Facile one-pot synthesis of resorcinol bis-C-glycosides possessing two identical sugar moieties

Article abstract of DOI:10.1055/s-2006-942526

Two identical C-glycoside moieties were efficiently installed in non-protected resorcinol derivatives by the Sc(OTf)₃-catalyzed one-pot procedure. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942526

2818
PAPER
Facile One-Pot Synthesis of Resorcinol Bis-C-Glycosides Possessing Two
Identical Sugar Moieties
Facile One-Pot
a
Synthesis
o
k
f
Resorcinol
a
Bis-
C
-Gly
hcosides ito Yamauchi, Yukie Watanabe, Keisuke Suzuki,* Takashi Matsumoto*
Department of Chemistry, Tokyo Institute of Technology and SORST-JST Agency, 2-12-1, O-okayama, Meguro-ku, Tokyo 152-8551,
Japan
Fax +81(3)57343531; E-mail: tmatsumo@chem.titech.ac.jp
Received 13 April 2006; revised 19 May 2006
resorcinol derivative (Scheme 1).4–6 Starting from mono-
Abstract: Two identical C-glycoside moieties were efficiently
protected resorcinol I, a variety of aryl bis-C-glycosides
installed in non-protected resorcinol derivatives by the Sc(OTf)3-
IV possessing two identical or different sugar moieties
were obtained by utilizing each of the two phenols as the
pivot for ensuring regioselective C-glycoside formation.
We found that the second C-glycoside formation was re-
markably accelerated by liberating both of the phenols in
the mono-C-glycoside precursor III, and was thereby ef-
ficiently catalyzed by various Lewis acids.
catalyzed one-pot procedure.
Key words: bis-C-glycoside, rearrangement reactions, resorcinol,
scandium(III) triflate, pluramycin
In contrast to the majority of aryl C-glycoside antibiotics,1
some members of the 4H-anthra[1,2-b]pyran C-glycoside
family, such as the pluramycins,2 uniquely have two C-
glycoside residues (Figure 1). The two sugar residues ef-
fect highly sequence-selective interaction with DNA to
make these molecules valuable probes in structural stud-
ies of DNA.3
These results prompted us to examine the direct installa-
tion of two identical sugars onto non-protected resorcinol
V in one pot as shown in Scheme 2. The reaction, if via-
ble, would substantially simplify access to bis-C-glyco-
sides possessing two identical sugars. The resulting bis-C-
glycosides could serve as useful intermediates to the plu-
ramycin analogues possessing two identical sugar moi-
eties, which would give further insights into the DNA
recognition by the C-glycoside structures. Now, we de-
scribe a facile procedure that realizes the envisioned one-
pot bis-C-glycosylation.
R
sugar
R
OH
O
O
O
sugar
pluramycin A
hedamycin
X
Y
Y
Z
Z
A
B
C
C
D
O
kidamycin
isokidamycin
saptomycin B
O
HO
HO
O
O
R
R
X
sugar-1
NMe2
O→C-glycoside
rearrangement
HO
OP
OP
I
II
O
O
sugar:
(P = protecting group)
NMe2
NMe2
HO
R'O
Z
X: R' = Ac
Y: R' = H
HO
O
HO
O
O
R
R
X
sugar-1
sugar-1
O
O→C-glycoside
rearrangement
OH
OH
O
O
III
R:
O
IV
sugar-2
A
B
D
C
Scheme 1 Bis-C-glycosylation of resorcinol derivatives by utilizing
the O→C-glycoside rearrangement.
Figure 1 The pluramycin-type bis-C-glycoside antibiotics.
In our efforts toward the synthesis of these natural prod-
ucts, we previously reported an efficient approach for
constructing the key bis-C-glycosyl arene structure by
performing the O→C-glycoside rearrangement twice on a
HO
HO
O
O
R
R
2 x
X
O→C-glycoside
rearrangement
OH
OH
V
O
VI
SYNTHESIS 2006, No. 17, pp 2818–2824
x
x.
x
x
.
2
0
0
6
Advanced online publication: 25.07.2006
DOI: 10.1055/s-2006-942526; Art ID: F05606SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 One-pot bis-C-glycosylation.

PAPER
Facile One-Pot Synthesis of Resorcinol Bis-C-Glycosides
2819
HO
HO
25 mol% Sc(OTf)3
OAc
OBn
CH3
Drierite®
O
CH3
OH
O
O
+
OBn
ClCH2CH2Cl
Bn
OBn
BnO
BnO
OH
–30→0 °C, 2.5 h
OBn
O
2
1
OBn
OBn
3
99%
Scheme 3 Sc(OTf)3-catalyzed one-pot bis-C-glycosylation of 2-methylresorcinol (1) with fucosyl acetate (2).
The initial study was carried out by the reaction of 2- shows that liberation of the two phenolic hydroxyls serves
methylresorcinol (1) and fucosyl acetate (2). Compound 1 not only to accelerate the C-glycoside formation from the
and three equivalents of 2 were treated with 25 mol% O-glycoside but also enables isomerization of the anomer-
Sc(OTf)3 in the presence of Drierite® in 1,2-dichloro- ic configuration of the C-glycoside linkage to the thermo-
ethane at –30 °C, and the reaction mixture was gradually dynamically favored one.
warmed (Scheme 3). During warming, TLC analysis
To assess the scope of this one-pot double C-glycosyla-
showed the appearance of some compounds, which con-
tion, a range of glycosyl acetates derived from various
verged to one at 0 °C. This final product proved to be the
sugars were subjected to the reaction with 2-methyl resor-
desired bis-C-glycoside 3, whose structure was already
cinol (1) as the model acceptor (Table 1, entries 1–5).
verified in the preceding work.4
Rhamnose-derived acetate 8 as a stereoisomer of 2, 2-
Scheme 4 shows the mechanism of the reaction; the prod-
uct distribution was investigated by varying the final tem-
perature. It was revealed that the O-glycosylation and the
deoxy-sugar derived acetates 9 and 10,8 and amino-sugar
derived acetates 10 and 11,9 gave the corresponding bis-
C-glycosides in good to high yield. In every run, the inter-
C-glycoside formation commenced at below –20 °C and
mediate O-glycoside, mono-C-glycoside, and mono-O-
made rapid progress in the temperature range –10 to 0 °C.
mono-C-glycoside were consumed by raising the reaction
Notably, the bis-O-glycoside 5 was not detected at any
temperature, and in the meanwhile the a/b ratio of the C-
stage. This is probably because isomerization of mono-O-
glycoside fully changed to give the bis-b-C-glycoside as
glycoside 4 to mono-C-glycoside 6 is still faster than bis-
the sole stereoisomer.
O-glycoside formation.7
Also notable are the configuration of the C-glycoside link-
ages in 6, 7, and 3, which were entirely b at any stage. This
Table 1 One-Pot Double C-Glycosylation
Entry
Resorcinol derivative
Glycosyl donor
Temp (°C)a
Product
Yield (%)
HO
CH3
OH
O
O
HO
OAc
OBn
OBn
Bn
CH3
O
BnO
OBn
O
1
0
99
OBn
BnO
OH
2
OBn
1
OBn
3
HO
CH3
O
BnO
OAc
BnO
OBn
OH
O
BnO
2
1
25
79
OBn
OBn
OBn
O
OBn
OBn
8
12
Synthesis 2006, No. 17, 2818–2824 © Thieme Stuttgart · New York

2820
T. Yamauchi et al.
PAPER
Table 1 One-Pot Double C-Glycosylation (continued)
Entry
Resorcinol derivative
Glycosyl donor
Temp (°C)a
Product
Yield (%)
HO
CH3
OH
O
BnO
OAc
BnO
O
BnO
3
1
–20
91
OBn
O
OBn
OBn
9
13
HO
CH3
OH
N3
BnO
O
O
4
1
BnO
20
62
N3
OAc
O
10
N3
BnO
14
HO
CH3
OH
O
O
OAc
OBn
N3
Bn
O
BnO
5
1
25
OBn
O
86
N3
BnO
11
N3
OBn
15
HO
I
O
OBn
O
HO
Bn
I
BnO
OH
OBn
O
6
2
8
2
10
98
OH
OBn
16
OBn
19
HO
I
O
BnO
BnO
OBn
OH
7
16
25
78
OBn
O
OBn
OBn
20
HO
O
O
OBn
OCH3
O
HO
O
Bn
BnO
OH
OCH3
OBn
O
8
5
73
OH
OBn
17
OBn
21
Synthesis 2006, No. 17, 2818–2824 © Thieme Stuttgart · New York

PAPER
Facile One-Pot Synthesis of Resorcinol Bis-C-Glycosides
2821
Table 1 One-Pot Double C-Glycosylation (continued)
Entry
Resorcinol derivative
Glycosyl donor
Temp (°C)a
Product
Yield (%)
HO
O
OCH3
O
BnO
BnO
OH
OBn
9
17
8
15
79
55
71
OBn
O
OBn
OBn
22
HO
O
O
CH3
O
HO
O
OBn
Bn
BnO
OH
10
CH3
2
–20
OBn
O
OH
OBn
18
OBn
23
HO
O
O
CH3
BnO
BnO
OBn
OH
11
18
8
20
OBn
O
OBn
OBn
24
a The reaction, starting from –30 °C, was gradually warmed and quenched at this temperature.
oratory, Department of Chemistry, Tokyo Institute of Technology
on a Perkin-Elmer 2400 instrument.
Application to the three resorcinol derivatives, which dif-
fer in the C2 substituent, broadened the scope of the
present method (Table 1, entries 6–11).
Bis-C-Glycosides; 1,3-Dihydroxy-2-methyl-4,6-bis(2,3,4-tri-O-
benzyl-b-L-fucopyranosyl)benzene (3); Typical Procedure
To a stirred mixture of Sc(OTf)3 (102 mg, 0.207 mmol), 2-methyl-
resorcinol (1; 100 mg, 0.806 mmol), and powdered Drierite® (2.4 g)
in DCE (20 mL), was added fucosyl acetate (2; 1.24 g, 2.60 mmol)
in DCE (20 mL) at –30 °C. The mixture was gradually warmed to 0
°C over 1.5 h, stirred at this temperature for 1 h, and then poured
into a sat. aq solution of NaHCO3 (20 mL). After filtration through
a pad of Celite, the products were extracted with EtOAc (1 × 60 mL,
then 2 × 10 mL), and the combined organic extracts were washed
with brine (20 mL), and dried over Na2SO4. Removal of the solvents
in vacuo and purification by silica gel chromatography (hexane–
acetone, 30:1) afforded C-glycoside 3; colorless prisms (Et2O); mp
131–132 °C; [a]D30 –18 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.26 (d, J = 6.0 Hz, 6 H), 2.17 (s,
3 H), 3.60–3.61 (m, 4 H), 3.71 (d, J = 1.6 Hz, 2 H), 3.84 (d, J = 10.2
Hz, 2 H), 4.14–4.15 (m, 4 H), 4.46 (d, J = 10.2 Hz, 2 H), 4.76 (d,
J = 12.0 Hz, 2 H), 4.77 (d, J = 12.2 Hz, 2 H), 4.82 (d, J = 12.0 Hz,
2 H), 5.11 (d, J = 12.2 Hz, 2 H), 6.71 (s, 1 H), 7.04–7.41 (m, 30 H),
7.95 (s, 2 H).
Iodine, ester, and ketone proved to be suitable substitu-
ents. Particularly notable is that the reaction is not affected
by conjugation of the aromatic ring with an electron-
accepting group (ester, ketone).
These C2 substituents, in association with the phenolic
hydroxyls, would allow flexible manipulation of the aro-
matic ring and hence the synthesis of a variety of function-
alized mono- and polyaromatic compounds with a bis-C-
glycoside structure.
In summary, we have developed a facile procedure for the
one-pot double C-glycosylation of non-protected resorci-
nol derivatives, which will find application in the synthe-
sis of biologically significant analogues of natural bis-C-
glycosides.
DCE was distilled over CaH2. All experiments were performed un-
der an Ar atmosphere. Melting points were determined on a Yanako
MP-S3 apparatus and are uncorrected. Optical rotations were mea-
sured on a JASCO RIP-1000 polarimeter. IR spectra were obtained
on a Horiba FT-710 spectrometer. NMR experiments were recorded
on either a JEOL JNMAL-300 or Lambda-400 MHz, instrument.
Combustion analyses were performed by the Microanalytical Lab-
13C NMR (75 MHz, CDCl3): d = 8.2, 17.5, 72.7, 74.4, 74.6, 75.3,
76.6, 78.5, 82.3, 83.9, 113.6, 114.3, 127.3, 127.4, 127.48, 127.53,
127.90, 127.95, 128.2, 128.4, 128.7, 137.9, 138.56, 138.64, 154.9.
Anal. Calcd for C61H64O10: C, 76.54; H, 6.74. Found: C, 76.24; H,
6.81.
Synthesis 2006, No. 17, 2818–2824 © Thieme Stuttgart · New York

2822
T. Yamauchi et al.
PAPER
1,3-Dihydroxy-2-methyl-4,6-bis(2,3,4-tri-O-benzyl-b-L-rham-
nopyranosyl)benzene (12)
HO
CH3
OH
White foamy solid; mp 50–51 °C; [a]D31 –19 (c 1.0, CHCl3).
HO
1H NMR (300 MHz, CDCl3): d = 1.42 (d, J = 6.0 Hz, 6 H), 2.15 (s,
3 H), 3.47 (dq, J = 9.3, 6.0 Hz, 2 H), 3.66 (dd, J = 9.3, 2.2 Hz, 2 H),
3.70 (t, J = 9.3 Hz, 2 H), 3.91 (d, J = 2.2 Hz, 2 H), 4.36 (d, J = 11.1
Hz, 2 H), 4.36 (s, 2 H), 4.60 (d, J = 11.1 Hz, 2 H), 4.65 (d, J = 12.0
Hz, 2 H), 4.68 (d, J = 10.7 Hz, 2 H), 4.71 (d, J = 12.0 Hz, 2 H), 4.97
(d, J = 10.7 Hz, 2 H), 6.33 (s, 1 H), 7.13–7.34 (m, 30 H), 8.08 (s, 2
H).
13C NMR (75 MHz, CDCl3): d = 8.2, 18.3, 72.0, 75.2, 75.6, 76.6,
79.1, 79.9, 82.5, 83.9, 113.3, 113.4, 123.8, 127.4, 127.5, 127.6,
127.8, 128.0, 128.1, 128.36, 128.39, 128.41, 137.8, 138.2, 138.3,
155.0.
CH3
O
1
+
OAc
OBn
O
OBn
O
OBn
BnO
mono-O-glycoside 4
OBn
BnO
2
BnO
BnO
HO
O
Anal. Calcd for C61H64O10: C, 76.54; H, 6.74. Found: C, 76.26; H,
6.69.
CH3
OH
O
BnO
CH3
O
1,3-Dihydroxy-2-methyl-4,6-bis(3,4-di-O-benzyl-2-deoxy-b-L-
arabino-hexopyranosyl)benzene (13)
OBn
30
O
Colorless needles (hexane); mp 76–77 °C, [a]D –31 (c 1.0,
O
OBn
OBn
OBn
CHCl3).
OBn
BnO
1H NMR (300 MHz, CDCl3): d = 1.38 (d, J = 6.0 Hz, 6 H), 1.94
(ddd, J = 13.6, 13.4, 11.9 Hz, 2 H), 2.12 (s, 3 H), 2.32 (ddd,
J = 13.4, 5.0, 1.7 Hz, 2 H), 3.21 (dd, J = 9.2, 8.9 Hz, 2 H), 3.53 (dq,
J = 9.2, 6.0 Hz, 2 H), 3.74 (ddd, J = 13.6, 8.9, 5.0 Hz, 2 H), 4.51 (dd,
J = 11.9, 1.7 Hz, 2 H), 4.62 (d, J = 11.8 Hz, 2 H), 4.69 (d, J = 11.0
Hz, 2 H), 4.70 (d, J = 11.8 Hz, 2 H), 4.99 (d, J = 11.0 Hz, 2 H), 6.42
(s, 1 H), 7.27–7.33 (m, 20 H), 7.95 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 7.9, 18.6, 37.4, 71.3, 75.4, 76.1,
78.4, 80.3, 83.5, 114.0, 116.0, 121.4, 127.58, 127.63, 127.8, 128.1,
128.39, 128.41, 138.27, 138.33, 154.1.
bis-O-glycoside 5
mono-C-glycoside 6
HO
CH3
O
O
OBn
Bn
BnO
O
O
OBn
Anal. Calcd for C47H52O8: C, 75.78; H, 7.04. Found: C, 75.89; H,
7.04.
OBn
BnO
mono-O-mono-C-glycoside 7
1,3-Dihydroxy-2-methyl-4,6-bis(2-azido-4-O-benzyl-2,3-
dideoxy-b-D-arabino-hexopyranosyl)benzene (14)
Colorless plates (EtOAc–hexane); mp 161–162 °C, [a]D +32 (c
1.5, CHCl3).
30
HO
IR (KBr): 2100 cm–1 (N=N=N).
CH3
O
O
1H NMR (300 MHz, CDCl3): d = 1.39 (d, J = 6.0 Hz, 6 H), 1.92
(ddd, J = 13.2, 12.0, 11.7 Hz, 2 H), 2.11 (s, 3 H), 2.21 (ddd,
J = 13.2, 4.8, 1.8 Hz, 2 H), 3.09 (t, J = 9.3 Hz, 2 H), 3.56 (dq,
J = 9.3, 6.0 Hz, 2 H), 3.67 (ddd, J = 12.0, 9.3, 4.8 Hz, 2 H), 4.56 (dd,
J = 11.7, 1.8 Hz, 2 H), 4.66 (d, J = 10.7 Hz, 2 H), 4.91 (d, J = 10.7
Hz, 2 H), 6.44 (s, 1 H), 7.31–7.39 (m, 10 H), 7.80 (s, 2 H).
OBn
BnO
Bn
OH
OBn
O
OBn
bis-C-glycoside 3
OBn
13C NMR (75 MHz, CDCl3): d = 7.9, 18.5, 37.2, 63.4, 75.4, 76.6,
78.4, 83.1, 114.2, 115.6, 121.5, 128.1, 128.3, 128.5, 137.3, 154.0.
Yield (%)
Final temp. (°C)a
Anal. Calcd for C33H38N6O6: C, 64.48; H, 6.23; N, 13.67. Found: C,
64.49; H, 6.51; N, 13.41.
2
4b
6c
7d
3e
–20
–15
–10
0
31
27
0
33
20
11
0
19
20
17
0
2
15
22
0
0
8
1,3-Dihydroxy-2-methyl-4,6-bis(3-azido-2,4-di-O-benzyl-3,6-
dideoxy-b-L-galactopyranosyl)benzene (15)
44
98
Amorphous solid; mp 57–58 °C; [a]D31 +56 (c 1.1, CHCl3).
0
a The temperature at which the reaction was quenched.
IR (NaCl): 2100 cm–1 (N=N=N).
b Total yield of the α-O- and β-O-glycosides.
1H NMR (300 MHz, CDCl3): d = 1.26 (d, J = 6.3 Hz, 6 H), 2.21 (s,
3 H), 3.59–3.66 (m, 8 H), 4.11 (s, 4 H), 4.39 (d, J = 9.9 Hz, 2 H),
4.71 (d, J = 11.7 Hz, 2 H), 5.02 (d, J = 11.7 Hz, 2 H), 6.64 (s, 1 H),
7.10–7.44 (m, 20 H), 7.90 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 8.1, 17.2, 66.8, 74.7, 75.1, 75.3,
77.4, 77.8, 82.7, 113.8, 114.1, 127.3, 127.7, 127.8, 127.97, 128.02,
128.4, 128.9, 137.1, 137.8, 155.3.
c Yield of the β-C-glycoside. The α-C-glycoside was not detected.
d Yield of the α-O-β-C-glycoside. The β-O-β-C-glycoside was not
detected.
e Yield of the bis-β-C-glycoside. Neither α-C-β-C- nor bis-α-C-
glycoside was detected.
Scheme 4 Mechanism of the reaction of 2-methylresorcinol (1) and
fucosyl acetate 2.
Synthesis 2006, No. 17, 2818–2824 © Thieme Stuttgart · New York

PAPER
Facile One-Pot Synthesis of Resorcinol Bis-C-Glycosides
2823
Anal. Calcd for C47H50N6O8: C, 68.26; H, 6.09; N, 10.16. Found: C,
68.00; H, 6.13; N, 9.90.
13C NMR (75 MHz, CDCl3): d = 18.4, 52.6, 71.9, 74.4, 75.2, 75.4,
76.3, 80.5, 84.5, 99.1, 117.0, 126.9, 127.4, 127.5, 127.6, 127.7,
128.06, 128.11, 128.31, 128.34, 134.9, 138.5, 138.6, 138.7, 155.8,
170.7.
1,3-Dihydroxy-2-iodo-4,6-bis(2,3,4-tri-O-benzyl-b-L-fucopyra-
nosyl)benzene (19)
Anal. Calcd for C62H64O12: C, 74.38; H, 6.44. Found: C, 74.10; H,
6.57.
Amorphous solid; mp 60–61 °C; [a]D30 +31 (c 1.4, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.24 (d, J = 6.3 Hz, 6 H), 3.58–
3.64 (m, 4 H), 3.70 (d, J = 2.2 Hz, 2 H), 3.87 (d, J = 10.5 Hz, 2 H),
4.05–4.15 (m, 4 H), 4.51 (d, J = 10.5 Hz, 2 H), 4.72–4.80 (m, 4 H),
4.78 (d, J = 11.9 Hz, 2 H), 5.07 (d, J = 11.9 Hz, 2 H), 6.82 (s, 1 H),
6.99–7.02 (m, 4 H), 7.12–7.17 (m, 6 H), 7.27–7.40 (m, 20 H), 8.70
(s, 2 H).
13C NMR (75 MHz, CDCl3): d = 17.4, 72.6, 74.3, 74.8, 75.3, 75.4,
76.0, 78.2, 81.6, 83.9, 114.6, 127.3, 127.5, 127.6, 128.0, 128.2,
128.3, 128.4, 128.6, 130.6, 137.6, 138.3, 138.4, 156.0.
1-[2,6-Dihydroxy-3,5-bis(2,3,4-tri-O-benzyl-b-L-fucopyrano-
syl)phenyl]ethanone (23)
Colorless oil; [a]D27 –21 (c 3.1, CHCl3).
IR (NaCl): 1622 cm–1 (C=O).
1H NMR (500 MHz, CDCl3): d = 1.24 (d, J = 6.4 Hz, 6 H), 2.69 (s,
3 H), 3.63 (q, J = 6.4 Hz, 2 H), 3.68 (dd, J = 9.2, 2.5 Hz, 2 H), 3.71
(q, J = 2.5 Hz, 2 H), 3.91 (d, J = 10.9 Hz, 2 H), 4.04 (dd, J = 9.4, 9.2
Hz, 2 H), 4.28 (d, J = 10.9 Hz, 2 H), 4.56 (d, J = 9.4 Hz, 2 H), 4.71
(s, 4 H), 4.75 (d, J = 11.8 Hz, 2 H), 5.11 (d, J = 11.8 Hz, 2 H), 6.90–
6.95 (m, 4 H), 7.06–7.13 (m, 6 H), 7.24–7.48 (m, 20 H), 7.59 (s, 1
H), 11.23 (br, 2 H).
Anal. Calcd for C60H61IO10: C, 67.41; H, 5.75. Found: C, 67.25; H,
5.82.
1,3-Dihydroxy-2-iodo-4,6-bis(2,3,4-tri-O-benzyl-b-L-rhamno-
pyranosyl)benzene (20)
13C NMR (75 MHz, CDCl3, 40 °C): d = 17.4, 33.7, 72.6, 74.5,
74.56, 74.59, 77.2, 78.1, 79.1, 84.5, 110.8, 117.1, 127.1, 127.3,
127.41, 127.45, 127.48, 127.8, 128.0, 128.2, 128.3, 135.8, 138.3,
138.6, 138.8, 160.3, 205.7.
Colorless oil; [a]D28 +3.9 (c 1.4, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.41 (d, J = 6.1 Hz, 6 H), 3.44–
3.53 (m, 2 H), 3.65–3.74 (m, 4 H), 3.94 (br s, 2 H), 4.29 (d, J = 11.5
Hz, 2 H), 4.44 (s, 2 H), 4.59 (d, J = 11.5 Hz, 2 H), 4.63–4.73 (m, 6
H), 4.95 (d, J = 10.7 Hz, 2 H), 6.76 (s, 1 H), 7.06–7.35 (m, 30 H),
8.13 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 18.3, 72.1, 74.8, 75.6, 77.4, 77.7,
78.3, 79.9, 80.5, 84.0, 114.4, 127.2, 127.4, 127.5, 127.7, 127.8,
128.08, 128.13, 128.14, 128.40, 128.43, 137.7, 138.2, 138.3, 154.8.
Anal. Calcd for C62H64O11: C, 75.59; H, 6.55. Found: C, 75.38; H,
6.34.
1-[2,6-Dihydroxy-3,5-bis(2,3,4-tri-O-benzyl-b-L-rhamnopyra-
nosyl)phenyl]ethanone (24)
Colorless oil; [a]D27 –48 (c 1.1, CHCl3).
IR (NaCl): 1622 cm–1 (C=O).
Anal. Calcd for C60H61IO10: C, 67.41; H, 5.75. Found: C, 67.16; H,
5.52.
1H NMR (500 MHz, DMSO-d6): d = 1.28 (d, J = 5.1 Hz, 6 H), 2.53
(s, 3 H), 3.49–3.54 (m, 4 H), 3.83–3.86 (m, 2 H), 3.99 (d, J = 11.5
Hz, 2 H), 4.06 (d, J = 2.4 Hz, 2 H), 4.43 (d, J = 11.5 Hz, 2 H), 4.63
(d, J = 11.8 Hz, 2 H), 4.64 (d, J = 11.1 Hz, 2 H), 4.73 (d, J = 11.8
Hz, 2 H), 4.80 (s, 2 H), 4.84 (d, J = 11.1 Hz, 2 H), 7.05–7.07 (m, 4
H), 7.15–7.20 (m, 6 H), 7.27–7.40 (m, 20 H), 7.58 (s, 1 H), 11.45
(br, 2 H).
Methyl 2,6-Dihydroxy-3,5-bis(2,3,4-tri-O-benzyl-b-L-fucopyra-
nosyl)benzoate (21)
Amorphous solid; mp 54–55 °C; [a]D26 –8.6 (c 1.1, CHCl3).
IR (NaCl): 1655 cm–1 (O=C–O).
1H NMR (300 MHz, CDCl3): d = 1.19 (d, J = 6.4 Hz, 6 H), 3.58–
3.65 (m, 2 H), 3.67–3.70 (m, 4 H), 4.02 (s, 3 H), 4.02 (d, J = 10.8
Hz, 2 H), 4.14 (dd, J = 9.7, 9.5 Hz, 2 H), 4.57 (d, J = 9.5 Hz, 2 H),
4.43 (d, J = 10.8 Hz, 2 H), 4.70–4.77 (m, 6 H), 5.07 (d, J = 12.1 Hz,
2 H), 6.95–6.98 (m, 4 H), 7.10–7.12 (m, 6 H), 7.23–7.43 (m, 20 H),
7.68 (s, 1 H), 10.1 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 17.4, 52.6, 72.7, 74.4, 74.7, 76.7,
77.3, 79.1, 84.8, 103.0, 117.6, 127.1, 127.36, 127.41, 127.44, 127.7,
127.97, 128.01, 128.1, 128.3, 135.7, 138.3, 138.7, 138.9, 158.6,
170.7.
13C NMR (125 MHz, DMSO-d6): d = 19.1, 34.3, 71.7, 75.0, 75.2,
76.2, 76.9, 77.5, 80.6, 83.9, 110.8, 116.9, 128.1, 128.19, 128.27 (2
C), 128.35, 128.7, 128.8, 129.06, 129.13, 135.4, 139.2, 139.5,
158.6, 206.6.
Anal. Calcd for C62H64O11: C, 75.59; H, 6.55. Found: C, 75.36; H,
6.42.
Mechanistic Study (Scheme 4)
The reaction of 2-methylresorcinol (1) and fucosyl acetate (2) was
quenched after warming to –20 °C, –15 °C, or –10 °C. The crude
mixture was carefully purified by silica gel chromatography (hex-
ane–acetone, 30:1) to give mono-O-mono-C-glycoside 7, bis-C-
glycoside 3, mono-a-O-glycoside a-4, mono-C-glycoside 6, and a
mixture of mono-C-glycoside 6 and mono-b-O-glycoside b-4,
which were eluted in that order.
Anal. Calcd for C62H64O12: C, 74.38; H, 6.44. Found: C, 74.12; H,
6.30.
Methyl 2,6-Dihydroxy-3,5-bis(2,3,4-tri-O-benzyl-b-L-rhamno-
pyranosyl)benzoate (22)
Granular crystals (Et2O–hexane); mp 112–114 °C; [a]D29 –43 (c 1.0,
CHCl3).
3-Hydroxy-2-methylphenyl 2,3,4-Tri-O-benzyl-a- and -b-L-fu-
copyranoside (a-4 and b-4)
a-4
IR (NaCl): 1670 cm–1 (O=C–O).
Colorless oil; [a]D22 –74 (c 1.3, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.43 (d, J = 6.0 Hz, 6 H), 3.51 (dq,
J = 8.4, 6.4 Hz, 2 H), 3.71 (dd, J = 9.6, 8.4 Hz, 2 H), 3.75 (dd,
J = 9.6, 1.6 Hz, 2 H), 4.04 (s, 3 H), 4.13 (d, J = 1.6 Hz, 2 H), 4.21
(d, J = 11.7 Hz, 2 H), 4.52 (d, J = 11.7 Hz, 2 H), 4.64 (s, 2 H), 4.68
(d, J = 10.8 Hz, 2 H), 4.69 (d, J = 11.8 Hz, 2 H), 4.74 (d, J = 11.8
Hz, 2 H), 4.96 (d, J = 10.8 Hz, 2 H), 7.01–7.04 (m, 4 H), 7.08–7.10
(m, 6 H), 7.22–7.39 (m, 20 H), 7.84 (s, 1 H), 9.85 (s, 2 H).
1H NMR (400 MHz, CDCl3): d = 1.11 (d, J = 6.4 Hz, 3 H), 2.15 (s,
3 H), 3.71 (d, J = 2.6 Hz, 1 H), 4.00 (q, J = 6.4 Hz, 1 H), 4.14 (dd,
J = 10.2, 2.6 Hz, 1 H), 4.20 (dd, J = 10.2, 3.2 Hz, 1 H), 4.66 (d,
J = 11.4 Hz, 1 H), 4.69 (d, J = 11.4 Hz, 1 H), 4.79 (d, J = 11.2 Hz,
1 H), 4.81 (d, J = 12.0 Hz, 1 H), 4.82 (s, 1 H), 4.92 (d, J = 12.0 Hz,
1 H), 5.03 (d, J = 11.2 Hz, 1 H), 5.47 (d, J = 3.2 Hz, 1 H), 6.47 (d,
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T. Yamauchi et al.
PAPER
J = 8.0 Hz, 1 H), 6.70 (d, J = 8.4 Hz, 1 H), 6.95 (dd, J = 8.4, 8.0 Hz,
1 H), 7.21–7.43 (m, 15 H).
127.59, 127.63, 127.9, 128.19, 128.22, 128.26, 128.36, 128.40,
128.42, 128.5, 137.8, 138.5, 138.6, 138.7, 138.8, 154.5, 156.6.
13C NMR (75 MHz, CDCl3): d = 8.4, 16.7, 67.3, 72.9, 73.2, 74.9,
76.4, 77.7, 78.8, 97.0, 107.6, 109.0, 113.8, 126.4, 127.3, 127.4,
127.5, 127.6, 128.1, 128.28, 128.34, 138.45, 138.50, 138.7, 154.3,
156.5.
Anal. Calcd for C61H64O10: C, 76.54; H, 6.74. Found: C, 76.79; H,
6.71.
References
Anal. Calcd for C34H36O6: C, 75.53; H, 6.71. Found: C, 75.77; H,
6.96.
(1) For reviews on aryl C-glycoside antibiotics, see:
(a) Hacksell, U.; Daves, G. D. Jr. Prog. Med. Chem. 1985,
22, 1. (b) Suzuki, K.; Matsumoto, T. In Recent Progress in
the Chemical Synthesis of Antibiotics and Related Microbial
Products, Vol. 2; Lukacs, G., Ed.; Springer: Berlin, 1993,
353. (c) Postema, M. H. D. C-Glycoside Synthesis; CRC:
Florida, 1995. (d) Bililign, T.; Griffith, B. R.; Thorson, J. S.
Nat. Prod. Rep. 2005, 22, 742.
b-4 (Selected Data)
1H NMR (400 MHz, CDCl3): d = 2.18 (s, 3 H, ArCH3), 4.95 (d,
J = 7.7 Hz, 1 H, anomeric H), 6.48 (d, J = 8.0 Hz, 1 H, ortho to OH),
6.63 (d, 1 H J = 8.0 Hz, para to OH), 6.97 (t, J = 8.0 Hz, 1 H, meta
to OH).
1,3-Dihydroxy-2-methyl-4-(2,3,4-tri-O-benzyl-b-L-fucopyrano-
syl)benzene (6)
(2) (a) Séquin, U. Prog. Chem. Org. Nat. Prod. 1986, 50, 58.
(b) Kondo, S.; Miyamoto, M.; Naganawa, H.; Takeuchi, T.;
Umezawa, H. J. Antibiot. 1977, 30, 1143. (c) Séquin, U.;
Ceroni, M. Helv. Chim. Acta 1978, 61, 2241. (d) Furukawa,
M.; Hayakawa, I.; Ohta, G.; Iitaka, Y. Tetrahedron 1975, 31,
2989.
(3) Hansen, M. R.; Hurley, L. H. Acc. Chem. Res. 1996, 29, 249.
(4) Yamauchi, T.; Watanabe, Y.; Suzuki, K.; Matsumoto, T.
Synlett 2006, 399.
(5) For the O→C-glycoside rearrangement, see:
(a) Matsumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron
Lett. 1988, 29, 6935. (b) Hosoya, T.; Takashiro, E.;
Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116,
1004. (c) Matsumoto, T.; Yamaguchi, H.; Tanabe, M.;
Yasui, Y.; Suzuki, K. Tetrahedron Lett. 2000, 41, 8393.
(d) Ben, A.; Yamauchi, T.; Matsumoto, T.; Suzuki, K.
Synlett 2004, 225. (e) See also: Kometani, T.; Kondo, H.;
Fujimori, Y. Synthesis 1988, 1005.
Colorless oil; [a]D28 +16 (c 3.5, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.21 (d, J = 6.4 Hz, 3 H), 2.14 (s,
3 H), 3.59 (q, J = 6.4 Hz, 1 H), 3.63 (dd, J = 2.4, 8.9 Hz, 1 H), 3.69
(d, J = 2.4 Hz, 1 H), 3.92 (d, J = 10.1 Hz, 1 H), 4.16 (dd, J = 9.4, 8.9
Hz, 1 H), 4.24 (d, J = 9.4 Hz, 1 H), 4.44 (d, J = 10.1 Hz, 1 H), 4.74
(d, J = 12.0 Hz, 1 H), 4.76 (d, J = 12.0 Hz, 1 H), 4.79 (d, J = 12.0
Hz, 1 H), 4.92 (s, 1 H), 5.10 (d, J = 12.0 Hz, 1 H), 6.30 (d, J = 8.2
Hz, 1 H), 6.85 (d, J = 8.2 Hz, 1 H), 7.02–7.08 (m, 2 H), 7.16–7.42
(m, 13 H), 7.93 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 8.0, 17.4, 72.7, 74.4, 74.5, 75.3,
76.5, 78.0, 82.2, 83.9, 106.0, 111.8, 116.0, 126.9, 127.4, 127.5,
127.58, 127.62, 127.9, 128.1, 128.2, 128.4, 128.6, 137.8, 138.48,
138.52, 154.8, 155.0.
Anal. Calcd for C34H36O6: C, 75.53; H, 6.71. Found: C, 75.28; H,
6.86.
(6) For other approaches to bis-C-glycosyl arenes, see:
(a) Parker, K. A.; Koh, Y.-h. J. Am. Chem. Soc. 1994, 116,
11149. (b) Kaelin, D. E. Jr.; Lopez, O. D.; Martin, S. F. J.
Am. Chem. Soc. 2001, 123, 6937. (c) Martin, S. F. Pure
Appl. Chem. 2003, 5, 63.
(7) Another possible explanation is that bis-O-glycoside 5, once
formed immediately rearranges to mono-O-mono-C-
glycoside 7. However, this is unlikely since it was previously
shown that protection of one hydroxyl group of a resorcinol
derivative remarkably retards the O→C-glycoside
rearrangement at the other hydroxyl; see ref. 4.
(8) Bartner, P.; Boxler, D. L.; Brambilla, R.; Mallams, A. K.;
Morton, J. B.; Reichert, P.; Sancilio, F. D.; Surprenant, H.;
Tomalesky, G.; Lukacs, G.; Olesker, A.; Thang, T. T.;
Valente, L.; Omura, S. J. Chem. Soc., Perkin Trans. 1 1979,
1600.
3-Hydroxy-2-methyl-4-(2,3,4-Tri-O-benzyl-b-L-fucopyrano-
syl)phenyl 2,3,4-Tri-O-benzyl-a-L-fucopyranoside (7)
Colorless oil; [a]D21 –33 (c 1.2, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.08 (d, J = 6.8 Hz, 3 H), 1.22 (d,
J = 6.4 Hz, 3 H), 2.18 (s, 3 H), 3.60 (q, J = 6.4 Hz, 1 H), 3.64 (dd,
J = 9.2, 2.8 Hz, 1 H), 3.71 (d, J = 1.6 Hz, 2 H), 3.91 (d, J = 10.0 Hz,
1 H), 3.98 (q, J = 6.8 Hz, 1 H), 4.15–4.20 (m, 3 H), 4.25 (d, J = 9.2
Hz, 1 H), 4.45 (d, J = 10.0 Hz, 1 H), 4.67–4.70 (m, 2 H), 4.74–4.83
(m, 5 H), 4.92 (d, J = 12.0 Hz, 1 H), 5.02 (d, J = 11.6 Hz, 1 H), 5.11
(d, J = 12.0 Hz, 1 H), 5.48 (d, J = 2.8 Hz, 1 H), 6.60 (d, J = 8.6 Hz,
1 H), 6.89 (d, J = 8.6 Hz, 1 H), 7.01–7.04 (m, 2 H), 7.11–7.43 (m,
28 H), 7.89 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 8.6, 16.6, 17.4, 67.3, 72.7, 73.1,
73.3, 74.4, 74.5, 74.9, 75.3, 76.4, 76.5, 77.3, 77.7, 78.0, 79.0, 82.3,
84.0, 96.9, 106.1, 115.8, 117.4, 126.8, 127.37, 127.44, 127.53,
(9) Hsu, D.-S.; Matsumoto, T.; Suzuki, K. Synlett 2005, 801.
Synthesis 2006, No. 17, 2818–2824 © Thieme Stuttgart · New York