Efficient synthesis of optically active gallocatechin-3-gallate derivatives via 6-endo-cyclization

Article abstract of DOI:10.1055/s-0028-1087371

Optically active dihydrobenzopyran derivatives are synthesized by 6-endo cyclization of corresponding epoxy-phenol, which is readily derived from the enantioselective epoxidation of 1,3-diarylpropene. Synthetic dihydrobenzopyrans are converted into (-)-5,7-dideoxy-gallocatechin gallate as well as (-)-5,7-dideoxy-epigallocatechin derivative. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087371

3234
LETTER
Efficient Synthesis of Optically Active Gallocatechin-3-gallate Derivatives via
6-endo-Cyclization
Synthesisof
Optic
a
allyActive
s
Gallocate
u
c
hin-3-gallat
o
e
D
erivatives Hirooka, Mariko Nitta, Takumi Furuta,1 Toshiyuki Kan*
School of Pharmaceutical Sciences, University of Shizuoka and Global COE Program, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Fax +81(54)2645745; E-mail: kant@u-shizuoka-ken.ac.jp
Received 1 September 2008
Scheme 1 illustrates the heart of our synthetic plan. Be-
Abstract: Optically active dihydrobenzopyran derivatives are syn-
cause a facile deprotection of the benzyl group and the in-
corporation of the galloyl moiety proceeded smoothly, the
crucial problem in the synthesis of 4 should be the stereo-
thesized by 6-endo cyclization of corresponding epoxy-phenol,
which is readily derived from the enantioselective epoxidation of
1,3-diarylpropene. Synthetic dihydrobenzopyrans are converted
into (–)-5,7-dideoxy-gallocatechin gallate as well as (–)-5,7- selective construction of 2,3-trans-dihydrobenzopyran
dideoxy-epigallocatechin derivative.
ring 6. We anticipated that 6 could be synthesized by 6-
endo-cyclization of epoxy-phenol 7, which could be
readily obtained by an asymmetric epoxidation6 of 8a.
Several selective 6-endo cyclization-mediated pyran ring
constructions have been reported.7 Because the reaction
should be accomplished by stabilizing the cation at the re-
action site, an electron-rich B-ring group should enable
dihydrobenzopyrane ring synthesis.
Key words: dihydrobenzopyran, 6-endo cyclization, enantioselec-
tive epoxidation, (–)-5,7-dideoxy-gallocatechin gallate
(–)-Epigallocatechin gallate (EGCG, 1) is a major constit-
uent of green tea extract, which has various bioactivities
such as cancer prevention and antiviral or antimicrobial
activity.2 Because these unique bioactivities are expected
to be candidates for drug development, the detailed struc-
ture–activity relationship (SAR) study3 has been a signif-
icant work. However, investigations of such bioactivities
have been limited to natural products and/or their deriva-
tives. Thus, developing an efficient and flexible synthetic
method has strongly been desired. Although many syn-
thetic efforts for catechin have been reported,2,3 there are
only a few examples of enantioselective syntheses.4 Dur-
ing the course of our synthetic investigation on the gallo-
catechins, we have found that synthetic 5,7-dideoxy-
epigallocatechin gallate (DO-EGCG, 3) possesses more
potent anti-influenza activities than natural EGCG (1).5
Inspired by this finding, we have launched an investiga-
tion into the synthesis of 5,7-dideoxy-gallocatechin gal-
late derivatives. Herein we report enantioselective
syntheses of 3 and 4 (Figure 1).
OBn
OBn
OBn
OBn
OBn
OBn
H
H
O
O
O
4
OH
O
6
OBn
5
OBn
OBn
OBn
B
OBn
OBn
OBn
OBn
OTBS
OH
OBn
O
7
8a
Scheme 1 Synthetic strategy of dideoxy-gallocatechin gallate
(DO-GCG, 4)
OH
OH
OH
OH
OH
OH
As shown in Scheme 2, condensation of the A- and B-
rings was accomplished by Julia–Kocienski reaction8 be-
tween aldehyde 10 and phenyltetrazole (PT)-sulfone 13.
The A-ring unit of aldehyde 10 was readily prepared in
two steps from commercially available 2-allylphenol (9).
Introducing a TBS group to 9 and oxidative cleavage of
the double bond furnished aldehyde 10.The PT-sulfone
13a was prepared by a condensation reaction of 3,4,5-
tribenzyloxybenzyl alcohol (11a) and PT-SH (12) under
Mitsunobu conditions and subsequent oxidation to the
sulfone. Upon treating the mixture of aldehyde 10 and PT-
sulfone 13a with LHMDS in THF, the Z-selective olefina-
tion reaction proceeded smoothly to provide 14a as a sin-
gle isomer in 95% yield. Although the reason for the high
Z-selectivity of this Julia–Kocienski reaction is unclear,8c
the selectivity and the reactivity depend on the protecting
H
O
H
O
R
O
R
O
O
O
R
OH
OH
R
OH
OH
OH
OH
1 (–)-EGCG 1: R = OH
3 (–)-DO-EGCG 3: R = H
2 (–)-GCG 2: R = OH
4 (–)-DO-GCG 4: R = H
Figure 1 Structure of EGCG derivatives
SYNLETT 2008, No. 20, pp 3234–3238
Advanced online publication: 26.11.2008
DOI: 10.1055/s-0028-1087371; Art ID: U09208ST
© Georg Thieme Verlag Stuttgart · New York
1
6
.1
2
.2
0
0
8

LETTER
Synthesis of Optically Active Gallocatechin-3-gallate Derivatives
3235
group at the B-ring of 13 as shown in Table 1. Because E- by Shi’s conditions11 in the presence of fructose derivative
isomer 8a9 was required to synthesize 4, the isomerization 15 (conditions B).
reaction was performed by treating 14a with a catalytic
amount of I2 to predominantly afford 8a.
As shown in Schemes 4, 2, 3-trans-dihydrobenzopyran 6
was constructed by a regio- and stereoselective 6-endo-
cyclization. Because treating 16 with TBAF, a basic 5-
1) TBSCl, imidazole
OTBS
OH
exo-cyclization (Baldwin’s rule), gave dihydrobenzofuran
17, the TBS group was deprotected in the presence of
AcOH to provide 7. Upon treating 7 with CSA, the desired
6-endo-cyclization reaction12 proceeded smoothly with a
high diastereoselectivity, and subsequent recrystallization
gave optically pure 6. Conversion from 6 to (–)-5,7-
dideoxy-gallocatechin gallate (4) was achieved in two
steps and involved the incorporation of gallic acid 18 and
the deprotection of benzyl groups under hydrogenation
conditions. An efficient synthesis of (–)-5,7-dideoxy-
gallocatechin gallate (4)13 was accomplished in nine steps
from 9.
DMF
A
2) O3; Me2S
CH2Cl2–MeOH
75% (2 steps)
O
9
10
Ph
N
N
1)
HS
OR
B
N
N
12
OR
OR
OR
DEAD, Ph3P
toluene
RO
RO
Ph
O
O
S
N
+ 10
OH
2) (NH4)6Mo7O24
H2O2, MeCN
94% (2 steps)
N
N
N
13a
11a R = Bn
OTBS
OBn
OR
BnO
OBn
OBn
A
OBn
OBn
OR
OR
I2
LHMDS
OTBS
OTBS
TBAF
O
CHCl3
98%
THF
95%
O
B
THF
85%
17
OH
RO
14a R = Bn
OR
16
OR
8a R = Bn
TBAF
AcOH
THF
Scheme 2 Stereoselective synthesis of olefin 14a and 8a
Table 1 Stereoselectivity of Julia–Kocienski Reaction
OBn
OBn
OBn
OBn
OBn
OBn
CSA
H
OH
O
13
14 (cis)
8 (trans)
Yield (%)
CH2Cl2
O
61% (2 steps)
92% ee
13a R = Bn
13b R = TBS
13c R = Ms
1
10
1
0
1
1
95
75
12
OH
7
6
cis/trans = 30:1
OR
OR
OBn
OBn
OBn
H
HO
O
OBn
OBn
OR
O
18
OBn
OBn
WSC⋅HCl, DMAP
CH2Cl2
O
OTBS
OTBS
OR
conditions
quant.
OBn
OBn
O
O
OR
8a
16
H2, Pd(OH)2
5 R = Bn
4 R = H
OR
5
4
A) DMDO, acetone, 85%
O
O
THF, MeOH
86%
O
B) 15, Oxone, MeCN–DMM
phosphorus buffer
70%, 92% ee
O
AcO
AcO
Scheme 4 Synthesis of (–)-5,7-dideoxy-gallocatechin gallate (4)
15
Scheme 3 Conversion to epoxide16 from 8a
The absolute configuration of synthetic 4 was confirmed
by comparing to natural (–)-gallocatechin (19) as shown
in Scheme 5. Selective mesylation of the phenols at the A-
ring of 19, which should occur through the corresponding
borate intermediate,14 was performed in the presence of
boric acid to provide 20. After protecting 20 with a TBS
group, the mesyloxy group was removed using Sajiki’s
protocol.15 Upon treating the mesylate under hydrogeno-
lysis conditions in the presence of diethylamine, the
mesyloxy group was smoothly removed to afford 21. On
the other hand, synthetic intermediate 6 was also convert-
With the requisite E-double bond of 8a in hand, the epoxi-
dation and cyclization were investigated. The desired ox-
idation and simultaneous epoxide-opening reaction10
occurred by treating with MCPBA under acidic condi-
tions. However, to avoid a side reaction, neutral and non-
nucleophilic DMDO was tested. As shown in Scheme 3,
treating 8a with DMDO caused the oxidation to proceed
smoothly to provide 16 in high yield (conditions A). For
an optically active compound, oxidation was performed
Synlett 2008, No. 20, 3234–3238 © Thieme Stuttgart · New York

3236
Y. Hirooka et al.
LETTER
OH
OH
B
OH
OH
OH
OH
H
MsCl
H3BO3
H
MsO
O
HO
O
A
NaOH aq
toluene
41%
OH
OH
OMs
OH
(–)-gallocatechin (19)
20
1) TBSCl
imidazole
DMF, 11%
2) H2, Pd/C
Et2NH
MeOH
12%
OTBS
OTBS
H
1) H2, Pd(OH)2
THF–MeOH
O
OTBS
6
2) TBSCl, imidazole
DMF
27% (2 steps)
OH
21
Scheme 5 Confirmation of absolute configuration of 4
ed into 21 through the deprotection of the benzyl groups conditions afforded (–)-5,7-dideoxy-epigallocatechin
and subsequent introduction of TBS groups. All spectral gallate (3).
data, including retention time on a chiral column, were
In conclusion, the enantioselective syntheses of (–)-5,7-
dideoxy-epigallocatechin gallate (3) and (–)-5,7-dideoxy-
identical regardless of how 21 was synthesized.16
As shown in Scheme 6, (–)-5,7-dideoxy-epigallocatechin gallocatechin gallate (4) were achieved using regioselec-
gallate (3) was synthesized by employing 14a using a sim- tive 6-endo-cyclization of optically active epoxides. Our
ilar reaction procedure as that to prepare 4. After Shi ep- synthesis features E- and Z-selective olefination and sub-
oxidation of 14a and the removal of TBS ether, treating sequent enantioselective Shi epoxidation protocol. Con-
the corresponding epoxy phenol with CSA enabled 6- sidering the mildness of our reaction conditions, the
endo-cyclization to proceed smoothly to provide 22 and 6 present synthesis should be compatible with a variety of
as a 1:1 mixture. Formation of 6 might be explained by a functional groups. Furthermore, substituted 2-allylphenol
cyclization reaction, which proceeds through quinone me- derivatives are also readily available. Hence, applying our
thide intermediate 25.10,17 Compared to 7, the steric hin- method should provide various gallocatechin derivatives,
drance of the cis-epoxide would make a direct inversion including 1 and 2. Further synthetic investigation and the
reaction difficult and would readily lead to quinone me- biologically evaluation of 3 and 4 are currently under in-
thide formation by a self-opening reaction of the epoxide. vestigation in our laboratory.
After incorporating 18, separation of 5 and 23 was readily
carried out by silica gel column chromatography.18 Final-
Acknowledgment
ly, deprotection of the benzyl ether by hydrogenolysis
The authors thank Mr. Masayuki Suzuki (Mitsui Norin Co., Ltd) for
OBn
kindly providing a sample of 19. The authors also acknowledge Pro-
fessor Hironao Sajiki (Gifu Pharmaceutical University) for his kind
suggestion about the reduction conditions. This work was financial-
ly supported by a Grant from the Novartis Foundation (Japan) for
Promotion of Science (2008), Takeda Science Foundation, and a
Grant-in-Aid for Scientific Research on Priority Areas 12045232
from the Ministry of Education, Culture, Sports, Science and Tech-
nology (MEXT) of Japan.
OBn
OBn
1) 15, Oxone
77%, 87% ee
H
14a
+
6
O
2) TBAF, AcOH
THF
3) CSA, CH2Cl2
48% (22 + 6)
(2 steps)
OH
22 87% ee
22 (cis)/6 (trans) = 1:1
OBn
OR
References and Notes
OBn
OBn
1)
OR
HO
(1) Present Address: Fine Organic Synthesis, Institute for
Chemical Research, Kyoto University, Uji, Kyoto 611-0011,
Japan.
(2) For recent review on catechin, see: (a) Nagle, D. G.;
Ferreira, D.; Zhou, Y.-D. Phytochemistry 2006, 67, 1849.
(b) Friedman, M. Mol. Nutr. Food Res. 2007, 51, 116.
(c) Wheeler, D. S.; Wheeler, W. J. Drug Dev. Res. 2004, 61,
45.
(3) For a recent SAR study of catechin, see: (a) Wan, S. B.;
Landis-Piwowar, K. R.; Kuhn, D. J.; Chen, D.; Dou, Q. P.;
Chan, T. H. Bioorg. Med. Chem. 2005, 13, 2177. (b) Moon,
Y.-H.; Lee, J.-H.; Ahn, J.-S.; Nam, S.-H.; Oh, D.-K.; Park,
H
O
O
O
18
OR
WSC⋅HCl, DMAP
CH2Cl2, quant.
O
22
+
6
OR
OR
2) separation
H2, Pd(OH)2
OR
23 R = Bn
3 R = H
23
3
THF, MeOH
quant.
Scheme 6 Synthesis of (–)-5,7-dideoxy-epigallocatechin gallate (3)
Synlett 2008, No. 20, 3234–3238 © Thieme Stuttgart · New York

LETTER
Synthesis of Optically Active Gallocatechin-3-gallate Derivatives
3237
D.-H.; Chung, H.-J.; Kang, S.; Day, D. F.; Kim, D. J. Argric.
Food Chem. 2006, 54, 1230. (c) Dell’Agli, M.; Bellosta, S.;
(11) Experimental Procedure for Shi Epoxidation
To a solution of 15 (77.0 mg, 0.255 mmol) in MeCN–DMM
(dimethyl methylether) (1:2, 2.7 mL) were successively
added 8a (100 mg, 0.156 mmol), Bu4N+HSO4– (2.4 mg, 7.0
mmol), phosphorus buffer (pH 9.18, 4 mL), Oxone (376 mg,
0.611 mmol), and K2CO3 (125 mg, 0.90 mmol) at 0 °C. After
being stirred for 25 min at 0 °C, H2O was added to the
reaction mixture, extracted with EtOAc, dried over anhyd
MgSO4, and evaporated. The residue was purified by
chromatography on silica gel column (n-hexane–EtOAc,
10:1) to afford 16 (71.5 mg, 70%) as a yellow oil. The ee of
16 was determined by HPLC analysis on a chiral stationary
phase under the conditions described below.
Rizzi, L.; Galli, G. V.; Canavesi, M.; Rota, F.; Parente, R.;
Bosisio, E.; Romeo, S. Cell. Mol. Life Sci. 2005, 62, 2896.
(4) (a) Zaveri, N. T. Org. Lett. 2001, 3, 843. (b) Li, L.; Chan,
T. H. Org. Lett. 2001, 3, 739. (c) Higuchi, T.; Ohmori, K.;
Suzuki, K. Chem. Lett. 2006, 35, 1006. (d) Kitade, M.;
Ohno, Y.; Tanaka, H.; Takahashi, T. Synlett 2006, 2827.
(e) Ding, T.-J.; Wang, X.-L.; Cao, X.-P. Chin. J. Chem.
2006, 24, 1618.
(5) Furuta, T.; Hirooka, Y.; Abe, A.; Sugata, Y.; Ueda, M.;
Murakami, K.; Suzuki, T.; Tanaka, K.; Kan, T. Bioorg. Med.
Chem. Lett. 2007, 17, 3095.
(6) Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124,
8792.
Spectral Data for 16
[a]D20 +14.1 (c 1.0, CHCl3). IR (neat): 1116, 1253, 1591,
2927, 3030 cm–1. 1H NMR (500 MHz, CDCl3): d = 0.24 (s,
6 H), 1.01 (s, 9 H), 2.93 (dd, J = 14.3, 5.2 Hz, 1 H), 3.04 (dd,
J = 14.3, 5.2 Hz, 1 H), 3.15 (td, J = 5.2, 2.0 Hz, 1 H), 3.58
(d, J = 2.0 Hz, 1 H), 5.02 (s, 2 H), 5.07 (s, 4 H), 6.57 (s, 2 H),
6.82 (dd, J = 7.9, 1.2 Hz, 1 H), 6.92 (td, J = 7.9, 1.2 Hz, 1 H),
(7) (a) Nicolau, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang,
C.-K. J. Am. Chem. Soc. 1989, 111, 5330. (b) Jain, A. C.;
Arya, P.; Nayyar, N. K. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 1983, 22, 1116. (c) For a recent
report, see: Matsuo, G.; Kawamura, K.; Hori, N.; Matsukura,
H.; Nakata, T. J. Am. Chem. Soc. 2004, 126, 14374. (d) For
the disubstituted epoxide, see: Oka, T.; Fujiwara, K.; Murai,
A. Tetrahedron 1996, 52, 12091.
(8) (a) Blakemore, P. R.; Cole, W. J.; Kocieński, P. J.; Morley,
A. Synlett 1998, 26. (b) Review of modified Julia reaction,
see: Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002,
2563. (c) Z-selective Julia olefination, see: Lebrun, M.-E.;
Marquand, P. L.; Berthelette, C. J. Org. Chem. 2006, 71,
2009.
7.13 (td, J = 7.9, 1.2 Hz, 1 H), 7.31–7.42 (m, 15 H). 13
C
NMR (68 MHz, CDCl3): d = –4.0, 18.3, 25.8, 33.0, 58.6,
62.2, 71.2, 75.2, 105.0, 118.4, 121.2, 127.4, 127.7, 127.8,
128.1, 128.5, 128.6, 130.7, 133.3, 137.0, 137.8, 153.0,
153.7. MS–FAB: m/z = 659 [M + H]+. HRMS: m/z calcd for
C42H47O5Si [M + H]+: 659.3193; found: 659.3167. HPLC
analysis: Daicel Chiralpak AD-H 0.46 cm ø x 25 cm, eluent:
7% IPA–hexane, flow rate: 0.5 mL/min, tR = 98.7 min
(96.2%), 109.7 min (3.7%).
(9) Although HWE reaction of 10 and phosphonate 24 provided
8a in good stereoselectivity, it resulted in a low yield
(Scheme 7).
(12) Experimental Procedure for 6-endo Cyclization
To a solution of 16 (127 mg, 0.193 mmol) in THF (4.5 mL)
were successively added AcOH (33 mL, 0.578 mmol) and
TBAF (1 M in THF, 231 mL, 0.231 mmol) at 0 °C under an
Ar atmosphere. After being stirred for 10 min at 0 °C, H2O
was added to the mixture and extracted with EtOAc, dried
over anhyd MgSO4, and evaporated to the crude product
(major constituent: 7; 185 mg) as a yellow oil. The crude 7
(185 mg) and CSA (45.4 mg, 0.193 mmol) were dissolved in
CH2Cl2 (4.5 mL) under an Ar atmosphere. After being
stirred for 30 min at 0 °C, H2O was added to the mixture and
extracted with CH2Cl2, dried over anhyd MgSO4, and
evaporated. The residue was purified by chromatography on
silica gel column (n-hexane–EtOAc, 3:1) to afford 6 (63.7
mg, 61%, 2 steps), containing a small amount of the
corresponding cis-isomer, as a yellow oil. The product (20.3
mg) was recrystallized from EtOAc–hexane to afford
optically pure trans-isomer 6 (13.7 mg, 67%). The ee of 6
was determined by HPLC analysis on a chiral stationary
phase under the conditions described below. Spectral date
for 6: [a]D +1.7 (c 0.84, CHCl3). IR (neat): 1132, 1246, 1597,
3032 cm–1. 1H NMR (500 MHz, CDCl3): d = 1.63 (d, J = 3.8
Hz, 1 H), 2.89 (dd, J = 15.8, 9.1 Hz, 1 H), 3.07 (dd, J = 15.8,
5.5 Hz, 1 H), 3.99 (dq, J = 15.8, 3.8 Hz, 1 H), 4.65 (d, J = 7.9
Hz, 1 H), 5.11–5.16 (m, 6 H), 6.73 (s, 2 H), 6.91–6.95 (m,
1 H), 7.11 (d, J = 7.3 Hz, 1 H), 7.16 (t, J = 7.3 Hz, 1 H),
7.25–7.44 (m, 16 H). 13C NMR (68 MHz, CDCl3): d = 32.9,
68.1, 71.2, 75.2, 81.9, 106.7, 116.4, 120.2, 121.1, 127.5,
127.7, 127.8, 127.9, 128.2, 128.47, 128.53, 130.0, 133.3,
136.8, 137.7, 138.7, 153.0, 153.9. MS.FAB: m/z = 544 [M]+.
HRMS: m/z calcd for C36H32O5 [M]+: 544.2250; found:
544.2264. HPLC analysis: Daicel Chiralcel OD 0.46 cm ø
x 25 cm, eluent: 10% IPA–hexane, flow rate: 0.5 mL/min,
tR: 77.8 min (>99%).
OBn
OTBS
OBn
OBn
LHMDS
8a
+
THF
30%
O
P
10
24
EtO
O
EtO
Scheme 7
(10) In acidic conditions, epoxide 16 was readily converted into
quinone methide intermediate 25, and sequential attack by
MCBA to benzyl position of 25 afforded 26 (Scheme 8).
OBn
OBn
OBn
OBn
OBn
OBn
MCPBA
CH2Cl2
OR
OR
O
8a
16
R = TBS
Ar
OBn
OBn
ArCOOH
OR
OBn
OBn
OBn
O
O
OR
OBn
OH
OH
26
Ar = 3-ClC6H4
25
(13) Spectral Data for 4
[a]D20 –73.5 (c 1.1, 50% acetone–H2O). IR (neat): 1230,
1336, 1693, 3287 cm–1. 1H NMR (270 MHz, acetone-d6):
d = 2.79 (dd, J = 16.2, 5.6 Hz, 1 H), 2.93 (dd, J = 16.2, 4.6
Scheme 8
Synlett 2008, No. 20, 3234–3238 © Thieme Stuttgart · New York

3238
Y. Hirooka et al.
LETTER
Hz, 1 H), 5.11 (d, J = 5.3 Hz, 1 H), 5.30 (q, J = 5.3 Hz, 1 H),
6.34 (s, 2 H), 6.76 (t, J = 7.9 Hz, 2 H), 6.97 (d, J = 6.6 Hz,
1 H), 6.98 (s, 2 H), 7.05 (t, J = 7.6 Hz, 1 H), 7.93 (br s, 6 H).
13C NMR (68 MHz, acetone-d6): d = 52,1, 70.5, 79.0, 106.3,
110.1, 110.2, 117.1, 120.4, 121.7, 121.8, 128.8, 131.0,
131.1, 133.6, 139.2, 146.2, 146.9, 155.0, 166.3. MS–FAB:
m/z = 427 [M + H]+. HRMS: m/z calcd for C22H19O9 [M +
H]+: 427.1029; found: 427.1049.
m/z = 617 [M + H]+. HRMS: m/z calcd for C33H57O5Si3 [M +
H]+: 617.3514; found: 617.3516. HPLC analysis: Daicel
Chiralpak AD-H 0.46 cm ø x 25 cm, eluent: hexane, flow
rate: 0.7 mL/min, tR: 30.5 min.
(17) A similar pyran ring construction through the quinone
methide intermediate has been reported, see: Noda, I.;
Horita, K.; Oikawa, Y.; Yonemitsu, O. Tetrahedron Lett.
1986, 27, 1917; although many 6-endo cyclizations of
epoxyalchol have been reported, cis-disubstituted epoxide
has yet to be reported.
(14) Van Dyk, M. S.; Steynberg, J. P.; Steynberg, P. J.; Ferreira,
D. Tetrahedron Lett. 1990, 31, 2643.
(15) Mori, A.; Mizusaki, T.; Ikawa, T.; Maegawa, T.; Monguchi,
(18) Experimental Procedure and Separation of
Diasteromers
Y.; Sajiki, H. Tetrahedron 2007, 63, 1270.
(16) Spectral Data for 21
Compounds 22 and 6 (33.5 mg, 61.5 mmol), 18 (81.3 mg,
184 mmol), WSC (29 mg, 154 mmol), and DMAP (0.8 mg,
6.2 mmol) were dissolved in CH2Cl2 (3 mL) under an Ar
atmosphere. After being stirred for 3 h at r.t., sat. NH4Cl aq
was added to the reaction mixture, extracted with CH2Cl2,
dried over anhyd MgSO4, and evaporated. The residue was
purified by chromatography on silica gel column (n-hexane–
EtOAc, 6:1) to afford 23 (33.3 mg, 56%, Rf = 0.42,
n-hexane–EtOAc, 3:1) and 5 (26.2 mg, 44%, Rf = 0.49,
n-hexane–EtOAc, 3:1).
[a]D20 –16.7 (c 0.075, CHCl3). IR (neat): 837, 1255, 1608,
3543 cm–1. 1H NMR (500 MHz, CDCl3): d = –0.30 (s, 3 H),
–0.08 (s, 3 H), 0.17 (m, 9 H), 0,78–0.98 (m, 30 H), 2.90 (dd,
J = 15.8, 5.5 Hz, 1 H), 3.08 (dd, J = 15.8, 5.5 Hz, 1 H), 3.93
(tt, J = 10.7, 3.1 Hz, 1 H), 4.57 (t, J = 8.5 Hz, 1 H), 5.23 (s,
1 H), 6.55 (s, 2 H), 6.87–6.90 (m, 2 H), 7.07 (d, J = 2.0 Hz,
1 H), 7.12 (t, J = 7.2 Hz). 13C NMR (68 MHz, CDCl3):
d = –5.2, –4.8, –4.5, –4.3, –0.01, 1.0, 17.9, 18.3, 25.7, 25.9,
26.2, 35.4, 69.2, 82.0, 107.5, 112.0, 112.3, 116.4, 120.6,
120.7, 127.5, 129.6, 129.8, 138.6, 142.9, 154.3. MS–FAB:
Synlett 2008, No. 20, 3234–3238 © Thieme Stuttgart · New York

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