Efficient synthesis of 8-oxa-bicyclo[3.2.1]octane derivatives from d-arabinose

Article abstract of DOI:10.1016/j.tetasy.2007.08.033

Our studies of the TIBAL-promoted Claisen rearrangement reaction and ring-closing metathesis (RCM) resulted in the development of an efficient synthetic route to polyfunctional seven-membered carbasugar synthons from d-arabinose. Moreover, the constructio

Full text of DOI:10.1016/j.tetasy.2007.08.033

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2326–2331
Efficient synthesis of 8-oxa-bicyclo[3.2.1]octane derivatives
from D-arabinose
Yi Liu, Tian-Xiang Han, Zhen-Jun Yang, Liang-Ren Zhang and Li-He Zhang*
The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
38 Xueyuan Road, Beijing 100083, PR China
Received 11 July 2007; accepted 23 August 2007
Abstract—Our studies of the TIBAL-promoted Claisen rearrangement reaction and ring-closing metathesis (RCM) resulted in the develop-
ment of an efficient synthetic route to polyfunctional seven-membered carbasugar synthons from D-arabinose. Moreover, the construc-
tion of 8-oxa-bicyclo[3.2.1]octane derivatives 10 and 13 was achieved by BCl3 or iodide-promoted intramolecular electrophilic addition
reactions, which were regio- and stereoselective.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
compounds,10 but the enantioselective synthesis and spe-
cific spatial distribution of the hydroxyl groups on the ring
are often problematic. In this report, the TIBAL-promoted
Claisen rearrangement of allyl vinyl ethers and ring-closing
metathesis (RCM) were used to construct the polyhydroxy-
cyclic heptenes. The hydroxycyclic heptene precursor pre-
pared could be converted to 8-oxa-bicyclo[3.2.1]octane
compounds in the presence of BCl3 or iodine (Fig. 1).
These reactions showed good regioselectivity and stereose-
lectivity. This methodology will provide a practical method
to prepare 8-oxa-bicyclo[3.2.1]octane compounds as a new
type of chiral building blocks.
Seven-membered carbocyclic compounds are widely pres-
ent as a structural motif in many biologically important
molecules and natural products.1 Similarly, 8-oxa-bicy-
clo[3.2.1]octane derivatives have been widely used as key
precursors for the synthesis of natural and unnatural prod-
ucts, such as sesquiterpenes (1,5-epoxysalvia-4(14)-ene),2
diterpenes (Cladiellin),3 alkaloids (Aspergillin PZ,2 pyrrol-
izidine alkaloids4), tropane analogues,5 and Phamoidride
B,6 which show interesting biological activities. Recently,
more attention has been paid to the synthesis of conform-
ationally restricted sugar analogues, because they are likely
to be resistant to the action of glycosidases and glycosyl
transferases.7
2. Results and discussion
Two strategies are available for the construction of 8-oxa-
bicyclo[3.2.1]octane derivatives. One is to create the cyclic
systems in one step employing reactions such as [4+3]
cycloaddition,3,8 oxidopyrylium [5+2] cycloaddition,4,6
and Prins-Pinacol reaction.2 Another is to create the cyclic
systems by stepwise processes, including SmI2-mediated
nucleophilic acyl addition9 and intramolecular oxymercu-
ration.5 At present, various methods have been used for
the conversion of sugars to seven-membered carbocyclic
Compound 1, as the starting material, was easily obtained
from D-arabinose.11 After Wittig olefination, the unsatu-
rated alcohol 2 was obtained in good yield.12 Alcohol 2
was oxidized with PCC to afford the known ketone 3.13
Ketone 3 was then reacted with an excess of vinylmagnesium
bromide in THF at ꢀ78 ꢁC to give the enol 4 exclusively.14
In the presence of iodine and a base, compound 5 was
obtained in 94% yield from compound 4, and the configu-
ration of C-5 in the formed sugar ring was retained.15
Following the elimination of HI by DBU, the key interme-
diate 6 was obtained in 67% overall yield from pentose 1.
The polyhydroxyl seven-membered carbasugars 7a and 7b
were then prepared by the TIBAL-promoted Claisen rear-
rangement from intermediate 6 (Scheme 1).
*
Corresponding author. Tel.: +86 10 82801700; fax: +86 10 82802724;
e-mail: zdszlh@bjmu.edu.cn
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.08.033

Y. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 2326–2331
2327
HO
HO
Claisen
OBn
OH
OBn
O
BnO
rearrangement
BnO
BnO
OBn
BnO
7a,7b
O
10
6
OBn
I
RCM
OBn
HO
HO
BnO
BnO
OBn
O
OBn
OBn
BnO
13
11a,11b
12a,12b
Figure 1. Synthesis of 8-oxa-bicyclo[3.2.1]octane derivatives.
BnO
BnO
OBn
OBn
OH
O
b
a
OH
OBn
OBn
2
1
BnO
BnO
OBn
O
OBn
OH
OBn
c
O
d
I
BnO
OBn
OBn
OBn
5
4
3
OBn
e
OH
OBn
O
f
BnO
BnO
BnO
OBn
6
7a,7b
˚
Scheme 1. Reagents and conditions: (a) Ph3PCH3Br, n-BuLi, THF, reflux, 3 h, 87.6%; (b) PCC, 4 A MS, DCM, 87.2%; (c) CH2CHMgBr, THF, ꢀ78 ꢁC,
3 h, 96.2%; (d) 5% I2 in ether, satd aq NaHCO3, THF, 5 h, 94.2%; (e) DBU, THF, 80 ꢁC, overnight, 97.0%; (f) 1 M TIBAL, toluene, 60 ꢁC, 3 h, 91%.
1
The structure of product 5 was determined by H and 13C
4
BnO
3
OBn
NMR spectra. The coupling constant between H-2 and H-3
(J2,3 = 5.0 Hz) agreed with the dihedral angle for a cis rela-
tionship. Additional support for the ‘b’ configurational
assignment of 5 came from the 13C NMR chemical shift
of C-1. The 13C NMR of compound 5 showed that C-1
was at 3.02 ppm. This was consistent with the reports from
Ohrui et al. that the 13C-chemical shifts of anomeric centers
in the 2,3-cis isomers of furanoses were 3–4 ppm upfield of
those of the corresponding 2,3-trans isomers,16 and the
chemical shift for C-1 of a isomer appeared at 7.14 ppm.17
O
I
OBn
OBnHO
2
3
BnO
4
I
OBn
2
H
Figure 2. Mechanism of the formation of compound 5.
generated at 60 ꢁC (Table 1). NMR spectra showed
that 7a and 7b were a pair of C-1 epimers. Moreover,
The likely mechanism for the formation of compound 5
was shown in Figure 2, in which an iodonium ion formed
at C-1 and C-2 was involved. Subsequent attack by the 5-
hydroxyl group from the least-hindered side led to the for-
mation of 5 with a favored conformation.18
Table 1. Optimization of reaction conditions for Claisen rearrangement
Temperature (ꢁC)
Yield (%)
7a
7b
60
80
90
100
Reflux
27
40
25
19
36
64
52
44
31
NDa
The Claisen rearrangement was under thermodynamical
control, and the ratio of 7a and 7b was related to the reac-
tion temperature (from 60 to 110 ꢁC). The results indicated
that the overall yields of 7a and 7b were decreased with an
increase of the temperature. The highest yield of 7b was
a ND: not detected.

2328
Y. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 2326–2331
cycloheptene 7b can easily be converted to 7a by a Mitsun-
obu reaction to form the O-Bz derivative 8, in which the
configuration was inverted at C1. After hydrolysis, 7a
was furnished (Scheme 2). According to the mechanism
of Claisen rearrangement reaction, the formation of a
seven-membered ring should be completed via an endo or
exo transition state (Fig. 3). Obviously, an attack from
the endo-side is favored due to less steric hindrance and
thus compound 7b is produced preferentially. The configu-
rations of C-2 and C-3 hydroxyls of cycloheptene 7a/7b
were the same as that of precursor 6. However, the orien-
tation of the C-1 hydroxyl group of 7a and 7b had been
identified by 1H NMR. The coupling constant of H-1
and H-2 (J1,2 value) of cycloheptene 7a was 3.0 Hz, similar
to the value of the reported analogue,19 indicating a cis
relationship between H-1 and H-2. Therefore, the hydroxyl
group was oriented in a b configuration. The configuration
of C-1 hydroxyl group of compound 7b was also confirmed
by the formation of compound 10.
The debenzylation of cycloheptene 7b was performed with
1 M BCl3 in CH2Cl2. However, the expected carbasugar 9
was not obtained in this reaction, and 8-oxa-bicy-
clo[3.2.1]octane 10 was formed instead.20 The 2D NOESY
NMR spectra of 10 showed strong NOE interactions
between H-3 and b-oriented H-6 and between H-3 and b-ori-
ented H-7, clearly indicating that H-3 and b-oriented H-6
and H-7 were located at the same orientation and the oxy-
gen bridge was located on the opposite side. The formation
of 8-oxa-bicyclo[3.2.1]octane 10 was likely achieved by the
attack of 1-hydroxyl group of 7b at the C4, C5 double
bond to form the oxygen bridge and the terminal olefin,
and after hydrolysis 10 was afforded (Scheme 3). According
to the structure of compound 10 and the stereochemistry
during the reaction, the C1 hydroxyl of compound 7b
was a-oriented.
a
OH
OBn
OBz
OBn
BnO
BnO
BnO
BnO
7b
8
b
OH
OBn
BnO
BnO
7a
To synthesize more 8-oxa-bicyclo[3.2.1]octane derivatives,
polyfunctional cycloheptene 12a/12b were obtained
from intermediate 3.21 Compound 3 was reacted with
Scheme 2. Reagents and conditions: (a) BzOH, Ph3P, DEAD, THF, rt,
3 h, 96.4%; (b) K2CO3, CH3OH, rt, 22 h, 84.5%.
OBn
OH
OBn
BnO
BnO
BnO
BnO
HO
OBn
OBn
BnO
BnO
endo
exo
7a
7b
BnO
BnO
H
endo
BnO
BnO
OBn
AlR3
Al
O
O
R
OH
OBn
BnO
BnO
H
exo
OH
Figure 3. The formation of compound 7a and 7b.
3
5
HO
HO
1
a
a
BnO
HO
6
OH
OH
2
4
7
1
OBn
OH
BnO
HO
O
7b
10
9
Cl2BO
BnO
-BCl2OH
OH -BnCl
OBn
O
HO
OBCl2
OBCl2
Cl2BO
BnO
Cl2BO
7b
HO
HO
H2O
O
OH
O
HO
10
10
Scheme 3. Reagents and conditions: (a) BCl3, DCM, ꢀ78 ꢁC, ꢀrt, 2 h, 71.2%.

Y. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 2326–2331
2329
4. Experimental
4.1. General experimental detail
BnO
HO
OBn
b
a
3
OBn
All chemicals were purchased as reagent grade and used
without further purification, unless otherwise noted. Sol-
vents were dried by refluxing for at least 24 h. Dichloro-
methane (CH2Cl2) was distilled over calcium hydride
(CaH2). Tetrahydrofuran (THF) and toluene was distilled
from sodium, indicated by diphenylketone. All reactions
were carried out under anhydrous conditions with freshly
distilled solvents, unless otherwise noted. Reactions were
monitored by thin-layer chromatography (TLC), and were
detected by an ethanol solution of phosphomolybdic acid.
Column chromatography was performed on silica gel (200–
300 mesh). NMR spectra were recorded with Varian INO-
VA-500 and Varian VXR-300. Chemical shifts were rela-
tive to TMS (d 0.0) as an internal standard. Mass spectra
were obtained on PE SCLEX QSTAR mass spectrometer.
Elemental analyses were performed on Varian ELIII ana-
lyzer. Optical rotations were measured at 20 2 ꢁC at the
sodium D line (589 nm) and were in units of deg mL
11a,11b
HO
BnO
HO
BnO
+
OBn
OBn
BnO
12a
BnO
12b
Scheme 4. Reagents and conditions: (a) Butenylmagnesium bromide,
THF, ꢀ10 ꢁC!rt, overnight, 75.6%; (b) Grubb’s catalyst, CH2Cl2, rt,
48 h, 86.3%.
butenylmagnesium bromide in THF at ꢀ10 ꢁC to yield
compounds 11a and 11b (5:1) in 75.6%, and the cyclization
of 11a and 11b was completed by the Grubb’s catalyst to
afford cycloheptene 12a/12b (5:1) in quantitative yield
(Scheme 4). Compound 12a was isolated easily by column
chromatography and treated with NIS in CH2Cl2 to give
8-oxa-bicyclo[3.2.1]octane 13 as a single regioisomer in
good yield (Scheme 5).
(dm g)ꢀ1
.
4.2. 2,5-Anhydro-3,4,6-tri-O-benzyl-1-iodo-5-vinyl-L-manno-
hexitol 5
1H NMR and HMQC confirmed that the oxygen bridge of
compound 13 was formed between C-1 and C-5 and the
iodine was bonded to C-2. Due to the effect of the iodine
heavy atom, the 13C-chemical shift of C-2 was shifted up-
field. 2D NOESY NMR spectra showed a strong NOE
interaction between H-4 and b-oriented H-6, demonstrat-
ing that H-4 and b-oriented H-6 were located on the same
face and the oxygen bridge was located on the opposite
To alkene 414 (2.63 g, 5.92 mmol) dissolved in THF
(42 mL) was added saturated aqueous NaHCO3 (50 mL,
60.0 mmol) under argon, followed by dropwise addition
of 5% solution of iodine in ether (152 mL, 29.9 mmol).
The reaction mixture was stirred for 6 h at rt, quenched
by the addition of NaS2O3 at 0 ꢁC, and extracted with
EtOAc for three times. Organic extracts were combined,
dried by NaSO4, filtered, and the solvent was evaporated.
The residue was purified by column chromatography on
1
side. Moreover, H NMR showed that there was a signal
peak for H-2 and H-3, revealing a cis relationship between
H-2 and H-3. The formation of an oxygen bridge was via a
manner of trans-attack of the 5-hydroxyl to an iodonium
ion. The reaction was stereoselective and no b-oxygen
bridge isomer was found (Scheme 5).
silica gel (petroleum ether/EtOAc, 50:1) to give 5 as a prim-
20
rose yellow oil (3.17 g, 94%). ½aꢁD ¼ þ18:1 (c 0.09,
1
CH2Cl2), H NMR (500 MHz, CDCl3): d 7.34–7.24 (m,
15H, H-arom.), 5.98 (dd, J6,7b = 11.0 Hz, J6,7a = 17.5 Hz,
1H, H-6), 5.40 (dd, J7a,7b = 1.5 Hz, J6,7a = 17.5 Hz, 1H,
H-7a), 5.13 (dd, J7a,7b = 1.5 Hz, J6,7b = 11.0 Hz, 1H, H-
7b), 4.56, 4.53 (dd, J = 12.0 Hz, 2H, CH2Ph), 4.56, 4.52
(dd, J = 12.0 Hz, 2H, CH2Ph), 4.51, 4.44 (dd, J =
3. Conclusion
12.0 Hz, 2H, CH2Ph), 4.50 (m, J1a,2 = 7.5 Hz, J1b,2
=
In summary, we have developed an efficient and highly regio-
selective and stereoselective method for the synthesis of
polyfunctional cyclic heptene synthons and 8-oxa-bicy-
clo[3.2.1]octane derivatives from D-arabinose. This syn-
thetic method could be applied for the synthesis of a
growing number of biologically active substances contain-
ing seven-membered rings and an 8-oxa-bicyclo[3.2.1]-
octane skeleton.
8.5 Hz, J2,3 = 5.0 Hz, 1H, H-2), 4.18 (dd, J2,3 = 5.0 Hz,
J3,4 = 3.0 Hz, 1H, H-3), 4.00 (d, J3,4 = 3.0 Hz, 1H, H-4),
3.61 (dd, J = 9.5 Hz, 1H, H-8), 3.39 (dd, J1a,2 = 7.5 Hz,
J1a,1b = 9.5 Hz, 1H, H-1a), 3.25 (dd, J1b,2 = 8.5 Hz,
J1a,1b = 9.5 Hz, 2H, H-1b). 13C NMR (75 MHz, CDCl3):
d 139.2 (C-6), 138.4, 137.8, 137.7 (3 · Cipso), 128.4–127.4
(aromatic C), 114.4 (C-7), 86.5 (C-5), 86.2 (C-2), 83.2 (C-
4), 80.4 (C-3), 73.5 (C-8), 72.9, 72.4, 72.2 (3 · CH2Ph),
1
OBn
I
I
HO
BnO
a
HO
BnO
2
6
2
3
5
5
4
BnO
OBn
OBn
BnO
O
BnO
OBn
13
12a
Scheme 5. Reagents and conditions: (a) NIS, CH2Cl2, 0 ꢁC!rt, overnight, 87%.

2330
Y. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 2326–2331
20
1
3.0 (C-1). MS (ESI-TOF, positive, m/z): 571 [M+H]+, 588
[M+NH4]+, 593 [M+Na]+. Anal. Calcd for C29H31IO4: C,
61.06; H, 5.48. Found: C, 61.09; H, 5.59.
Compound 7b: ½aꢁD ¼ ꢀ28:4 (c 0.12, MeOH), H NMR
(500 MHz, CDCl3): d 7.36–7.23 (m, 15H, H-arom.), 6.34
(t, J = 7.0 Hz, 1H, H-5), 4.66, 4.53 (dd, J = 12.0 Hz, 2H,
CH2Ph), 4.63, 4.51 (dd, J = 12.0 Hz, 2H, CH2Ph), 4.52,
4.47 (dd, J = 12.0 Hz, 2H, CH2Ph), 4.27 (d, J2,3 = 6.0 Hz,
4.3. (2S,3S,4S)-3,4-Dibenzyloxy-2-benzyloxymethyl-5-
methylene-2-vinyl-tetrahydro furan 6
1H, H-3), 3.96 (s, 3H, H-1 and H-8), 3.71 (t, J2,3
=
6.0 Hz, 1H, H-2), 3.67 (d, J = 6.5 Hz, 1H, OH), 2.59–2.53
(m, 1H, H-6a), 2.03–1.94 (m, 2H, H-6b and H-7a), 1.78–
1.71 (m, 1H, H-7b). 13C NMR (125 MHz, CDCl3): d
138.3, 138.3, 138.0 (3 · Cipso), 136.8 (C-4), 133.2 (C-5),
128.4–127.5 (aromatic C), 79.3 (C-2), 79.0 (C-3), 74.2 (C-
1), 73.6 (C-8), 73.1, 72.2, 72.0 (3 · CH2Ph), 29.9 (C-7),
20.9 (C-6). MS (ESI-TOF, positive, m/z): 445 [M+H]+,
462 [M+NH4]+, 467 [M+Na]+, 483 [M+K]+. Anal. Calcd
for C29H32O4: C, 78.35; H, 7.26. Found: C, 78.15; H, 6.99.
To iodide 5 (2.00 g, 3.51 mmol) dissolved in THF (51 mL)
was dropwise added DBU (4.2 mL, 28.08 mmol) under
argon, and the mixture was then stirred for 20 h at 80 ꢁC,
cooled to room temperature, and concentrated. The residue
was purified on a silica gel column (0.1% Et3N in cyclohex-
ane/EtOAc, 120:1) to afford 6 as a colorless oil (1.50 g,
1
97%). H NMR (500 MHz, C6D6): d 7.26–7.05 (m, 15H,
H-arom.), 5.93 (dd, J7,8b = 11.0 Hz, J7,8a = 17.5 Hz, 1H,
H-7), 5.51 (dd, J8a,8b = 1.5 Hz, J7,8a = 17.5 Hz, 1H, H-
8a), 5.03 (dd, J8a,8b = 1.0 Hz, J7,8b = 11.0 Hz, 1H, H-8b),
4.92 (dt, J6a,6b = 1.5 Hz, J4,6a = 5.5 Hz, 1H, H-6a), 4.74
(t, J6a,6b = 1.5 Hz, 1H, H-6b), 4.56, 4.47 (dd, J = 11.5 Hz,
2H, CH2Ph), 4.44, 4.39 (dd, J = 12.0 Hz, 2H, CH2Ph),
4.39, 4.32 (dd, J = 12.0 Hz, 2H, CH2Ph), 4.32 (t,
J = 1.5 Hz, 1H, H-3), 4.11 (d, J4,6a = 5.5 Hz, 1H, H-4),
3.69 (dd, J = 10.0 Hz, 2H, H-9). 13C NMR (125 MHz,
C6D6): d 160.8 (C-5), 138.9, 138.8, 138.5 (3 · Cipso), 138.2
(C-7), 128.5–127.6 (aromatic C), 114.9 (C-8), 87.3 (C-6),
86.5 (C-2), 83.7 (C-3), 82.8 (C-4), 73.8 (C-9), 73.0, 72.3,
71.6 (3 · CH2Ph). MS (ESI-TOF, positive, m/z): 443
[M+H]+, 460 [M+NH4]+, 465 [M+Na]+, 481 [M+K]+.
Anal. Calcd for C29H30O4: C, 78.71; H, 6.83. Found: C,
78.47; H, 6.64.
4.5. (1R,2R,3R)-4-Benzyloxymethyl-2,3-dibenzyloxy-
cyclohept-4-enyl benzoate 8
To a solution of Ph3P (240 mg, 0.92 mmol) in dry THF
(3 mL) previously cooled in ice bath was added dropwise
2.2 M DEAD in toluene (0.42 mL, 0.92 mmol) under
argon. After 30 min, this solution was added dropwise to
a solution of alcohol 7b (203 mg, 0.45 mmol) and benzoic
acid (84 mg, 0.68 mmol) in dry THF (10 mL), which was
also cooled in an ice bath under argon. The mixture was
stirred for 30 min at 0 ꢁC, then stirred at rt for 3 h. The vol-
atiles were removed and the residue was purified on a silica
gel column (petroleum ether/acetone, 55:1) to yield 8 as a
colorless oil (225 mg, 96.4%). 1H NMR (300 MHz,
CDCl3): d 8.01 (m, 2H, H-arom.), 7.58–7.18 (m, 18H, H-
arom.), 6.13 (dd, J5,6a = 9.0 Hz, J5,6b = 4.5 Hz, 1H, H-5),
5.72 (dt, J1,7a = 1.8 Hz, J1,7b = 2.1 Hz, J1,2 = 11.7 Hz, 1H,
H-1), 4.70, 4.59 (dd, J = 12.3 Hz, 2H, CH2Ph), 4.57, 4.53
(dd, J = 12.9 Hz, 2H, CH2Ph), 4.51, 4.44 (dd, J =
12.0 Hz, 2H, CH2Ph), 4.21 (d, J2,3 = 15.0 Hz, 1H, H-3),
4.4. (1R and 1S,2R,3R)-4-Benzyloxymethyl-2,3-dibenzyl-
oxycyclohepta-4-ene-1-ol 7a and 7b
To a solution of compound 6 (850 mg, 1.92 mmol) in tolu-
ene (65 mL) was added dropwise 1 M TIBAL (19 mL,
19.0 mmol) in toluene at rt under argon. The mixture was
stirred at 60 ꢁC for 3 h, cooled down to 0 ꢁC, and quenched
with 20% aqueous NaOH solution. The mixture was
extracted with toluene. The organic layers were combined,
dried, and concentrated. The residue was purified on a sil-
ica gel column (petroleum ether/acetone, 20:1). Two prod-
ucts 7a as a colorless oil (230 mg, 27%) and 7b as a
4.19 (s, 1H, H-1, H-8a), 3.92 (dd, J1,2 = 12.0 Hz, J2,3
=
15.0 Hz, 1H, H-2), 3.91 (s, 1H, H-8b), 2.52–2.43 (m, 1H,
H-6a), 2.23–2.08 (m, 2H, H-6b and H-7a), 1.89 (m, 1H,
H-7b). 13C NMR (75 MHz, CDCl3): d 165.6 (PhCO),
138.5, 138.4, 138.4 (3 · Cipso), 136.8 (BzCipso), 132.8 (C-
5), 130.6 (C-4), 129.7–127.5 (aromatic C), 76.7 (C-1), 76.2
(C-2), 75.7 (C-8), 74.5 (C-3), 73.4, 71.8, 70.9 (3 · CH2Ph),
27.0 (C-7), 22.6 (C-6). MS (ESI-TOF, positive, m/z): 566
[M+NH4]+, 571 [M+Na]+, 587 [M+K]+. Anal. Calcd for
C36H36O5: C, 78.81; H, 6.61. Found: C, 78.52; H, 6.35.
colorless oil (546 mg, 64%) were obtained. Compound 7a:
20
½aꢁD ¼ ꢀ63:1 (c 0.08, MeOH), 1H NMR (500 MHz,
CDCl3): d 7.35–7.21 (m, 15H, H-arom.), 6.12 (dd, J =
5.0 Hz, J = 9.0 Hz, 1H, H-5), 4.63, 4.46 (dd, J = 11.5 Hz,
2H, CH2Ph), 4.59, 4.44 (dd, J = 12.0 Hz, 2H, CH2Ph),
4.51, 4.43 (dd, J = 12.0 Hz, 2H, CH2Ph), 4.32 (d,
4.6. Hydrolysis of compound 8
Compound 8 (271 mg, 0.49 mmol) was dissolved in MeOH
(7 mL) and treated with K2CO3 (340 mg, 2.46 mmol). The
solution was stirred at rt for 22 h. The reaction solution
was subsequently filtered and concentrated. The residue
was purified on a silica gel column (petroleum ether/ace-
tone, 20:1) to give 7a as a colorless oil (185 mg, 84.5%).
J2,3 = 6.5 Hz, 1H, H-3), 4.14 (dd, J1,2 = 3.0 Hz, J1,7
=
7.0 Hz, 1H, H-1), 3.93 (dd, J1,2 = 3.0 Hz, J2,3 = 6.5 Hz
1H, H-2), 3.89 (dd, J = 12.0 Hz, 2H, H-8), 2.32–2.26 (m,
1H, H-6a), 2.19 (br, 1H, OH), 2.14–2.07 (m, 1H, H-6b),
1.78–1.65 (m, 2H, H-7). 13C NMR (125 MHz, CDCl3): d
138.7, 138.3 (3 · Cipso), 136.4 (C-4), 133.5 (C-5), 128.4–
127.4 (aromatic C), 79.4 (C-2), 75.2 (C-8), 74.3 (C-3),
73.2 (CH2Ph), 72.0 (C-1), 71.8, 71.1 (2 · CH2Ph), 30.8
(C-7), 22.2 (C-6). MS (ESI-TOF, positive, m/z): 445
[M+H]+, 462 [M+NH4]+, 467 [M+Na]+, 483 [M+K]+.
Anal. Calcd for C29H32O4: C, 78.35; H, 7.26. Found: C,
78.11; H, 6.92.
4.7. (1S,2S,3R,5R)-4-Methylene-8-oxa-bicyclo[3.2.1]-
octane-2,3-diol 10
To compound 7b (28 mg, 0.063 mmol) dissolved in CH2Cl2
(3 mL) was dropwise added 1 M BCl3 (0.5 mL, 0.50 mmol)
in CH2Cl2 at ꢀ78 ꢁC under argon. The mixture was then

Y. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 2326–2331
2331
Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124,
9726–9728; (f) Tanino, K.; Onuki, K.; Asano, K.; Miyashita,
M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am.
Chem. Soc. 2003, 125, 1498–1500; (g) Goldmann, A.; Milat,
M. L.; Ducrot, P. H.; Lallemand, J. Y.; Maille, M.; Lepingle,
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2127; (h) Murali Krishna, U.; Trivedi, G. K. Tetrahedron
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stirred and warmed to 0 ꢁC over 2 h, quenched with
MeOH, and concentrated. The residue was purified on a
silica gel column (CH2Cl2/MeOH, 30:1) to afford 10 as a
20
white solid (7 mg, 71%). ½aꢁD ¼ ꢀ16:7 (c 0.10, MeOH),
1H NMR (500 MHz, DMSO-d6): d 5.14 (d, J = 4.5 Hz,
1H, C2–OH), 5.06 (d, J = 6.0 Hz, 1H, C3–OH), 4.89
(t, J3,8a = 2.5 Hz, 1H, H-8a), 4.92 (t, J3,8b = 2.5 Hz, 1H,
H-8b), 4.52 (d, J = 7.0 Hz, 1H, H-5), 4.08 (dd, J1,2
=
2. Overman, L. E.; Velthuisen, E. J. Org. Lett. 2004, 6,
3853–3856.
3. Molander, G. A.; Czako’, B.; Jean, D. J. St. J. Org. Chem.
2006, 71, 1172–1180.
4. Hodgson, D. M.; Avery, T. D.; Donohue, A. C. Org. Lett.
2002, 4, 1809–1811.
5. Nguyen, G.; Perlmutter, P.; Rose, M. L.; Vounatsos, F. Org.
Lett. 2004, 6, 893–895.
4.5 Hz, J1,7a = 7.5 Hz, 1H, H-1), 3.81–3.77 (m,
J2,3 = 8.5 Hz, J3,8 = 2.5 Hz, 1H, H-3), 3.30–3.26 (m,
J1,2 = 4.5 Hz, J2,3 = 8.5 Hz, 1H, H-2), 2.00–1.94 (m, 1H,
H-7a), 1.88–1.83 (m, 1H, H-6b), 1.70–1.63 (m, 1H,
H-7b), 1.58–1.53 (m, 1H, H-6a). 13C NMR (125 MHz,
DMSO-d6): d 150.0 (C-4), 105.9 (C-8), 79.0 (C-5), 77.3
(C-1), 75.8 (C-2), 70.5 (C-3), 28.8 (C-6), 23.5 (C-7). MS
(ESI-TOF, positive, m/z): 174 [M+NH4]+, 179 [M+Na]+.
HRFAB-MS (m/z): calcd for C8H12O3H [M+H]+,
157.0859; found, 157.0852.
6. Ohmori, N. J. Chem. Soc., Perkin Trans. 1 2002, 755–767.
7. Fawcett, J.; Grifith, G. A.; Percy, J. M.; Uneyama, E. Org.
Lett. 2004, 6, 1277–1280.
´
8. (a) Angle, M. M.; Francisca, G.; Consuelo, B. Lett. Org.
Chem. 2005, 2, 475–479; (b) Harwata, M.; Ghosh, S. K.;
Hong, X.-C.; Wacharasindhu, S.; Kirchhoefer, P. J. Am.
Chem. Soc. 2003, 125, 2058–2059; (c) Molander, G. A.; Jean,
D. J. St.; Haas, J. J. Am. Chem. Soc. 2004, 126, 1642–1643.
9. Jean, D. J. St.; Cheng, E. P.; Bercot, E. A. Tetrahedron Lett.
2006, 47, 6225–6227.
10. (a) Marco-Contelles, J.; de Opazo, E. J. Org. Chem. 2002, 67,
3705–3717; (b) Marco-Contelles, J.; de Opazo, E. Tetra-
hedron Lett. 2000, 41, 2439–2441; (c) Hanna, I.; Ricard, L.
Org. Lett. 2000, 2, 2651–2654; (d) Marco-Contelles, J.; de
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O.; Dure’ault, A.; Depezay, J. C. Tetrahedron Lett. 1992, 33,
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4.8. (1S,2S,3S,4R,5S)-2,3-Dibenzyloxy-1-benzyloxymethyl-
4-iodo-8-oxa-bicyclo[3.2.1]octane 13
To compound 12a21 (339 mg, 0.763 mmol) dissolved in
CH2Cl2 (10 mL) was added NIS (189 mg, 0.839 mmol) in
CH2Cl2 at 0 ꢁC under argon. The mixture was stirred over-
night and warmed to rt and concentrated. The residue was
purified on a silica gel column (petroleum ether/EtOAc,
20
50:1) to give 13 as a white solid (378 mg, 87%). ½aꢁD
¼
1
ꢀ38:8 (c 0.37, CH2Cl2), H NMR (500 MHz, CDCl3): d
7.37–7.23 (m, 15H, H-arom.), 4.67 (t, J4,5 = 1.0 Hz,
J3,4 = 5.0 Hz, 1H, H-4), 4.49, 4.39 (dd, J = 12.0 Hz, 2H,
CH2Ph), 4.45, 4.36 (dd, J = 12.0 Hz, 2H, CH2Ph), 4.43
(m, 3H, CH2Ph and H-5), 3.74 (d, J = 8.5 Hz, 1H, H-8a),
3.57 (d, J2,3 = 1.5 Hz, 1H, H-2), 3.49 (dt, J2,3 = 1.5 Hz,
J3,4 = 5.0 Hz, 1H, H-3), 3.32 (d, J = 8.5 Hz, 1H, H-8b),
2.55–2.50 (m, 1H, H-6a), 2.29–2.24 (m, 1H, H-7a), 1.89–
1.79 (m, 2H, H-6b and H-7b). 13C NMR (125 MHz,
CDCl3): d 138.0, 137.7, 137.5 (3 · Cipso), 128.5–127.6 (aro-
matic C), 82.9 (C-1), 80.1 (C-5), 77.5 (C-3), 77.0 (C-2), 73.5,
73.2, 72.8 (3 · CH2Ph), 72.3 (C-8), 33.5 (C-4), 29.4 (C-7),
25.4 (C-6). MS (ESI-TOF, positive, m/z): 571 [M+H]+,
588 [M+NH4]+, 593 [M+Na]+. Anal. Calcd for
C29H31IO4: C, 61.06; H, 5.48. Found: C, 60.96; H, 5.56.
11. van der Klein, P. A. M.; de Nooy, A. E. J.; van der Marel, G.
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Acknowledgments
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This study was supported by the National Natural Sciences
Foundation of China (Grant No. 20332010) and the Min-
istry of Science and Technology of China (Grant No.
2005BA711A04).
19. (a) Jia, C.; Zhang, Y. M.; Zhang, L. H. Tetrahedron:
Asymmetry 2003, 14, 2195–2199; (b) Sisu, E.; Sollogoub,
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