Synthesis of trans-fused tetrahydrooxepins: stereoselective allylation of sulfur or fluoro-substituted tetrahydrooxepins

Article abstract of DOI:10.1016/j.carres.2007.11.018

An efficient route to the trans-fused tetrahydrooxepin corresponding to the E ring of ciguatoxin was developed. Wide screening of allylation reactions of sulfur or fluoro-substituted tetrahydrooxepin revealed that the optimum method for obtaining the β-allylation product selectively was the use of a combination of allyltrimethylsilane and TiCl₄ with 6-fluoro-7-hydroxytetrahydrooxepin.

Full text of DOI:10.1016/j.carres.2007.11.018

Available online at www.sciencedirect.com
Carbohydrate Research 343 (2008) 443–452
Synthesis of trans-fused tetrahydrooxepins: stereoselective
allylation of sulfur or fluoro-substituted tetrahydrooxepins
Shoji Kobayashi,a,* Makiko Horib and Masahiro Hiramab
aDepartment of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai 599-8531, Japan
bDepartment of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 25 September 2007; accepted 15 November 2007
Available online 23 November 2007
Abstract—An efficient route to the trans-fused tetrahydrooxepin corresponding to the E ring of ciguatoxin was developed. Wide
screening of allylation reactions of sulfur or fluoro-substituted tetrahydrooxepin revealed that the optimum method for obtaining
the b-allylation product selectively was the use of a combination of allyltrimethylsilane and TiCl4 with 6-fluoro-7-
hydroxytetrahydrooxepin.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Allylation; Tetrahydrooxepin; Titanium tetrachloride; Ciguatoxin
1. Introduction
tetrahydrooxepin, which corresponds to the E ring of
1 (Fig. 1). In particular, by considering the structurally
simplified and readily accessible bicyclic model 3 as an
alternative to the DE ring, we developed a strategy
which ultimately resulted in the first synthesis of the
ABCDE ring segment (2) of 1.2,3
During the course of our recent synthetic studies of
ciguatoxin (1),1 the principal toxin responsible for cigua-
tera seafood poisoning, we have continuously worked
on the development of an efficient route to trans-fused
H
H
J
HO
O
H
O
I
H
H
O
OH
H
O
H
H
H
H
A
O
H
G
K
O
H
O
D
O
B
H
C
H
O
H
O
E
H
H
O
M
H
H
O
L
F
HO
H
HO
O
H
H
OH
H
1
OH
H
H
H
H
O
H
H
OR
A
H
O
O
D
B
E
OH
C
O
(D)
O
E
O
H
H
H
NAPO
H
H
2
O
H
NAPO
H
ONAP
H
3
Figure 1. Structures of ciguatoxin (1), the ABCDE ring segment (2), and the DE ring model (3). NAP = 2-naphthylmethyl.
*
Corresponding author. Tel.: +81 72 254 9670; fax: +81 72 254 9695; e-mail: koba@c.s.osakafu-u.ac.jp
0008-6215/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.11.018

444
S. Kobayashi et al. / Carbohydrate Research 343 (2008) 443–452
or NIS/AgOTf8 activators afforded the a-allylation
product 8a exclusively in moderate yields (entries 1
and 2). Similarly high a-selectivity was observed in the
case of sulfoxides, irrespective of the type of C-7-protec-
tive group used (entries 3 and 4). To the best of our
knowledge, this is the first application of the Tf2O/
DTBMP activation system9 to a C-nucleophile. As
reported previously,2 allylation of the corresponding
sulfone also gave a-product 8a predominately (entries
5 and 6), while a reversal of a/b selectivity was observed
for the C-7-hydroxyl sulfone (entries 7 and 8). In addi-
tion to this remarkable b-selectivity, it should be pointed
out that addition of the C-nucleophile proceeded in
preference to intermolecular O-alkylation (dimerization)
even in the presence of free hydroxyl groups. Since the
time-consuming processes in entry 8 provoked side reac-
tions when applied to functionalized molecules,2 we next
examined anomeric fluoride, a stable and highly reactive
glycosydation precursor.10 Application of the activators
Cp2HfCl2/AgClO4 or Cp2TiCl2/AgClO4,11 or the use of
BF3ꢀEt2O,12 generated allylation product 8a in high
yield with a-selectivity (entries 9–11). Since neighboring
ester groups and polar solvents have been known to
facilitate b-nucleophilic attack by stabilizing the cationic
intermediate, we attempted to use C-7-pivalate and
CH3CN (entries 12 and 13). However, only a marginal
improvement in selectivity was observed as the reaction
time was prolonged (entry 13). Eventually, we again
focused our attention on the C-7-hydroxyl substrate.
Whereas the application of Cp2HfCl2/AgClO4 or
BF3ꢀEt2O activators gave disappointing results due to
competition with intermolecular O-alkylation (entry
14), the use of TiCl4 gave rise to the desired b-adduct
3b in 70% yield with good selectivity (entry 16). Notably,
allylation was completed within 10 min even at ꢁ100 °C,
and a/b selectivity was independent of the C-6-stereo-
chemistry of the starting fluoride.
OTBS
SPh
N
Cl
Cl
N
Mes
Mes
Ph
Ru
H
Cl
H
O
(D)
OTBS
PCy3
O
AgOTf, DTBMP
CH2Cl2, reflux
19 h, 72%
CH2Cl2, MS4A
—45 to —30 °C
100%
O
SPh
OH
H
H
5
4
SiMe3
H
7
H
H
H
OR
OTBS
O
Lewis acid
CH2Cl2
mCPBA
O
E
(D)
CH2Cl2, 0 °C
1.5 h, 89%
O
O
SO2Ph
SPh
H
H
H
H
6
7a: R = TBS
7b: R = H
H
H
H
H
OR
OR
O
O
+
6R
6S
O
O
H
H
H
H
3a: R = TBS
3b: R = H
8a: R = TBS
8b: R = H
1) Dess-Martin periodinane, 100%
2) DBU, 6R:6S = 5:1
3) NaBH4, CeCl3·7H2O, 44% (2 steps)
Scheme 1. Strategy for constructing trans-fused tetrahydrooxepin.
DTBMP = 2,6-di-tert-butyl-4-methylpyridine, TBS = tert-butyldi-
methylsilyl, mCPBA = m-chloroperbenzoic acid, TBAF = tetrabutyl-
ammonium fluoride.
Our strategy to access 3 involved three key transfor-
mations, as shown in Scheme 1: (1) AgOTf-mediated
O,S-acetal formation4 (4 to 5), (2) ring-closing meta-
thesis5 (5 to 6), and (3) Lewis acid-mediated allylation
of anomeric sulfone6 (7 to 3). Although this approach is
fast and offers a high yield, stereocontrol at the anomer-
ic center has been a formidable challenge, because Lewis
acid-mediated substitution normally occurs from the a-
side due to the anomeric effect of the ring oxygen. For
instance, allylation of 7a provided the a-adduct 8a
rather than the b-adduct 3a, regardless of the type of
Lewis acid used. In our previous communication, we
discovered that the b-adduct 3b was formed preferen-
tially when TiCl4 was employed with the C-7-hydroxyl
derivative 7b.2 However, these conditions could not be
applied to the highly functionalized ABCDE ring
segment 2, since they were accompanied by side reac-
tions arising from the depressed reactivity of the C-7-
hydroxyl sulfone.2 Therefore, we continued our screen-
ing of allylation reactions using other substrates and a
variety of activators. Herein, we provide a summary of
allylation reactions of sulfur- or fluoro-substituted
tetrahydrooxepins and our development of a method
for obtaining the b-adduct selectively using 6-fluoro-7-
hydroxytetrahydrooxepin.
Since some alkylmagnesium and alkylaluminum re-
agents can react with glycosyl fluorides in the absence
of a Lewis acid,13,14 we also examined allylation reac-
tions with allylmetal species (entries 17–21). However,
the desired isomers (3a or 3b) were not obtained prefer-
entially under any of the conditions examined.
It has been well established in previous studies15 that
formation of the a-product 8a in the C-8-OTBS series
can be rationalized by the anomeric effect, which causes
the C-nucleophile to approach from the pseudo-axial
side (Fig. 2).16 In contrast, in the case of the C-7-unpro-
tected alcohol, the cationic intermediate is stabilized by
We expected the formation of 3b in the reaction of the C-7-hydroxyl
substrate with allylmagnesium bromide (entry 20) through an
epoxide-like intermediate akin to 11 (see Fig. 2). However, the only
product obtained was homoallyl alcohol 9, which presumably arose
from abstraction of the C-7-hydrogen followed by enol-keto tauto-
merization and allylation to the resulting enone.
2. Results and discussion
Our experiments are summarized in Table 1. Direct ally-
lation of TBS-protected phenyl sulfide with NBS/TfOH7

S. Kobayashi et al. / Carbohydrate Research 343 (2008) 443–452
Table 1. Allylation of sulfur- or fluoro-substituted tetrahydrooxepinsa,b
445
H
H
OH
H
H
H
H
H
SiMe3
conditions
OR
OR
OR
O
O
O
O
7
+
6R
6S
6
O
O
O
O
X
H
H
H
H
H
H
H
9
R = TBS, Piv, H
3a: R = TBS
8a: R = TBS
X = SPh, S(O)Ph, SO2Ph, F
3b: R = H
8b: R = H
3c: R = Piv
8c: R = Piv
Entry
X
R
Activators
Solvent
Temperature (°C)
Time (h)
Yieldc (%)
Ratio (3:8)d
˚
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16f
SPh
SPh
S(O)Ph
S(O)Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
F
F
F
F
F
TBS
TBS
TBS
Piv
TBS
TBS
H
NBS, TfOH, MS 4 A
NIS, AgOTf
Tf2O, DTBMP
Tf2O, DTBMP
EtAlCl2
TiCl4
AlCl3
TiCl4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ꢁ50 to 0
ꢁ25
8.5
22
1.3
19
0.8
0.3
17
11
1.2
17
0.5
0.5
15
0.4
48
53
57
62
<33
73
74
81
62
92
90
87
54
56
<49
84
70
<5:>95
<5:>95
<5:>95
<5:>95e
20:80
31:69
60:40
84:16
<5:>95
<5:>95
<5:>95
12:88
34:66e
57:43
ꢁ78
ꢁ78 to ꢁ15
ꢁ78 to ꢁ60
ꢁ78
ꢁ78 to 0
ꢁ78
H
˚
˚
TBS
TBS
TBS
TBS
Piv
H
Cp2HfCl2, AgClO4, MS 4 A
Cp2TiCl2, AgClO4, MS 4 A
ꢁ78 to ꢁ50
ꢁ78 to 10
ꢁ30
BF3ꢀEt2O
BF3ꢀEt2O
BF3ꢀEt2O
BF3ꢀEt2O
TMSOTf
TiCl4
ꢁ30
ꢁ50 to 15
ꢁ30
F
F
F
H
H
ꢁ78 to 15
ꢁ100
13:87
87:13
0.2
17
F
F
F
F
F
TBS
TBS
TBS
H
CH2@CHCH2MgBr
CH2@CHCH2MgBr
(CH2@CHCH2)3Al
CH2@CHCH2MgBr
(CH2@CHCH2)3Al
CH2Cl2
Et2O
Et2O
Et2O
Et2O
20
20
0 to 20
20
0 to 20
0.5
1.5
3
1.5
2
100
92
30
9 (86)
3b (15),
39:61
41:59
60:40
18
19g
20
21g
H
9 (56)
a For fluorotetrahydrooxepins, a 1:1.7 (b-fluoride:a-fluoride) mixture was used.
b For entries 17–21, reactions were performed in the absence of allyltrimethylsilane.
c Isolated yield.
d Determined by 1H NMR (500 MHz, CDCl3).
e Determined after cleavage of pivalate by DIBAL at ꢁ60 °C.
f For entry 16, the same results were obtained from each C-6-stereoisomer.
g Triallylaluminum was prepared in situ from 3 equiv of allylmagnesium bromide and 1 equiv of AlCl3 in Et2O.
To evaluate the generality of TiCl4-mediated b-selec-
tive allylation, other C-nucleophiles were tested. In con-
trast to the C-7-protected fluorotetrahydroxepin, which
afforded the a-adduct 12 predominantly (Eq. 1), TiCl4-
mediated alkylation of the corresponding C-7-alcohol
with trimethylsilylketene acetal furnished the b-adduct
SiMe3
H
H
H
H
H
[Ti]
OTBS
O
O
O
O
H
O
H
H
10
11
SiMe3
8a
3b
OTMS
H
H
H
H
Figure 2. A possible model to explain the stereochemical outcome.
OTBS
OTBS
O
O
OEt
7
6S
6
ð1Þ
ð2Þ
CO2Et
BF3·Et2O, CH2Cl2
—40 to 20 °C
4 h, 51%
O
O
F
H
H
H
partial epoxide formation (11), which allows SN2-like
attack of the C-nucleophile, generating the b-isomer
3b.17 It is unclear, however, whether the conformational
difference between the TBS ether and the unprotected
alcohol plays a role in the stereochemical outcome.
However, it is clear that the C-7-protective group, as
well as the presence of a Lewis acid, is a critical factor
in deciding stereoselectivity.
12: 6S:6R = 2.5:1
6R:6S = 1.1.7
OTMS
OEt
H
H
H
H
OH
6
F
OH
O
O
7
6R
CO2Et
13: exclusive
TiCl4, CH2Cl2
—78 to —50 °C
3 h, 20%
O
O
H
H
H
6R:6S = 1.1.7

446
S. Kobayashi et al. / Carbohydrate Research 343 (2008) 443–452
13 exclusively (Eq. 2). It appears that the lower
yield may be attributed to the depressed nucleophilicity
of trimethylsilylketene acetal compared to allyl-
trimethylsilane.
on a JASCO DIP-370 digital polarimeter. Flash column
chromatography was performed with 40–50 lm Silica
Gel 60N (Kanto Chemical Co., Inc.). All reactions sen-
sitive to air or moisture were carried out under argon or
nitrogen atmosphere in dry, freshly distilled solvents
under anhydrous conditions. Dry solvents purchased
from Kanto Chem. Co. were also used.
3. Conclusion
In conclusion, an efficient route to the trans-fused tetra-
hydrooxepin, which corresponds to the E ring of cigua-
toxin, was developed.à This work demonstrated that
allylation of fluorotetrahydrooxepin bearing an adjacent
hydroxyl group is a viable synthesis method, although it
has so far been limited to the substrates used herein. We
are currently testing the further applicability of this
methodology to fluorotetrahydropyrans and fluor-
otetrahydrofurans as well as its potential for synthesiz-
ing other C-glycosides.
4.2. Preparation of allylation precursors
4.2.1. ((1R,2S)-1-(Phenylthio)-1-((2R,3S)-2-vinyltetrahy-
dro-2H-pyran-3-yloxy)but-3-en-2-yloxy)-tert-butyldimeth-
ylsilane (5). To a solution of (2S)-1-phenylthio-2-tert-
butyldimethylsilyloxy-3-butene (427 mg, 1.45 mmol) in
CCl4 (6 mL) was added N-chlorosuccinimide (233 mg,
1.74 mmol). The mixture was stirred for 1 h at room
temperature and the precipitate was filtered. Concentra-
tion of the filtrate gave the corresponding a-chloro-
sulfide. To
a suspension of alcohol 4 (93.0 mg,
˚
0.726 mmol) and MS 4 A (powdered, activated,
320 mg) in CH2Cl2 (4 mL) were added AgOTf
(369 mg, 1.67 mmol) and 2,6-di-tert-butyl-4-methylpyri-
dine (417 mg, 2.03 mmol) at ꢁ45 °C. After being stirred
for 10 min, a solution of a-chlorosulfide in CH2Cl2
(4 mL) was added and the resulting mixture was stirred
for 40 min at ꢁ30 °C. The mixture was eluted (hexane/
EtOAc = 0.67) through a short plug of silica gel to give
a pale yellow oil that was further purified by flash col-
umn chromatography (silica gel, hexane/EtOAc = 150
to 100 to 50) to give O,S-acetal 5 (305 mg, 100%). Com-
4. Experimental
4.1. General methods
1H and 13C NMR spectra were recorded on a Varian
Mercury 200 (200 MHz), a Varian 400MR (400 MHz),
a Varian INOVA-500 (500 MHz), or a JEOL JNM-
ECP500 spectrometer. IR spectra were recorded on
a Perkin–Elmer Spectrum BX FT-IR spectrometer.
Matrix assisted laser desorption ionization time-of-flight
mass spectra (MALDI-TOFMS) were recorded on an
Applied Biosystems Voyager DE STR SI-3 instrument
using a-cyano-4-hydroxy cinnamic acid as a matrix.
Electron spray ionization time-of-flight mass spectra
(ESI-TOFMS) were recorded on an Applied Biosystems
Mariner instrument. Electron ionization mass spectra
(EI MS) were recorded on a JEOL MS700 spectrometer.
High resolution electron spray ionization Fourier-trans-
form ion cyclotron resonance mass spectra (HR-ESI
FT-ICR MS) were recorded on a Bruker Daltonics
APEX III instrument. Optical rotations were recorded
27:0
pound 5: ½aꢂD +7.2 (c 0.40, CHCl3); 1H NMR
(200 MHz, CDCl3) d 0.01 (s, 3H, SiMe3), 0.02 (s, 3H,
SiMe3), 0.89 (s, 9H, tBu), 1.35–1.44 (m, 1H, H-40),
1.50–1.65 (m, 2H, H-50), 2.16–2.22 (m, 1H, H-40), 3.27
(ddd, 1H, J = 10.0, 9.0, 4.5 Hz, H-30), 3.33 (dt, 1H,
J = 11.5, 2.5 Hz, H-60), 3.57 (br dd, 1H, J = 9.0,
6.0 Hz, H-20), 3.85–3.90 (m, 1H, H-60), 4.32–4.34 (m,
1H, H-2), 4.81 (d, 1H, J = 3.5 Hz, H-1), 5.15 (ddd,
1H, J = 11.0, 2.0, 1.0 Hz, H-4), 5.23 (dt, 1H, J = 10.5,
1.5 Hz, CH2@CH–), 5.28 (dt, 1H, J = 8.0, 1.5 Hz,
H-4), 5.32 (dt, 1H, J = 7.5, 1.5 Hz, CH2@CH–), 5.91
(ddd, 1H, J = 17.5, 10.5, 6.0 Hz, CH2@CH–), 5.98
(ddd, 1H, J = 17.0, 10.5, 6.0 Hz, H-3), 7.21–7.47 (m,
H-5, Ph); 13C NMR (50 MHz, CDCl3) d ꢁ4.6, ꢁ4.4,
18.4, 25.4, 26.0, 31.0, 67.4, 76.8, 78.0, 81.4, 95.8, 116.9,
127.3, 129.1, 132.6, 135.8, 136.6, 137.6; FT-IR (neat) m
3076, 2954, 2927, 2855, 1645, 1584, 1472, 1439, 1362,
1254, 1216, 1089 cmꢁ1; MALDI-TOFMS [M+Na]+
calcd for C23H36NaO3SiS: 443.3; found, 443.2; HRMS
(EI, 70 eV) [MꢁSPh]+ calcd for C17H31O3Si: 311.2042;
found, 311.2027.
à Although we wished to apply the newly developed allylation
conditions to the preparation of a fully functionalized ABCDE ring
segment (15), we faced a serious problem in converting phenyl sulfide
into the corresponding fluoride. Fluorination proceeded in less than
48% yield even under carefully chosen conditions. It appears that the
diallylic moiety of the A ring is highly sensitive to fluorination
conditions. In the event, we were unable to obtain sufficient quantities
of fluoride to test this methodology.
H
H
O
H
H
H
A
O
D
OTBS
B
C
O
O
H
H
4.2.2.
((4aS,6R,7S,9aR)-6-(Phenylthio)-3,4,4a,6,7,9a-
O
H
X
NAPO
NAPO
H
H
hexahydro-2H-1,5-dioxa-benzocyclohepten-7-yloxy)-tert-
butyldimethylsilane (6). A solution of diene 5 (181 mg,
0.431 mmol) and second generation Grubbs’ catalyst
ONAP
DAST, NBS, CH2Cl2
—55 to —35 °C, <48%
14: X = SPh
15: X = F (β:α = 1:2.2)

S. Kobayashi et al. / Carbohydrate Research 343 (2008) 443–452
447
(36.6 mg, 0.0431 mmol) in CH2Cl2 (43 mL) was refluxed
for 19 h. Et3N (170 lL) was added and the mixture was
concentrated. The residue was purified by flash column
chromatography (silica gel, hexane/EtOAc = 200 to
50) to give a seven-membered ring 6 (122 mg, 72%).
saturated NH4Cl solution. The aqueous phase was ex-
tracted with EtOAc, and the combined organic phase
was washed with brine and dried over anhydrous
MgSO4. After concentration, the residue was purified
by flash column chromatography (silica gel, hexane/
27:0
1
Compound 6: ½aꢂD +110 (c 0.990, CHCl3); H NMR
(200 MHz, CDCl3) d 0.14 (s, 3H, SiMe3), 0.18 (s, 3H,
SiMe3), 0.94 (s, 9H, tBu), 1.40–1.47 (m, 1H, H-4),
1.53–1.60 (m, 2H, H-3), 1.72–1.78 (m, 1H, H-4), 3.16
(ddd, 1H, J = 11.1, 9.0, 4.5 Hz, H-4a), 3.25–3.30 (m,
1H, H-2), 3.77 (ddd, 1H, J = 9.0, 4.5, 2.0 Hz, H-9a),
3.82–3.86 (m, 1H, H-2), 4.39 (ddd, 1H, J = 9.0, 4.0,
2.0 Hz, H-7), 4.91 (d, 1H, J = 9.0 Hz, H-6), 5.58 (dt,
1H, J = 13.0, 2.0 Hz, H-8), 5.69 (dt, 1H, J = 13.0,
2.5 Hz, H-9), 7.22–7.30 (m, 3H, Ph), 7.45–7.48 (m, 2H,
Ph); 13C NMR (125 MHz, CDCl3) d ꢁ4.5, ꢁ4.3, 18.3,
25.4, 26.0, 30.3, 67.6, 74.1, 80.5, 80.7, 93.5, 127.3,
128.7, 132.5, 132.8, 134.3, 134.5; FT-IR (neat) m 3059,
2951, 2885, 2856, 1731, 1584, 1472, 1463, 1439, 1389,
1361, 1258, 1217, 1186, 1091, 1039 cmꢁ1; HR-ESI FT-
ICR MS [M+Na]+ calcd for C21H32NaO3SSi:
415.1734; found, 415.1734.
EtOAc = 3.6) to give
a
corresponding alcohol
(73.4 mg, 0.264 mmol, 81%).
mCPBA (199 mg, 0.750 mmol) was added to a solu-
tion of the above alcohol (73.4 mg, 0.264 mmol) in
CH2Cl2 (2.6 mL) at 0 °C. The mixture was stirred for
2 h at 0 °C and quenched with Et3N (368 lL,
2.64 mmol). After concentration, the residue was puri-
fied by flash column chromatography (silica gel, hex-
ane/EtOAc = 2) to give sulfone 7b (66.4 mg, 81%).
27:0
1
Compound 7b: ½aꢂD +15 (c 0.98, CHCl3); H NMR
(500 MHz, CDCl3) d 1.37–1.46 (m, 1H, H-4), 1.47–
1.63 (m, 2H, H-3), 1.64–1.70 (m, 1H, H-4), 3.15 (ddd,
1H, J = 11.0, 9.5, 5.0 Hz, H-4a), 3.26 (dt, 1H,
J = 11.5, 3.0 Hz, H-2), 3.68 (br d, 1H, J = 9.5 Hz, H-
9a), 3.73 (br s, 1H, OH), 3.83 (br dd, 1H, J = 11.5,
4.5 Hz, H-2), 4.34 (d, 1H, J = 9.0 Hz, H-6), 4.74 (br d,
1H, J = 9.5 Hz, H-7), 5.60 (s, 2H, H-8, H-9), 7.59 (t,
2H, J = 8.5 Hz, Ph), 7.72 (br t, 1H, J = 7.0 Hz, Ph),
7.95 (br d, 2H, J = 8.0 Hz, Ph); 13C NMR (125 MHz,
CDCl3) d 25.1, 30.0, 67.6, 69.4, 79.8, 82.1, 95.8, 129.1,
129.9, 130.8, 132.2, 134.6, 136.0; FT-IR (KBr) m 3408,
3069, 3031, 2974, 2945, 2855, 2822, 1655, 1584, 1449,
1388, 1323, 1292, 1278, 1266, 1242, 1211, 1150,
1084 cmꢁ1; MS (EI, 70 eV) m/z (%): 169 ([MꢁSO2Ph]+,
27), 151 (21), 125 (19), 123 (16), 97 (20), 95 (16), 84 (42),
81 (42), 77 (80), 71 (100).
4.2.3. ((4aS,6R,7S,9aR)-6-Benzenesulfonyl-3,4,4a,6,7,9a-
hexahydro-2H-1,5-dioxa-benzocyclohepten-7-yloxy)-tert-
butyldimethylsilane (7a). To a solution of sulfide 6
(27.6 mg, 0.0704 mmol) in CH2Cl2 (1.4 mL) was added
mCPBA (41.1 mg, 0.154 mmol) at 0 °C. The mixture
was stirred for 1.4 h at 0 °C and quenched with Et3N
(118 lL, 0.844 mmol). After concentration, the residue
was purified by flash column chromatography (silica
gel, hexane/EtOAc = 5) to give sulfone 7a (26.5 mg,
26:5
89%). Compound 7a: ½aꢂD +45.1 (c 0.724, CHCl3);
4.2.5. ((4aS,6R,7S,9aR)-6-(Phenylsulfinyl)-3,4,4a,6,7,9a-
hexahydro-2H-1,5-dioxa-benzocyclohepten-7-yloxy)-tert-
1H NMR (200 MHz, CDCl3) d 0.18 (s, 3H, SiMe3),
0.24 (s, 3H, SiMe3), 0.96 (s, 9H, tBu), 1.04–1.11 (m,
1H, H-4), 1.15–1.25 (m, 1H, H-3), 1.34–1.49 (m, 2H,
H-3, H-4), 3.00 (ddd, 1H, J = 10.5, 8.5, 4.5 Hz, H-4a),
3.20 (dt, 1H, J = 11.5, 3.0 Hz, H-2), 3.67 (ddd, 1H,
J = 9.0, 4.5, 2.0 Hz, H-9a), 3.78 (br d, 1H, J = 11.0,
4.5 Hz, H-2), 4.39 (d, 1H, J = 8.0 Hz, H-6), 4.90 (ddd,
1H, J = 8.0, 4.5, 2.3 Hz, H-7), 5.54 (dt, 1H, J = 13.0,
2.3 Hz, H-8), 5.67 (dt, 1H, J = 13.0, 2.5 Hz, H-9), 7.52
(t, 2H, J = 8.8 Hz, Ph), 7.62 (br t, 1H, J = 7.5 Hz, Ph),
7.90 (d, 2H, J = 7.5 Hz, Ph); 13C NMR (125 MHz,
CDCl3) d ꢁ4.6, ꢁ4.4, 18.3, 25.1, 26.0, 29.6, 67.5, 70.5,
79.9, 80.6, 95.7, 128.7, 129.5, 132.4, 133.5, 133.6,
138.2; FT-IR (film) m 2951, 2857, 1472, 1328, 1259,
1155, 1116, 1014 cmꢁ1; MALDI-TOFMS [M+Na]+
calcd for C21H32NaO5SiS: 447.2; found, 447.1.
butyldimethylsilane. To
a
solution of sulfide
6
(20.0 mg, 0.0510 mmol) in CH2Cl2 (1 mL) was added
mCPBA (40.6 mg, 0.153 mmol) at ꢁ50 °C. The mixture
was stirred for 1 h at –50 °C and quenched with satu-
rated Na2S2O3 solution. The aqueous phase was ex-
tracted with EtOAc, and the combined organic phase
was washed with saturated NaHCO3 solution and brine,
and dried over anhydrous MgSO4. After concentration,
the residue was purified by flash column chromatogra-
phy (silica gel, hexane/EtOAc = 3 to 2) to give a corre-
sponding sulfoxide (20.8 mg, 100%) as
a
2.5:1
1
diastereomeric mixture. H NMR (400 MHz, CDCl3) d
0.16 (s, 6H, TBS minor), 0.21 (s, 3H, TBS major), 0.28
(s, 3H, TBS major), 0.93 (s, 9H, TBS minor), 0.98 (s,
9H, TBS), 1.06–1.90 (m, 8H, H-3, H-4 major and min-
or), 2.78 (td, 1H, J = 9.7, 4.9 Hz, H-4a), 3.17–3.25 (m,
1H, H-2 major), 3.25–3.32 (m, 1H, H-2 minor), 3.63
(br d, 1H, J = 9.0 Hz, H-9a minor), 3.69–3.79 (m, 3H,
H-2 major, H-9a major, H-4a minor), 3.84–3.91 (m,
1H, H-2 minor), 3.91 (d, 1H, J = 9.3 Hz, H-6 major),
4.40 (d, 1H, J = 6.4 Hz, H-6 minor), 4.61 (br t, 1H,
J = 5.5 Hz, H-7 minor), 4.81 (dq, 1H, J = 9.0, 2.2 Hz,
4.2.4. (4aS,6R,7S,9aR)-6-Benzenesulfonyl-3,4,4a,6,7,9a-
(7b).
hexahydro-2H-1,5-dioxa-benzocyclohepten-7-ol
TBAF (1.0 M solution in THF, 488 lL, 0.488 mmol)
was added to a solution of TBS ether 6 (128 mg,
0.325 mmol) in THF (3.3 mL). The mixture was stirred
for 12.5 h at ambient temperature and quenched with

448
S. Kobayashi et al. / Carbohydrate Research 343 (2008) 443–452
H-7 major), 4.81 (br d, 1H, J = 13, 2.2 Hz, H-8 major),
5.69 (dt, 1H, J = 13, 2.3 Hz, H-9 major), 5.75 (br d, 1H,
J = 12 Hz, H-9 minor), 5.86 (ddd, 1H, J = 12, 4.6,
2.4 Hz, H-8 minor); FT-IR (film) m 3059, 2951, 2929,
2855, 1471, 1443, 1389, 1362, 1307, 1257, 1217, 1108,
1092, 1047, 1015, 953, 864 cmꢁ1; MS (EI, 70 eV) m/z
(%): 351 ([MꢁtBu]+, 11), 283 (74), 211 (60), 156 (65),
139 (62), 75 (100), 73 (99), 71 (94).
the residue was purified by flash column chromatogra-
phy (silica gel, hexane/EtOAc = 20) to give fluoride as
a
1.7:1 diastereomeric mixture (99.2 mg, 91%,
1
6S:6R = 1.7:1). H NMR (500 MHz, CDCl3) d 0.09 (s,
6H, SiMe3), 0.10 (s, 6H, SiMe3), 0.90 (s, 9H, tBu),
0.90 (s, 9H, tBu), 1.42–1.51 (m, 1H, H-4 major), 1.54–
1.63 (m, 1H, H-4 minor), 1.64–1.72 (m, 4H, H-3 major
and minor), 2.00–2.06 (m, 1H, H-4 major), 2.14–2.19
(m, 1H, H-4 minor), 3.27–3.37 (m, 2H, H-2 major and
minor), 3.43 (ddd, 1-H, J = 10.5, 9.0, 4.5 Hz, H-4a min-
or), 3.71 (dt, 1H, J = 9.0, 2.0 Hz, H-9a minor), 3.83–
3.92 (m, 4H, H-2, H-4a, H-9a major, and H-2 minor),
4.25–4.30 (m, 1H, H-7 minor), 4.46 (br d, 1H,
J = 25 Hz, H-7 major), 5.03 (dd, 1H, J = 51, 7.0 Hz,
H-6 minor), 5.34 (br d, 1H, J = 51 Hz, H-6 major),
5.44–5.49 (m, 1H, H-9 minor), 5.52 (br d, 1H,
J = 12.0 Hz, H-9 major), 5.62 (br d, 1H, J = 13.0 Hz,
H-8 minor), 5.65 (br d, 1H, J = 12.0, 2.0 Hz, H-8
major); FT-IR (film) m 2952, 2930, 2856, 1471, 1439,
1389, 1362, 1257, 1219, 1099, 1062, 1005, 962, 938,
4.2.6. (4aS,6R,7S,9aR)-6-(Phenylsulfinyl)-3,4,4a,6,7,9a-
hexahydro-2H-1,5-dioxa-benzocyclohepten-7-yl pivalate.
To a solution of 7-hydroxy-6-phenylthiotetrahydro-
oxepin (101 mg, 0.364 mmol) in CH2Cl2 (3.6 mL) were
added pyridine (294 lL, 3.64 mmol) and PivCl
(134 lL, 1.09 mmol). The mixture was stirred for 5 days
at room temperature and concentrated. The residue was
purified by flash column chromatography (silica gel,
hexane/EtOAc = 5) to give a corresponding pivalate
(132 mg, 100%).
To a solution of the above pivalate (15.4 mg,
0.0425 mmol) in CH2Cl2 (0.8 mL) was added mCPBA
(33.8 mg, 0.127 mmol) at ꢁ40 °C. The mixture was stir-
red for 30 min at ꢁ40 °C and quenched with saturated
Na2S2O3 solution, then saturated NaHCO3 solution.
The aqueous phase was extracted with EtOAc and the
organic phase was dried over anhydrous MgSO4. After
concentration, the residue was purified by flash column
chromatography (silica gel, hexane/EtOAc = 1.5) to
give a corresponding sulfoxide (16.1 mg, 100%) as a
1.3:1 diastereomeric mixture. 1H NMR (400 MHz,
CDCl3) d 1.26 (s, 9H, Piv), 1.31 (s, 9H, Piv), 1.30–1.70
(m, 7H, H-3, H-4), 2.00–2.05 (m, 1H, H-4 major),
2.90–2.98 (m, 1H, H-4a minor), 3.21–3.31 (m, 2H, H-2
major and minor), 3.43–3.50 (m, 1H, H-4a major),
3.65 (br d, 1H, J = 9.3 Hz, H-9a major), 3.77–3.90 (m,
3H, H-2 major and minor, H-9a minor), 4.25 (d, 1H,
J = 9.5 Hz, H-6 major), 4.64 (br d, 1H, J = 8.6 Hz, H-
6 minor), 5.39 (br d, 1H, J = 8.6 Hz, H-7 minor), 5.52
(br d, 1H, J = 13 Hz, H-8 major), 5.55 (br d, 1H,
J = 12 Hz, H-8 minor), 5.63 (br d, 1H, J = 13 Hz, H-9
major), 5.72 (br d, 1H, J = 12.0 Hz, H-9 minor), 5.72
(br d, 1H, J = 8.6 Hz, H-7 minor); FT-IR (film) m
3066, 2955, 2926, 2853, 1735, 1574, 1479, 1443, 1397,
911 cmꢁ1
;
HRMS (EI, 70 eV) [M]+ calcd for
C15H27FO3Si: 302.1714; found, 302.1667.
4.2.8. (4aS,6R,7S,9aR)-6-Fluoro-3,4,4a,6,7,9a-hexahy-
dro-2H-1,5-dioxa-benzocyclohepten-7-ol. To a solution
of 7-tert-butyldimethylsilyloxy-6-fluorotetrahydrooxe-
pin (6S:6R = 1.7:1, 108 mg, 0.357 mmol) in THF
(4 mL) was added TBAF (1.0 M solution in THF,
535 lL, 0.535 mmol). The mixture was stirred for
30 min at room temperature and concentrated. The resi-
due was purified by flash column chromatography (silica
gel, hexane/EtOAc = 5 to 3 to 1) to give a corresponding
C-7-alcohol as a 1.7:1 diastereomeric mixture (60.6 mg,
90%, 6S:6R = 1.7:1). Separation of the C-6-epimer was
performed after acetylation of the C-7-alcohol with
Ac2O and pyridine in the presence of DMAP. Methanol-
ysis of each C-7-acetate with K2CO3 reproduced the dia-
27:0
stereomerically pure C-6-fluorides. (6S)-Isomer: ½aꢂD
1
ꢁ88 (c 0.11, CHCl3); H NMR (500 MHz, CDCl3) d
1.48–1.55 (m, 1H, H-4), 1.65–1.75 (m, 2H, H-3), 2.02–
2.07 (m, 1H, H-4), 2.08 (d, 1H, J = 10 Hz, OH), 3.29–
3.34 (m, 1H, H-2), 3.84 (br dd, 1H, J = 9.0, 2.0 Hz, H-
9a), 3.88–3.93 (m, 1H, H-2), 3.94 (td, 1H, J = 9.5,
5.0 Hz, H-4a), 4.44 (br dd, 1H, J = 25, 9.0 Hz, H-7),
5.52 (br d, 1H, J = 52 Hz, H-6), 5.53–5.57 (m, 1H, H-
9), 5.70 (dt, 1H, J = 12.0, 2.5 Hz, H-8); FT-IR (film) m
3294, 3168, 2945, 2928, 2853, 2819, 1466, 1424, 1372,
1278, 1140, 1092, 1041, 956, 750 cmꢁ1
.
4.2.7. ((4aS,6R,7S,9aR)-6-Fluoro-3,4,4a,6,7,9a-hexahy-
dro-2H-1,5-dioxa-benzocyclohepten-7-yloxy)-tert-buty-
ldimethylsilane. To a solution of sulfide 6 (142 mg,
0.362 mmol) in CH2Cl2 (5.6 mL) were added DAST
(81.4 lL, 0.616 mmol) and NBS (83.5 mg, 0.471 mmol)
at ꢁ50 °C. The mixture was gradually warmed to
ꢁ30 °C over 40 min with stirring and quenched with sat-
urated NaHCO3 solution. The aqueous phase was ex-
tracted with EtOAc and the combined organic phase
was washed with saturated Na2S2O3 solution and brine,
and dried over anhydrous MgSO4. After concentration,
1349, 1262, 1170, 1103, 1076, 1049, 984, 957 cmꢁ1
;
HRMS (EI, 70 eV) [M]+ calcd for C9H13FO3:
27:0
188.0849; found, 188.0846. (6R)-Isomer: ½aꢂD ꢁ32 (c
0.724, CHCl3); 1H NMR (500 MHz, CDCl3) d 1.58–
1.66 (m, 1H, H-4), 1.65–1.74 (m, 2H, H-3), 2.18–2.22
(m, 1H, H-4), 2.20 (s, 1H, OH), 3.32–3.37 (m, 1H, H-
2), 3.41 (td, 1H, J = 10, 5.0 Hz, H-4a), 3.73 (br dd, 1H,
J = 9.0, 2.0 Hz, H-9a), 3.90–3.95 (m, 1H, H-2), 4.31–
4.37 (m, 1H, H-7), 5.06 (dd, 1H, J = 51, 7.0 Hz, H-6),

S. Kobayashi et al. / Carbohydrate Research 343 (2008) 443–452
449
5.51–5.56 (m, 1H, H-9), 5.69 (br d, 1H, J = 13.5 Hz,
H-8); FT-IR (film) m 3332, 3228, 2916, 2852, 1464,
1397, 1335, 1284, 1265, 1222, 1149, 1108, 1054, 1039,
1019, 957 cmꢁ1. Anal. Calcd for C9H13FO3: C, 57.44;
H, 6.96. Found: C, 57.38; H, 7.32.
were added allyltrimethylsilane (10 equiv), NIS
(3 equiv), and AgOTf (1.5 equiv) at ꢁ25 °C. The mix-
ture was stirred for 22 h at ꢁ25 °C and quenched with
saturated Na2S2O3 solution, then saturated NaHCO3
solution. The aqueous phase was extracted with EtOAc,
and the organic phase was washed with brine and dried
over anhydrous MgSO4. After concentration, the resi-
due was purified by flash column chromatography (silica
gel, hexane/EtOAc = 20) to give allylation product 8a
(57%) and recovery of 6 (24%).
4.2.9.
hydro-2H-1,5-dioxa-benzocyclohepten-7-yl pivalate. To
solution of 6-fluoro-7-hydroxytetrahydrooxepin
(4aS,6R,7S,9aR)-6-Fluoro-3,4,4a,6,7,9a-hexa-
a
(6S:6R = 1.7:1, 14.4 mg, 0.0765 mmol) in CH2Cl2
(2 mL) were added pyridine (471 lL, 3.83 mmol) and
PivCl (236 lL, 1.91 mmol). The mixture was stirred for
7 days at room temperature and concentrated. The resi-
due was purified by flash column chromatography (silica
gel, hexane/EtOAc = 20:5) to give a corresponding C-8-
pivalate as a 1.7:1 diastereomeric mixture (19.0 mg, 91%,
4.3.3. General procedure for allylation of sulfoxide with
Tf2O/DTBMP activators. To a solution of sulfoxide
(1 equiv)
and
2,6-di-tert-butyl-4-methylpyridine
(5.2 equiv) in CH2Cl2 (40 mL/mmol) was added Tf2O
(2.6 equiv) at ꢁ78 °C. The mixture was stirred for
3 min at ꢁ78 °C followed by addition of allyltrimethyl-
silane (20 equiv). The resulting mixture was stirred for
the indicated times at the indicated temperatures, as
shown in Table 1, and then quenched with saturated
NaHCO3 solution. The aqueous phase was extracted
with EtOAc, and the organic phase was washed with
brine and dried over anhydrous MgSO4. After concen-
tration, the residue was purified by flash column chro-
matography (silica gel, hexane/EtOAc) to give
allylation product 8a or 8c.
1
9S:9R = 1.7:1). H NMR (500 MHz, CDCl3) d 1.22 (s,
9H, Piv), 1.23 (s, 9H, Piv), 1.47–1.55 (m, 1H, H-4 major),
1.58–1.66 (m, 1H, H-4 minor), 1.66–1.74 (m, 4H, H-3
major and minor), 2.02–2.07 (m, 1H, H-4 major), 2.16–
2.21 (m, 1H, H-4 minor), 3.29–3.39 (m, 2H, H-2 major
and minor), 3.53 (td, 1H, J = 10.5, 5.0 Hz, H-4a minor),
3.81 (dt, 1H, J = 9.5, 2.0 Hz, H-9a minor), 3.88–3.95 (m,
4H, H-1, H-4a, H-9a major, and H-2 minor), 5.29 (dd,
1H, J = 51, 7.5 Hz, H-6 minor), 5.35–5.39 (m, 1H, H-9
minor), 5.42 (br d, 1H, J = 13.0 Hz, H-9 major), 5.43
(br d, 1H, J = 51 Hz, H-6 major), 5.44–5.49 (m, 1H, H-
7 minor), 5.52 (br d, 1H, J = 25 Hz, H-7 major), 5.76
(br d, 2H, J = 13.0 Hz, H-6 major and minor); FT-IR
(film) m 2959, 2853, 1736, 1480, 1461, 1397, 1149, 1116,
4.3.4. General method for allylation of sulfone with Lewis
acid. To a solution of sulfone 7a or 7b (1 equiv) in
CH2Cl2 (25 mL/mmol) were added allyltrimethylsilane
(3–6 equiv) and Lewis acid (3–6 equiv) at ꢁ78 °C. The
mixture was stirred at the indicated temperature for
the indicated times as shown in Table 1 and quenched
with saturated NaHCO3 solution. The aqueous phase
was extracted with EtOAc, and the organic phase was
washed with brine and dried over anhydrous Na2SO4.
After concentration, the residue was purified by flash
column chromatography (silica gel, hexane/EtOAc) to
give allylation products 3a, 8a, 3b, or 8b.
1099, 1065, 1043, 1022, 958 cmꢁ1
.
4.3. Allylation of sulfide, sulfoxide, sulfone, and fluoride
4.3.1. Allylation of 6 with NBS/TfOH activators. To a
˚
suspension of sulfide 6 (1 equiv) and MS 4 A (powdered,
activated, 200 wt % of 6) in CH2Cl2 (15 mL/mmol) were
added allyltrimethylsilane (5 equiv), NBS (1.5 equiv),
and TfOH (0.1 equiv) at ꢁ50 °C. The mixture was stir-
red for 1.7 h at ꢁ50 °C and allyltrimethylsilane
(5 equiv), NBS (1.5 equiv) and TfOH (0.1 equiv) were
further added to the mixture in four portions at intervals
of 1.7 h. The reaction mixture was stirred for 8.5 h at
ꢁ50 °C to 0 °C, and then quenched with saturated
Na2S2O3 solution, then saturated NaHCO3 solution.
The aqueous phase was extracted with EtOAc, and the
organic phase was washed with brine and dried over
anhydrous MgSO4. After concentration, the residue
was purified by flash column chromatography (silica
gel, hexane/EtOAc = 20) to give allylation product 8a
(53%) and recovery of 6 (24%). The C-6-stereochemistry
of 8a was identified by NOE experiments after removal
of TBS group with TBAF.
4.3.5. Allylation of fluoride with Cp2HfCl2/AgClO4
activators. To a suspension of Cp2HfCl2 (3 equiv), Ag-
˚
ClO4 (6 equiv), and MS 4 A (powdered, activated,
200 wt % of fluoride) in CH2Cl2 (20 mL/mmol) was
added allyltrimethylsilane (20 equiv). The mixture was
stirred for 10 min at room temperature and cooled to
ꢁ78 °C. A solution of anomeric fluoride (1 equiv) in
CH2Cl2 (20 mL/mmol) was added and the mixture was
stirred for 1.2 h at ꢁ78 °C to ꢁ50 °C. The reaction mix-
ture was quenched with saturated NaHCO3 solution and
filtered through a pad of Celite. The filter cake was
washed with EtOAc and the filtrate was dried over anhy-
drous MgSO4. After concentration, the residue was
purified by flash column chromatography (silica gel,
hexane/EtOAc = 20) to give allylation product 8a
(92%).
4.3.2. Allylation of 6 with NIS/AgOTf activators. To a
solution of sulfide 6 (1 equiv) in CH2Cl2 (23 mL/mmol)

450
S. Kobayashi et al. / Carbohydrate Research 343 (2008) 443–452
4.3.6. Allylation of fluoride with Cp2TiCl2/AgClO4 acti-
vators. To a suspension of Cp2TiCl2 (3 equiv), AgClO4
(6 equiv), and MS 4 A (powdered, activated, 200 wt %
4.3.10. General method for allylation of fluoride with
allylmagnesium bromide. To a solution of fluoride
(1 equiv) in CH2Cl2 (50 mL/mmol) or Et2O was added
allylmagnesium bromide (0.82 M solution in Et2O,
4 equiv). The mixture was stirred at 20 °C for the indi-
cated times as shown in Table 1 and quenched with sat-
urated NH4Cl solution. The aqueous phase was
extracted with EtOAc, and the organic phase was
washed with brine and dried over anhydrous MgSO4.
After concentration, the residue was purified by flash
column chromatography (silica gel, hexane/EtOAc) to
give allylation products 3a–c, 8a–c, or 9.
˚
of fluoride) in CH2Cl2 (20 mL/mmol) was added allyltri-
methylsilane (20 equiv). The mixture was stirred for
10 min at room temperature and cooled to ꢁ78 °C. A
solution of anomeric fluoride (1 equiv) in CH2Cl2
(20 mL/mmol) was added and the mixture was gradually
warmed to 10 °C over 17 h with stirring. The reaction
mixture was quenched with saturated NaHCO3 solution
and filtered through a pad of Celite. The filter cake was
washed with EtOAc and the filtrate was dried over anhy-
drous MgSO4. After concentration, the residue was
purified by flash column chromatography (silica gel,
hexane/EtOAc = 20) to give allylation product 8a
(90%).
4.3.11. General method for allylation of fluoride with
triallylaluminum. Allylmagnesium bromide (0.6 M
solution in Et2O, 15 equiv) was added to AlCl3 (5 equiv)
and the mixture was stirred for 1 h at 0 °C. A solution of
fluoride (1 equiv) in Et2O (100 mL/mmol) was added
and the mixture was stirred at 0 °C to 20 °C for the indi-
cated times as shown in Table 1. The reaction mixture
was quenched with saturated NH4Cl solution and the
aqueous phase was extracted with EtOAc. The organic
phase was washed with saturated NH4Cl4, water, and
brine, and dried over anhydrous MgSO4. After concen-
tration, the residue was purified by flash column chro-
matography (silica gel, hexane/EtOAc) to give
allylation products 3a, 8a, 3b, or 9.
4.3.7. General method for allylation of fluoride with
BF3ꢀEt2O. To a solution of fluoride (1 equiv) in
CH2Cl2 (25 mL/mmol) or CH3CN (25 mL/mmol) were
added allyltrimethylsilane (20 equiv) and BF3ꢀEt2O
(3 equiv). The mixture was stirred at the indicated tem-
perature for the indicated times as shown in Table 1 and
quenched with saturated NaHCO3 solution. The aque-
ous phase was extracted with EtOAc, and the organic
phase was washed with brine and dried over anhydrous
MgSO4. After concentration, the residue was purified by
flash column chromatography (silica gel, hexane/
EtOAc) to give allylation products 3a–c and 8a–c.
4.3.12.
(4aS,6S,7S,9aR)-6-Allyl-3,4,4a,6,7,9a-hexa-
30:0
hydro-2H-1,5-dioxa-benzocyclohepten-7-ol (8b). ½aꢂD
1
4.3.8. Allylation of fluoride with TMSOTf. To a solu-
tion of fluoride (1 equiv) in CH2Cl2 (30 mL/mmol) were
added allyltrimethylsilane (20 equiv) and TMSOTf
(1.5 equiv) at ꢁ78 °C. The mixture was stirred for 1 h
at ꢁ78 °C and TMSOTf (3 equiv) was further added
to the mixture. The reaction mixture was stirred for
48 h at ꢁ78 °C to 10 °C and quenched with saturated
NaHCO3 solution. The aqueous phase was extracted
with EtOAc, and the organic phase was washed with
brine and dried over anhydrous MgSO4. After concen-
tration, the residue was purified by flash column chro-
matography (silica gel, hexane/EtOAc = 6 to 1.5) to
give allylation products 3b and 8b (84%).
+9.1 (c 0.31, CHCl3); H NMR (500 MHz, CDCl3) d
1.40–1.49 (m, 1H, H-4), 1.63–1.70 (m, 2H, H-3), 1.95–
1.99 (m, 1H, H-4), 2.30–2.36 (m, 1H, allyl), 2.54–2.60
(m, 1H, allyl), 3.28–3.33 (m, 1H, H-2), 3.57 (ddd, 1H,
J = 11.0, 9.5, 4.8 Hz, H-4a), 3.87–3.97 (m, 3H, H-1,
H-6, H-9a), 4.40 (dd, 1H, J = 4.3, 2.3 Hz, H-7), 5.08–
5.17 (m, 2H, allyl), 5.64 (s, 2H, H-8, H-9), 5.80–5.88
(m, 1H, allyl); 13C NMR (125 MHz, CDCl3) d 25.6,
31.5, 33.4, 67.9, 72.5, 72.7, 76.6, 79.4, 117.2, 130.8,
132.9, 135.3; FT-IR (neat) m 3354, 3265, 2924, 2848,
2819, 1642, 1447, 1421, 1375, 1262, 1223, 1124, 1092,
1070, 1051, 1010, 963, 942, 917, 889, 849 cmꢁ1; ESI-
TOFMS [M+Na]+ calcd for C12H18NaO3: 233.1154;
found, 233.1151.
4.3.9. Allylation of fluoride with TiCl4. To a solution of
fluoride (1 equiv) in CH2Cl2 (20 mL/mmol) were added
allyltrimethylsilane (6 equiv) and TiCl4 (1.0 M solution
in toluene, 4 equiv) at ꢁ100 °C. The mixture was stirred
for 10 min at ꢁ100 °C and quenched with saturated
NaHCO3 solution. The resulting suspension was filtered
through a pad of Celite and washed with EtOAc. The fil-
trate was extracted with EtOAc, and the organic phase
was washed with water, brine and dried over anhydrous
MgSO4. After concentration, the residue was purified by
flash column chromatography (silica gel, hexane/
EtOAc = 4) to give allylation products 3b and 8b (70%).
4.3.13.
(4aS,6R,7S,9aR)-6-Allyl-3,4,4a,6,7,9a-hexa-
24:0
hydro-2H-1,5-dioxa-benzocyclohepten-7-ol (3b). ½aꢂD
1
+27.2 (c 0.520, CHCl3); H NMR (500 MHz, CDCl3)
d 1.41–1.49 (m, 1H, H-4), 1.63–1.68 (m, 2H, H-3),
2.02–2.07 (m, 1H, H-4), 2.23–2.29 (m, 1H, allyl), 2.53–
2.59 (m, 1H, allyl), 3.19 (ddd, 1H, J = 11.5, 9.0,
4.5 Hz, H-4a), 3.28–3.34 (m, 1H, H-2), 3.38 (dt, 1H,
J = 8.0, 3.0 Hz, H-6), 3.71 (ddd, 1H, J = 9.0, 4.0,
2.5 Hz, H-9a), 3.87–3.91 (m, 1H, H-2), 4.13 (ddd, 1H,
J = 9.0, 4.0, 2.5 Hz, H-7), 5.07–5.15 (m, 2H, allyl),
5.57 (dt, 1H, J = 13.0, 2.0 Hz, H-8), 5.65 (dt, 1H,

S. Kobayashi et al. / Carbohydrate Research 343 (2008) 443–452
451
J = 13.0, 2.3 Hz, H-9), 5.91–5.99 (m, 1H, allyl); 13C
NMR (125 MHz, CDCl3) d 25.6, 31.0, 37.9, 67.7, 73.9,
80.0, 81.2, 84.3, 117.0, 132.3, 133.8, 135.3; FT-IR (neat)
m 3418, 3075, 2943, 2868, 1641, 1436, 1335, 1313, 1262,
1218, 1112, 1039, 992, 959, 915, 849 cmꢁ1; ESI-TOFMS
[M+Na]+ calcd for C12H18NaO3: 233.1154; found,
233.1163.
31.3, 36.0, 60.9, 67.9, 72.8, 73.3, 74.0, 78.8, 130.0,
133.2, 172.0; FT-IR (film) m 3449, 3033, 2938, 2854,
1735, 1443, 1372, 1260, 1177, 1092, 1034, 968 cmꢁ1
;
HR-ESI FT-ICR MS [M+Na]+ calcd for C13H20NaO5:
279.1203; found, 279.1203.
4.4.2. Alkylation of 6-fluoro-7-hydroxytetrahydrooxepin
with TiCl4. To a solution of 6-fluoro-7-hydroxytetra-
hydrooxepin (6R:6S = 1:1.7, 10.4 mg, 0.0553 mmol) in
CH2Cl2 (2 mL) were added 1-ethoxy-1-[(trimethylsilyl)-
oxy]ethane (177 mg, 1.11 mmol) and TiCl4 (24.4 lL,
0.221 mmol) at ꢁ78 °C. The mixture was stirred for
3 h at ꢁ78 °C to ꢁ50 °C and quenched with saturated
NaHCO3 solution. The aqueous phase was extracted
with EtOAc, and the combined organic phase was
washed with brine and dried over anhydrous MgSO4.
After concentration, the residue was purified by flash
column chromatography (silica gel, hexane/EtOAc = 3
to 2) to give b-alkylation product 13 (2.8 mg, 20%).
4.3.14. (4aS,9aR)-7-Allyl-3,4,4a,6,7,9a-hexahydro-2H-
1,5-dioxa-benzocyclohepten-7-ol (9). For major isomer:
1H NMR (500 MHz, CDCl3) d 1.44–1.54 (m, 1H, H-4),
1.64–1.72 (2H, H-3), 2.05–2.12 (m, 1H, H-4), 2.45 (dd,
1H, J = 12, 7.4 Hz, allyl), 2.50 (dd, 1H, J = 12, 7.3 Hz,
allyl), 3.20–3.26 (m, 1H, H-4a), 3.29–3.35 (m, 1H, H-
2), 3.51 (d, 1H, J = 11.9 Hz, H-6), 3.71 (d, 1H,
J = 11.9 Hz, H-6), 3.82 (br d, 1H, J = 9.2 Hz, H-9a),
3.86–3.92 (m, 1H, H-2), 5.20 (d, 1H, J = 17.4 Hz, allyl),
5.23 (d, 1H, J = 8.7 Hz, allyl), 5.51 (br d, 1H,
J = 12.8 Hz, H-8), 5.67 (d, 1H, J = 12.8 Hz, H-9),
5.81–5.90 (m, 1H, allyl); 13C NMR (125 MHz, CDCl3)
d 25.6, 31.1, 42.3, 67.7, 75.1, 77.3, 80.9, 81.1, 120.4,
131.4, 132.8, 136.8; FT-IR (film) m 3435, 3075, 2942,
2861, 1639, 1434, 1372, 1312, 1262, 1218, 1129, 1093,
1063, 1038, 999, 963, 917, 849 cmꢁ1; HR-ESI FT-ICR
MS [M+Na]+ calcd for C12H18NaO3: 233.1148; found,
233.1149.
27:0
1
Compound 13: ½aꢂD +20 (c 0.25, CHCl3); H NMR
(500 MHz, CDCl3) d 1.28 (t, 3H, J = 7.5 Hz, Et),
1.40–1.44 (m, 1H, H-4), 1.45–1.68 (m, 2H, H-3), 1.95
(br d, 1H, J = 7.0 Hz, OH), 1.96–2.03 (m, 1H, H-4),
2.51 (dd, 1H, J = 15, 8.0 Hz, CH2CO2Et), 2.84 (dd,
1H, J = 15, 3.5 Hz, CH2CO2Et), 3.25 (ddd, 1H,
J = 11.5, 9.0, 5.0 Hz, H-4a), 3.26–3.32 (m, 1H, H-2),
3.71 (br dd, 1H, J = 9.0, 2.0 Hz, H-9a), 3.83 (td, 1H,
J = 9.0, 4.0 Hz, H-6), 3.85–3.90 (m, 1H, H-2), 4.11–
4.17 (m, 1H, H-7), 4.17 (q, 2H, J = 7.5 Hz, Et), 5.60
(br d, 1H, J = 13.5 Hz, H-8), 5.67 (dt, 1H, J = 13.5,
2.0 Hz, H-9); 13C NMR (125 MHz, CDCl3) d 14.4,
25.5, 31.0, 39.6, 60.8, 67.7, 73.8, 80.1, 81.1, 81.7, 132.8,
133.7, 172.2; FT-IR (film) m 3428, 3070, 3048, 2929,
2856, 1723, 1464, 1428, 1375, 1261, 1219, 1113, 1042,
959, 849 cmꢁ1; HR-ESI FT-ICR MS [M+Na]+ calcd
for C13H20NaO5: 279.1203; found, 279.1203.
4.4. Alkylation of fluoride with trimethylsilylketene acetal
4.4.1. Alkylation of 7-tert-butyldimethylsilyloxy-6-fluor-
otetrahydrooxepin with BF3ꢀEt2O. To a solution of 7-
tert-butyldimethylsilyloxy-6-fluorotetrahydrooxepin (6R:
6S = 1:1.7, 12.5 mg, 0.0413 mmol) and 1-ethoxy-1-[(tri-
methylsilyl)oxy]ethane (132 mg, 0.826 mmol) in CH2Cl2
(1.5 mL) was added BF3ꢀEt2O (10.5 lL, 0.0826 mmol) at
ꢁ40 °C. The mixture was stirred for 4 h at ꢁ40 °C to
ꢁ20 °C and quenched with saturated NaHCO3 solution.
The aqueous phase was extracted with EtOAc and the
combined organic phase was dried over anhydrous
MgSO4. After concentration, the residue was purified
by flash column chromatography (silica gel, hexane/
EtOAc = 5 to 3) to give a 2.5:1 mixture of alkylation
product 12 (7.8 mg, 51%, 6S:6R = 2.5:1). The C-6-ste-
reochemistry of the major isomer was identified by
NOE experiments after removal of TBS group with
Acknowledgment
This work was supported by a Grant-in-Aid for Scien-
tific Research (Wakate B) from the Japan Society for
the Promotion of Science (JSPS).
References
25:5
TBAF. C-7-alcohol of (6S)-12: ½aꢂD +8.5 (c 0.082,
CHCl3); 1H NMR (500 MHz, CDCl3) d 1.28 (t, 3H,
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1.94 (m, 1H, H-4), 2.12 (br d, 1H, J = 8.0 Hz, OH),
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H-8, H-9); 13C NMR (125 MHz, CDCl3) d 14.4, 25.6,
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