A novel one-step method for the synthesis of C-5-substituted O 6,5′-cyclopyrimidine nucleoside analogues in ammonia water

Article abstract of DOI:10.1021/jo7026245

(Chemical Equation Presented) A novel one-step method for preparing C-5-substituted O⁶,5′-cyclopyrimidine nucleoside analogues is reported. This method employs molecular iodine to mediate the cyclization from the 5′-O-hydroxyl group of the sugar ring and C-6 at the position of the nitrogen base in ammonia water under mild conditions without any other aprotic organic solvent.

Full text of DOI:10.1021/jo7026245

tion of physical properties with respect to structural character-
istics. Some of these have been used to examine the relationship
between the circular dichroism (CD) spectra and the N-glycosyl
conformation.
A Novel One-Step Method for the Synthesis of
C-5-Substituted O6,5′-Cyclopyrimidine Nucleoside
Analogues in Ammonia Water
Gui-Rong Qu,* Bo Ren, Hong-Ying Niu, Zhi-Jie Mao, and
Hai-Ming Guo*
SCHEME 1
College of Chemistry and EnVironmental Science, Henan
Normal UniVersity, Xinxiang 453007, Henan, P. R. China
ghm@henannu.edu.cn
ReceiVed December 12, 2007
There are some reports about the synthesis of a number of
O6,5′-cyclonucleosides.8-13 For example, the 2′,3′-O-isopropy-
lidenpyrimidine nucleoside 1 with excess N-halogenosuccin-
imides (NBS, NIS) in an aprotic solvent (such as DMF,
DMSO)14 will be converted into a 5,6-saturated cyclonucleosides
2 intermediate which presumably converted to O6,5′-cyclo-
nucleoside 3 by the loss of hydrogen halide (Scheme 1). This
method includes two steps and need organic solvent and strong
base. So convenient and simple method for the synthesis of
O6,5′-cyclonucleosides is more desirable. Herein, we report a
one-step method for the synthesis of C-5-substituted O6,5′-
cyclopyrimidine nucleoside analogues under mild conditions.
Compared to the old methods, this method is easy to operate
and low toxic by using molecular iodine to mediate the
cyclization in ammonium water.
A novel one-step method for preparing C-5-substituted O6,5′-
cyclopyrimidine nucleoside analogues is reported. This
method employs molecular iodine to mediate the cyclization
from the 5′-O-hydroxyl group of the sugar ring and C-6 at
the position of the nitrogen base in ammonia water under
mild conditions without any other aprotic organic solvent.
We initially attempted to obtain 2′,3′-O-isopropylidene-5-
iodouridine by the reaction between molecular iodine and 2′,3′-
O-isopropylideneuridine in ammonia water. However, two
products were shown by TLC analysis of the reaction mixture
after 30 min at 60 °C (Scheme 2). One was confirmed as 1c by
NMR. We first expected the other product as 2′,3′-O-isopro-
pylidene-O6,5′-cyclouridine 3f which was obtained by treatment
of 2′,3′-O-isopropylidene-5-halogenouridine in alkaline media
Cyclic analogues of nucleosides are compounds in which the
additional cycle is formed between the sugar ring and the
nitrogen base. First discovered by Todd and co-workers, these
compounds have received more and more attention.1 Cyclo-
nucleosides have served as useful synthetic intermediates2 and
in the introduction of a variety of functionalities into the
heterocyclic and carbohydrate moieties of nucleosides.3,4 They
are expected to have a potential biological impact especially
toward enzymatic repair processes.5 Cyclonucleosides are also
important in connection with nucleoside configurational studies.6
The shaping of the O-bridge between the hydroxymethyl group
and position 6 of pyrimidine makes the nucleoside a confor-
mationally fixed one.7 Their rigid structures facilitate interpreta-
1
as described by Honjo et al. and others.4,12,15 However, the H
NMR spectrum showed clearly the signals corresponding to the
vinylic protons (5: δ 5.64 and 7.80 ppm) disappeared and two
methine proton signals at δ 4.022 and 4.668 (2d, 2H, each J )
12.4 Hz, C5′-H) which are characteristic of the O6,5′-cyclopy-
(6) (a) Saenger, W. Angew. Chem. 1973, 85, 680. (b) Lee, C. H.; Evans,
F. E.; Sarrna, R. H. J. Biol. Chem. 1975, 250, 1290. (c) Evans, F. E.; Sarrna,
R. H. J. Am. Chem. Soc. 1975, 97, 3215. (d) ZernliEka, J. J. Am. Chem.
Soc. 1975, 97, 5896 and references cited therein.
(7) Yuichi, Y.; Yoshiko, Y.; Katsunori, W.; Shinya, S.; Hiroki, T. Synlett
2007, 111.
(8) Lipkin, D.; Cori, C.; Sano, M. Tetrahedron Lett. 1968, 9, 5993.
(9) Falco, E. A.; Otter, B. A.; Fox, J. J. J. Org. Chem. 1970, 35, 2326.
(10) Lipkin, D.; Rabi, J. A. J. Am. Chem. Soc. 1971, 93, 3309.
(11) Lipkin, D.; Howard, F.; Nowotny, D.; Sano, M. Abstracts, Sixth
International Congress on Biochemistry, New York, 1964, pp 1-117.
(12) Otter, B. A.; Falco, E. A.; Fox, J. J. J. Org. Chem. 1969, 34, 1390.
(13) Chang, P. K. J. Org. Chem. 1965, 30, 3913.
(1) (a) Clark, V. M.; Todd, A. R.; Zussman, J. J. Chem. Soc. 1951, 2952.
(b) Vina, D.; Quezada, E.; Santana, L.; Uriarte, E. Tetrahedron 2006, 62,
9949. (c) Yuichi, Y.; Yoshiko, Y.; Katsunori, W.; Shinya, S.; Hiroki, T.
Synlett 2007, 111. (d) Yoshimura, Y.; Kumamoto, H.; Baba, A.; Takeda,
S.; Tanaka, H. Org. Lett. 2004, 6, 1793. (e) Dahl, O.; Jensen, J.; Petersen
M. A.; Henriksen, U. Org. Biol. Chem. 2005, 3, 1964. (f) Boesen, T.;
Madsen, C.; Pedersen, D. S.; Nielsen, B. M.; Petersen, A. B.; Petersen M.
A.; Munck, M.; Henriksen, U.; Nielsen, C.; Dahl O. Org. Biol. Chem. 2004,
2, 1245.
(2) Fox, J. J. Pure Appl. Chem. 1969, 18, 223.
(3) Sako, M.; Saito, T.; Kameyama, K.; Hirota, K.; Maki, Y. Synthesis
1987, 9, 829.
(4) Maruyama, T.; Kimura, S.; Sato, Y.; Honjo, M. J. Org. Chem. 1983,
48, 2719.
(5) Muller, E.; Gasparutto, D.; Jaquinod, M.; Romieu, A.; Cadet, J.
Tetrahedron 2000, 56, 8689.
(14) Vina, D.; Quezada, E.; Santana, L.; Uriarte, E. Tetrahedron 2006,
62, 9949.
(15) Maruyama, T.; Sato, S.; Honjo, M. Chem. Pharm. Bull. 1982, 30,
2688.
10.1021/jo7026245 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/27/2008
2450
J. Org. Chem. 2008, 73, 2450-2453

TABLE 1. Effect of Reaction Conditions on Cyclization of
Nucleosidesa
SCHEME 2
entry
base
T (°C)
time (h)
yieldb (%)
1
2
3
4
5
6
7
8
9
NH3‚H2O
60
60
60
60
60
60
25
60
60
80
100
2
3
4
4
5
90
50
52
NaOHc
c
K2CO3
EtNH2
Et3N
46
trace
trace
83
42
90
DMAPc
NH3‚H2O
NH3‚H2O
NH3‚H2O
NH3‚H2O
NH3‚H2O
5
48
0.5
2
2
2
10
11
85
87
a The reaction was conducted with 1a (1 mmol), I2 (761 mg, 3 mmol),
and base (3 mL) at 60 °C. b Isolated yields based on 1a. c 3 equiv of base
and 5 mL of H2O were used.
TABLE 2. Halogen Effects on Cyclization of Nucleosidesa
entry
X2
T (°C)
time (h)
yieldb (%)
1
free
free
Br2
I2
60
60
25
60
2
2
0.5
2
0
0
0
2c
3
4
90
a The reaction was conducted with 1a (1 mmol), X2 (761 mg, 3 mmol),
and NH3 water (3 mL, 45 mmol). b Isolated yields based on 1a. c 1c was
instead of 1a.
SCHEME 3
5 and 6). Thus, ammonia water became the best choice for the
reaction. The influence of the temperature on the kinetics of
the cyclization was also conducted (entries 7-11). When the
temperature was 60 °C, the cyclization of nucleosides went very
smoothly within 2 h to afford the best results. When the reaction
temperature was lower than 60 °C, lower yields were obtained
(entries 7 and 8). When the reaction temperature was higher
than 60 °C, no obvious variation in yields was observed (entries
10 and 11). So the optimal reaction temperature was 60 °C. It
was noteworthy that the products could also be obtained in good
yield when the reaction was conducted at room temperature
(entry 7) within 2 days.
To investigate the influence of iodine, we carried out the
reaction without iodine under the same conditions. As shown
in Table 2, 1a or 1c was failed to convert into cyclization
counterparts 3a in ammonia water without iodine (entries 1 and
2). The treatment of 1a with bromine in ammonia water gave
only 2′,3′-O-isopropylidene-5-bromouridine 1f which was iden-
tified by comparison with an authentic sample,17 no formation
of cyclization products in this reaction was shown by TLC
analysis (entry 3). That is to say, iodine was essential to the
reaction. Because molecular iodine is easy to sublimate under
microwave irradiation and the concentration of iodine in the
solution might be low, lower yield was obtained when lower
equivalents of iodine (1 or 2 equiv) were used.
rimidine nucleosides,16 were observed. On the other hand, the
13C NMR of the signal corresponding to the carbonyl at position
5 of 1a was shifted from δ 101.6 to 61.0 ppm for 3a due to
heavy atom effect of halogen of C-5. HMBC, HMQC, and
COSY spectra also ascertained that the H-5′ signals of anhydro
nucleosides contained an oxygen bridge between C-5′ and C-5-
substituted aglycon. HRMS data showed that [M + Na+] was
430.9691. So the product was proved to be 3a. It is noteworthy
that when the reaction time prolonged up to 2 h, 1c was not
detected and 3a was obtained in 90% isolated yields. Further-
more, 3a can also be prepared starting from 1c under the same
conditions in 95% yield within 0.5 h. On the other hand,
treatment of the 2′,3′-O isopropylidenecytidine 1b with I2/NH3‚
H2O for 4 h at 60 °C resulted in the formation of the cyclization
derivatives 3b in good yield (Scheme 3). It could be concluded
that 2′,3′-O-isopropylidenpyrimidine compounds could be di-
rectly converted to corresponding cyclonucleosides in ammonia
water by using molecular iodine to mediate the cyclization.
The influences of reaction conditions were examined as
summarized in Table 1. When ammonia water was used as a
base for the reaction, excellent yield was observed (entry 1).
Sodium hydroxide, potassium carbonate, and ethylamine could
also be used as the bases, and lower yields were observed
(entries 2-4). However, no product was obtained by employing
Et3N or 4-dimethylaminopyridine (DMAP) as the bases (entries
In order to study the application of this method, the influence
of different substituents in nucleosides bases was examined. The
obtained products are shown in Table 3. As can be seen, C-5-
substituted 2′,3′-O-isopropylidenpyrimidine nucleosides could
be easily converted into the corresponding cyclonucleosides in
short reaction times with good to high yields (Table 3). When
starting from C-5 unsubstituted pyrimidines, the reaction led to
(17) (a) Ueda, T. Chem. Pharm. Bull. 1960, 8, 455. (b) Smrt, J.; Sorm,
F. Collect. Czech. Chem. Commmun. 1960, 25, 553. (c) Kochetkov, N. K.;
Budovsky, E. I.; Shibaev, V. N.; Yeliseeva, G. I.; Grachev, M. A.;
Demushkin. V. P. Tetrahedron 1963, 19, 1207.
(16) Cadet, J.; Kan, L. S.; Wang, S. Y. J. Am. Chem. Soc. 1978, 100,
6715.
J. Org. Chem, Vol. 73, No. 6, 2008 2451

TABLE 3. Cyclization Using Different C-5-Substituted
Nucleosidesa
SCHEME 5
entry
R1
R2
R3
product
time (h)
yieldb (%)
1
2
3
4
5
OH
OH
NH2
NH2
NH2
H
I
H
F
I
I
I
F
Br
3a
3a
3b
3d
3e
2
0.5
4
3
4
83
90
80
75
63
In summary, we have developed a novel one-step efficient
synthetic method to prepare 5-substituted O6,5′-cyclopyrimidine
nucleoside analogues. Compared to the old method, which
usually contains two or more steps, this new method has only
one step and the yield is high. This method has several
advantages such as operational simplicity, low cost, and low
toxicity by using molecular iodine instead of N-halogenosuc-
cinimides to mediate the cyclization. Organic solvents are
avoided in this method by using ammonia water both as a base
and as a solvent. The advantages of this strategy make it possible
to generate C-5-substituted O6,5′-cyclopyrimidine nucleosides
directly and to be applied in advanced functional organic
materials and medicinal chemistry. Further work is in progress
in order to elucidate the mechanisms for these reactions and to
determine the scope of the ring-closing reactions of the
cyclonucleosides with common nucleophiles.
Br
a The reaction was conducted with substituents (1 mmol), I2 (761 mg, 3
mmol), and NH3 water (3 mL, 45 mmol) at 60 °C. b Isolated yields.
SCHEME 4
Experimental Section
5-iodo-O6,5′-cyclopyrimidine (entries 1 and 3). When 5-bro-
mocytidine or 5-fluorocytidine was used, 5-bromo-O6,5′-cyclo-
cytidine or 5-fluoro-O6,5′-cyclocytidine was obtained (entries
4 and 5). These interesting observations showed that this
synthetic pathway could lead to the preparation of various
5-substituted-O6,5′-cyclopyrimidine nucleosides. In addition, the
2′- and 3′-hydroxyl groups are protected with bis-isopropylidene,
which facilitates intramolecular coupling of the 5′-hydroxyl
group of the sugar moiety with pyrimidine and purine base
moieties.
Unprotected nucleosides gave only a small amount of the
corresponding pyrimidine cyclonucleosides even after prolonged
reaction time under the same conditions as that of uridine or
cytidine. The reason of this difference might be that the
isopropylidene ring “forces the furanose ring into a conformation
that favors the proximity of the hydroxy group to the uracil
double bond”.18
There is an interesting fact to be addressed (Scheme 4).
Treatment of 1f with iodine in ammonia water gave 3f with
loss of bromine at position 5 which is different from that
described above (Table 3).
When this procedure was applied to other purine nucleosides
derivatives 4 (Scheme 5), to our delight, the corresponding
cyclonucleosides 2′,3′-O-isopropylidene-O8,5′-cycloadenosine
5a and 2′,3′-O-isopropylidene-O8,5′-cycloinosine 5b were ob-
tained in good isolated yield (5a: 34%; 5b: 30%). Moreover,
its operational simplicity was efficient compared with the
reported results19,20 (two steps or more complex procedure and
in 23% yield).
Typical Experimental Procedure for the Cyclization Reaction
of Nucleosides with Iodine in Ammonia Water. 5-Iodo-2′,3′-O-
isopropylidene-O6,5′-cyclouridine (3a). 2′,3′-O-isopropylideneu-
ridine 1a (1 mmol) and ammonia water (3 mL, 45 mmol) were put
in a 10 mL glass vial equipped with a small magnetic stirring bar.
To this was added I2 (761 mg, 3 mmol) at 60 °C under empty
balloon. After 2 h of stirring at the same temperature, the mixture
was quenched with H2O and satd aq Na2SO3, and was extracted
with Et2O (3 × 20 mL). The organic layer was washed with brine
and dried over Na2SO4 to provide crude product which was purified
with flash column chromatography on silica gel to give pure 3a.
1
Yield: 83%. White solid. Mp: 186-190 °C. H NMR (DMSO-
d6, 400 MHz): δ 11.70 (s, 1H, NH), 6.25 (s, 1H, H-1′), 4.99 (d, J
) 5.6 Hz, 1H, H-2′), 4.91 (d, J ) 5.6 Hz, 1H, H-3′), 4.67 (d, J )
12.4 Hz, 1H, H-5′), 4.63 (s, 1H, H-4′), 4.01 (d, J ) 12.4 Hz, 1H,
H-5′), 1.42 (s, 3H, CH3), 1.28 (s, 3H, CH3). 13C NMR (DMSO-d6,
100 MHz): 161.1 (C, C-4), 160.2 (C, C-6), 149.5 (C, C-2), 111.6
[C, C(CH3)2], 89.6 (CH, C-1′), 84.5 (CH, C-3′), 83.6 (CH, C-4′),
81.8 (CH, C-2′), 76.9 (CH2, C-5′), 61.0 (C, C-5), 26.0 (CH3, CCH3),
24.4 (CH3, CCH3). HRMS: calcd for C12H13IN2NaO6 [M + Na+]
430.9716, found 430.9691.
Preparation of 2′,3′-O-Isopropylidene-O8-5′-cyclopurine Nu-
cleosides 5. 2′,3′-O-Isopropylidenepurine nucleosides 4 (1 mmol)
and ammonia water (3 mL, 45 mmol) were put in a 10 mL glass
vial equipped with a small magnetic stirring bar. To this was added
I2 (761 mg, 3 mmol) at 60 °C under empty balloon. After 8 h of
stirring at the same temperature, the mixture was quenched with
H2O and satd aq Na2SO3. The product was purified by flash column
chromatography on silica gel to give pure 5.
2′,3′-O-Isopropylidene-O8,5′-Cycloadenosine (5a). Yield: 34%.
1
White solid. Mp: 226-227 °C; H NMR (DMSO-d6, 400 MHz):
(19) Ikehara, M.; Kaneko, M. J. Am. Chem. Soc. 1968, 90, 497.
(20) Capon, R. J.; Trotter, N. S. J. Nat. Prod. 2005, 68, 1689.
(18) Reist, E. J.; Beniter, A.; Goodman, L. J. Org. Chem. 1964, 29, 554.
2452 J. Org. Chem., Vol. 73, No. 6, 2008

δ 8.11 (s, 1H), 7.10 (s, 2H), 6.03 (s, 1H), 5.10 (d, J ) 5.6 Hz, 1H),
4.90 (d, J ) 5.6 Hz, 1H), 4.75 (s, 1H), 4.64 (d, J ) 12.4 Hz, 1H),
4.13 (d, J ) 12.4 Hz, 1H), 1.46 (s, 3H), 1.30 (s, 3H). 13C NMR
(DMSO-d6, 100 MHz): 154.8, 153.1, 152.0, 147.6, 114.4, 111.9,
85.8, 85.2, 84.8, 80.9, 74.3, 25.9, 24.3.
111.9, 86.3, 85.4, 84.8, 80.9, 74.2, 25.9, 24.3. HRMS: calcd for
C13H14N4NaO5 [M + Na+] 329.0862, found 329.0858.
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (20772024) for financial support.
2′,3′-O-Isopropylidene-O8,5′-cycloinosine (5b). Yield: 30%.
Supporting Information Available: Experimental details,
characterization data, and NMR spectra for compounds 1c,f,
3a,b,d-f, and 5a,b. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
White solid. Mp: 166-168 °C. H NMR (DMSO-d6, 400 MHz):
δ 12.40 (s, 1H), 8.05 (s, 1H), 5.99 (s, 1H), 5.09 (d, J ) 5.6 Hz,
1H), 4.92 (d, J ) 5.6 Hz, 1H), 4.75 (s, 1H), 4.62 (dd, J ) 13.2 Hz,
1.6 Hz, 1H), 4.11 (d, J ) 13.2 Hz, 1H), 1.46 (s, 3H), 1.30 (s, 3H).
13C NMR (DMSO-d6, 100 MHz): 155.8, 152.4, 145.9, 145.8, 119.5,
JO7026245
J. Org. Chem, Vol. 73, No. 6, 2008 2453