Synthesis of 6,5′-C-cyclouridine by a novel tandem radical 1,6-hydrogen transfer and cyclization reaction

Article abstract of DOI:10.1055/s-2006-956464

C-Cyclonucleosides are conformational mimics and, as such, are suitable for investigating steric interactions between nucleosides and the enzymes that utilize them. To achieve the synthesis of C-cyclouridine, we developed a novel tandem radical 1,6-hydrogen transfer and cyclization of a 6-phenylselenouridine derivative, which gave 5,6-dihydro-C-cyclouridine in good yields. The synthesis of 6,5′-C-cyclouridine was accomplished by recovery of the double bond of 5,6-dihydro-C-cyclouridine and subsequent deprotection. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-956464

LETTER
111
Synthesis of 6,5¢-C-Cyclouridine by a Novel Tandem Radical 1,6-Hydrogen
Transfer and Cyclization Reaction
S
ynthesis of 6,5
¢
-
C
u
-Cyclouridin
i
e
chi Yoshimura,* Yoshiko Yamazaki, Katsunori Wachi, Shinya Satoh, Hiroki Takahata*
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Fax +81(22)2752013; E-mail: yoshimura@tohoku-pharm.ac.jp
Received 31 August 2006
thesis of C-cyclonucleosides is in the method used to con-
struct the carbon–carbon bridge. Typically, an
intramolecular glycosylation reaction6 and a radical
cyclization7 of branched sugar/nucleosides are used for
Abstract: C-Cyclonucleosides are conformational mimics and, as
such, are suitable for investigating steric interactions between nu-
cleosides and the enzymes that utilize them. To achieve the synthe-
sis of C-cyclouridine, we developed a novel tandem radical 1,6-
hydrogen transfer and cyclization of a 6-phenylselenouridine deriv- constructing a skeleton of C-cyclonucleosides. A tandem
ative, which gave 5,6-dihydro-C-cyclouridine in good yields. The
synthesis of 6,5¢-C-cyclouridine was accomplished by recovery of
the double bond of 5,6-dihydro-C-cyclouridine and subsequent
clic system of natural products.9 Indeed several examples
deprotection.
reaction of radical hydrogen transfer (HT) and cyclization
has recently attracted attention for the synthesis of the cy-
of the synthesis of 8,5¢-C-cycloadenosine using tandem
radical HT–cyclization have been reported.10 However,
Key words: nucleosides, radical reactions, tandem reactions, cy-
clizations, selenium
there are no examples of pyrimidine C-cyclonucleosides,
e.g. 1 (Figure 1).
Conformationally fixed nucleoside analogues are a
O
N
O
N
unique class of nucleosides that can be used as a tool for
investigating steric interactions between nucleosides or
nucleotides and the enzymes that utilize them.
RCl
DBU
DMF
r.t.
R
O
NH
N
O
TBSO
TBSO
O
O
O
O
NH
O
O
O
O
NH
R2
R1
N
O
N
O
4a: R = PBM (97%)
4b: R = BOM (97%)
3
O
O
O
N
(PhSe)2
LiHMDS
THF
HO
OH
HO
OH
R
N
1a: R1 = OH, R2 = H
1b: R1 = H, R2 = OH
2
PhSe
TBSO
–80 °C
O
O
Figure 1 Structures of C-cyclonucleosides
O
O
To date, various conformationally fixed nucleosides were
reported.1–5 Among them, the nucleosides, the sugar puck-
ering of which were fixed in specific conformation, were
proved to be promising for use as an antisense/antigene4,5
as well as a biological tool.2
5a: R = PBM (92%)
5b: R = BOM (83%)
Scheme 1 Synthesis of 6-phenylselenouridine derivatives
A decade ago, we also reported on the synthesis of another
class of conformationally fixed nucleoside derivatives,
bridged by a carbon–carbon bond between the base and
sugar moieties.6 Those are referred to C-cyclonucleosides
and can be considered as a conformational analogue
around the glycosidic bond.6,7 Indeed, C-cyclonucleosides
were proved to be useful for investigating recognition of
glycosyl conformation by enzymes.8 The key to the syn-
On the other hand, we recently reported on the facile syn-
thesis of 5¢-deoxy-6,5¢-C-cyclouridine (2),11 one of the
pyrimidine C-cyclonucleosides mentioned above, 2 lacks
a 5¢-hydroxyl group, which is important for recognition by
enzymes. A tandem radical 1,6-HT–cyclization would be
suitable for the synthesis of 1 having a hydroxyl group at
the 5¢-position. In this report, we describe a novel synthe-
sis of 6,5¢-C-cyclouridine (1) via the use of a tandem rad-
ical 1,6-HT and cyclization reaction.
Compound 3, which can be easily obtained from uridine,
was protected at the N-3 position with a p-methoxybenzyl
(PBM) group to give 4a in good yield. Using previously
SYNLETT 2007, No. 1, pp 0111–0114
Advanced online publication: 20.12.2006
DOI: 10.1055/s-2006-956464; Art ID: U10306ST
© Georg Thieme Verlag Stuttgart · New York
0
4.
0
1.
2
0
0
7

112
Y. Yoshimura et al.
LETTER
reported C-6 lithiation method,11 the reaction of 4a by similar manner, the reaction of 5b gave 6b and 7b in 46%
treatment with lithium hexamethyldisilazide (LiHMDS) and 9% yields, respectively, along with the formation of
in the presence of diphenyl diselenide gave a 6-phenyl- 4b (30%).
seleno derivative 5a in 92% yield. In a similar reaction
sequence, compound 3 was also converted into a 3-benz-
yloxymethyl-6-phenylseleno derivative 5b (Scheme 1).
A possible reaction mechanism is shown in Scheme 3.
There are two possibilities. First, the C-6 radical interme-
diate A, formed as the result of the reaction of 5 with TT-
Following our initial plan, we examined the tandem radi- MSS and AIBN, gives rise to 1,6-HT to produce the C-5¢
cal 1,6-HT–cyclization of 5a. It has been reported that the radical intermediate B. The fact that the radical cycliza-
treatment of 6-phenylthiouridine with tributyltin hydride tion reaction preferentially produces the S-epimer reveals
in the presence of AIBN resulted in the formation of 6- that the intermediate B preferentially adopts the confor-
tributylstannyluridine, excluding a phenylthio group, un- mation shown in Scheme 3, which has an anti-conforma-
der radical conditions.12 In order to avoid this reaction, tion around the glycosidic bond with a trans-orientation
tris(trimethylsilyl)silane (TTMSS) was used in place of around the C4¢–5¢ bond. The subsequent radical cycliza-
tributyltin hydride. To a refluxing toluene solution of 5a tion of B gives the 5¢-S-epimer. The second possibility is
was added a toluene solution of TTMSS and AIBN over that the C-6 radical generated as mentioned above prefer-
one hour using a syringe pump.13 Thin-layer chromatog- entially abstracts the pro-S hydrogen of C-5¢, and the re-
raphy (TLC) of the reaction mixture showed the formation sulting B immediately cyclizes to form 6. At the present
of three products after seven hours.
time, it is not clear which mechanism is more plausible.
To clarify this problem, the influence of steric bulkiness
and the electrostatic effect of 5¢-protecting group on the
stereochemistry of the radical cyclization product will be
next issue to be studied.
5a or 5b
TTMSS
AIBN
PhMe
reflux
To synthesize 6,5¢-C-cyclouridine, the double bond be-
tween C-5 and C-6 needs to be recovered. This can be
achieved by the introduction of a leaving group at C-5 and
a subsequent elimination reaction. Treatment of 6a with
LiHMDS (2 equiv) at –80 °C followed by benzenesulfo-
nyl chloride gave a diastereomeric mixture of 8a, which
was further treated with DBU (5 equiv) in 1,4-dioxane at
80 °C, producing the 6,5¢-C-cyclouridine derivative 9a in
69% yield from 6a. The same reaction sequence was ap-
plied to 6b to give 9b in 61% yield. Attempts were made
to remove the N3-protecting group. Deprotection of the
BOM group of 9b was attempted by reducing agents [e.g.
H2, Pd(OH)2 in EtOH; Pd black, HCO2H in MeOH]. How-
ever, all attempts were unsuccessful. On the other hand,
deprotection of the PMB group of 9a under oxidative con-
ditions (CAN in MeCN and H2O) successfully gave com-
pound 10 in good yield. The TBS group of 10 was
removed by treatment with TBAF to give the 6,5¢-C-cyc-
O
N
O
R
O
R
N
N
TBSO
H
H
N
O
O
H
O
H
O
TBSO
+
O
O
O
7a: R = PBM (11%)
7b: R = BOM (9%)
6a: R = PBM (60%)
6b: R = BOM (46%)
Scheme 2 A tandem radical 1,6-HT–cyclization reaction of 4a
and 4b
One of the compounds was identical to 4a (24%), formed
through the simple radical deselenation of 5a. The other
two products were determined to be the desired products
6a and 7a (6a: 60%, 7a: 11%). Based on 1H NMR spectral
data, the structure of the less polar 6a was determined to
be the 5¢-S-epimer,14 as shown in Scheme 3, and the more
polar 7a was assigned as the 5¢-R-epimer (Scheme 2). In a
1
louridine derivative 11 with 81% yield. The H NMR
spectrum of 11 was consistent with that reported by Otter
et al.15 The conversion of 11 to 6,5¢-C-cyclouridine (1a)
has also been reported (Scheme 4).15
O
R
N
O
O
R
R
H
H
O
TTMSS
AIBN
PhMe
N
N
TBSO
N
O
O
O
H
H
N
H
O
1,6-HT
N
O
TBSO
5
H
TBSO
O
O
O
O
O
O
6
B
A
Scheme 3 The speculated reaction mechanism of the tandem radical 1,6-HT–cyclization of 5
Synlett 2007, No. 1, 111–114 © Thieme Stuttgart · New York

LETTER
Synthesis of 6,5¢-C-Cyclouridine
113
Balzarini, J.; Mitsuya, H.; Boyer, P. L.; Hughes, S. H.;
O
N
Marquez, V. E. J. Med. Chem. 2003, 46, 3292. (e) Comin,
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Lett. 2006, 8, 705.
Cl
R
O
1) LiHMDS
N
THF
–80 °C
DBU
1,4-dioxane
80 °C
H
6a
or
H
O
(2) (a) Marquez, V. E.; Ezzitouni, A.; Russ, P.; Siddiqui, M. A.;
Ford, H.; Feldman, R. J.; Mitsuya, H.; George, C.; Barchi, J.
J. J. Am. Chem. Soc. 1998, 120, 2780. (b) Marquez, V. E.;
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Ben-Kasus, T.; Agbaria, R. J. Am. Chem. Soc. 2005, 127,
15145.
2) PhSO2Cl
TBSO
6b
O
O
8a: R = PBM
8b: R = BOM
(3) (a) Paquette, L. A.; Seekamp, C. K.; Kahane, A. L. J. Org.
Chem. 2003, 68, 8614. (b) Paquette, L. A.; Kahane, A. L.;
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T.; Imanishi, T. Tetrahedron Lett. 1997, 38, 8735.
(5) Singh, S. K.; Nielsen, P.; Koshkin, A. A.; Wengel, J. Chem.
Commun. 1998, 455.
O
O
R
NH
N
CAN
H
H
MeCN
H2O
N
O
N
O
TBSO
TBSO
O
O
(6) (a) Yoshimura, Y.; Sano, T.; Matsuda, A.; Ueda, T. Chem.
Pharm. Bull. 1988, 36, 162. (b) Yoshimura, Y.; Matsuda,
A.; Ueda, T. Nucleosides Nucleotides 1988, 7, 409.
(c) Yoshimura, Y.; Matsuda, A.; Ueda, T. Chem. Pharm.
Bull. 1989, 37, 660. (d) Yoshimura, Y.; Matsuda, A.; Ueda,
T. Chem. Pharm. Bull. 1990, 38, 389.
(7) (a) Matsuda, A.; Muneyama, K.; Nishida, T.; Sato, T.; Ueda,
T. Nucleic Acids Res. 1976, 3, 3349. (b) Ueda, T.; Usui, H.;
Shuto, S.; Inoue, H. Chem. Pharm. Bull. 1984, 32, 3410.
(c) Ueda, T.; Shuto, S.; Satoh, M.; Inoue, H. Nucleosides
Nucleotides 1985, 4, 401. (d) Suzuki, Y.; Matsuda, A.;
Ueda, T. Chem. Pharm. Bull. 1987, 35, 1808; and references
cited therein. (e) Yoshimura, Y.; Ueda, T.; Matsuda, A.
Tetrahedron Lett. 1991, 32, 4549. (f) Yoshimura, Y.; Otter,
B. A.; Ueda, T.; Matsuda, A. Chem. Pharm. Bull. 1992, 40,
1761.
O
O
O
O
10 (72% from 9a)
9a: R = PBM (69% from 6a)
9b: R = BOM (61% from 6b)
O
N
NH
O
H
TBAF
THF
HO
O
ref. 13
1a
81%
O
O
11
(8) (a) Ueda, T.; Usui, H.; Shuto, S.; Inoue, H. Chem. Pharm.
Bull. 1984, 32, 3410. (b) Yamagata, Y.; Tomita, K.; Usui,
H.; Sano, T.; Ueda, T. Chem. Pharm. Bull. 1989, 37, 1971.
(9) 1,5-Hydrogen-transfer–radical cyclization, see: (a) Curran,
D. P.; Kim, D.; Liu, H. T.; Shen, W. J. Am. Chem. Soc. 1988,
110, 5900. (b) Snieckus, V.; Cuevas, J.-C.; Sloan, C. P.; Liu,
H.; Curran, D. P. J. Am. Chem. Soc. 1990, 112, 896.
(c) Kittaka, A.; Asakura, T.; Kuze, T.; Tanaka, H.; Yamada,
N.; Nakamura, K. T.; Miyasaka, T. J. Am. Chem. Soc. 1999,
64, 7081. (d) Sha, C.-K.; Hsu, C.-W.; Chen, Y.-T.; Cheng,
S.-Y. Tetrahedron Lett. 2000, 41, 9865. (e) Takasu, K.;
Ohsato, H.; Ihara, M. Org. Lett. 2003, 5, 3017. (f) Beaufils,
F.; Dénès, F.; Renaud, P. Org. Lett. 2004, 6, 2563.
(g) Sukeda, M.; Matsuda, A.; Shuto, S. Tetrahedron 2005,
61, 7865.
Scheme 4 Synthesis of 6,5¢-C-cyclouridine
In summary, a novel tandem radical 1,6-HT–cyclization
reaction of 6-phenylselenouridine derivative was devel-
oped. The reaction gave a 5,6-dihydro-C-cyclouridine de-
rivative having a 5¢S configuration predominantly, which
was successfully converted into 6,5¢-C-cyclouridine. As a
result, we report on a new entry to pyrimidine C-cyclo-
nucleosides. Studies of the reaction mechanism are in
progress and the results will be reported elsewhere.
Acknowledgment
(10) (a) Mastuda, A.; Tezuka, M.; Ueda, T. Tetrahedron 1978,
34, 2449. (b) G ani, D.; Johnson, A. W.; Lappert, M. F. J.
Chem. Soc., Perkin Trans. 1 1981, 3065. (c) Flyunt, R.;
Bazzanini, R.; Chatgilialoglu, C.; Mulazzani, Q. C. J. Am.
Chem. Soc. 2000, 122, 4225. (d) Chatgilialoglu, C.; Guerra,
M.; Mulazzani, Q. C. J. Am. Chem. Soc. 2003, 125, 3839.
(e) Chatgilialoglu, C.; Duca, M.; Ferreri, C.; Guerra, M.;
Ioele, M.; Mulazzani, Q. C.; Strittmatter, H.; Giese, B.
Chem. Eur. J. 2004, 10, 1249. (f) Navacchia, M. L.;
Chatgilialoglu, C.; Montevecchi, P. C. J. Org. Chem. 2006,
71, 4445. (g) Otter, B. A.; Falco, E. A.; Fox, J. J. J. Org.
Chem. 1976, 41, 3133.
The authors are grateful to Prof. Hiromichi Tanaka, Showa Univer-
sity, for helpful discussions. This work was supported in part by a
grant from The Foundation for Japan Chemical Research (Y.Y.) and
by a Grant-in-Aid for Scientific Research (No. 18590103), JSPS
(Y.Y.).
References and Notes
(1) (a) Ezzitouni, A.; Russ, P.; Marquez, V. E. J. Org. Chem.
1997, 62, 4870. (b) Shin, K. J.; Moon, H. R.; George, C.;
Marquez, V. E. J. Org. Chem. 2000, 65, 2172.
(11) Yoshimura, Y.; Kumamoto, H.; Baba, A.; Takeda, S.;
Tanaka, H. Org. Lett. 2004, 6, 1793.
(12) Tanaka, H.; Hayakawa, H.; Obi, K.; Miyasaka, T.
Tetrahedron Lett. 1985, 26, 6229.
(c) Yoshimura, Y.; Moon, H. R.; Choi, Y.; Marquez, V. E. J.
Org. Chem. 2002, 67, 5938. (d) Choi, Y.; George, C.;
Comin, M. J.; Barchi, J. J.; Kim, H. S.; Jacobsen, K. A.;
Synlett 2007, No. 1, 111–114 © Thieme Stuttgart · New York

114
Y. Yoshimura et al.
LETTER
[M+]: 518.2448; found: 518.2444. Anal. Calcd for
C26H38N2O7Si: C, 60.21; H, 7.38; N, 5.40. Found C, 60.49;
H, 7.49; N, 5.41.
(13) Tandem 1,6-HT–Radical Cyclization of 5a; Typical
Procedure
To a refluxing solution of 5a (2.00 g, 2.97 mmol) in toluene
(200 mL) was added slowly a solution of TTMSS (2.29 mL,
7.43 mmol) and AIBN (488 mg, 2.97 mmo) in toluene (30
mL) over 1 h by using a syringe pump. After the mixture was
kept under reflux for 6 h, the solvent was removed under
reduced pressure. The residue was purified by silica gel
column chromatography (10–20% EtOAc in hexane) to give
6a (920 mg, 60%), 4a (370 mg, 24%), and 7a (160 mg, 11%)
in order of fractions eluted.
Data for 7a
1H NMR (400 MHz, CDCl3): d = 7.35 (2 H, d, J = 8.7 Hz),
6.81 (2 H, d, J = 8.7 Hz), 6.10 (1 H, s), 4.89 (1 H, d, J = 14.0
Hz), 4.85 (1 H, d, J = 14.0 Hz), 4.56 (1 H, d, J = 5.8 Hz),
4.54 (1 H, d, J = 5.3 Hz), 4.31 (1 H, d, J = 2.4 Hz), 3.77 (3
H, s), 3.48 (1 H, t, J = 2.9 Hz), 3.39 (1 H, dt, J = 4.0, 10.5
Hz), 2.95 (1 H, dd, J = 11.1, 16.4 Hz), 2.46 (1 H, dd, J = 4.8,
16.9 Hz), 1.51 (3 H, s), 1.31 (3 H, s), 0.91 (9 H, s), 0.13 (3
H, s), 0.10 (3 H, s). 13C NMR (100 MHz, CDCl3): d = 168.2,
158.9, 152.4, 130.4, 129.6, 113.7, 113.2, 86.9, 84.7, 82.8,
79.3, 65.6, 55.2, 49.2, 43.2, 33.0, 25.8, 25.7, 24.6, 18.1, –4.6,
–4.8. HRMS (EI): m/z calcd for C26H38N2O7Si [M+]:
518.2448; found: 518.2435. Anal. Calcd for C26H38N2O7Si:
C, 60.21; H, 7.38; N, 5.40. Found C, 60.23; H, 7.56; N, 5.40.
(14) The stereochemistry of 9a was determined by comparison of
1H NMR spectrum of 2¢,3¢-O-isopropylidene-6,5¢-C-cyclo-
5,6-dihydrouridine reported previously: Sugawara, T.; Otter,
B. A.; Ueda, T. Tetrahedron Lett. 1988, 29, 75.
Data for 6a
1H NMR (400 MHz, CDCl3): d = 7.34 (2 H, d, J = 8.7 Hz),
6.82 (2 H, d, J = 8.2 Hz), 6.04 (1 H, s), 4.91 (1 H, d, J = 14.0
Hz), 4.82 (1 H, d, J = 14.0 Hz), 4.79 (1 H, d, J = 5.8 Hz),
4.49 (1 H, d, J = 5.8 Hz), 4.22 (1 H, d, J = 4.3 Hz), 3.78 (3
H, s), 3.59 (1 H, dd, J = 4.4, 8.3 Hz), 3.08 (1 H, ddd, J = 4.1,
8.7, 12.6 Hz), 2.96 (1 H, dd, J = 4.1, 16.2 Hz), 2.46 (1 H, dd,
J = 12.3, 16.2 Hz), 1.50 (3 H, s), 1.33 (3 H, s), 0.90 (9 H, s),
0.13 (3 H, s), 0.10 (3 H, s). 13C NMR (100 MHz, CDCl3):
d = 167.1, 159.0, 151.4, 130.4, 129.5, 113.7, 113.0, 86.7,
83.4, 83.0, 78.0, 69.6, 55.2, 51.4, 43.3, 35.9, 25.9, 25.6, 24.7,
17.7, –4.4, –4.9. HRMS (EI): m/z calcd for C26H38N2O7Si
(15) Otter, B. A.; Falco, E. A.; Fox, J. J. J. Org. Chem. 1976, 41,
3133.
Synlett 2007, No. 1, 111–114 © Thieme Stuttgart · New York

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