.0, 153.5, 151.4, 113.2,
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112.5, 86.7, 85.8, 85.7, 81.4, 74.4, 55.1, 54.3, 26.1, 24.6; FTIR (film, cmꢀ1): 2988, 2941,
2870, 1613, 1560, 1479, 1390, 1365, 1218, 1061; ESIꢀHRMS [M+H]+ calcd for
C15H19N4O6 m/z 351.1299, found 351.1297.
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2’, 3'-O-isopropylidene-2-amino-6-phenethylamino-5'-O, 8-cycloguanosine (4f).
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Yield: 25 mg, 17%; white solid, mp: 219 – 220 C. Rf = 0.38 (PE:EA = 1:2, v/v); H
NMR (400 MHz, CDCl3): δ 7.33 – 7.26 (m, 2H), 7.23 – 7.16 (m, 3H), 6.20 (s, 1H), 5.34
(br s, 1H), 5.05 (d, J = 5.6 Hz, 1H), 4.74 (d, J = 5.6 Hz, 1H), 4.68 (s, 2H), 4.64 (s, 1H),
4.40 (dd, J = 2.0, 12.8 Hz, 1H), 4.10 (d, J = 12.8 Hz, 1H), 3.82 (br s, 2H), 2.92 (t, J = 7.0
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Hz, 2H), 1.54 (s, 3H), 1.34 (s, 3H); C NMR (100 MHz, CDCl3): δ 159.4, 154.2, 151.2,
149.5, 139.0, 128.8, 128.6, 126.4, 113.1, 109.1, 86.3, 85.8, 85.7, 81.5, 74.2, 42.0, 36.1,
26.1, 24.7; FTIR (film, cmꢀ1): 3387, 3320, 3018, 2987, 2930, 2854, 1603, 1565, 1497,
1455, 1394, 1218, 1065; ESIꢀHRMS [M+H]+ calcd for C21H25N6O4 m/z 425.1932, found
425.1935.
2’, 3'-O-isopropylidene-2-iodo-6-phenethylamino-5'-O, 8-cycloadenosine (4g).Yield:
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151 mg, 81%; white solid, mp: 116 – 118 C. Rf = 0.60 (PE:EA = 1:2, v/v); H NMR
(400 MHz, CDCl3): δ 7.31 – 7.20 (m, 5H), 6.35 (s, 1H), 5.62 (br s, 1H), 5.04 (d, J = 5.6
Hz, 1H), 4.72 (d, J = 5.6 Hz, 1H), 4.68 (s, 1H), 4.45 (d, J = 12.8 Hz, 1H), 4.15 (d, J =
12.8 Hz, 1H), 3.86 (br s, 2H), 2.93 (t, J = 7.2 Hz, 2H), 1.54 (s, 3H), 1.35 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 153.2, 152.7, 138.5, 128.8, 128.7, 126.6, 119.1, 114.9, 113.4,
86.7, 85.8, 85.7, 81.3, 74.6, 42.1, 35.8, 26.1, 24.7; FTIR (film, cmꢀ1):3286, 3018, 2987,
2938, 2870, 1620, 1566, 1495, 1376, 1300, 1275, 1218, 1064; ESIꢀHRMS [M+H]+ calcd
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for C21H23IN5O4 m/z 536.0789, found 536.0791.
2’, 3'-O-isopropylidene-2-choloro-6-cyclohexylamino-5'-O, 8-cycloadenosine (4h).
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Yield: 133 mg, 90%; white solid, mp: > 250 C. Rf = 0.68 (PE:EA = 1:2, v/v); H NMR
(400 MHz, CDCl3): δ 6.35 (s, 1H), 5.44 (d, J = 8.0 Hz, 1H), 5.07 (d, J = 5.6 Hz, 1H),
4.69 (s, 1H), 4.48 (dd, J = 2.0, 12.8 Hz, 1H), 4.17 (d, J = 12.8 Hz, 1H), 4.16 (m, 1H),
2.06 – 2.03 (m, 2H), 1.77 – 1.66 (m, 2H), 1.65 – 1.63 (m, 1H), 1.54 (s, 3H), 1.50 – 1.41
(m, 2H), 1.35 (s, 3H), 1.29 – 1.21 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 153.7, 153.1,
147.8, 113.8, 113.3, 86.7, 85.8, 85.7, 81.3, 74.5, 49.2, 33.2, 26.1, 25.5, 24.7, 24.6; FTIR
(film, cmꢀ1): 3403, 2974, 2932, 2853, 1621, 1566, 1497, 1445, 1380, 1247, 1066;
ESIꢀHRMS [M+H]+ calcd for C19H25ClN5O4 m/z 422.1590, found 422.1588.
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2’, 3'-O-cyclohexylidene-6-methoxyethylamino-5'-O, 8-cycloadenosine (4i).Yield:
115 mg, 81%; white solid, mp: 158 – 159 oC. Rf = 0.25 (PE:EA = 1:2, v/v); 1H NMR (400
MHz, CDCl3): δ 8.30 (s, 1H), 6.36 (s, 1H), 5.85 (t, J = 5.2 Hz, 1H), 5.06 (d, J = 5.6 Hz,
1H), 4.73 (d, J = 5.6 Hz, 1H), 4.68 (s, 1H), 4.46 (dd, J = 1.6, 12.8 Hz, 1H), 4.16 (d, J =
12.8 Hz, 1H), 3.80 (br s, 2H), 3.57 (t, J = 5.2 Hz, 2H), 3.35 (s, 3H), 1.77 – 1.73 (m, 2H),
1.66 – 1.62 (m, 2H), 1.57 – 1.54 (m, 4H), 1.39 – 1.37 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 153.6, 153.2, 152.6, 147.5, 115.4, 114.1, 86.7, 85.8, 85.4, 80.9, 74.4, 71.2, 58.8,
40.5, 35.8, 34.2, 24.9, 23.9, 23.7; FTIR (film, cmꢀ1): 3305, 2936, 2860, 1624, 1583, 1560,
1499, 1379, 1238, 1114, 1058; ESIꢀHRMS [M+H]+ calcd for C19H26N5O5 m/z 404.1928,
found 404.1926.
2’, 3'-O-cyclohexylidene-6-cyclohexylamino-5'-O, 8-cycloadenosine (4j).Yield: 131
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mg, 88%; white solid, mp: 210 – 211 C; Rf = 0.60 (PE:EA = 1:2, v/v); H NMR (400
MHz, CDCl3): δ 8.32 (s, 1H), 6.39 (s, 1H), 5.38 (d, J = 8.4 Hz, 1H), 5.08 (d, J = 5.6 Hz,
1H), 4.75 (d, J = 5.6 Hz, 1H), 4.70 (s, 1H), 4.49 (dd, J = 1.6, 13.0 Hz, 1H), 4.18 (d, J =
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13.0 Hz, 1H), 4.17 (m, 1H), 2.08 – 2.06 (m, 2H), 1.78 – 1.21 (m, 18H); C NMR (100
MHz, CDCl3): δ 153.1, 153.0, 152.7, 147.5, 115.1, 114.0, 86.7, 85.8, 85.4, 80.9, 74.4,
49.2, 35.8, 34.2, 33.4, 25.6, 24.9, 24.8, 23.9, 23.7; FTIR (film, cmꢀ1): 3418, 2987, 2931,
2855, 1619, 1558, 1493, 1448, 1367, 1239, 1058; ESIꢀHRMS [M+H]+ calcd for
C22H30N5O4 m/z 428.2292, found 428.2290.
2’, 3'-O-cyclohexylidene-2-ethylthio-6-phenethylamino-5'-O, 8-cycloadenosine (4k).
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Yield: 146 mg, 82%; white solid, mp: 121 – 122 C; Rf = 0.68 (PE:EA = 1:2, v/v); H
NMR (400 MHz, CDCl3): δ 7.30 – 7.18 (m, 5H), 6.33 (s, 1H), 5.70 (br s, 1H), 5.04 (d, J
= 5.6 Hz, 1H), 4.71 (d, J = 5.6 Hz, 1H), 4.66 (s, 1H), 4.42 (d, J = 12.8 Hz, 1H), 4.12 (d, J
= 12.8 Hz, 1H), 3.86 (br s, 2H), 3.22 (dq, J = 7.2, 14.4 Hz, 1H), 3.14 (dq, J = 7.2, 14.4 Hz,
1H), 2.93 (t, J = 7.0 Hz, 2H), 1.77 (m, 2H), 1.66 – 1.65 (m, 2H), 1.56 (m, 4H), 1.44 –
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1.40 (m, 5H); C NMR (100 MHz, CDCl3): δ 164.5, 153.1, 152.3, 148.5, 139.0, 128.8,
128.6, 126.4, 113.9, 112.5, 86.6, 85.8, 85.4, 80.9, 74.4, 42.0, 36.0, 35.8, 34.1, 25.6, 25.0,
24.0, 23.7, 15.0; FTIR (film, cmꢀ1): 3304, 3031, 2960, 2937, 2863, 1619, 1584, 1562,
1496, 1448, 1359, 1222, 1057; ESIꢀHRMS [M+H]+ calcd for C26H32N5O4S m/z 510.2170,
found 510.2164.
Preparation of 2’, 3'ꢀOꢀisopropylideneadenosine (1b)
Triethyl orthoformate (1 mL) and SOCl2 (5.4 g, 0.045 mol) were subsequently and
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slowly added into the solution of adenosine (4 g, 0.015 mol) in acetone (80 mL). The
resulted mixture was stirred at room temperature overnight. After neutralization with
solution of sodium carbonate, the solution was cooled to crystallize. After filtration, 2’,
3'ꢀOꢀisopropylideneadenosine (1b) was obtained as white solid (4.2 g, 91% yield). mp:
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215 – 216 C. Rf = 0.26 (EA: CH3OH = 1:15, v/v); H NMR (400 MHz, DMSOꢀd6): δ
8.37 (s, 1H), 8.19 (s, 1H), 7.39 (br s, 2H), 6.16 (d, J = 2.8 Hz, 1H), 5.37 (dd, J = 2.8, 6.0
Hz, 1H), 5.28 (t, J = 6.0 Hz, 1H), 4.99 (dd, J = 2.4, 6.0 Hz, 1H), 4.25 (m 1H), 3.63 – 3.52
(m, 2H), 1.56 (s, 3H), 1.34 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6): δ 156.1, 152.6,
148.8, 139.7, 119.1, 113.0, 89.6, 86.3, 83.2, 81.3, 61.6, 27.0, 25.1; FTIR (neat, cmꢀ1):
3297, 2989, 2940, 1630, 1583, 1562, 1508, 1445, 1318, 1208, 1064. ESIꢀHRMS [M+H]+
calcd for C13H18N5O4, m/z 308.1353, found 308.1352.
Preparation of 5'ꢀO, 8ꢀcycloadenosine
2’, 3'ꢀOꢀisopropylideneꢀ5'ꢀO, 8ꢀcycloadenosine (2b, 200 mg, 0.66 mmol) was
dissolved in the mixture solvents CH3OHꢀH2OꢀCF3COOH (20 mLꢀ10 mLꢀ10 mL) and
refluxed for 5 h. Then, the reaction mixture was evaporated under reduced pressure and
the residue was purified by chromatography on silica gel (CH2Cl2/MeOH: 10/1). The
desired 5'ꢀO, 8ꢀcycloadenosine was finally obtained as a white solid (116 mg, 67%).
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mp: >250 C; Rf = 0.26 (EA: CH3OH = 1: 5, v/v); H NMR (400 MHz, DMSOꢀd6): δ
8.12 (s, 1H), 7.07 (s, 2H), 5.98 (s, 1H), 5.65 (d, J = 6.4 Hz, 1H), 5.35 (d, J = 5.2 Hz, 1H),
4.59 (d, J = 12.8 Hz, 1H), 4.56 (s, 1H), 4.46 (dd, J = 5.6, 5.2 Hz, 1H), 4.25 (dd, J = 5.6,
6.4 Hz), 4.09 (d, J = 12.8 Hz, 1H); 13C NMR (100 MHz, DMSOꢀd6): δ 154.7, 153.3,
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151.9, 147.6, 114.3, 88.7, 88.1, 77.2, 74.7, 71.1; FTIR (neat, cmꢀ1): 3421, 3300, 2960,
2926, 2855, 1648, 1552, 1413, 1327, 1207, 1086; ESIꢀHRMS [M+H]+ calcd for
C10H12N5O4, m/z 266.0884, found 266.0880.
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Radical trapping experiment
Under ambient atmosphere, substrate 1c (112 mg, 0.35 mmol) , CuCl (17.3 mg, 0.175
mmol) and TEMPO (109.4 mg, 0.7 mmol) were suspended in DMF (3 mL) in a 15 mL
vial. DTBP (154 mg, 1.05 mmol) was then added to the mixture. The vial was sealed with
a Teflon lined cap, and the reaction was heated at 80 oC for 12 h. Then, the reaction
mixture was diluted with ethyl acetateꢀH2O (100ꢀ15 mL). A 1M HCl (0.1 mL) was added
to the mixture. The organic and the aqueous layers were separated and the organic layer
was washed with brine (3×25 mL).The organic layer was dried over MgSO4, filtered, and
concentrated. The resulting oil was purified by chromatography on silica gel to afford
white
solid
2’,3'ꢀOꢀisopropylideneꢀ6ꢀmethylaminoꢀ5'ꢀoxoꢀ4’ꢀ(2,2,6,6ꢀtetramethyl
o
piperidinꢀ1ꢀyl)ꢀoxyladenosine (2c’, 68 mg, 42%). mp: 180 C; Rf = 0.37 (PE:EA = 1:2,
v/v). 1H NMR (400 MHz, CDCl3): δ 9.71 (s, 1H), 8.41 (s, 1H), 7.94 (s, 1H), 6.33 (s, 1H),
5.95 (d, J = 5.6 Hz, 1H), 5.90 (m, 1H), 5.68 (d, J = 5.6 Hz, 1H), 3.20 (br s, 3H), 1.50 –
1.48 (m,1H), 1.44 (s, 3H), 1.40 (s, 3H), 1.37 (s, 3H), 1.37 – 1.31 (m, 2H), 1.31 – 1.25 (m,
13
2H), 1.22 – 1.20 (m, 1H), 0.93 (s, 3H), 0.91 (s, 3H), 0.15 (s, 3H); C NMR (100 MHz,
CDCl3): δ 190.5, 155.5, 153.1, 148.3, 140.0, 120.1, 114.6, 114.0, 90.1, 87.0, 82.8, 61.5,
60.9, 39.96, 39.86, 33.4, 31.8, 27.6, 25.8, 25.1, 20.4, 19.8, 16.6; FTIR (film, cmꢀ1): 3440,
3287, 3110, 2978, 2934, 2872, 2854, 1741, 1625, 1579, 1536, 1445, 1377, 1215, 1074;
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ESIꢀHRMS [M+H]+ calcd for C23H35N6O5, m/z 475.2663, found 475.2665.
ASSOCIATED CONTENTS
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Supporting Information
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Copies of 1H and 13C NMR spectral for the products are available free of charge via the
Internet at http://pubs.acs.org
.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: dhg@mail.buct.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from the National Natural Science Foundation of
China (Grant 21272022).
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