Asymmetric induction in cyclohexadienones carrying α-D-glucopyranosyl moiety

Article abstract of DOI:10.1016/j.tet.2016.10.068

Cyclohexadienone derivatives possessing α-D-glucopyranosyl moiety were designed and synthesized using chemical oxidation or electrochemical oxidation with boron-doped diamond electrode in the final stage. In the chiral induction studies, catalytic hydroge

Full text of DOI:10.1016/j.tet.2016.10.068

Tetrahedron 72 (2016) 8428e8435
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric induction in cyclohexadienones carrying
a- -glucopyranosyl moiety
D
,
b
,
d
,
Saki Yajima a, Tsuyoshi Saitoh a
*, Kohei Kawa a, Kensuke Nakamura c,
Hiroshi Nagase b, Yasuaki Einaga a d, Shigeru Nishiyama a
,
,
d
a Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan
b International Institute for Integrative Sleep Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba 305-8575, Japan
c Department of Life Science and Informatics, Maebashi Institute of Technology, Kamisadori 460-1, Maebashi 371-0816, Japan
d JST CREST/ACCEL, 3-14-1 Hiyoshi, Yokohama 223-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclohexadienone derivatives possessing
a-D-glucopyranosyl moiety were designed and synthesized
Received 20 September 2016
Received in revised form
28 October 2016
Accepted 31 October 2016
Available online 3 November 2016
using chemical oxidation or electrochemical oxidation with boron-doped diamond electrode in the final
stage. In the chiral induction studies, catalytic hydrogenation provided high diastereoselectivity (dr ratio:
> 9:1). Conformational analyses of the C-glucoside structures were performed by NOE experiments and
force field calculations, and supported the observed regio-selectivity.
© 2016 Elsevier Ltd. All rights reserved.
Keywords:
Cyclohexadienone
Diastereoselective hydrogenation
Hypervalent iodobenzene
Anodic oxidation
Boron-doped diamond electrodes
1. Introduction
D) as intermediates of natural marine spiroisoxazoline products,
such as aerothionins,7 calafianin,7 and fistularins.8 The absolute
Highly reactive cyclohexadienones have been synthesized by
oxidation of appropriately functionalized phenol precursors, and
utilized as synthetic intermediates of natural products and bio-
logically important substances (Fig. 1). In a relatively early inves-
tigation, a plausible biomimetic synthesis of asatone, a component
of Asarum taitonense H.,1 was achieved through spontaneous
dimerization of the cyclohexadienone (type B), which was pro-
duced by anodic oxidation of the corresponding phenol (A). Closely
related synthesis of penicillone A2a and asatone2b was reported
using a chemical oxidant [PhI(OAc)2 (PIDA)].2 Cationic cyclo-
hexadienones (type C) have been generated by chemical3 and
electrochemical methods,1b,4 and utilized as cationic dienes in
DielseAlder reactions, leading to bicyclic derivatives,5 or as scaf-
folds for continuous cyclization reactions.6
configurations of several members were confirmed using optically
active intermediates, which were obtained successfully in pure
form by diastereomeric separation.7 Acquisition of optically active
cyclohexadienones has attracted a great deal of attention in
connection with structural determination and biological activities.
For this purpose, enantioselective oxidation of the corresponding
phenols has been reported by substrate or reagent control meth-
odologies. An example of the former was the oxidation of O-
glycosyl catechol to the corresponding cyclohexadienone, which
was automatically converted to the bicyclo [2.2.2]octanes.9 The
latter was reported by application of chiral hypervalent iodine
oxidants.
In the present investigation, we examined the scope and limi-
tation of the chiral induction onto cyclohexadienone substrates
attached to sugars through C-glycosidic linkage (type F), which
were synthesized from the precursor E. Although the above-
mentioned ortho-dienones are prone to DielseAlder-type dimer-
ization, the para isomer is relatively stable and can be isolated.1b,10
The relatively rigid conformation of the C-glycoside was expected
to affect the stereochemical contribution of the sugar to the
We have synthesized another series of cyclohexadienones (type
* Corresponding author. International Institute for Integrative Sleep Medicine,
University of Tsukuba, Tennodai 1-1-1, Tsukuba 305-8575, Japan. Tel./fax.: þ81 29
853 6568.
E-mail address: tsuyoshi-saito.gf@u.tsukuba.ac.jp (T. Saitoh).
http://dx.doi.org/10.1016/j.tet.2016.10.068
0040-4020/© 2016 Elsevier Ltd. All rights reserved.

S. Yajima et al. / Tetrahedron 72 (2016) 8428e8435
8429
OMe
O
3a was accompanied by the corresponding C-glycoside 4a as a
minor product (entry 1).
MeO
R2
MeO OMe
O
OMe
Oxid.
ROH
OMe
OMe
MeO
O
MeO
Substrates 2b and 2c with higher electron density of the aro-
matic ring, provided no C-glycosides (4b and 4c, entries 2, 3).
Further assessment of Lewis acids revealed that TMSOTf (entry 4;
ratio of O-glycoside vs. C-glycoside ¼ 46:31) and HfCl4 (entry 5;
12:46) affected the desired conversion to afford O to C glycosyl
migration (3a to 4a) (Table 2).14 The former case gave better ma-
terial balance than the latter.
R1
O
R2
R3
O
RO
OMe
O
MeO
B
Asatone derivatives
R1
O
R3
OH
R2
A
Oxid.
ROH
Bicyclo
or poly cyclic products
R1
O
R3
O
C
O
O
NH(CH2)4NH
N
N
O
2.1. Oxidation of glycosides
O
O
O
O
Br
Carafianin
Br
As conversion of phenols to dienone structures proceeded by a
two-electron oxidation process, chemical oxidation of the product
4a with PIDA in MeOH was examined. Smooth conversion by the
plausible reaction process provided the desired dienone 5 in 77%
yield (Scheme 1). In contrast, further attempts by anodic oxidation
of 3b provided no expected products. In our previous work, similar
difficulties had been circumvented by protection of the phenols.11
Thus, 4a was methylated under standard reaction conditions to
give the methylether 6 in 97% yield. The anodic oxidation of 6 was
inspected under several reaction conditions. As outlined in Table 3,
the desired reaction proceeded only when BDD electrode was used
as anode (entry 3). In our previous study of electrolysis on BDD
electrodes, we reported the generation of methoxyradicals on BDD
electrodes better than the others and methoxyradicals mediated
the anodic oxidation of dimethoxybenzene.15 This observation
suggested that the oxidative methoxylation and followed oxidation
reactions would be mediated by methoxyradicals. In addition, in
the flow cell system which manipulate methoxy radicals, 5 was
provided in 49% yield along with the recovered educt 6 (entry 4).
OMe
N
O
O
O
O
Br
OH
Br
O
O
O
Br
Br
OMe
NH(CH2)4NH
N
O
N
N
O
N
H
D
O
OH
HO
Br
OH
Br
HO
Br
Br
Br
Br
OMe
OMe
OMe
Aerothionin
Hemifisutularin
O
OH
sugar
Oxid.
ROH
RO
RO
sugar
R
R
E
F
Fig. 1. 2,4- and 2,5-Cyclohexadienones in natural products.
regioselectivity in the cyclohexadienone moiety. In contrast to the
C-glycosides, upon oxidation of catechol O-glycosides (type A,
R1 ¼ sugar), the stability of the oxocarbenium ion will support
nucleophilic attack of the carbon attached to the glycosyl moiety,
producing the corresponding acetal (type B, R1 ¼ sugar).2,6 From
among several protocols for synthesis of F from E,11 we employed
the Oe to C-glycosidic conversion to give the corresponding
phenolic substrates, followed by oxidation to yield the desired
cyclohexadienone bearing a glycosyl residue (type F, R’ ¼ sugar).
Catalytic hydrogenation reactions of the optically active cyclo-
hexadienone derivatives were determined.
2.2. Catalytic hydrogenation
During manipulation of the cyclohexadienone attached to the
glycosyl moiety 5, Pd/C-catalyzed hydrogenation was found to
provide a diastereomeric mixture in 31% yield (7a/7b ¼ 48:52),
although partial deprotection of Bn groups caused low yields (entry
1 in Table 4). To improve the yield of the reaction, Bn protecting
groups of the glycosyl moiety were replaced with other acyl groups,
including Ac (9), Bz (10), and Boc (11), through 7 and 8 (Scheme 2).
In the reaction entries using the synthetic acyl derivatives, the Bz
derivative 10 gave the highest selectivity and yield (13a and 13b in
75% and 8% yields, entry 3 in Table 4).
2. Results and discussion
The required C-glycoside was synthesized according to the
Schmidt protocol,12 which involves coupling of the glycosyl imi-
dates with phenol derivatives in the presence of TMSOTf to give the
corresponding O-glycosides, along with the C-glycosides.13 Among
a-D-glucopyranosyl phenol substrates synthesized by coupling of
the imidate 1 and phenols 2aec (Table 1), the 3-methoxy derivative
In the hydrogenation reactions of 10, protic solvents facilitated
the production of the aromatic compound 15 as main products
(entries 3 and 5 in Table 5), while aprotic solvents suppressed
generation of 15. This is probably because protic solvent allows
Table 1
Synthesis of Oe and C-glycosides.
Table 2
Synthesis of C-glycoside 4a through OeC migration.
Entries
Lewis Acid
Yields (%)
O-Glycoside 3a
C-Glycoside 4a
Entries
Phenol substrates 2
Yield (%)
1
2
3
4
5
ZrCl4 (>10 eq.)
Sc(OTf)3 (>10 eq.)
Yb(OTf)3 (>10 eq.)
HfCl4 (1 eq.)
no reaction
no reaction
no reaction
12
O-Glycoside 3
C-Glycoside 4
1
2
3
a: R1, 3, 4 ¼ H, R2 ¼ OMe
b: R3, 4 ¼ H, R1, 2 ¼ OMe
c: R1 ¼ H, R2, 3, 4 ¼ OMe
73
90
80
16
0
0
46
31
TMSOTf (5 eq.)
46

8430
S. Yajima et al. / Tetrahedron 72 (2016) 8428e8435
Table 5
Effects of solvents on diastereoselective hydrogenationa.
Scheme 1. Phenol oxidation into 2,5-cyclohexadienone.
Table 3
Anodic oxidation of C-glycoside 6a.
Entry
Anode
Flow rate (mL/min)
Yield (%)d
6
5
Entries
Solvent
Yields (%)b
dr ratio
Batchb
1
(a:b)
10
13a
13b
15
GC
Pt
BDD
e
e
e
80
75
28
e
1
2
3
4
5
6
7
dioxane
THF
tBuOH
acetone
EtOH
2.3
7.5
12.5
2.1
24.3
38
59
65
n.d.
75
23
43
59
7
6
n.d.
8
0.2
3
n.d.
n.d.
40
1
49
90:10
92:8
n.d.
90:10
99:1
93:7
93:7
2
3
e
26
Flow cellc
4
5
6
BDD
BDD
BDD
0.005
0.01
0.003
34
11
0
49
37
44
DMF
MeOH/EtOAc
16
n.d.
n.d.
4
a
10 mM solution of 6 in 2% KOH MeOH solution was used.
a
b
c
Pt wire cathode, current density 8.0 mA, 13 Fmol-1
.
Reaction conditions: cyclohexadienone in acetone (0.05 M), 5% Pd/C (10 mol%),
2 atmosphere, room temperature.
Pt plate cathode, current density 0.8 mAcmꢀ2, 10 Fmol-1
Isolated yield.
.
H
b
d
Isolated yield.
Table 4
the glycosyl moiety. Similarly, 13b showed a correlation between C-
8 carrying trans-relationship to C-7 and C-2 (Fig. 2). To support the
NMR-based structural elucidation, lowest energy conformations of
12a and 12b were calculated by MOE (Molecular Operating Envi-
ronment, ver. moe 2012.1001) using the Born solvation model with
the dielectric constant of CHCl3 (4.8). As indicated in Fig. 2, the
configurations at C-7 in 12a and 12b were in good accordance with
those obtained by the NOE measurement. The same C-7 configu-
rations in 7a,b, 13a,b, and 14a,b as 12a,b were confirmed by
chemical conversion of the protecting groups. Although the 6R
Hydrogenation of C-glycosides 5, 9e11a.
Entries
Educts (R)
Yields (%)b
dr (a:b)
1
2
3
4
5 (Bn)
7a (15)
7b (16)
12b (14)
13b (8)
14b (11)
42:58
78:22
90:10
73:27
9 (Ac)
10 (Bz)
11 (Boc)
12a (49)
13a (75)
14a (30)
a
Reaction conditions: cyclohexadienone in acetone (0.05 M), 5% Pd/C (10 mol%),
H2 atmosphere, room temperature.
b
Isolated yield.
Scheme 2. Synthesis of 9e10.
proton migration to generate the corresponding arylic system. The
highest regioselectivity was achieved in acetone as solvent. Inter-
estingly, the preferential 13a-type diastereoselectivity was
observed in all of the solvents we used. Structures of the products
were confirmed by NOE experiments. In 13a, C-8 proton with a cis-
relationship to the C-7 proton was correlated with the C-2 proton of
Fig. 2. Structures of 12a and 12b and NOE correlations.

S. Yajima et al. / Tetrahedron 72 (2016) 8428e8435
8431
configuration in the hydrogenated derivatives was dominantly
produced in the acyl derivatives (12, 13, and 14), the benzyl de-
rivative 7 showed the opposite stereoselectivity. To confirm the
reaction prospect, theoretical calculations were carried out to es-
timate the opposite stereoselectivity. To confirm the reaction
prospect, theoretical calculations were carried out to estimate the
conformational abundance ratio in solution. Conformers of com-
pounds 5, 9, 10, and 11 were corrected with the following condi-
tions. Stability of each conformers are within 2.75 kcal/mol from
the global minimum, and each structures are at least 0.015 Å root
mean square distance (RMSD) apart from each other. The diaste-
reomer ratio predicted by the calculation agreed quite well with the
experimental data (Table 6). This observation indicated that the
theoretical calculation can reproduce the remarkable effect of the
substrate conformations in solutions.
solvent, unless otherwise stated. High-resolution mass spectra
were obtained on Waters LCT Piemier XE (ESI). Preparative and
analytical TLC were carried out on silica gel plate (Kieselgel 60 F254,
E. Merck AG., Germany) using UV light and/or 5% molybdophos-
phoric acid in ethanol for detection. Kanto silica 60 N (spherical,
neutral, 105e210 mM) was used for column chromatography.
4.1.1. (2R,3R,4S,5R)-3,4,5-Tris(benzyloxy)-2-((benzyloxy)methyl)-6-
(3-methoxyphenoxy)tetrahydro-2H-pyran (3a) and 5-methoxy-2-
((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)
tetrahydro-2H-pyran-2-yl)phenol (4a)
To
a
stirring mixture of 112 (200 mg, 0.29 mmol), 3-
methoxyphenol (2a, 0.025 mL, 0.8 mmol), and MS4A (150 mg) in
anhydrous CH2Cl2 (1 mL) was added TMSOTf (4 mL, 0.03 mmol) in
ꢁ
CH2Cl2 (0.5 mL). After being stirred at ꢀ30 C for 30 min, the re-
action temperature was raised to room temperature. After 15 h, the
reaction was quenched by the addition of sat. aq. NaHCO3. The
resulting mixture was filtered through a Celite pad. The filtrate was
washed with sat. aq. NaHCO3, and brine, dried (Na2SO4). After
concentration in vacuo, the residue was purified by silica gel col-
umn chromatography (CHCl3: hexane: EtOAc ¼ 4/8/1) to afford 3a17
as a colorless oil (109 mg, 73%, ~1:1 mixture) and 4a12b as a
3. Conclusion
In conclusion, cyclohexadienone derivatives carrying the
a-D-
glucopyranosyl moiety were designed and synthesized using
chemical or anodic oxidation in the final oxidative stage. In the
chiral induction reactions, catalytic hydrogenation provided high
diastereoselectivity, although low yields and stereoselectivity were
observed in 1,2-nucleophilic addition reaction.16,17 The conforma-
tions of the C-glucoside structures responsible for the selectivity
were examined by NOE experiments and force field calculations.
colorless oil (24.0 mg, 16%), respectively. 3a (
(400 MHz, CDCl3)
7.39e7.08 (m, 20H), 7.16 (dd, J ¼ 8.3, 8.3 Hz, 1H),
a
-isomer): 1H NMR
d
6.69 (dd, J ¼ 8.3, 2.3 Hz, 1H), 6.66 (dd, J ¼ 2.5, 2.3 Hz, 1H), 6.58 (dd,
J ¼ 8.3, 2.5 Hz, 1H), 5.46 (d, J ¼ 3.6 Hz, 1H), 5.05 (d, J ¼ 10.6 Hz, 1H),
4.88 (d, J ¼ 11.2 Hz, 1H), 4.86 (d, J ¼ 11.2 Hz, 1H), 4.79 (d, J ¼ 12.1 Hz,
1H), 4.68 (d, J ¼ 12.1 Hz, 1H), 4.59 (d, J ¼ 12.0 Hz, 1H), 4.49 (d,
J ¼ 10.6 Hz, 1H), 4.41 (d, J ¼ 12.0 Hz, 1H), 4.19 (dd, J ¼ 9.2, 9. Hz, 1H),
3.87 (ddd, J ¼ 10.3, 3.0, 2.0 Hz, 1H), 3.78 (dd, J ¼ 10.3, 9.2 Hz, 1H),
3.75 (s, 3H), 3.72 49 (dd, J ¼ 10.8, 2.5 Hz, 1H), 3.72 (dd, J ¼ 9.2,
4. Experimental section
4.1. General information
3.0 Hz, 1H), 3.57 (dd, J ¼ 10.8, 2.0 Hz, 1H). 3a (
(400 MHz, CDCl3)
7.39e7.08 (m, 20H), 7.16 (dd, J ¼ 8.3, 8.3 Hz, 1H),
b
-isomer): 1H NMR
All reactions were carried out under an argon atmosphere un-
less otherwise noted. Dry THF, dry Et2O and dry CH2Cl2 were pur-
chased from Kanto Chemical Co., Inc. Optical rotations were
measured on a JASCO P-2200 digital polarimeter with a sodium (D
line) lamp. IR spectra were recorded on a JASCO Model A-202
spectrophotometer. 1H NMR spectra and 13C NMR spectra were
d
6.69 (dd, J ¼ 8.3, 2.3 Hz, 1H), 6.66 (dd, J ¼ 2.5, 2.3 Hz, 1H), 6.58 (dd,
J ¼ 8.3, 2.5 Hz, 1H), 5.00 (d, J ¼ 3.6 Hz, 1H), 5.05 (d, J ¼ 10.6 Hz, 1H),
4.88 (d, J ¼ 11.2 Hz, 1H), 4.86 (d, J ¼ 11.2 Hz, 1H), 4.79 (d, J ¼ 12.1 Hz,
1H), 4.68 (d, J ¼ 12.1 Hz, 1H), 4.59 (d, J ¼ 12.0 Hz, 1H), 4.49 (d,
J ¼ 10.6 Hz, 1H), 4.41 (d, J ¼ 12.0 Hz, 1H), 4.19 (dd, J ¼ 9.2 Hz, 9.2 Hz,
1H), 3.87 (ddd, J ¼ 10.3, 3.0, 2.0 Hz, 1H), 3.78 (dd, J ¼ 10.3, 9.2 Hz,
1H), 3.72 (s, 3H), 3.72 (dd, J ¼ 10.8, 2.5 Hz, 1H), 3.72 (dd, J ¼ 9.2,
3.0 Hz, 1H), 3.57 (dd, J ¼ 10.8, 2.0 Hz, 1H). 4a: 1H NMR (400 MHz,
obtained on JNM-a400, JNM-AL400 and JNM-ECX400 spectrome-
ters in deuterated solvent. Deuteriochloroform was used as a
Table 6
CDCl3)
d
7.84 (s,1H), 7.01e7.34 (m, 20H), 7.06 (d, J ¼ 8.3 Hz,1H), 6.52
Conformation of C-glycosides and comparison of selectivity.
(d, J ¼ 2.7 Hz, 1H), 6.47 (dd, J ¼ 2.7, 8.4 Hz, 1H), 4.98e4.37 (m, 8H),
3.93e3.67 (m, 6H), 3.77 (s, 3H), 3.57 (d, J ¼ 9.6 Hz, 1H).
4.1.2. (2R,3R,4S,5R)-3,4,5-Tris(benzyloxy)-2-((benzyloxy)methyl)-
6-(2,3-dimethoxyphenoxy)tetrahy dro-2H-pyran (3b)
A mixture of 1 (50.0 mg, 0.0732 mmol), 2,3-dimethoxyphenol
(2b, 18
(0.5 mL) was treated with TMSOTf (10
(0.5 mL), essentially by the same procedure as the case of 3a and 4a,
to afford 3b as a colorless oil (44.6 mg, 90%,
ratio ¼ 2:1).
Chromatographic separation provided both of the glycosides in
mL, 0.138 mmol) and MS4A (100 mg) in anhydrous CH2Cl2
mL, 0.0769 mmol) in CH2Cl2
a/b
21
pure form. 3b (
b
-isomer): [
a
]
D
ꢀ 7.4 (c 1.0, CHCl3); IR (film) 2863,
1086 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d 7.33e7.25 (m, 18H), 7.11
(dd, J ¼ 7.3, 2.0 Hz, 2H), 6.88 (t, J ¼ 8.5 Hz, 1H), 6.72 (dd, J ¼ 8.5,
1.2 Hz, 1H), 6.60 (dd, J ¼ 8.5, 1.2 Hz, 1H), 5.49 (d, J ¼ 3.4 Hz, 1H), 4.99
(d, J ¼ 10.7 Hz, 1H), 4.84 (d, J ¼ 10.7 Hz, 1H), 4.82 (d, J ¼ 10.7 Hz, 1H),
4.73 (s, 2H), 4.54 (d, J ¼ 12.2 Hz, 1H), 4.46 (d, J ¼ 10.7 Hz, 1H), 4.36
(d, J ¼ 12.2 Hz, 1H), 4.18 (t, J ¼ 9.3 Hz, 1H), 4.01 (dt, J ¼ 10.2, 2.3 Hz,
1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.75e3.67 (m, 4H), 3.56 (dd, J ¼ 10.7,
Comp.
dr ratio (a:b)
Experimental
Calculated
2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 153.7, 150.9, 140.2, 138.9,
5
9
10
11
42:58
78:22
90:10
73:27
11:89
90:10
92:8
138.4, 138.3, 138.0, 128.52, 128.49, 128.47, 128.2, 128.1, 128.0, 127.93,
127.85, 127.8, 127.7, 123.6, 111.3, 107.1, 97.3, 81.9, 80.0, 77.6, 75.8,
75.2, 73.6, 73.1, 68.4, 61.3, 56.2. HRMS (ESI) calcd for C42H44O8Na,
64:36

8432
S. Yajima et al. / Tetrahedron 72 (2016) 8428e8435
22
699.2934 (MþNa), found m/z 699.2936.3b (
a
-isomer): [
a
]
D
þ82.3
(d, J ¼ 9.3 Hz, 1H), 4.67 (d, J ¼ 12.2 Hz, 1H), 4.66 (d, J ¼ 11.5 Hz, 1H),
4.54 (d, J ¼ 12.2 Hz,1H), 4.44 (d, J ¼ 10.3 Hz,1H), 3.96 (d, J ¼ 10.3 Hz,
1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.82e3.72 (m, 5H), 3.60 (ddd, J ¼ 9.9,
1.8, 0.9 Hz, 1H).
(c 1.0, CHCl3); IR (film) 2937, 1086 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.40e7.17 (m, 20H), 6.95 (t, J ¼ 8.4 Hz, 1H), 6.85 (dd, J ¼ 8.4, 1.3 Hz,
1H), 6.66 (dd, J ¼ 8.4, 1.3 Hz, 1H), 5.21 (d, J ¼ 10.7 Hz, 1H), 4.99 (d,
J ¼ 11 Hz, 1H), 4.99 (d, J ¼ 11 Hz, 1H), 4.86 (d, J ¼ 10.7 Hz, 1H), 4.85
(d, J ¼ 10 Hz, 1H), 4.83 (d, J ¼ 10.7 Hz, 1H), 4.59 (d, J ¼ 10 Hz, 1H),
4.57 (d, J ¼ 10.7 Hz,1H), 4.53 (d, J ¼ 12.0 Hz,1H), 3.88 (s, 3H), 3.86 (s,
4.2.3. 4,4,5-Trimethoxy-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-
6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)cyclohexa-2,5-
dien-1-one (5) via anodic oxidation
3H), 3.80e3.62 (m, 6H); 13C NMR (100 MHz, CDCl3)
d 153.8, 153.3,
151.6, 139.3, 138.7, 138.4, 138.2, 138.1, 128.6, 128.5, 128.5, 128.1,
128.0, 127.9, 127.8, 127.7, 123.9, 110.1, 106.9, 102.5, 84.8, 81.9, 77.8,
75.9, 75.2, 74.9, 73.6, 69.0, 61.1, 56.2, 55.0. HRMS (ESI) calcd for
A solution of 6 (20.0 mg, 0.0303 mmol) in MeOH (3 mL) con-
taining KOH (47.0 mg) as a supporting salt was electrolyzed under
constant current electrolysis conditions using BDD, platinum or
glassy carbon as an anode and platinum wire or plate as a cathode.
The reaction mixture was diluted with EtOAc and washed with H2O.
The organic layer was washed with brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by PTLC (hexane:
EtOAc ¼ 2/1, two times developped) to afford 5 as a yellow oil.
Synthesis of Ac (9), Bz (10), and Boc (11) protected C-glycosides.
C
42H44O8Na, 699.2934 (MþNa), found m/z 699.2910.
4.1.3. (2R,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-2-((benzyloxy)
methyl)-6-(3,4,5-trimethoxyphenoxy)tetrahydro-2H-pyran (3c).19
A mixture of 1 (45.0 mg, 0.659 mmol), 3,4,5-trimethoxyphenol
(2c, 13 mg, 0.0706 mmol), and MS4A (100 mg) in anhydrous
CH2Cl2 (0.5 mL) was reacted with TMSOTf (10
CH2Cl2 (0.5 mL), essentially by the same procedure as the case of 3a
and 4a, to afford 3c ( -glycoside) as a colorless oil (37.0 mg, 80%,
only
isomer). Chromatographic separation provided 3c: 1H NMR
(500 MHz)
5.06 (d, J ¼ 10.8 Hz, 1H), 4.91e4.81 (m, 4H), 4.68 (d, J ¼ 12.0 Hz, 1H),
4.59 (d, J ¼ 12.0 Hz, 1H), 4.48 (d, J ¼ 10.7, 1H), 4.46 (d, J ¼ 10.8, 1H),
4.18 (t, J ¼ 9.2 Hz, 1H), 3.92e3.88 (m, 1H), 3.79e3.76 (m, 10H),
3.75e3.70 (m, 4H), 3.59 (dd, J ¼ 10.6, 2.0, 1H).
mL, 0.0769 mmol) in
4.2.4. (2R,3R,4R,5S,6S)-2-(Acetoxymethyl)-6-(3,3,4-trimethoxy-6-
oxocyclohexa-1,4-dien-1-yl)tetrahydro-2H-pyran-3,4,5-triyl
triacetate (9)
a
a
d
7.41e7.20 (m, 20H), 6.35 (s, 2H), 5.40 (d, J ¼ 3.5 Hz,1H),
To a solution of 4a (336 mg, 0.520 mmol) in CH2Cl2 (5 mL) were
added TBSCl (235 mg, 1.56 mmol) and imidazole (106 mg,
1.56 mmol) at 0 ꢁC. After being stirred at room temperature for 2 h,
the reaction was quenched by the addition of sat. aq. NaHCO3, and
extracted with CHCl3. The organic layer was washed with brine,
dried (Na2SO4). After concentration in vacuo, the residue was pu-
rified by silica gel column chromatography (CHCl3: hexane:
4.2. Typical procedures for oxidation of C-glycosides
EtOAc ¼ 4/1/1) to afford a siloxy ether (286 mg, 72%): [
a
]
21 þ20.8 (c
D
4.2.1. 4,4,5-Trimethoxy-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-
6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)cyclohexa-2,5-
dien-1-one (5) via chemical oxidation
1.00, CHCl3); IR (film) 2858, 1065 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.37e7.17 (m, 20H), 7.00 (d, J ¼ 3.6 Hz,1H), 6.55 (dd, J ¼ 8.8, 2.0 Hz,
1H), 6.36 (d, J ¼ 2.0 Hz, 1H), 4.94 (d, J ¼ 11.1 Hz, 1H), 4.89 (d,
J ¼ 10.3 Hz, 1H), 4.87 (d, J ¼ 11.1 Hz, 1H), 4.75 (br s, 1H), 4.65 (d,
J ¼ 12.5 Hz, 1H), 4.64 (d, J ¼ 10.3 Hz, 1H), 4.53 (d, J ¼ 12.5 Hz, 1H),
4.40 (d, J ¼ 11.0 Hz, 1H), 4.06 (d, J ¼ 11.0 Hz, 1H), 3.78 (s, 3H,
overlapped with 4H signals), 3.68e3.56 (m, 2H), 0.99 (s, 9H), 0.21
To a solution of 4a (23.0 mg, 0.0356 mmol) in methanol (2.6 mL)
was added PhI(OAc)2 (34.5 mg, 0.107 mmol) at 0 ꢁC. After being
stirred at room tempertature for 2 h, the reaction was quenched by
the addition of sat. aq. Na2S2O3, and extracted with CHCl3. The
organic layer was washed with brine, dried (Na2SO4), then
concentrated in vacuo. The residue was purified by PTLC (hexane:
(s, 3H), 0.20 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 160.2, 154.9, 138.9,
138.6, 138.5, 138.4, 128.53, 128.45, 128.42, 128.38, 128.2,128.1, 127.9,
127.8, 127.60, 127.58, 127.3, 122.6, 106.5, 105.2, 87.2, 84.0, 79.6, 78.5,
77.5, 77.4, 77.2, 76.8, 75.7, 75.3, 74.4, 73.5, 69.3, 55.3, 25.9,
18.4, ꢀ4.2, ꢀ4.4. HRMS (ESI) calcd for C47H56O7NaSi, 783.3693
(MþNa), found m/z 783.3677.
EtOAc ¼ 3/1) to afford 5 as a yellow oil (19.4 mg, 77%). [
(c 1.00, CHCl3); IR (film) 1677, 1093 cmꢀ1
CDCl3)
a
]
19 ꢀ 16.9
D
;
1H NMR (400 MHz,
d
7.33e7.12 (m, 20H), 6.76 (s, 1H), 5.66 (s, 1H), 4.87e4.88 (m,
2H), 4.85 (d, J ¼ 10.8 Hz, 1H), 4.72 (d, J ¼ 11.0 Hz, 1H), 4.63 (d,
J ¼ 10.8 Hz, 1H), 4.61 (d, J ¼ 12.0 Hz, 1H), 4.55 (d, J ¼ 12.0 Hz, 1H),
4.54 (d, J ¼ 9.6 Hz, 1H), 4.44 (d, J ¼ 11.0 Hz, 1H), 3.81 (s, 3H, over-
lapped with 3H signals), 3.74e3.69 (m, 3H), 3.58e3.54 (m, 2H), 3.28
To a solution of the siloxy ether (130 mg, 0.171 mmol) in MeOH
(2.5 mL) was added 5% PdeC (10 mol %). After being stirred under
H2 atmosphere at room temperature for 2 h, the reaction mixture
was filtered and the filtrate was concentrated in vacuo. To a solution
of the resulting residue in pyridine (1.0 mL) was added Ac2O
(1.0 mL) at 0 ꢁC. After 3 h, the reaction was quenched by sat. aq.
NH4Cl and extracted with EtOAc. The organic layer was washed
with brine, dried (Na2SO4). The filtrate was concentrated in vacuo.,
and the residue was purified by silica gel column chromatography
(hexane: EtOAc ¼ 2/1) to afford an acetyl derivative as a colorless oil
(s, 3H), 3.27 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 168.5, 138.7, 138.4,
138.2, 138.0,128.6,128.5, 128.4, 128.1, 127.9, 127.9, 127.8, 127.7, 127.7,
104.2, 94.5, 86.9, 79.5, 78.5, 77.4, 75.7, 75.2, 75.2, 75.0, 73.5, 69.1,
56.3, 51.7, 51.5; HRMS (ESI) calcd for C43H47O9, 707.3200 (MþH),
found m/z 707.3222.
4.2.2. (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)
methyl)-6-(2,4-dimethoxyphenyl)tetrahydro-2H-pyran (6)
(71.9 mg, 74% yield): [
a
]
23 ꢀ 2.2 (c 1.00, CHCl3); IR (film) 1757 cmꢀ1
;
D
To a solution of 4a (120 mg, 0.186 mmol) in DMF (2.0 mL) were
added K2CO3 (31.0 mg, 0.224 mmol) and CH3I (0.015 mL,
0.241 mmol) at 0 ꢁC. After being stirred at room temperature for 2 h,
the reaction was quenched by sat. aq. NH4Cl and extracted with
Et2O. The organic layer was washed with brine, then dried
(Na2SO4). The filtrate was concentrated in vacuo, and the residue
was purified by PTLC to afford (2R,3R,4R,5S,6S)-3,4,5-
tris(benzyloxy)-2-((benzyloxy)methyl)-6-(2,4-dimethoxyphenyl)
tetrahydro-2H-pyran as a colorless oil (6, 79.4 mg, 97%)18: 1H NMR
1H NMR (400 MHz, CDCl3)
d
7.27 (d, J ¼ 8.8 Hz, 1H), 6.52 (dd, J ¼ 8.8,
2.4 Hz, 1H), 6.33 (d, J ¼ 2.4 Hz, 1H), 5.35 (t, J ¼ 9.5 Hz, 1H), 5.28 (t,
J ¼ 9.5 Hz, 1H), 5.20 (t, J ¼ 9.5 Hz, 1H), 4.85 (d, J ¼ 9.5 Hz, 1H), 4.24
(dd, J ¼ 12.3, 4.7 Hz, 1H), 4.09 (dd, J ¼ 12.3, 2.1 Hz, 1H), 3.76 (ddd,
J ¼ 9.5, 4.7, 2.1 Hz, 1H), 3.75 (s, 3H), 2.051 (s, 3H), 2.047 (s, 3H), 2.01
(s, 3H), 1.79 (s, 3H), 1.04 (s, 9H), 0.27 (s, 3H), 0.24 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d 170.9, 170.6, 169.7, 169.3, 160.8, 155.1, 129.0,
118.9, 106.5, 105.4, 77.4, 76.3, 75.0, 71.5, 68.9, 62.6, 55.4, 25.9, 20.90,
20.86, 20.80, 20.6, 18.4, ꢀ4.0, ꢀ4.3. HRMS (ESI) calcd for
(400 MHz, CDCl3)
d
7.38e7.18 (m, 19H), 6.93 (d, J ¼ 9.0 Hz, 1H,
C
27H40O11NaSi, 591.2238 (MþNa), found m/z 591.2222.
overlapped with 1H signal), 6.54 (dd, J ¼ 9.0, 2.3 Hz, 1H), 6.47 (d,
To a solution of the acetyl ester (291 mg, 0.512 mmol) in THF
J ¼ 2.3 Hz, 1H), 4.97 (d, J ¼ 11.5 Hz, 1H), 4.89 (d, J ¼ 11.5 Hz, 2H), 4.75
(10.3 mL) and H2O (9.0 mL) were added AcOH (30 mL) and TBAF

S. Yajima et al. / Tetrahedron 72 (2016) 8428e8435
8433
(0.5 mL,1 M solution in THF) at 0 ꢁC. After 18 h, the reaction mixture
4.2.6. (2R,3R,4R,5S,6S)-2-(((tert-butoxycarbonyl)oxy)methyl)-6-
(3,3,4-trimethoxy-6-oxocyclohexa-1,4-dien-1-yl)tetrahydro-2H-
pyran-3,4,5-triyl tri-tert-butyl tricarbonate (11)
A solution of the siloxy ether of 4a (74 mg, 0.0973 mmol) in
MeOH (1.5 mL) was submitted to catalytic hydrogenation in the
presence of 5% PdeC (10 mol %). A crude product was acylated with
was diluted with EtOAc, and washed with brine, dried (Na2SO4).
The filtrate was concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexane: EtOAc ¼ 2/1) to afford a
phenol as a colorless oil (211 mg, 91%).
To a solution of the phenol (211 mg, 0.465 mmol) in MeOH
(5.0 mL) was added PhI(OAc)2 (450 mg, 1.40 mmol) at 0 ꢁC. After
being stirred at room temperature for 1 h, the reaction was
quenched by sat. aq. Na2S2O3 and extracted with CHCl3. The organic
layer was washed with brine, dried over anhydrous (Na2SO4). The
filtrate was concentrated in vacuo. The residue was purified by silica
gel column chromatography (CHCl3: hexane: EtOAc ¼ 4/4/1) to
(Boc)2O (0.10 mL) and TEA (0.33 mL) in THF (2 mL) to afford a Boc
21
ester as a colorless oil (54.5 mg, 70% yield): [
a
]
þ7.4 (c 1.00,
D
CHCl3); IR (film) 1759 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d 7.30 (d,
J ¼ 8.4 Hz, 1H), 6.49 (dd, J ¼ 8.4, 2.4 Hz, 1H), 6.31 (d, J ¼ 2.4 Hz, 1H),
5.13 (t, J ¼ 9.4 Hz, 1H), 5.06 (t, J ¼ 9.4 Hz, 1H), 4.97 (t, J ¼ 9.4 Hz, 1H),
4.83 (d, J ¼ 9.4 Hz, 1H), 4.24 (dd, J ¼ 12.0, 5.4 Hz, 1H), 4.12 (dd,
J ¼ 12.0, 2.6 Hz, 1H), 3.79 (ddd, J ¼ 9.4, 5.4, 2.6 Hz, 1H), 3.73 (s, 3H),
1.47 (s, 9H), 1.45 (s, 9H), 1.43 (s, 9H), 1.26 (s, 9H), 1.01 (s, 9H), 0.26 (s,
afford 9 as a yellow oil (115 mg, 48%): [
(film) 1751 cmꢀ1
a
]
22 ꢀ 40.5 (c 1.00, CHCl3); IR
D
;
1H NMR (400 MHz, CDCl3)
d
6.77 (d, J ¼ 0.6 Hz,
1H), 5.62 (s, 1H), 5.33 (t, J ¼ 9.6 Hz, 1H), 5.14 (t, J ¼ 9.6 Hz, 1H), 5.03
(t, J ¼ 9.6 Hz, 1H), 4.68 (dd, J ¼ 9.6, 0.6 Hz, 1H), 4.26 (dd, J ¼ 12.3,
4.8 Hz, 1H), 4.11 (dd, J ¼ 12.3, 2.4 Hz, 1H), 3.82 (s, 3H), 3.77 (ddd,
J ¼ 9.6, 4.8, 2.4 Hz, 1H), 3.32 (s, 3H), 3.31 (s, 3H), 2.08 (s, 3H), 2.04 (s,
3H), 0.23 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 160.7, 155.3, 153.3,
152.6, 152.2, 152.0, 149.4, 146.9, 106.1, 105.1, 85.3, 83.1, 82.6, 82.2,
77.8, 77.4, 77.2, 76.2, 73.8, 72.0, 65.2, 55.4, 27.86, 27.84, 27.78, 27.6,
26.0, 25.8, 21.2, 18.4, 14.3, ꢀ4.1, ꢀ4.3. HRMS (ESI) calcd for
3H), 2.00 (s, 3H), 1.91 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
184.1,
C
39H64O15NaSi, 823.3912 (MþNa), found m/z 823.3911.
170.8, 170.2, 169.8, 169.2, 138.97, 138.96, 138.2, 103.8, 94.5, 76.2,
74.2, 72.8, 71.8, 68.7, 62.3, 56.4, 51.73, 51.69, 20.9, 20.77, 20.76, 20.6.
HRMS (ESI) calcd for C23H30O13Na, 537.1584 (MþNa), found m/z
537.1560.
A solution of the ester (10 mg, 0.0125 mmol) and TBAF
(0.0125 mL) in THF (0.25 mL) was kept at room temperature for 4 h,
to afford a phenol as colorless oil (7.7 mg, 90%): [
a]
23 ꢀ 16.0 (c 1.00,
D
CHCl3); IR (film) 3437, 1757 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
6.94
(s, 1H), 6.90 (d, J ¼ 8.5 Hz, 1H), 6.45 (d, J ¼ 2.5 Hz, 1H), 6.36 (dd,
J ¼ 8.5, 2.5 Hz, 1H), 5.12 (t, J ¼ 9.6 Hz, 1H), 5.02 (t, J ¼ 9.6 Hz, 2H),
4.50 (d, J ¼ 9.6 Hz, 1H), 4.37 (dd, J ¼ 12.2, 5.1 Hz, 1H), 4.18 (dd,
J ¼ 12.2, 2.5 Hz, 1H), 3.86 (ddd, J ¼ 9.6, 5.1, 2.5 Hz, 1H), 3.73 (s, 3H),
1.47 (s, 9H),1.45 (s, 9H),1.44 (s, 9H),1.24 (s, 9H); 13C NMR (100 MHz,
4.2.5. (2R,3R,4R,5S,6S)-2-((benzoyloxy)methyl)-6-(3,3,4-
trimethoxy-6-oxocyclohexa-1,4-dien-1-yl)tetrahydro-2H-pyran-
3,4,5-triyl tribenzoate (10)
A solution of the siloxy ether of 4a (580 mg, 0.763 mmol) in
MeOH (10 mL) was submitted to catalytic hydrogenation in the
presence of 5% PdeC (10 mol %). A crude product was benzoylated
CDCl3) d 161.5, 156.9, 153.3, 152.6, 152.1, 151.3, 129.6, 112.7, 106.4,
103.0, 83.6, 82.9, 82.8, 80.7, 77.4, 76.6, 76.3, 73.3, 71.0, 64.3, 55.4,
28.6, 28.5, 28.4, 27.8, 27.7, 27.5. HRMS (ESI) calcd for C33H50O15Na,
709.3047 (MþNa), found m/z 709.3025.
with BzCl (0.87 mL) in pyridine (7.4 mL) and CHCl3 (1 mL) to afford a
21
benzoyl ester as a colorless oil (598 mg, 93% yield): [
a]
þ12.2 (c
Oxidation of the phenol (7.50 mg, 0.0109 mmol) in MeOH (1 mL)
D
1.00, CHCl3); IR (film) 1734 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
8.01
with PhI(OAc)2 (10 mg, 0.0311 mmol) afford 11 as a yellow oil
21
(dd, J ¼ 8.5, 1.2 Hz, 2H), 7.94 (dd, J ¼ 8.5, 1.2 Hz, 2H), 7.83 (dd, J ¼ 8.3,
1.5 Hz, 2H), 7.76 (dd, J ¼ 8.3, 1.0 Hz, 2H), 7.53e7.26 (m, 13H), 6.55
(dd, J ¼ 8.5, 2.3 Hz, 1H), 6.24 (d, J ¼ 2.3 Hz, 1H), 5.95 (t, J ¼ 9.6 Hz,
1H), 5.81 (t, J ¼ 9.6 Hz, 2H), 5.23 (d, J ¼ 9.6 Hz,1H), 4.61 (dd, J ¼ 12.2,
2.9 Hz, 1H), 4.47 (dd, J ¼ 12.2, 5.0 Hz, 1H), 4.21 (ddd, J ¼ 9.6, 5.0,
2.9 Hz, 1H), 3.71 (s, 3H), 1.08 (s, 9H), 0.21 (s, 3H), 0.17 (s, 3H); 13C
(5.9 mg, 73%): [
a
]
D
ꢀ 23.5 (c 1.00, CHCl3); IR (film) 1759,
1254 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
6.77 (s, 1H), 5.61 (s, 1H),
5.10 (t, J ¼ 9.6 Hz, 1H), 4.90 (t, J ¼ 9.6 Hz, 1H), 4.85 (t, J ¼ 9.6 Hz, 1H),
4.66 (d, J ¼ 9.6 Hz, 1H), 4.27 (dd, J ¼ 12.1, 5.4 Hz, 1H), 4.13 (dd,
J ¼ 12.1, 2.4 Hz, 1H), 3.79 (ddd, J ¼ 9.6, 5.4, 2.4 Hz, 1H), 3.78 (s, 3H),
3.298 (s, 3H), 3.296 (s, 3H), 1.46 (s, 18H), 1.44 (s, 9H), 1.37 (s, 9H); 13
C
NMR (100 MHz, CDCl3)
d
166.4, 166.1, 165.5, 165.1, 160.7, 154.9,
NMR (100 MHz, CDCl3) d 183.8, 168.7, 153.3, 152.4, 152.20, 152.16,
133.5, 133.2, 133.1, 133.1, 130.0, 129.89, 129.85, 129.8, 129.4, 129.2,
129.1, 128.51, 128.47, 128.41, 128.38, 128.20, 119.2, 106.8, 105.4, 77.4,
76.8, 75.3, 72.6, 70.2, 63.8, 55.3, 26.0, 25.7, 18.5, 18.1, ꢀ3.4, ꢀ4.1.
HRMS (ESI) calcd for C47H48O11SiNa, 839.2864 (MþNa), found m/z
839.2873.
138.9, 138.0, 104.1, 94.6, 83.2, 82.74, 82.67, 82.5, 77.0, 76.2, 74.9, 72.1,
71.5, 65.0, 56.3, 51.8, 51.7, 27.9, 27.81, 27.77, 27.7. HRMS (ESI) calcd
for C35H54O17Na, 769.3259 (MþNa), found m/z 769.3251.
4.3. Typical procedure for hydrogenation of C-glycosides
A solution of the ester (578 mg, 0.708 mmol) and TBAF (0.70 mL)
in THF (14.1 mL), AcOH (41
temperature for 12 h, to afford a phenol as colorless oil (456 mg,
92%).
Oxidation of the phenol (160 mg, 0.228 mmol) in MeOH (5.7 mL)
with PhI(OAc)2 (222 mg, 0.689 mmol) afford 10 as a yellow oil
m
L), and H2O (12
m
L) was kept at room
To a solution of substrate (20 mg) in solvent (0.05 M) was added
5% PdeC (10 mol %). After being stirred under H2 atmosphere at
room temperature for 2e9 h, the reaction mixture was filtered, and
concentrated in vacuo. The resulting residue was purified by PTLC
(hexane: EtOAc ¼ 1/1e1/3, two times developed) to give the cor-
responding products.
(134 mg, 77%): [
NMR (400 MHz, CDCl3)
a
]
21 ꢀ 20.6 (c 1.00, CHCl3); IR (film) 1734 cmꢀ1; 1H
D
d
8.02 (dt, J ¼ 6.8, 1.5 Hz, 2H), 7.93 (dt,
J ¼ 6.9, 1.5 Hz, 2H), 7.83 (dt, J ¼ 6.9, 1.5 Hz, 2H), 7.80 (dt, J ¼ 7.0,
1.5 Hz, 2H), 7.57e7.24 (m, 12H), 6.88 (s, 1H), 6.00 (t, J ¼ 9.8 Hz, 1H),
5.76 (t, J ¼ 9.8 Hz, 1H), 5.58 (t, J ¼ 9.8 Hz, 1H), 5.52 (s, 1H), 5.08 (d,
J ¼ 9.8 Hz, 1H), 4.64 (dd, J ¼ 12.2, 3.1 Hz, 1H), 4.49 (dd, J ¼ 12.2,
5.0 Hz, 1H), 4.23 (ddd, J ¼ 9.8, 5.0, 3.1 Hz, 1H), 3.73 (s, 3H), 3.25 (s,
4.3.1. (R) ꢀ3,4,4-Trimethoxy-6-((2S,3S,4R,5R,6R)-3,4,5-
tris(benzyloxy)-6-(methoxymethyl)tetrahydro-2H-pyran-2-yl)
cyclohex-2-en-1-one (7a) and (S)-3,4,4-trimethoxy-6-
((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(methoxymethyl)
tetrahydro-2H-pyran-2-yl)cyclohex-2-en-1-one (7b)
3H), 3.22 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
178.8, 169.0, 166.3,
7a: [
a]
ꢀ 56.5 (c 1.00, CHCl3); IR (film) 1652, 1616 cmꢀ1
;
1H
24
D
165.9, 165.43, 165.41, 139.1, 138.2, 133.6, 133.5, 133.3, 133.26, 130.0,
129.91, 129.88, 129.83, 129.75, 129.0, 128.93, 128.88, 128.57, 128.53,
128.50, 128.40, 103.9, 94.6, 76.7, 74.5, 73.2, 72.2, 69.9, 63.2, 56.3,
51.67, 51.66. HRMS (ESI) calcd for C43H38O13Na, 785.2210 (MþNa),
found m/z 785.2209.
NMR (400 MHz, CDCl3) d 7.32e7.18 (m, 20H), 5.26 (s, 1H), 4.94 (d,
J ¼ 11.2 Hz, 1H), 4.91 (d, J ¼ 10.5 Hz, 1H), 4.87 (d, J ¼ 11.2 Hz, 1H),
4.82 (d, J ¼ 11.0 Hz, 1H), 4.71 (d, J ¼ 11.0 Hz, 1H), 4.60 (d, J ¼ 10.5 Hz,
1H), 4.57 (d, J ¼ 12.0 Hz, 1H), 4.50 (d, J ¼ 12.0 Hz, 1H), 4.24 (t,
J ¼ 9.3 Hz, 1H), 3.69 (s, 3H), 3.69e3.65 (m, 2H), 3.59 (t, J ¼ 9.3 Hz,

8434
S. Yajima et al. / Tetrahedron 72 (2016) 8428e8435
2H), 3.44 (ddd, J ¼ 9.3, 4.8, 2.4 Hz, 1H), 3.36 (s, 3H), 3.27 (dd, J ¼ 7.2,
2.4 Hz,1H), 3.24 (s, 3H), 3.05 (ddd, J ¼ 12.5, 4.8, 1.6 Hz, 1H), 2.36 (dd,
J ¼ 12.5, 4.8 Hz, 1H), 2.13 (t, J ¼ 12.5 Hz, 1H); 13C NMR (100 MHz,
1H), 2.10 (t, J ¼ 12.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 195.0,
172.7, 166.3, 165.9, 165.4, 165.1, 133.5, 133.4, 133.2, 129.9, 129.83,
129.79, 129.77, 129.03, 128.96, 128.9, 128.63, 128.56, 128.48, 128.45,
128.4, 128.3, 103.3, 97.4, 76.7, 75.0, 70.0, 69.8, 63.6, 56.0, 51.1, 49.1,
45.0, 31.8. HRMS (ESI) calcd for C43H40O13Na, 787.2367 (MþNa),
CDCl3)
d 197.1, 172.0, 138.8, 138.63, 138.56, 138.3, 128.55, 128.45,
128.41, 128.2, 127.91, 127.89, 127.8, 127.7, 127.68, 127.64, 127.61,
104.5, 97.6, 87.9, 80.0, 79.0, 78.8, 77.4, 75.5, 75.2, 74.7, 73.5, 69.3,
56.1, 51.1, 49.0, 43.0, 34.4. HRMS (ESI) calcd for C43H48O9Na,
found m/z 787.2347.13b: [
a
]
22 þ45.4 (c 1.00, CHCl3); IR (film) 2942,
D
1732 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
8.00 (dd, J ¼ 8.3,1.1 Hz, 2H),
731.3196 (MþNa), found m/z 731.3195.7b: [
a
]
D
21 þ4.7 (c 1.00, CHCl3);
7.93 (dd, J ¼ 8.4, 1.2 Hz, 2H), 7.90 (dd, J ¼ 8.2, 1.2 Hz, 2H), 7.80 (dd,
J ¼ 8.2, 1.2 Hz, 2H), 7.56e7.24 (m, 12H), 5.95 (t, J ¼ 9.8 Hz, 1H), 5.63
(t, J ¼ 9.8 Hz, 1H), 5.55 (t, J ¼ 9.8 Hz, 1H), 5.32 (s, 1H), 4.79 (dd,
J ¼ 9.8, 1.1 Hz, 1H), 4.51 (dd, J ¼ 12.1, 3.1 Hz, 1H), 4.39 (dd, J ¼ 12.1,
4.9 Hz, 1H), 4.15 (ddd, J ¼ 9.8, 4.9, 3.1 Hz, 1H), 3.70 (s, 3H), 3.41 (s,
3H), 3.15 (s, 3H), 2.67 (m, 2H), 2.22 (t, J ¼ 13.5 Hz, 1H); 13C NMR
IR (film) 1652, 1616 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.34e7.20
(m, 20H), 5.41 (s, 1H), 4.96 (d, J ¼ 11.2 Hz, 1H), 4.91 (d, J ¼ 11.2 Hz,
1H), 4.89 (d, J ¼ 10.8 Hz, 1H), 4.82 (d, J ¼ 10.8 Hz, 1H), 4.68 (d,
J ¼ 10.7 Hz, 1H), 4.64 (d, J ¼ 10.7 Hz, 1H), 4.54 (d, J ¼ 12.1 Hz, 1H),
4.47 (d, J ¼ 12.1 Hz, 1H), 4.25 (dd, J ¼ 10.2, 1.2 Hz, 1H), 3.81e3.63 (m,
4H), 3.76 (s, 3H), 3.49e3.42 (m, 2H), 3.34 (s, 3H), 3.28 (s, 3H), 3.06
(ddd, J ¼ 12.7, 4.6,1.2 Hz, 1H), 2.29 (dd, J ¼ 12.7, 4.6 Hz,1H), 2.16 (dd,
(100 MHz, CDCl3)
d 196.5, 173.3, 166.2, 165.9, 165.6, 165.4, 133.6,
133.5, 133.3, 133.1, 130.03, 129.97, 129.91, 129.89, 129.8, 129.1, 129.0,
128.6, 128.54, 128.46, 128.4, 103.7, 97.6, 77.5, 77.4, 77.2, 76.8, 76.1,
75.6, 75.0, 69.9, 69.1, 63.1, 56.2, 50.9, 49.4, 29.6. HRMS calcd for
J ¼ 12.7, 12.7 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 197.4, 172.2,
138.8, 138.6, 138.4, 138.2, 128.6, 128.5, 128.40, 128.38, 128.0, 127.9,
127.84, 127.78, 127.72, 127.71, 127.58, 104.3, 97.8, 87.6, 79.2, 78.7,
77.9, 77.4, 76.0, 75.6, 75.1, 75.0, 73.4, 68.9, 56.2, 51.2, 48.9, 43.2, 30.9.
HRMS (ESI) calcd for C43H48O9Na, 731.3196 (MþNa), found m/z
731.3171.
C
43H40O13Na, 787.2367 (MþNa), found m/z 787.2350.15:
24
[a
]
ꢀ 48.7 (c 1.00, CHCl3); IR (film) 3447, 1730 cmꢀ1
;
1H NMR
D
(400 MHz, CDCl3)
d
8.09 (dd, J ¼ 8.3, 1.3 Hz, 2H), 7.93 (dd, J ¼ 8.4,
1.2 Hz, 2H), 7.83 (dd, J ¼ 8.1, 1.3 Hz, 2H), 7.82 (dd, J ¼ 8.3, 1.3 Hz, 2H),
7.61e7.25 (m, 12H), 6.92 (s, 1H), 6.48 (s, 1H), 6.46 (s, 1H), 6.04 (t,
J ¼ 9.8 Hz,1H), 5.88 (t, J ¼ 9.8 Hz,1H), 5.83 (t, J ¼ 9.8 Hz,1H), 4.90 (d,
J ¼ 9.8 Hz, 1H), 4.66 (dd, J ¼ 12.4, 2.7 Hz, 1H), 4.58 (dd, J ¼ 12.4,
3.9 Hz, 1H), 4.32 (ddd, J ¼ 9.8, 3.9, 2.7 Hz, 1H), 3.78 (s, 3H), 3.37 (s,
4.3.2. (2R,3R,4R,5S,6S)-2-(Acetoxymethyl)-6-((R)-4,5,5-
trimethoxy-2-oxocyclohex-3-en-1-yl)tetrahydro-2H-pyran-3,4,5-
triyl triacetate (12a) and (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-
((S)-4,5,5-trimethoxy-2-oxocyclohex-3-en-1-yl)tetrahydro-2H-
pyran-3,4,5-triyl triacetate (12b)
3H); 13C NMR (100 MHz, CDCl3)
d 166.3, 166.1, 165.2, 164.6, 150.5,
149.9, 142.3, 133.7, 133.5, 133.42, 133.40, 130.01, 129.95, 129.9, 129.8,
129.7,129.5,129.1,128.9,128.8,128.7,128.6,128.5,128.4,111.6,110.7,
102.3, 80.8, 76.9, 74.0, 71.6, 69.1, 62.6, 56.1, 55.9. HRMS (ESI) calcd
for C42H37O12Na, 733.2285 (MþNa), found m/z 733.2270.
12a: [
(400 MHz, CDCl3)
a
]
28 ꢀ 122.7 (c 1.00, CHCl3); IR (film) 1752 cmꢀ1; 1H NMR
D
d
5.27 (t, J ¼ 9.4 Hz, 1H), 5.27 (s, 1H), 5.18 (t,
J ¼ 9.4 Hz, 1H), 5.04 (t, J ¼ 9.4 Hz, 1H), 4.20 (dd, J ¼ 9.4, 2.5 Hz, 1H),
4.15 (dd, J ¼ 12.4, 5.3 Hz, 1H), 4.08 (dd, J ¼ 12.4, 2.6 Hz, 1H), 3.73 (s,
3H), 3.68 (ddd, J ¼ 9.8, 5.3, 2.6 Hz,1H), 3.38 (s, 3H), 3.24 (s, 3H), 2.99
(ddd, J ¼ 12.7, 4.7, 2.5 Hz, 1H), 2.43 (dd, J ¼ 12.8, 4.7 Hz, 1H), 2.0 (dd,
J ¼ 12.8, 12.7 Hz, 1H), 2.06 (s, 3H), 2.00 (s, 3 H), 1.96 (s, 3H), 1.90 (s,
4.3.4. (2R,3R,4R,5S,6S)-2-(((tert-butoxycarbonyl)oxy)methyl)-6-
((R)-4,5,5-trimethoxy-2-oxocyclohex-3-en-1-yl)tetrahydro-2H-
pyran-3,4,5-triyl tri-tert-butyl tricarbonate (14a) and
(2R,3R,4R,5S,6S)-2-(((tert-butoxycarbonyl)oxy)methyl)-6-((S)-
4,5,5-trimethoxy-2-oxocyclohex-3-en-1-yl)tetrahydro-2H-pyran-
3H); 13C NMR (100 MHz, CDCl3)
d
195.1, 172.9, 170.8, 170.4, 169.7,
169.6, 103.2, 97.4, 76.5, 76.3, 74.8, 69.5, 68.7, 62.6, 56.3, 51.2, 49.1,
44.7, 32.1, 20.9, 20.8, 20.8. HRMS (ESI) calcd for C23H32O13Na,
3,4,5-triyl tri-tert-butyl tricarbonate (14b)
21
21
539.1741 (MþNa), found m/z 539.1754.12b: [
a]
ꢀ 9.6 (c 1.00,
14a: [
a]
ꢀ 61.7 (c 1.00, CHCl3); IR (film) 1759 cmꢀ1
;
1H NMR
D
D
CHCl3); IR (film) 1751 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
5.38 (s,
(400 MHz, CDCl3)
d
5.29 (s, 1H), 5.25 (t, J ¼ 9.6 Hz, 1H), 4.98 (t,
1H), 5.23 (t, J ¼ 9.9 Hz, 1H), 5.05 (t, J ¼ 9.9 Hz, 1H), 5.04 (t, J ¼ 9.9 Hz,
1H), 4.41 (dd, J ¼ 10.2,1.6 Hz,1H), 4.20 (dd, J ¼ 12.4, 4.5 Hz,1H), 3.98
(dd, J ¼ 12.4, 2.3 Hz, 1H), 3.76 (s, 3H), 3.68 (ddd, J ¼ 10.0, 4.5, 2.3 Hz,
1H), 3.41 (s, 3H), 3.22 (s, 3H), 2.56 (ddd, J ¼ 12.7, 4.8,1.6 Hz,1H), 2.47
(dd, J ¼ 12.7, 4.8 Hz, 1H), 2.10 (dd, J ¼ 12.7, 12.7 Hz, 1H), 2.05 (s, 3H),
2.03 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H); 13C NMR (100 MHz, CDCl3)
J ¼ 9.6 Hz, 1H), 4.77 (t, J ¼ 9.6 Hz, 1H), 4.20 (dd, J ¼ 12.0, 6.5 Hz, 1H),
4.10 (dd, J ¼ 12.0, 2.7 Hz, 1H), 4.03 (dd, J ¼ 9.6, 2.2 Hz, 1H), 3.71 (s,
3H), 3.39 (s, 3H), 3.23 (s, 3H), 3.00 (ddd, J ¼ 12.7, 4.7, 2.2 Hz, 1H),
2.40 (dd, J ¼ 12.6, 4.7 Hz, 1H), 1.44 (dd, J ¼ 12.6, 12.7 Hz, 1H), 1.47 (s,
3H), 1.45 (s, 3H), 1.44 (s, 3H), 1.41 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
195.1, 172.2, 153.2, 152.5, 152.2, 152.1, 103.9, 97.5, 83.1, 82.7, 82.54,
d
196.2, 173.3, 170.8, 170.4, 169.8, 103.7, 97.5, 75.7, 75.1, 74.8, 68.6,
82.52, 77.6, 77.0, 76.2, 72.4, 71.9, 65.5, 56.1, 51.1, 49.2, 44.0, 32.8,
68.4, 62.0, 56.3, 51.1, 49.2, 42.9, 29.7, 20.9, 20.8, 20.8, 20.8, 20.7.
HRMS (ESI) calcd for C23H32O13Na, 539.1741 (MþNa), found m/z
539.1750.
27.9, 27.84, 27.78. HRMS calcd for C35H56O17Na, 771.3415 (MþNa),
23
found m/z 771.3397.14b: [
a]
þ10.0 (c 1.00, CHCl3); IR (film)
D
1759 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 5.36 (s, 1H), 5.03 (t,
J ¼ 9.8 Hz, 1H), 4.83 (t, J ¼ 9.8 Hz, 2H), 4.39 (dd, J ¼ 9.8, 1.5 Hz, 1H),
4.23 (dd, J ¼ 12.1, 4.2 Hz, 1H), 4.05 (dd, J ¼ 12.1, 2.6 Hz, 1H), 3.74 (s,
3H), 3.67 (ddd, J ¼ 9.8, 4.2, 2.6 Hz, 1H), 3.40 (s, 3H), 3.19 (s, 3H), 2.67
(ddd, J ¼ 12.7, 4.5, 1.5 Hz, 1H), 2.56 (dd, J ¼ 12.7, 4.5 Hz, 1H), 2.09 (t,
J ¼ 12.7 Hz, 1H), 1.455 (s, 9H), 1.448 (s, 18H), 1.445 (s, 9H); 13C NMR
4.3.3. (2R,3R,4R,5S,6S)-2-((benzoyloxy)methyl)-6-((R)-4,5,5-
trimethoxy-2-oxocyclohex-3-en-1-yl)tetrahydro-2H-pyran-3,4,5-
triyl tribenzoate (13a), (2R,3R,4R,5S,6S)-2-((benzoyloxy)methyl)-6-
((S)-4,5,5-trimethoxy-2-oxocyclohex-3-en-1-yl)tetrahydro-2H-
pyran-3,4,5-triyl tribenzoate (13b) and (2R,3R,4R,5S,6S)-2-
((benzoyloxy)methyl)-6-(2-hydroxy-4,5-dimethoxyphenyl)
(100 MHz, CDCl3)
d 196.0, 173.0, 153.3, 152.6, 152.4, 152.1, 103.8,
97.6, 83.0, 82.5, 82.3, 75.8, 74.9, 71.5, 71.0, 64.5, 56.2, 50.9, 49.2, 42.9,
29.9, 27.90, 27.86, 27.8, 27.7. HRMS (ESI) calcd for C35H56O17Na,
771.3415 (MþNa), found m/z 771.3433.
tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (15)
23
13a: [
a
]
D
ꢀ 51.4 (c 1.00, CHCl3); IR (film) 2947, 1730 cmꢀ1
;
1H
NMR (400 MHz, CDCl3)
d
8.02 (dd, J ¼ 8.3, 1.0 Hz, 2H), 7.90 (dd,
J ¼ 8.3, 1.0 Hz, 2H), 7.84 (dd, J ¼ 8.3, 1.5 Hz, 2H), 7.79 (dd, J ¼ 8.3,
1.5 Hz, 2H), 7.56e7.24 (m, 12H), 5.87 (t, J ¼ 9.7 Hz, 1H), 5.75 (t,
J ¼ 9.7 Hz, 1H), 5.64 (t, J ¼ 9.7 Hz, 1H), 4.98 (s, 1H), 4.68 (dd, J ¼ 9.7,
2.2 Hz, 1H), 4.58 (dd, J ¼ 12.0, 2.8 Hz, 1H), 4.42 (dd, J ¼ 12.0, 5.6 Hz,
1H), 4.17 (ddd, J ¼ 9.8, 5.6, 2.8 Hz, 1H), 3.47 (s, 3H), 3.36 (s, 3H), 3.19
(s, 3H), 3.13 (ddd, J ¼ 12.5, 4.9, 2.4 Hz, 1H), 2.56 (dd, J ¼ 12.5, 4.9 Hz,
4.4. Computational studies
Theoretical calculations were carried out using MOE (Molecular
Operating Environment, ver. moe 2012.1001) with force field
(MMFF94x).20 Low Mode MD (initial temperature ¼ 400 K)
implemented in MOE was used for the conformational search.

S. Yajima et al. / Tetrahedron 72 (2016) 8428e8435
8435
9. Luo S-Y, Jang Y-J, Liu J-Y, Chu C-S, Liao C-C, Hung S-C. Angew Chem Int Ed.
2008;47:8082e8085.
Solvent effects were included by Distance or Born approximations.
10. Bosset C, Coffinier R, Peixoto PA, et al. Angew Chem Int Ed. 2014;53:1e6.
11. An example, see Saitoh T, Suzuki E, Takasugi A, et al. Bioorg Med Chem Lett.
2009;19:5383e5386.
Acknowledgments
12. (a) Schmidt RR, Michel M. Angew Chem Int Ed Engl. 1980;19:731e732;
(b) Mahling J-A, Schmidt RR. Synthesis. 1993;3:325e328.
13. Hanzner H, Palmacci ER, Seeberger PH. Org Lett. 2002;4:2965e2967.
14. Matsumoto T, Hosoya T, Suzuki K. Synlett. 1991:709e711.
15. Sumi T, Saitoh T, Natsui K, et al. Angew Chem Int Ed. 2012;51:5443e5446.
16.
This study was supported by Grants-in-Aid for Scientific
Research C, MEXT (Grant 23510262), MEXT-Supported Programs
for the Strategic Research Foundation at Private Universities (Grant
S1201020), and ACCEL, JST.
References
1. (a) Iguchi M, Nishiyama A, Terada Y, Yamamura S. Tetrahedron Lett. 1977;51:
4511e4514;
(b) Yamamura S. In: Rappoport Z, ed. The Chemistry of Phenols; Part 2. Chi-
chester): Wiley; 2003:1153e1346; Ch. 17.(c) Yamamura S. Oxidation of phe-
nols. In: PATAI'S Chemistry of Functional Groups. John Wiley & Sons, Ltd; 2009.
2. (a) Hsu D-S, Liao C-C. Org Lett. 2007;9:4563e4565;
(b) Kurti L, Szilagyi L, Antus S, Nogradi M. Eur J Org Chem. 1999;10:2579e2581.
3. (a) Büchi G, Chu P-S. J Am Chem Soc. 1981;103:2718e2721;
(b) Tamura Y, Yakura T, Haruta J, Kita Y. J Org Chem. 1987;52:3927e3930.
4. (a) Dolson MG, Swenton SS. J Org Chem. 1981;46:177e179;
1,2-Addition reaction of 5 with Grignard and alkyl lithium nucleophiles pro-
vided the corresponding adducts in low to moderate yields with low diaster-
eoselectivities. Optimized result was obtained in the reaction with MeMgCl/
THF 40 ꢁC, which afforded the product in 56% yield with 1:3 diastereoselection.
Contribution of reaction temperature indicated the steric hindrance of the
substrate, which seemed to impede smooth attack of the reagent to the
reactive point.
(b) Deffieux D, Fabre I, Courseille C, Quideau S.
4458e4465.
J Org Chem. 2002;67:
17. Totani K, Nagatsuka T, Yamaguchi S, Takao K, Ohba S, Tadano K. A good
example for diastereoselective 1,4-addition to acyclic enone carrying glycosyl
moiety. J Org Chem. 2001;66:5965e5975.
18. Yamanoi T, Fujioka A, Inazu T. Bull Chem Soc Jpn. 1994;67:1488e1491.
19. Palmacci ER, Seeberger PH. Org Lett. 2001;3:1547e1550.
5. (a) Chiba K, Tada M. J Chem Soc, Chem Commun. 1994:2485e2486;
(b) Chiba K, Arakawa T, Tada M. J Chem Soc, Perkin Trans. 1998;1:2939e2942;
(c) Banfield SC, Kerr MA. Can J Chem. 2004;82:131e138.
6. Deajardins S, Maertens G, Canesi S. Org Lett. 2014;16:4928e4931.
7. Ogamino T, Obata R, Nishiyama S. Tetrahedron Lett. 2006;47:727e731.
8. Kubo H, Matsui K, Saitoh T, Nishiyama S. Tetrahedron. 2014;70:6392e6397.
20. Halgren TA. J Comp Chem. 1996;17:490e519.