Total synthesis of cytosaminomycin C

Article abstract of DOI:10.1246/cl.2008.1038

The first synthesis of cytosaminomycin C has been accomplished by employing intramolecular glycosylation for the β-selective formation of the 2′-deoxyhexopyranosyl nucleoside part as a key reaction. Copyright

Full text of DOI:10.1246/cl.2008.1038

1038
Chemistry Letters Vol.37, No.10 (2008)
Total Synthesis of Cytosaminomycin C
Hideyuki Sugimuraꢀ1;2 and Risa Watanabe2
1Department of Chemistry & Biological Science, Aoyama Gakuin University,
5-10-1 Fuchinobe, Sagamihara 229-8558
2Graduate School of Education, Yokohama National University,
79-2 Tokiwadai, Hodogaya-ku, Yokohama 240-8501
(Received July 18, 2008; CL-080706; E-mail: sugimura@chem.aoyama.ac.jp)
a, b
AcO
AcO
c, d, e
The first synthesis of cytosaminomycin C has been accom-
AcO
AcO
AcO
O
O
MP
O
O
O
SPh
SPh
plished by employing intramolecular glycosylation for the ꢀ-
selective formation of the 20-deoxyhexopyranosyl nucleoside
part as a key reaction.
TBSO
AcO
1
2
3
OMe
N
f
g
O
N
HO
Cytosaminomycins A–D are novel anticoccidial antibiotics
isolated from the cultured broth of Streptomyces amakusaensis
KO-8119.1 The structure, closely related to the amicetin family
antibiotics, features the presence of a unique 1-(2,6-dideoxyhex-
opyranosyl)cytosine in which the 40-hydroxy is glycosylated by
an amino sugar called amosamine (Figure 1). Amicetin was first
isolated in the early 1950s by several groups,2–5 and the correct
structure was established in 1963 by Steavens et al.6 To date,
structurally related disaccharide nucleosides have been found
by several groups,7–11 and the cytosaminomycin is the most re-
cent entry in this group. The synthetic study of these disacchar-
ide nucleosides is significantly important in order to not only
elucidate their relation between the structures and biological
properties, but also to design novel artificial molecules related
to these nucleoside antibiotics.12 However, only one total syn-
thesis of such a disaccharide nucleoside was accomplished by
Steavens et al. in 1972.13 Recently, we briefly reported the
formal synthesis of cytosamine, in which the 20,30,60-trideoxy-
hexopyranosyl pyrimidine nucleoside was prepared via the intra-
molecular-pyrimidine-delivery method established by our group
for the stereoselective synthesis of ꢀ-20-deoxynucleosides.14,15
In this letter, we describe the total synthesis of cytosaminomycin
C based on this synthetic strategy.
O
PMBO
SPh
O
TBSO
PMBO
TBSO
SPh
4
5
Scheme 1. Reagents & conditions: (ꢂa) Ph3P–HBr, MeOH, rt,
.
23 h, 86%; (b) PhSH, BF3 OEt2, 0 C to rt, 21 h, 89%; (c)
NaOMe, 0 ꢂC, 3 h, 99%; (d) p-MeOC6H4CH(OMe)2,
.
HBF4 OEt2, DMF, rt, 3 h, quant.; (e) t-BuMe2SiCl, Imidazole,
DMF, rt, 15 h, 91%; (f) DIBAL, CH2Cl2, 0 ꢂC to rt, 9.5 h,
86%; (g) NaH, DMF, then 2-chloro-4-methoxypyrimidine,
DMF, ꢁ40 to ꢁ20 ꢂC, 26 h, 76%.
benzylidene acetal in 3 with DIBAL led to the 4-O-p-methoxy-
benzyl derivative 4, which was treated with sodium hydride and
then 2-chloro-4-methoxypyrimidine to give the intramolecular
glycosylation substrate 5.
The intramolecular glycosylation was carried out using
Me2S(SMe)BF4 as a promoter in acetonitrile at ꢁ20 ꢂC
(Scheme 2). The resulting ꢁ-oxocarbenium ion would be trapped
by the lone pair of the pyrimidine nitrogen, leading to the cyclic
pyrimidinium intermediate. The successive addition of a 1 M so-
dium hydroxide solution hydrolyzed this intermediate to yield
the pyrimidine-migration product. After purification by silica
gel chromatography, the desired 2-deoxy-ꢀ-hexopyranosyl
nucleoside 6 was obtained in 74% isolated yield along with
12% of the C-1 hydrolyzed product 7.
The synthesis commenced with the preparation of the
intramolecular-glycosylation substrate as shown in Scheme 1.
Commercially available tri-O-acetyl-D-glucal (1) was converted
to the phenyl 2-deoxy-1-thio-D-glucoside 2 according to the
literature method.16,17 Following removal of the acetyl groups,
the C4 and C6 hydroxys were protected as a p-methoxybenzyli-
dene acetal and the C3 hydroxy was protected as a silyl ether,
affording compound 3. Reductive cleavage of the p-methoxy-
With the 20-deoxy-ꢀ-nucleoside 6 in hand, our next goal
OMe
OMe
OMe
N
N
N
N
O
O
N
O
N
a
OTBS
O
O
O
PMBO
TBSO
PMBO
TBSO
SPh
S
A: R=
OPMB
C
O
Me
5
O
Me2N
HO
OMe
O
N
NH R
NHMe
Me
HO
N
O
O
N
HO
B: R= C
O
O
N
OMe
O
N
HO
O
+
PMBO
N
O
PMBO
TBSO
OH
TBSO
C: R= C
O
Cytosaminomycinc A – D
6
7
D: R=
C
O
Scheme 2. Reagents
&
conditions: (a) Me2S(SMe)BF4,
M.S.4A, MeCN, ꢁ20 ꢂC, 5 h, then 1 M NaOHaq., ꢁ20 ꢂC to
Figure 1.
0 ꢂC, 2 h, 74% (6), 12% (7).
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.10 (2008)
1039
O
N
OMe
O
N
OMe
10% Pd/C as the catalyst to give the corresponding amine,
which was followed by reductive methylation by the successive
addition of aqueous HCHO, affording compound 16. The treat-
ment of 16 with a methanol solution saturated by ammonia at
100 ꢂC yielded the cytosine derivative. The reductive debenzyla-
tion was carried out using 10% Pd/C and HCl aq as catalysts un-
der hydrogen. Finally, the selective acylation of the 4-amino
group in the resulting free nucleoside gave the cytosaminomycin
C (17).19 The 1H and 13C NMR data of the synthetic sample were
identical to those described in the literature.1 The ꢀ-anomer was
not isolated in sufficient quantity to identify.
a, b
c
Me
Me
O
O
6
PMBO
TBSO
HO
N
N
TBSO
8
9
Me
O
N3
BnO
d
O
N
OMe
Me
BnO
O
O
Me
N
RO
O
N3
BnO
Me
F
O
BnO
13: R = N3
BnO
11: R = TBS
12: R = H
BnO
10
Scheme 3. Reagents & conditions: (a) I2, PPh3, Py, rt, 5 h, 84%;
(b) Bu3SnH, AlBN, toluene, reflux, 14 h, 94%; (c) DDQ,
CH2Cl2–H2O, rt, 2 h, 79%; (d) 10, AgOTf, SnCl2, M.S.4A,
Et2O–ClCH2CH2Cl (9:1), 0 ꢂC to rt, 18 h, 16% (11, ꢁ-anomer),
39% (12, ꢁ-anomer), 26% (13, anomeric mixtures).
In conclusion, we have achieved the first total synthesis
of cytosaminomycin C, demonstrating the efficacy of the
intramolecular glycosylation strategy for the construction of
cytosamine-type disaccharide nucleoside skeletons.
was the ꢁ-selective glycosylation at the 40 position of the 20,60-
dideoxynucleoside 9. We planned to utilize a procedure
using benzylated glycosyl fluorides by activation with a Agþ-
salt and SnII system as a promising approach.18 The requisite
acceptor 9 was prepared via the following sequence: (i) treat-
ment of the nucleoside 6 with iodine and triphenylphosphine
in pyridine, (ii) reduction of the resulting iodo group with
Bu3SnH in the presence of AIBN, and (iii) deprotection of the
40-O-PMB group of 8 by treating with DDQ. The resulting
nucleoside 9 was glycosylated with glycosyl fluoride 1015
using AgOTf and SnCl2 as promoters to afford the glycosylated
products (Scheme 3). However, besides the desired product 11
(16% isolated yield), the 30 desilylated compound 12 and its
glycosylated product 13 were obtained in 39% and 26% yields,
respectively. This unexpected lability of the TBS group under
the glycosylation conditions prompted us to change the 30 pro-
tecting group into a more stable one prior to the glycosylation
reaction (Scheme 4).
Thus, after displacement of the 30-O-TBS group with the Bn
group, the 40-O-PMB group was removed to give the 40 free
nucleoside 14 in a good total yield. Glycosylation of 14 with
the donor 10 under the same conditions described above provid-
ed the desired disaccharide nucleoside 15 in 97% yield with a
moderate ꢁ-selectivity (ꢁ:ꢀ = 3.3:1). The ratio was determined
by a 1H NMR analysis, though the ꢁ- and ꢀ-anomers were
inseparable at this stage. Subsequent reduction of the 400-azido
group in 15 was accomplished in a hydrogen atmosphere using
We thank the Asahi Kasei Pharma Corporation for their
financial support.
References and Notes
1
K. Haneda, M. Shinose, A. Seino, N. Tabata, H. Tomoda, Y.
Iwai, S. Omura, J. Antibiot. 1994, 47, 774; K. Shiomi, K. Haneda,
H. Tomoda, Y. Iwai, S. Omura, J. Antibiot. 1994, 47, 782.
M. H. McCormick, M. M. Hoehn, Antibiot. Chemother. 1953, 3,
718.
C. DeBoer, E. L. Caron, J. W. Hinman, J. Am. Chem. Soc. 1953,
75, 499.
Y. Hinuma, M. Kuroya, T. Yajima, K. Ishihara, S. Hanada, K.
Watanabe, K. Kikuchi, J. Antibiot. Ser. A 1955, 8, 148.
S. Tatsuoka, K. Nakagawa, M. Inoue, S. Fujii, J. Pharm. Soc.
Chem. 1955, 75, 1206.
C. L. Stevens, P. Blumbergs, F. A. Daniker, J. Am. Chem. Soc.
1963, 85, 1552.
P. Sensi, A. M. Greco, G. G. Gallo, G. Rolland, Antibiot.
Chemother. 1957, 7, 645.
T. H. Haskell, A. Ryder, R. P. Frohardt, S. A. Fusari, Z. L.
Jakubowski, Q. R. Bartz, J. Am. Chem. Soc. 1958, 80, 743.
M. Konishi, M. Kimeda, H. Tsukiura, H. Yamamoto, T.
Hoshiya, T. Miyaki, K. Fujisawa, H. Koshiyama, H. Kawaguchi,
J. Antibiot. 1973, 26, 752.
2
3
4
5
6
7
8
9
10 J. R. Evans, G. Weare, J. Antibiot. 1977, 30, 604.
11 J. Itoh, S. Miyadoh, J. Antibiot. 1992, 45, 846.
12 For a review: L. M. Lerner, in Chemistry of Nucleosides and
Nucleotides, ed. by L. B. Towensend, Pienum Press, New York,
1991, Vol. 2, p. 27.
13 C. L. Stevens, J. Nemec, G. H. Ransford, J. Am. Chem. Soc.
1972, 94, 3280.
14 H. Sugimura, K. Sujino, Nucleosides, Nucleotides Nucleic Acids
1998, 17, 53.
15 H. Sugimura, K. Watanabe, Synth. Commun. 2001, 31, 2313.
16 D. W. Engers, M. J. Bassindale, B. L. Pagenkopf, Org. Lett.
2004, 6, 663.
Me
O
N3
BnO
O
N
OMe
O
N
OMe
Me
d
a, b, c
Me
BnO
O
HO
BnO
8
O
N
O
N
BnO
14
15
Me
O
BnO
Me2N
BnO
17 R. J. Ferrier, R. H. Furneaux, Carbohydr. Res. 1976, 52, 63.
18 T. Mukaiyama, Y. Murai, S. Shoda, Chem. Lett. 1981, 431.
g, h, i
e, f
O
O
N
OMe
Cytosaminomycin C
Me
O
N
30
19 Compound 17: ½ꢁꢃD +104ꢂ (c 0.4, MeOH); 1H NMR (400 MHz,
BnO
17
CDCl3): ꢂ 1.24 (d, J ¼ 6:3 Hz, 3H), 1.36 (d, J ¼ 6:1 Hz, 3H),
1.49–1.57 (m, 1H), 1.92 (s, 3H), 2.14 (t, J ¼ 10 Hz, 1H), 2.22
(s, 3H), 2.47 (s, 6H), 2.51–2.55 (m, 1H), 3.11 (t, J ¼ 9:0 Hz,
1H), 3.58 (dq, J ¼ 6:0, 9.1 Hz, 1H), 3.70 (dd, J ¼ 3:8, 9.3 Hz,
1H), 3.78–3.81 (m, 1H), 3.93–3.97 (m, 2H), 5.04 (d, J ¼
3:8 Hz, 1H), 5.82–5.84 (m, 2H), 7.54 (d, J ¼ 7:5 Hz, 1H), 7.82
(d, J ¼ 7:5 Hz, 1H), 8.83 (br, 1H); 13C NMR (100 MHz, CDCl3):
ꢂ 18.0, 19.6, 20.6, 27.8, 38.3, 41.5, 65.9, 68.8, 70.2, 70.9, 74.0,
74.4, 81.1, 88.6, 97.2, 102.3, 117.6, 143.7, 154.8, 158.8, 162.8,
165.5.
16
Scheme 4. Reagents & conditions: (a) Bu4NF, THF, rt, 1 h; (b)
NaH, BnBr, DMF, 0 ꢂC, 2 h, 93% (2 steps); (c) DDQ, CH2Cl2–
H2O, rt, 2 h, 86%; (d) 10, AgOTf, SnCl2, M.S.4A, Et2O–
ClCH2CH2Cl (9:1), 0 ꢂC to rt, 18 h, 97% (ꢁ:ꢀ = 3.3:1); (e)
H2, Pd/C, MeOH, rt, 17 h; (f) HCHO, H2, Pd/C, rt, 22 h, 82%
(2 steps); (g) NH3, MeOH, 100 ꢂC, 16 h, 94%; (h) H2, Pd/C,
HCl aq., MeOH, rt, 70%; (i) Me3SiCl, Py, then 3-methylcrotoyl
chloride, rt, 25%.
Published on the web (Advance View) August 30, 2008; doi:10.1246/cl.2008.1038