Bis-C-glycosylation of resorcinol derivatives by an O→C-glycoside rearrangement

Article abstract of DOI:10.1055/s-2006-932463

An efficient method for bis-C-glycosylation of resorcinol derivatives was developed by utilizing the O→C-glycoside rearrangement, where each of the two phenols serves as the pivot for selective and high-yield installation of two same or different sugar mo

Full text of DOI:10.1055/s-2006-932463

LETTER
399
Bis-C-Glycosylation of Resorcinol Derivatives by an O→C-Glycoside
Rearrangement
B
is-C-Glycosyl
a
ation of Re
k
sorcinol
D
er
a
ivative
s
hito 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 9 December 2005
unique structure, these compounds are attractive targets
for total synthesis. To date, two elaborate approaches for
constructing the key bis-C-glycosyl arene structure have
appeared, i.e. the one based on the glycosyl anion chemis-
try by Parker4a and the other utilizing the Diels–Alder re-
action of the C-glycosylated furan with a benzyne by
Martin.4b However, there still exists a need to develop
more efficient procedures towards the synthesis of these
natural products and their analogues.
Abstracts: An efficient method for bis-C-glycosylation of resorci-
nol derivatives was developed by utilizing the O→C-glycoside re-
arrangement, where each of the two phenols serves as the pivot for
selective and high-yield installation of two same or different sugar
moieties.
Key words: bis-C-glycoside, C-glycosylation, rearrangement, re-
sorcinol, scandium(III) triflate, pluramycin
Aryl C-glycosides constitute a growing class of natural
products, in which the sugar is directly connected to func-
tionalized polyaromatic chromophore through a C–C
bond (Figure 1).1 Most of these compounds have one C-
glycoside residue at the ortho position or at the para posi-
tion of a phenolic hydroxyl group as in aquayamycin (1)
and the gilvocarcins (2), while some of the 4H-anthra[1,2-
b]pyran C-glycosides, e.g. pluramycin A (3) and kidamy-
cin (4), have two C-glycoside residues.2
In our continuing study on the synthesis of aryl C-glyco-
side antibiotics, we previously reported a reliable method
of aryl C-glycosidation, the O→C-glycoside rearrange-
ment,5,6a which enables regioselective formation of the
aryl C-glycoside linkage at the ortho position of a phenol
through the Lewis acid promoted one-pot reactions in-
cluding the O-glycosylation of a phenol to form O-glyco-
side and the subsequent migration of the sugar moiety.
Notably the reaction tolerates various functionalities on
the phenol, enabling further manipulations of the aromatic
nuclei. These features have been demonstrated in success-
ful applications to the total synthesis of several natural
aryl C-glycosides, including 1 and 2.5b,c
OH
MeO
OH
O
O
HO
MeO
OH
Me
H
OH
O
HO
HO
O
OH
O
O
In this communication, we wish to describe a new synthe-
sis of aryl bis-C-glycosides by performing the O→C-gly-
coside rearrangement twice on a resorcinol derivative
(Scheme 1). Use of two phenols as the pivots ensures re-
gioselective and high yield C-glycoside formations, there-
by enabling efficient access to various bis-C-glycosides
possessing two same or different sugar moieties.
R
OH
O
OH
aquayamycin (1)
R = Me: gilvocarcin M (2a)
R = vinyl: gilvocarcin V (2b)
R
OH
O
O
O
O
Me2N
R'O
HO
HO
O
O
R
R
O
X
O
sugar-1
O
O→C-glycoside
rearrangement
OP
OP
R =
R =
, R' = Ac: pluramycin A (3)
, R' = H: kidamycin (4)
NMe2
I
II
HO
(P = protecting group)
HO
HO
O
O
O
Figure 1 Natural aryl C-glycoside antibiotics
R
R
X
sugar-1
sugar-1
O→C-glycoside
rearrangement
OH
OH
These bis-C-glycoside antibiotics are used as probe in bio-
chemical research because of highly sequence-selective
intercalation into DNA, resulting in specific alkylation.3
Due to such biochemical significance as well as the
III
O
IV
sugar-2
Scheme 1 Bis-C-glycosylation of resorcinol derivative by utilizing
the O→C-glycoside rearrangement.
SYNLETT 2006, No. 3, pp 0399–0402
1
5.
0
2.
2
0
0
6
Advanced online publication: 06.02.2006
DOI: 10.1055/s-2006-932463; Art ID: U31205ST
© Georg Thieme Verlag Stuttgart · New York

400
T. Yamauchi et al.
LETTER
First, four model compounds 8a–d were prepared for out that use of Drierite®, instead of MS4A, significantly
examining the introduction of the second C-glycoside facilitates the catalytic reaction to completion (run 3).9
residue, which possess a non-protected phenol at the para Sc(OTf)3, BF3·OEt2, Me3SiOTf also catalyzed the reac-
position of the sugar residue (Scheme 2).
tion in combination with Drierite®. Among them, the
Sc(OTf)3–Drierite® combination was most effective, as
the reaction was completed at 0 °C to give the bis-C-gly-
coside 9 in 98% yield (run 5).
According to the previously reported procedure,6 fucosyl
acetate 5 and mono-protected 2-methylresorcinol 6 were
treated with 10 mol% of Sc(OTf)3 in the presence of
Drierite® in 1,2-dichloroethane at –30 °C, and the mixture Typical procedure for the synthesis of bis-C-glycoside 9
was allowed to warm. The O-glycosidation and the sub- by the Sc(OTf)3–Drierite® combination is as follows: to a
sequent migration of the sugar proceeded cleanly to give stirred mixture of Sc(OTf)3 (21.7 mg, 44 mmol), mono-C-
b-C-glycoside 7 in 95% yield, after quenching the reac- glycoside 8e (94.3 mg, 0.175 mmol), powdered Drierite®
tion at 0 °C.7 C-Glycoside 7 was converted to compounds (0.55 g) in 1,2-dichloroethane (11 mL), was added acetate
8a–d by protecting the phenol with four different groups 5 (173 mg, 0.363 mmol) in 1,2-dichloroethane (4 mL) at
followed by desilylation.
–30 °C. After the temperature was gradually raised to 0 °C
over 4 hours, the mixture was poured into saturated aque-
ous NaHCO3 solution. After filtration through a Celite®
pad, the products were extracted with EtOAc (3×), and the
combined organic extracts were washed with brine, and
dried over Na2SO4. Removal of the solvents in vacuo and
purification on silica gel chromatography (hexane–
acetone = 3:1) afforded bis-C-glycoside 9 as a foamy
solid (163 mg, 98%), which was recrystallized from
diethyl ether to give colorless prisms.10
HO
OAc
10 mol% Sc(OTf)3
Drierite®
CH3
O
OBn
+
OBn
ClCH2CH2Cl
–30 to 0 °C
BnO
OTBDPS
5
6
95%
HO
RO
1) protectiona
CH3
CH3
OH
O
O
O
O
2) Bu4NF,
THF, 0 °C
(83–92%)b
OBn
OBn
Bn
Bn
BnO
BnO
OTBDPS
Table 1 Reactions of Diol 8e and Fucosyl Acetate 5 with Various
Lewis Acids
7
8a: R = Me, 8b: R = Bn
8c: R = Ac, 8d: R = Bz
HO
OAc
CH3
OH
O
conditions
Scheme 2 Synthesis of the model glycosyl acceptors possessing the
C-glycoside residue. Reagents and conditions for the protections:
for 8a: (MeO)2SO2, K2CO3, DMF, 40 °C (91%); for 8b: BnBr,
Et4NHSO4, CH2Cl2, 2 M NaOH aq (73%); for 8c: Ac2O, DMAP, py-
ridine (93%); for 8d: PhCOCl, DMAP, pyridine (quant). b Yields for
the desilylation.
O
OBn
+
O
a
OBn
OBn
BnO
Bn
BnO
BnO
8e
5
HO
HO
CH3
OH
CH3
O
O
O
O
OBn
OBn
Bn
Bn
With mono-C-glycosides 8a–d in hand, we examined the
second C-glycosylation with the glycosyl donor 5. Unfor-
tunately, the reactions under various conditions were not
productive, as the migration of the sugar proved to be very
sluggish. Though we could obtain the desired bis-C-gly-
coside from 8a, the yield was not satisfactory and many
side products accompanied.8 Compound 8b–d failed to
give the bis-C-glycoside.
BnO
O
O
OBn
O
OBn
OBn
OBn
BnO
OBn
9
10
Run Lewis acid (equiv)
Additive
MS4A
Temp Time Yield of 9
(°C) (h) (%)a
1
2
3
Cp2HfCl2 (1.2), AgOTf
(2.4)
0
3
86
However, we were pleased to find the reaction of the non-
protected variant 8e, prepared by desilylation of 7
[Bu4NF, THF, 0 °C, 98%], nicely underwent the second
C-glycosylation under catalysis of various Lewis acids to
give stereoselectively bis-b-C-glycoside 9.
Cp2HfCl2 (0.25), AgOTf MS4A
(0.5)
20
5.5 36b
Cp2HfCl2 (0.25), AgOTf Drierite® 10
(0.5)
4
93
Table 1 shows selected results of the reactions, where diol
8e and 2 equivalents of 5 were treated with various Lewis
acids in the presence of dehydrating agent (molecular
sieves 3A, 4A, 5A, or Drierite®) in 1,2-dichloroethane at
–30 °C and allowed to warm to the temperature designat-
ed by T (°C). The reaction with a combination of
Cp2HfCl2 (1.2 equiv) and AgOTf (2.4 equiv)5 in the pres-
ence of MS4A proceeded cleanly to give the desired bis-
C-glycoside 9 in 86% yield by raising the temperature to
0 °C (run 1), while the reaction with a catalytic amount of
the reagents was incomplete (run 2). However, it turned
4
5
6
7
Sc(OTf)3 (0.25)
Sc(OTf)3 (0.25)
BF3·OEt2 (0.25)
Me3SiOTf (0.25)
MS4A
25
0
5.5 21c
Drierite®
4
6
98
83
Drierite® 10
Drierite® 25
4.5 93
a The stereoselectivity was b/a = >99/<1 in every run.
b Mono-C-mono-O-glycoside 10 was obtained in 44%, and 11% of the
starting material 8e was recovered.
c Compound 10 was obtained in 18%, and 37% of 8e was recovered.
Synlett 2006, No. 3, 399–402 © Thieme Stuttgart · New York

LETTER
Bis-C-Glycosylation of Resorcinol Derivatives
401
To examine applicability of this method, we prepared derivatives by utilizing the two phenols as the pivots in the
mono-C-glycosylated resorcinols 13 and 1611 as the O→C-glycoside rearrangement. It was found that the
glycosyl acceptors, which possess an iodine or an ester second C-glycoside formation is remarkably facilitated by
moiety, instead of the methyl in 8e, at the position be- liberating both phenols in the mono-C-glycoside and that
tween the phenolic hydroxyl groups (Scheme 3). The Sc(OTf)3–Drierite® combination is most effective as the
reactions were examined for all possible combinations of promoter. In light of the facile procedure as well as appli-
the glycosyl acceptors 8e, 13, 16 and the glycosyl donors cability to various sugars and 2-substituted resorcinol
5, 17, 18 (see Figure 2), according to the procedure derivatives, the present method will find utility in the syn-
described above. The results are summarized in Table 2.
thesis of bis-C-glycoside natural products and their ana-
logues. Studies on the synthesis of the pluramycin-type
antibiotics are currently under investigation.
Diol 8e also reacted with rhamnosyl acetate 17 cleanly
and stereoselectively (run 2). The configuration of the
newly formed C-rhamnoside bond was exclusively b, and
none of the b-C-fucosyl-a-C-rhamnosyl isomer or other
stereoisomers was obtained.
Table 2 Reactions between Glycosyl Acceptors 8e, 13, 16 and the
Glycosyl Donors 5, 17, 18
HO
Glycosyl acetate 18, derived from 2-deoxy sugar (L-oli-
vose), proved to be more reactive than 5 and 17 in both
steps in the O→C-glycoside rearrangement, i.e. the O-
glycosidation and the isomerization to the C-glycoside, so
that the reaction with diol 8e went to completion at lower
temperature (run 3). Also in this case, the stereoselectivity
was perfect to furnish the b-C-glycoside as a single
isomer.
R
O
5
O
OBn
Bn
BnO
OH
OBn
O
OBn
9: R = CH3
19: R = I
20: R = CO2CH3
OBn
HO
HO
R
R
HO
HO
O
O
OBn
Bn
O
25 mol% Sc(OTf)3
Drierite®
17
O
I
I
O
OBn
Bn
BnO
O
BnO
OH
5
+
OH
OBn
ClCH2CH2Cl
–30 to 20 °C
8e: R = CH3
13: R = I
Bn
OBn
BnO
OTBDPS
OR
O
11
12: R = TBDPS
13: R = H
OBn
16: R = CO2CH3
97%
21: R = CH3
22: R = I
23: R = CO2CH3
Bu4NF, THF
0 °C (94%)
OBn
conditions:
25 mol% Sc(OTf)3, Drierite®
ClCH2CH2Cl
–30 °C then warmup to T °C
HO
HO
25 mol% Sc(OTf)3
Drierite®
HO
CO2CH3
O
CO2CH3
O
O
R
5
+
O
O
OBn
Bn
18
OBn
ClCH2CH2Cl
–30 to 5 °C
Bn
BnO
OR
BnO
OH
14
15: R = allyl
16: R = H
80%
Pd(OAc)2, PPh3
HCO2H, Et3N
1,4-dioxane, 0 °C
(95%)
O
OBn
OBn
24: R = CH3
25: R = I
26: R = CO2CH3
Scheme 3
Run
Glycosyl
acceptor
Glycosyl
donor
Temp
(°C)
Product
Yield
(%)a
OAc
OAc
O
O
BnO
BnO
1
2
3
4
5
6
7
8
9
8e
5
17
18
5
0
10
–10
5
9
21
24
19
22
25
20
23
26
97
77
85
91
70
57
78
78
53
BnO
OBn
OBn
17
18
Figure 2
13
Diols 13 and 16 also worked nicely as glycosyl acceptors.
The reactions with 5 (runs 4, 7) and 17 (runs 5, 8) afforded
the corresponding bis-C-glycosides in high yields and ste-
reoselectively. Unfortunately, the yields of the reactions
with glycosyl donor 18 (runs 6, 9) were slightly lower. In
these cases, decomposition of the highly reactive donor 18
took place before completion of the O-glycosylation.
17
18
5
5
–15
10
5
16
17
18
–10
In summary, we have described that two C-glycoside
moieties can be efficiently installed stepwise in resorcinol
a The stereoselectivity was b:a = >99:<1 in every run.
Synlett 2006, No. 3, 399–402 © Thieme Stuttgart · New York

402
T. Yamauchi et al.
LETTER
CH3O
References and Notes
25 mol% Sc(OTf)3
Drierite®
CH3
OH
O
+
5
O
(1) (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.
1,2-dichloroethane
–30 to T °C
(2 equiv)
OBn
Bn
BnO
8a
CH3O
CH3O
CH3
CH3
O
O
O
O
(2) (a) Séquin, U. Prog. Chem. Org. Nat. Prod. 1986, 50, 58.
(b) Pluramycin, A.; 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) Kidamycin: 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) (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.
(5) (a) Matsumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron
Lett. 1988, 29, 6935. (b) See also: Kometani, T.; Kondo, H.;
Fujimori, Y. Synthesis 1988, 1005. (c) Matsumoto, T.;
Yamaguchi, H.; Tanabe, M.; Yasui, Y.; Suzuki, K.
Tetrahedron Lett. 2000, 41, 8393. (d) Hosoya, T.;
Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc.
1994, 116, 1004.
(6) (a) Ben, A.; Yamauchi, T.; Matsumoto, T.; Suzuki, K.
Synlett 2004, 225. (b) For a review on the use of Sc(OTf)3
in organic synthesis, see: Kobayashi, S. Eur. J. Org. Chem.
1999, 15.
OBn
OBn
Bn
Bn
BnO
BnO
O
OH
OBn
O
O
OBn
OBn
OBn
BnO
OBn
27
28
O
OBn
CH3O
Sc2+
+
H
OMe
CH3
OH
CH3
O
O
O
OBn OBn
OBn
OBn
O
H or
sugar
Bn
BnO
29
A
OBn
OBn
Yield (%)a
T (°C)
8a
27
28
29
–15
0
25
60
96
15
0
0
29
0
0
0
0
12
27
48b
68c
37
0
0
a Isolated yield of each product.
b α/β = 3.0/1.
c α/β = 1/2.4.
(7) Procedure for the Preparation of Mono-C-Glycoside 7.
To a stirred mixture of Sc(OTf)3 (67.0 mg, 0.136 mmol),
mono-protected resorcinol derivative 6 (1.00 g, 2.76 mmol),
powdered Drierite® (1.4 g) in 1,2-dichloroethane (27 mL),
was added fucosyl acetate 5 (659 mg, 1.38 mmol) in 1,2-
dichloroethane (8 mL) at –30 °C. After the temperature was
gradually raised to 0 °C during 4.5 h, the mixture was poured
into sat. aq NaHCO3 solution. After filtration through a
Celite® pad, the products were extracted with EtOAc (3×),
and the combined organic extracts were washed with brine,
and dried over Na2SO4. Removal of the solvents in vacuo
and purification by silica gel chromatography (hexane–
acetone–CH2Cl2 = 20:1:1) afforded C-glycoside 7 (1.02 g,
95%); mp 120–121 °C (hexane–EtOAc).
(8) The reaction of compound 8a and fucosyl acetate 5 (2 equiv)
under the Sc(OTf)3-promoted conditions [25 mol% of
Sc(OTf)3, Drierite®, 1,2-dichloroethane, –30 °C to T °C] is
shown below. The outcome was not satisfactory, but was
better than those from other attempted conditions. When the
reaction was stopped at 0 °C, the desired bis-C-glycoside 28
was obtained in 48% yield along with the O-glycoside 27
(29%). This shows that the protection of one of the phenolic
hydroxyls remarkably retards both of the O-glycosylation
and the migration of the sugar [note: the reaction of 8e and 5
went to completion at 0 °C]. Further warming of the reaction
accelerated the O-glycosidation and the migration of the
sugar, but also caused undesired reactions to give many side
products including 29 as the main constituent, which was
most probably formed by the hydride shift from the C(5) of
the sugar to the C(1) (see A). The yield of 28 did not exceed
68%. Prolongation of the reaction time around 0 °C did not
give better result (Scheme 4).
Scheme 4
J = 6.0 Hz, H-6), 2.17 (s, 3 H, ArCH3), 3.60–3.61 (m, 4 H,
H-2,5), 3.71 (d, 2 H, J = 1.6 Hz, H-4), 3.84 (d, 2 H, J = 10.2
Hz, benzylic), 4.14–4.15 (m, 4 H, H-1,3), 4.46 (d, 2 H,
J = 10.2 Hz, benzylic), 4.76 (d, 2 H, J = 12.0 Hz, benzylic),
4.77 (d, 2 H, J = 12.2 Hz, benzylic), 4.82 (d, 2 H, J = 12.0
Hz, benzylic), 5.11 (d, 2 H, J = 12.2 Hz, benzylic), 6.71 (s, 1
H, ArH), 7.04–7.41 (m, 30 H, PhCH2), 7.95 (s, 2 H, ArOH).
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. ORTEP drawing of 9 is
shown below (Figure 3).
Figure 3
(9) Molecular sieves (5A) are also usable but the reactions
thereof required somewhat higher temperature and longer
reaction period.
(11) TBDPS ether, when employed as the protecting group of a
phenolic hydroxyl of methyl 2,6-dihydroxybenzoate, did not
survive in the reaction. Thus, we opted for the allyl ether
instead.
(10) Bis-C-glycoside 9: mp 131–132 °C; [a]D30 –18.0 (c 1.02,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 1.26 (d, 6 H,
Synlett 2006, No. 3, 399–402 © Thieme Stuttgart · New York