Intramolecular aldol cyclization of C-4-ulopyranosyl-2′-oxoalkanes controlled by steric effects. Asymmetric synthesis of substituted 8-oxabicyclo[3.2.1]octanones and -octenones and cyclopentenones

Article abstract of DOI:10.1016/j.carres.2004.08.008

Whereas C-2- and 4-ulopyranosyl compounds (C-2- and C-4-ulosides) can be converted to cyclopentenones under base conditions through β-elimination and ring contraction, base-initiated β-elimination of C-glycosyl 2′-aldehydes and 2′-ketones results in the f

Full text of DOI:10.1016/j.carres.2004.08.008

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 2475–2485
Intramolecular aldol cyclization of
C-4-ulopyranosyl-20-oxoalkanes controlled by steric effects.
Asymmetric synthesis of substituted 8-oxabicyclo[3.2.1]octanones
and -octenones and cyclopentenones
Wei Zou,a,* Huawu Shaoa and Shih-Hsiung Wub
aInstitute for Biological Sciences, National Research Council of Canada, Ottawa, ON, Canada K1A 0R6
bInstitute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan
Received 26 May 2004; accepted 13 August 2004
Available online 21 September 2004
Abstract—Whereas C-2- and 4-ulopyranosyl compounds (C-2- and C-4-ulosides) can be converted to cyclopentenones under base
conditions through b-elimination and ring contraction, base-initiated b-elimination of C-glycosyl 20-aldehydes and 20-ketones results
in the formation of acyclic a,b-unsaturated aldehydes or ketones. By combining both molecular features we synthesized 1-C-(4-
ulopyranosyl)-2-oxoalkanes 6, 13, and 20 and investigated their reactions when they were treated with base. Both a- and b-anomers
of C-(4-ulopyranosyl)acetaldehydes 6 and 13 underwent a fast intramolecular aldol reaction between the C-5 enolate and 20-alde-
hyde to form optically pure 8-oxabicyclo[3.2.1]octanones, which further transformed to 8-oxabicyclo[3.2.1]octenones 14 and 15 by
b-elimination. However, this aldol reaction did not occur when 1-C-(4-ulopyranosyl)propan-2-one 20 was treated with base because
of steric hindrance exerted by the additional methyl group. Instead, an alternate C-3 enolization led to b-elimination and further
electro-ring opening to form an acyclic enol, which was then converted through a disrotatory intramolecular aldol cyclization to
a cis-substituted cyclopentenone 21.
Crown Copyright ꢀ 2004 Published by Elsevier Ltd. All rights reserved.
Keywords: Aldol reaction; b-Elimination; Cyclization; Asymmetric synthesis; Oxabicycles; Cyclopentenones
1. Introduction
methods. Herein, we describe a enantioselective synthe-
sis of 8-oxabicyclo[3.2.1]octanones and -octenones from
C-(4-ulopyranosyl)acetaldehydes by an intramolecular
aldol cyclization between a C-5 enolate and the 20-alde-
hydo group. Because of steric hindrance, the above aldol
reaction was not possible in the case of 1-C-(4-ulopyrano-
syl)propan-2-one. Instead, an alternate C-3 enolization
led to 2,3-b-elimination and further electro-ring open-
ing to an enol derivative. An intramolecular aldol cyc-
lization between C-1 and C-5 carbonyl then followed
to provide racemic cis-substituted cyclopentenone
derivatives.
Carbohydrates have long been considered versatile start-
ing materials for natural product syntheses because of
their inherent chirality and unique chemistry associated
with their rigid conformations.1 As synthetically useful
intermediates to natural products2 and herbicides,3 8-
oxabicyclo[3.2.1] derivatives have been mainly prepared
employing various [5+2] cycloadditions4 and [3+4] allyl
cation–furan cycloadditions.5 Considering some of the
natural products that can be derived from oxabicycles
are functionalized with various substituents,6 a carbohy-
drate approach to oxabicycles is an attractive and
probably advantageous alternative over the existing
2. Results and discussion
It is known that C-2- and C-4-ulosides can be con-
verted by base treatment to cyclopentenones through a
*
Corresponding author. Tel.: +1 613 991 0855; fax: +1 613 952 9092;
e-mail: wei.zou@nrc-cnrc.gc.ca
0008-6215/$ - see front matter Crown Copyright ꢀ 2004 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.08.008

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W. Zou et al. / Carbohydrate Research 339 (2004) 2475–2485
ring-contraction rearrangement,7 and also that 20-oxo-
alkyl C-glycosides can be converted to an acyclic a,b-
unsaturated aldehyde (ketone) under basic conditions
through C-10 enolization and b-elimination.8 However,
it is not known what would occur when 1-C-(4-ulo-
pyranosyl)-20-oxoalkyl compounds [C-(20-oxoalkyl)-4-
ulosides], which combine both of the above structural
features, are treated with base. Three reactions are pos-
sible upon base treatment of 1-C-(4-ulopyranosyl)-20-
oxoalkyl compounds: (1) formation of a C-3 enolate
leading to b-elimination and further rearrangement to
cis-substituted cyclopentenones7 without the involve-
ment of the 20-carbonyl group; (2) formation of C-10
and C-3 enolates resulting in double b-eliminations to
yield acyclic 1,6-dioxo-2,4-dienes, which by an aldol cyc-
lization could be converted to trans-substituted cyclo-
pentenones;9 and (3) deprotonation at C-3 or C-5,
followed by an intramolecular aldol reaction to the 20-
carbonyl group to give oxabicycles. Thus we synthesized
the a- and b-anomers of 1-C-(4-ulopyranosyl)acetalde-
hyde compounds 6 and 13, as well as the 1-C-(4-ulo-
pyranosyl)propan-2-one 20 to investigate reaction
selectivities and mechanisms.
Ph
O
OAc
O
1. 0.1% NaOMe
O
AcO
AcO
2. PhCH(OMe)2/H+
O
HO
OH
2 (74%)
OAc
1
BnBr/NaH
Ph
OBn
O
O
HO
O
NaCNBH3/H+
O
BnO
BnO
OBn
OBn
4 (88%)
3 (71%)
PCC
OBn
OBn
1. O3
2. Me2S
O
O
O
O
BnO
O
BnO
OBn
6 (70%)
OBn
5 (90%)
Scheme 1.
2.1. Synthesis of C-(2,3,6-tri-O-benzyl-a-D-xylo-hex-4-
ulopyranosyl)acetaldehyde (6)
side through an anomeric epimerization.8 The acetoxy
derivative 8 was then isolated in good yield after NaBH4
reduction and acetylation as shown in Scheme 2. Regio-
selective ring opening of the 4,6-O-benzylidene ring sys-
tem of 8 afforded 4-OH C-glycoside 9 in moderate yield.
Since both 8 and 9 have the same Rf on TLC in various
solvent systems, we had difficulty monitoring the reac-
tion progress. Therefore, aliquots of the reaction mix-
C-Allyl a-glycoside 1 was used as starting material as
shown in Scheme 1. The synthesis of compound 4 from
1 followed previously described procedures,8c which
included (1) removal of the Ac groups by treatment of
1
with 0.1% NaOMe; (2) benzylidenation using
PhCH(OMe)2 in MeCN to afford 2; and (3) benzylation
with BnBr–NaH in DMF to give 3-C-(2,3-di-O-benzyl-
1
4,6-O-benzylidene-a-D-galactopyranosyl)propene
(3).
ture were analyzed by H NMR spectroscopy to verify
Both 2 and 3 were obtained in good yields by crystalli-
zation without column chromatography. Regioselective
reductive-ring opening of the 4,6-O-benzylidene ring
system of 3 with NaCNBH3–HCl10 produced 4 with a
free 4-OH group. After oxidation of the 4-OH using
PCC in CH2Cl2, C-allyl-4-uloside 5 was isolated in
excellent yield. Finally, 6 was obtained from 5 by ozon-
olysis and subsequent treatment with Me2S (see Scheme
1).
the completion of the reaction by monitoring the disap-
pearance of the benzylidene proton resonance at d
5.49ppm. Oxidation of the 20,4-diols, obtained from 9
by O-deacetylation using PCC gave the 20-carboxylic
acid 10 as a major product and the desired 20-aldehyde
13 as a minor product. DMSO–Ac2O11 was therefore
used to oxidize both hydroxy groups to afford the C-
(4-ulo-b-D-pyranosyl)acetaldehyde 13 in 71% yield. We
also attempted an alternative approach for the synthesis
of 13 in order to circumvent the ambiguity encountered
in the reductive-ring opening of 8 to 9. Thus, C-allyl gly-
coside 4, which already had a free 4-OH, was first con-
verted by ozonolysis to the 20-aldehyde 11, which in
turn was epimerized with 4% NaOMe to its b-anomer
12. Unlike compound 8, 20-aldehyde 12 was isolated
without reduction and acetylation, and its 4-OH group
was subsequently oxidized with DMSO–Ac2O to give
13 in 80% yield. Apparently, the latter approach is more
practical because of fewer steps involved and higher
overall yield.
2.2. Synthesis of C-(2,3,6-tri-O-benzyl-b-D-xylo-hex-4-
ulopyranosyl)acetaldehyde (13)
C-Allyl a-glycoside 3 was converted to the ozonide by
bubbling O3 into a solution of 3 in CH2Cl2. When this
ozonide intermediate was treated with Me2S overnight,
20-oxoethyl compound 7 crystallized from the reaction
mixture and was obtained in over 90% yield. Treatment
of 7 with base (4% NaOMe or 1% K2CO3) effectively
converted 7 to the more stable C-(20-oxoethyl) b-glyco-

W. Zou et al. / Carbohydrate Research 339 (2004) 2475–2485
2477
3
4
O
OBn
R2
NaOMe or
K2CO3/MeOH
1
BnO
1. O3
2. Me2S
2
O8
1. O3
2. Me2S
3
4
6
7
O
R1
Ph
6
OBn
5
O
r/s > 8:1
HO
O
O
14-r R1 = H, R2 = OH (71%)
14-s R1 = OH, R2 = H
BnO
O
BnO
O
OBn
7 (92%)
OBn
11 (82%)
O
OBn
R1
1. NaOMe
2. NaBH3
3. Ac2O/Py
NaOMe or
K2CO3/MeOH
1
BnO
2
O8
NaOMe
3
4
13
7
Ph
O
R2
OBn
6
5
O
HO
O
s/r > 8:1
O
15-s R1 = H, R2 = OH (78%)
15-r R1 = OH, R2 = H
BnO
OAc
8 (76%)
BnO
O
OBn
OBn
12 (68%)
Scheme 3.
NaCNBH3/H+
Ac2O/DMSO
OBn
OBn
50% of the protons at C-6 (dH 1.80 and 2.59ppm), the
remainder having been replaced by deuterium (see
Scheme 4). Although the pKa values for the uloside ring
protons are not available, the pKa of the a-proton in
cyclohexanone has a pKa ꢀ 10–12.12 Thus the signifi-
cantly high acidity of H-3 and H-5 in comparison to
the protons at C-10 of the 20-aldehydo compound 6
(pKa ꢀ 16)13 overwhelmingly favors the C-5 enolization
leading to subsequent aldolization to the 20-aldehydo
group. b-Elimination of the C-10 enolate to an acyclic
conjugated aldehyde was negligible.
1. 0.1%NaOMe
2. Ac2O/DMSO
HO
O
O
O
BnO
BnO
OAc
9 (50%)
O
13 (70-80%)
OBn
OBn
1. 0.1%NaOMe
2. PCC
OBn
O
O
O
As expected, when the b-anomer of the C-(4-ulo-
pyranosyl)acetaldehyde 13 was subjected to the same
basic conditions, we obtained oxabicycles 15-r and 15-
s in comparable yield and stereoselectivity (ds > 8:1)
(see Scheme 3). Similarly, only pure 15-s was obtained
BnO
OH
OBn
10
Scheme 2.
1
by chromatography. The H and 13C NMR spectra of
2.3. Intramolecular aldol cyclization to oxabicycles
15-s are identical to those of 14-r, and the optical rota-
tion analysis provided further evidence that they are
enantiomers. The positive optical rotation of 15-s ([a]D
+102, c 0.7) observed in chloroform is of the same mag-
nitude but of opposite sign to that of 14-r ([a]D ꢁ102, c
0.2) suggesting that both 14 and 15 are optically pure.
The results confirm that the limited C-10 enolization in
With both a- and b-anomers of the C-(4-ulopyranos-
yl)acetaldehydes in hand, we first treated the a-anomer
6 with base (4% NaOMe or 1% K2CO3 in MeOH),
and after 2days at room temperature, 6 was completely
converted to a new spot with lower Rf on TLC (1:1
EtOAc–hexanes). After purification by silica gel chro-
matography, we obtained a mixture of two diasteromers
(14-r and 14-s) in 70–80% yield in a ratio of >8:1 based
on 1H NMR analysis (see Scheme 3). An attempt to sep-
arate the two diastereomers by chromatography resulted
only in the isolation of pure 14-r and a mixture of 14-r/
14-s. Both the diastereoselectivity of the reaction and the
chemical yield were reproducible using different bases.
In addition, when the reaction was performed under
1% K2CO3–CD3OD conditions, we isolated oxabicyclic
14-r-D. 1H NMR analysis indicated that 14-r-D had
O
O
OBn
OH
BnO
K2CO3/CD3OD
6
D: 50%
H: 50%
H
D(H)
(H)D
14-r-D
Scheme 4.

2478
W. Zou et al. / Carbohydrate Research 339 (2004) 2475–2485
gesting an R-configuration at C-7. This assignment was
OBn
O
O
further supported by the observation of additional
NOEs between H-3 (4.45ppm) and 7-OH (2.01ppm)
and between H-3 (4.45ppm) and H-6a (2.22ppm) in 16
(see Fig. 1). Because the minor diastereoisomers, 14-s
and 15-r, were not obtained in their pure form, their
β-elimination
aldol reaction
14-r
6
BnO
BnO
BnO
HO
16
17
1
1
proton chemical shifts and H–1H and H–13C correla-
tions were therefore assigned based on selective 1D
TOCSY in conjunction with other 2D NMR experi-
ments (COSY, NOESY, and ROESY). The NOEs
observed in 15-r between H-5 (4.99ppm) and H-6b
(2.43ppm) and between H-6a (2.07ppm) and H-7
(4.49ppm) (see Fig. 1) confirmed that its C-7 is in the
R-configuration.
OBn
O
O
β-elimination
aldol reaction
O
Scheme 5.
C-(4-ulopyranosyl)acetaldehyde 6 did not result in b-
elimination and epimerization at the anomeric center.
Thus, this intramolecular aldol cyclization provides
a method for the enantioselective synthesis of 8-
oxabicyclo[3.2.1]octenones.
Oxabicyclo[3.2.1] ring systems such as those of com-
pounds 14, 15, and 16 are useful intermediates. With
the availability of selective bridgehead opening by tran-
sition-metal catalysts15 and other reagents,16 such mole-
cules may be converted to other cyclic and acyclic
compounds with multiple stereocenters.
Having successfully demonstrated C-(4-ulopyranos-
yl)acetaldehydes as versatile intermediates for the enan-
tioselective synthesis of oxabicycles, we next attempted
to extend the same chemistry to the 1-C-(4-ulopyrano-
syl)propane-2-one 20.
The low level of deuterium replacement at C-6 in 14-r-
D suggests a fast intramolecular aldol reaction in 6. In
fact, we were able to isolate oxabicycle 16 when the reac-
tion was worked up before its completion. Based on the
TLC analysis, compound 16 was indeed formed as an
intermediate very quickly from 6 in the presence of base
via an aldol reaction between the C-5 enolate and the
20-aldehydo group, which was then converted slowly
through b-elimination to 14-r (see Scheme 5). It is known
that the H-5 of a pyranoside is the most reactive under
certain conditions,14 and the fact that neither the elimina-
tion product 17 nor its rearrangement product (cyclopen-
tenone) were obtained indicates that a C-5 enolization,
and not a C-3 enolization, dominated. Thus, we were able
to conclude that 17 is unlikely an intermediate to 14 unless
a fast aldol reaction between its C-5 enolate and 20-alde-
hyde occurs immediately following 2,3-b-elimination.
The structure and the stereochemistry of compounds
14-r/14-s, 15-s/15-r, and 16 were unambiguously deter-
mined based on various 2D NMR analyses. Strong
NOEs in 14-r were observed between H-4 (6.17ppm)
and H-6a (1.80ppm), between H-6b (2.59ppm) and H-
7 (4.73ppm), and between H-6b (2.59ppm) and H-5
(4.84ppm), among others as illustrated in Figure 1, sug-
2.4. Synthesis of 1-C-(2,3,6-tri-O-benzyl-a-D-xylo-hex-4-
ulopyranosyl)propan-2-one (20) and its rearrangement
Treatment of the C-glycosyl acetaldehyde 7 with
MeMgBr in a binary solvent (2:1 Et2O–toluene) pro-
vided the 20-alcohol 18 in 81% yield as a mixture of
two diastereoisomers (see Scheme 6). The ratio of the
diastereomers was 2:3 as indicated by the integration of
1
the methyl group, a doublet at d 1.23ppm in the H
NMR spectrum. Although the two diastereoisomers
were separable by column chromatography, their abso-
lute stereochemistries were not determined. Instead, the
mixture was used directly for the reductive-ring opening
of the 4,6-O-benzylidene compound to obtain 19, which
was another mixture of two 20,4-diols obtained in 60%
yield. Further oxidation using PCC provided the 1-C-
BnO
H
H
BnO
O
O
H
O
OH
H
H
H
OBn
H
strong NOE
H
1
8 O
2
1
2
8
7
1
4
5
3
strong NOE
BnO
H
3
5
6
O
4
H
Hb
BnO
2
BnO
H
Ha
5
H
H
7
8O
3
7
HO
Hb
4
HO
6
H
Hb
6
BnO
strong NOE
Ha
Ha
H
H
strong NOE
weak NOE
strong NOE
15-r
16
14-r
Figure 1. Some of NOEs observed in compounds 14-r, 15-r, and 16.

W. Zou et al. / Carbohydrate Research 339 (2004) 2475–2485
2479
Ph
O
OBn
HO
O
O
OH
O
MeMgBr
NaCNBH3/H+
OH
7
BnO
BnO
OBn
OBn
19 (60%)
18 (81%)
PCC
OBn
O
6
OBn
O
NaOMe or
K2CO3/MeOH
1
O
BnO
O
OH
2
5
3
4
BnO
OBn
20 (70%)
O
21 (49-65%)
Scheme 6.
(4-ulopyranosyl)propan-2-one 20 in 70% yield. However,
upon the treatment of 20 with base (4% NaOMe and 1%
K2CO3–MeOH) at room temperature for 2days, the
major product with a lower Rf was cyclopentenone 21
(49–65% yield). No oxabicycle was isolated.
Steric effects are known to be critical to the stereo-
chemistry of intramolecular aldol reactions in a pre-ex-
isting ring system.17 In the aldol cyclization to 14 and
15, the C-5 enolates 22 and 23 derived from 6 and 13,
respectively, adopt twisted chair conformations as
shown in Scheme 7. Coordination between the C-5 eno-
late and the C-20 aldehydo group can then occur, which
in turn directs the stereochemistry of the aldol reaction.
We assume that the C-5 enolization of 20 took place in a
similar way to form 24; however, due to steric hindrance
exerted by the methyl group of the 20-keto group, the
distance and trajectory angle between the C-5 enolate
and the 20-keto group would not allow an aldol reaction
to occur (see Scheme 7). Consequently, the equilibrium
was tipped to the less favorable C-3 enolate 25, followed
by 2,3-b-elimination to 26 and further rearrangement to
cyclopentenone 21. This rearrangement is stereoselec-
tive, and both alkyl substituents on the cyclopentenone
are always in cis-configurations regardless of the ano-
meric configuration of the starting C-ulosides.7
Scheme 7.
OH
O
O
R2
Three possible intermediates for a similar rearrange-
ment of 4-ulosides were proposed by Caddick et al.18
(see Chart 1). These intermediates are (1) an enol deriv-
ative from electro-ring opening, (2) a biradical from a
1,2-Wittig rearrangement, and (3) an epoxide from
nucleophilic ring opening. We have evidence that the
cyclopentenones were formed through an enol interme-
diate similar to 28 (see Scheme 7) initially formed via
27 by a electro-ring opening because (1) a migration of
the allyl double bond occurred when C-allyl-2-ulosides
were treated with base and (2) both a- and b-C-glyco-
sides afforded the same cyclopentenone product.7
O
-
R2
O
O
R2
(3)
OR1
(1)
OR1
(2)
Chart 1. Possible intermediates proposed by Caddick et al.
Although this aldol cyclization is highly stereoselective,
its origin and mechanism were not thoroughly investi-
gated in previous reports.7,18 Now it is clear to us that
the stereoselectivity in the formation of racemic

2480
W. Zou et al. / Carbohydrate Research 339 (2004) 2475–2485
ment at 293K. Chemical shifts are given in ppm down-
R1
field from the signal of internal Me4Si and were assigned
on the basis of 2D 1H COSY and 1H–13C chemical-shift
correlated experiments. Melting points were measured
without calibration. All chemicals were purchased from
Aldrich Chemical Co. and used without further
purification.
R1
O
-O
LUMO
BnO
R2
R2
Disrotatory ring closure
HOMO
3.2. 3-C-(4,6-O-Benzylidene-a-D-galactopyranosyl)pro-
pene (2)
A solution of 1 (15g, 40mmol) in 0.1% NaOMe
(200mL) was kept at room temperature for 4h and
was neutralized by the addition of Dowex-50 (H+).
The filtrate was concentrated to a residue. To a suspen-
sion of the above residue in MeCN (100mL) was added
PhCH(OMe)2 (10mL, 66mmol) and p-TsOH (0.3g).
The mixture was stirred at room temperature overnight.
Crystals were collected by filtration and recrystallized
from EtOAc to give 2 as needles (8.7g, 74%) with mp
170–171ꢁC; [a]D +79.2 (c 0.67, CHCl3); 1H NMR
(CDCl3): d 2.32–2.53 (m, 2H, CH2–CH@CH2), 3.58 (s,
1H, H-5), 3.77 (m, 1H, H-2), 4.04 (d, 1H, H-6a, J
12.4Hz), 4.14 (dd, 1H, H-3, J 6.0, 9.2Hz), 4.23–4.25
(m, 2H, H-4, 6b), 4.30 (m, 1H, H-1), 5.08–5.16 (m,
2H, CH@CH2), 5.54 (s, 1H, CHPh), 5.85 (m, 1H,
CH@CH2), 7.37–7.50 (m, 5H, Ph); 13C NMR (CDCl3):
d 28.8 (C-10), 63.2 (C-5), 69.6 (C-3), 70.0 (C-6), 70.4
(C-2), 75.8 (C-1), 76.0 (C-4), 101.6 (CHPh), 117.0
(CH@CH2), 126.5, 128.4, 129.4, 135.0 (CH@CH2),
137.6; HRFABMS: calcd for C16H21O5 (M+H) m/z
293.1389; found m/z 293.1438.
R1
OH
OH
R1
+
R2
R2
racemic
Figure 2. Orbital correlation for the ring contraction to
cyclopentenones.
cis-substituted cyclopentenones is determined by the
orbital symmetry between the LUMO of the carbonyl
group and the HOMO of the enol as illustrated in Figure
2.19 Thus, the new r-bond can only be formed through a
disrotatory ring closure between the HOMO and
LUMO components of the intermediate 28 to afford
product 21 with two alkyl substitutions on the same
side. It is also expected, based on this analysis, that
the electro-ring closure from 28 to 26 could take place
(also see Scheme 7) through a conrotatory cyclization
between the LUMO and HOMO p-orbitals. This was
supported by the isolation of both anomers of the C-
2-eno-4-uloside after base treatment of the C-4-uloside.7
In summary, we have described two intramolecular al-
dol cyclizations on 1-C-(4-ulopyranosyl)-2-oxoalkanes
with high chemical and stereoselectivities. The C-5 eno-
late of C-(4-ulopyranosyl)acetaldehydes (20-aldehydes)
formed by base treatment attacked the 20-aldehydo
group to afford optically pure 8-oxabicycles, whereas
this aldol reaction was not possible in the case of 1-C-
(4-ulopyranosyl)propan-2-one (the 20-ketones) because
of the steric hindrance of the methyl group. Conse-
quently, the alternative C-3 enolization led to 2,3-b-
elimination, followed by an electro-ring opening to an
enol intermediate. Subsequent intramolecular aldol cyc-
lization between C-1 and C-5 carbonyl group resulted in
the formation of a cis-substituted cyclopentenone.
3.3. 3-C-(2,3-Di-O-benzyl-4,6-O-benzylidene-a-D-galacto-
pyranosyl)propene (3)
To a solution of 2 (5g, 17mmol) in DMF (100mL) was
added 60% NaH (2.0g, 50mmol), and the mixture was
stirred for 30min prior to the addition of BnBr (5mL,
0.042mol). After stirring overnight the mixture was di-
luted by the addition of 1:1 EtOAc–H2O (300mL).
The organic phase was washed twice with water, dried,
and concentrated to a syrup. Crystals were obtained
upon addition of hexanes. Recrystallization from
EtOAc–hexanes gave 3 as needles (5.7g, 71%): mp
1
138ꢁC; [a]D +99.5 (c 0.4, CHCl3); H NMR (CDCl3):
d 2.37 and 2.51 (m and m, 2H, CH2–CH@CH2), 3.44
(s, 1H, H-5), 3.75 (dd, 1H, H-3, J 3.6, 9.2Hz), 3.98 (d,
1H, H-6a, J 12.0Hz), 4.17–4.25 (m, 3H, H-2, 4, 6b),
4.32 (m, 1H, H-1), 4.64 and 4.82 (d and d, 1H each,
CH2Ph, J 11.6Hz), 4.77 (s, 2H, CH2Ph), 5.05 and 5.09
(d and d, 1H each, CH2–CH@CH2, J 10.4, 17.2Hz),
5.49 (s, 1H, CHPh), 5.82 (m, 1H, CH2–CH@CH2),
7.26–7.55 (m, 15H, 3 · Ph); 13C NMR (CDCl3): d 29.7
(C-10), 63.2, 70.2, 71.8, 73.8, 74.8 (2), 75.9, 76.8, 101.4
(CHPh), 116.7 (CH@CH2), 126.6, 127.7, 127.8, 128.3,
3. Experimental section
3.1. General methods
1H and 13C NMR spectra were recorded in CDCl3 at
400 and 100MHz, respectively, with a Varian instru-

W. Zou et al. / Carbohydrate Research 339 (2004) 2475–2485
2481
128.5, 129.0, 135.3 (CH@CH2), 138.0, 138.8, 138.9;
HRFABMS: calcd for C30H33O5 (M+H) m/z 473.2328;
found m/z 473.2599.
HRFABMS: calcd for C30H33O5 (M+H) m/z 473.2328;
found m/z 473.2236.
3.6. C-(2,3,6-Tri-O-benzyl-a-D-xylo-hex-4-ulopyranos-
yl)acetaldehyde (6)
3.4. 3-C-(2,3,6-Tri-O-benzyl-a-D-galactopyranosyl)pro-
pene (4)
To a solution of 5 (100mg, 0.212mmol) in CH2Cl2
(15mL) was bubbled with O3 at ꢁ72ꢁC until the starting
material was disappeared (30min). The solution was
concentrated, and the residue was treated with Me2S
(1mL) overnight at room temperature. After evapora-
tion of the solvent under vacuum, the residue was sub-
jected to column chromatography (1:2 EtOAc–hexane)
to afford product 6 as crystals (70mg, 70%). Recrystalli-
zation from EtOAc–hexane gave mp 97–98ꢁC (needles);
[a]D +49.3 (c 0.6, CHCl3); 1H NMR (CDCl3): d 2.71 (dd,
1H, CH2–CH@O, J 6.0, 17.2Hz), 2.77 (ddd, 1H,
CH2–CH@O, J 2.0, 7.0, 17.2Hz), 3.79 (dd, 1H, H-6a,
J 4.0, 10.8Hz), 3.86–3.91 (m, 2H, H-2, 6b), 4.24
(d, 1H, H-3, J 5.6Hz), 4.34 (dd, 1H, H-5, J 4.0,
5.6Hz), 4.43 and 4.68 (d and d, 1H each, CH2Ph,
J 12.0Hz), 4.49 and 4.81 (d and d, 1H each, CH2Ph,
J 11.6Hz), 4.54 (s, 2H, CH2Ph), 4.72 (m, 1H, H-1),
7.22–7.36 (m, 15H, 3 · Ph), 9.72 (s, 1H, CHO);13C
NMR (CDCl3): d 43.9 (C-10), 68.6, 70.2, 73.4, 73.5,
73.8, 80.0, 80.3, 82.2, 128.0, 128.4, 128.8, 137.5, 137.9,
138.2, 200.1 (C@O), 205.1 (C-4); HRFABMS: calcd
for C29H31O6 (M+H) m/z 475.2121; found m/z
475.2345.
˚
To a mixture of 3 (2.5g, 5.3mmol), 3A molecular sieves
(3g), NaCNBH3 (2.5g, 39.7mmol), and a few crystals of
methyl orange in THF (50mL) was added satd HCl–
Et2O at 0ꢁC until a pink color persisted. After 2h the
reaction mixture was filtered, and the filtrate was
washed subsequently with water, aq NaHCO3 and
water, dried, and concentrated. Purification by chroma-
tography (1:1 EtOAc–hexanes) afforded 4 as a syrup
(2.2g, 88%): [a]D +51.4 (c 1.0, CHCl3); 1H NMR
(CDCl3): d 2.42 (dd, 2H, CH2–CH@CH2, J 6.8,
8.0Hz), 2.63 (d, 1H, 4-OH, J 2.0Hz), 3.63–3.69 (m,
2H, H-3, 6a), 3.75–3.82 (m, 2H, H-5, 6b), 3.97 (dd,
1H, H-2, J 5.6, 8.8Hz), 3.99–4.14 (m, 2H, H-1, 4),
4.54 and 4.57 (d and d, 1H each, CH2Ph, J 12.0Hz),
4.61 and 4.72 (d and d, 1H each, CH2Ph, J 11.6Hz),
4.71 (s, 2H, CH2Ph), 5.04–5.13 (m, 2H, CH2–
CH@CH2), 5.82 (m, 1H, CH2–CH@CH2), 7.25–7.37
13
(m, 15H, 3 · Ph); C NMR (CDCl3): d 30.2 (C-10),
67.8 (C-4), 69.6 (C-6), 69.8 (C-5), 72.5 (CH2Ph), 73.5
(CH2Ph), 73.8 (2) (C-1, CH2Ph), 75.9 (C-2), 78.0 (C-
3), 117.1 (CH@CH2), 127.9, 128.0, 128.6, 128.7, 135.1
(CH@CH2), 138.3 (2), 138.6; HRFABMS: calcd for
C30H35O5 (M+H) m/z 475.2484; found m/z 475.2444.
3.7. C-(2,3-Di-O-benzyl-4,6-O-benzylidene-a-D-galacto-
pyranosyl)acetaldehyde (7)
3.5. 3-C-(2,3,6-Tri-O-benzyl-a-D-xylo-hex-4-ulopyranos-
yl)propene (5)
To a solution of 3 (7g, 14.8mmol) in CH2Cl2 (150mL)
was bubbled with O3 at ꢁ72ꢁC for 1h. The residue ob-
tained after removal of solvent was treated with Me2S
(20mL) overnight at room temperature. The crystals
from the reaction mixture were collected and washed
with hexanes to afford 7 (6.5g, 92%). Recrystallization
from EtOAc gave mp 169–170ꢁC (needles); [a]D +58.5
To a solution of 4 (1.0g, 2.11mmol) in CH2Cl2 (20mL)
˚
was added 4A molecular sieves (2.0g), NaOAc (0.5g),
and PCC (1.0g, 4.64mmol). The mixture was stirred at
room temperature for 3h and filtered through Celite.
The combined filtrate was washed with water, NaHCO3
and water, dried, and concentrated. Purification by
chromatography afforded 5 as crystals (0.9g, 90%).
Recrystallization from EtOAc–hexanes gave mp 97–
1
(c 1.72, CHCl3); H NMR (CDCl3): d 2.61 (ddd, 1H,
CH2–CH@O, J 4.0, 9.6, 16.0Hz), 2.85 (dd, 1H, CH2–
CH@O, J 4.8, 16.0Hz), 3.43 (s, 1H, H-5), 3.68 (dd,
1H, H-3, J 3.2, 10.0Hz), 3.97 (br d, 1H, H-6a, J
12.4Hz), 4.15 (d, 1H, H-6b, J 12.4Hz), 4.22 (d, 1H,
H-4, J 3.2Hz), 4.27 (dd, 1H, H-2, J 6.0, 9.6Hz), 4.64
and 4.85 (d and d, 1H each, CH2Ph, J 11.6Hz), 4.75
(s, 2H, CH2Ph), 4.89 (m, 1H, H-1), 5.48 (s, 1H, CHPh),
7.26–7.53 (m, 15H, 3 · Ph), 9.68 (d, 1H, CHO, J 3.2Hz);
13C NMR (CDCl3): d 41.4 (C-10), 64.1 (C-5), 70.0 (C-6),
71.0 (C-1), 71.8 (CH2Ph), 74.2 (CH2Ph), 74.4 (C-4), 74.9
(C-2), 77.0 (C-3), 101.3 (CHPh), 126.5, 127.9, 128.0,
128.3, 128.6, 129.1, 137.8, 138.4, 200.5 (CHO); HR-
FABMS: calcd for C29H31O6 (M+H) m/z 475.2121;
found m/z 475.2133.
1
98ꢁC (needles); [a]D +69.8 (c 0.53, CHCl3); H NMR
(CDCl3):
d 2.45 (m, 2H, CH2–CH@CH2), 3.81–
3.84 (m, 3H, H-2, 6a, 6b), 4.15–4.20 (m, 2H, H-1, 3),
4.34 (dd, 1H, H-5, J 5.0, 5.0Hz), 4.50 and 4.81 (d and
d, 1H each, CH2Ph, J 12.0Hz), 4.52 and 4.71 (d
and d, 1H each, CH2Ph, J 11.6Hz), 4.55 and 4.56 (d
and d, 1H each, CH2Ph, J 12.0Hz), 5.05–5.13 (m, 2H,
CH@CH2), 5.81 (m, 1H, CH@CH2), 7.22–7.36 (m,
13
15H, 3 · Ph); C NMR (CDCl3): d 33.1 (C-10), 68.6
(C-6), 73.29 (CH2Ph), 73.34 (CH2Ph), 73.6 (CH2Ph),
74.0 (C-1), 78.6 (C-5), 80.6 (C-2), 81.9 (C-3), 117.6
(CH@CH2), 127.8, 128.1, 128.2, 128.3, 128.5, 128.6,
134.4 (CH@CH2), 137.3, 137.8, 138.2, 205.1 (C-4);

2482
W. Zou et al. / Carbohydrate Research 339 (2004) 2475–2485
3.8. 1-Acetoxy-2-(2,3-di-O-benzyl-4,6-O-benzylidene-b-
D-galactopyranosyl)ethane (8)
3.10. 2-C-(2,3,6-Tri-O-benzyl-b-D-xylo-hex-4-ulopyranos-
yl)acetic acid (10)
A solution of 7 (0.3g, 0.633mmol) in 4% NaOMe (5mL)
was stirred at room temperature overnight. NaBH4
(40mg) was added, the solution was evaporated after
0.5h, and the residue was extracted with EtOAc
(3 · 10mL). After evaporation of the solvent under vac-
uum, the residue was acetylated in 1:1 Ac2O–pyridine
(10mL) to obtain crystalline 8 (0.25g, 76%) after chro-
matography (1:1 EtOAc–hexanes). Recrystallization
from EtOAc–hexanes gave mp 114–115ꢁC; [a]D +56.7
A solution of 9 (95mg) in 0.1% NaOMe (5mL) was kept
at room temperature for 2h and neutralized by the addi-
tion of Dowex-50 (H+). The filtrate was concentrated to
a residue. To a solution of above residue in CH2Cl2
(10mL) was added NaOAc (0.2g) and PCC (0.5g).
The mixture was stirred overnight at room temperature
and filtered through Celite. The filtrate was concentrated
to a residue. Purification by chromatography (2:1–10:1
EtOAc–hexanes gradient) afforded 10 as a syrup
(51mg, 57%) and a small amount of 13: [a]D +35.9 (c
1
(c 0.46, CHCl3); H NMR (CDCl3): d 1.88 and 2.26
1
(m and m, 1H each, CH2–CH2O), 2.02 (s, 3H, Ac),
3.29 (s, 1H, H-5), 3.37 (ddd, 1H, H-1, J 2.0, 9.2,
9.2Hz), 3.63 (dd, 1H, H-3, J 3.2, 8.8Hz), 3.72 (dd, 1H,
H-2, J 8.8, 9.6Hz), 3.97 (br d, 1H, H-6a, J 12.4Hz),
4.20 (d, 1H, H-4, J 3.2Hz), 4.21–4.30 (m, 3H, H-6b,
CH2OAc), 4.65 and 4.99 (d and d, 1H each, CH2Ph, J
10.8Hz), 4.72 and 4.77 (d and d, 1H each, CH2Ph, J
12.0Hz), 5.49 (s, 1H, CHPh), 7.26–7.55 (m, 15H,
1.54, CHCl3); H NMR (CDCl3): d 2.50 (dd, 1H each,
CH2–CO2H, J 8.0, 16.0Hz), 2.81 (dd, 1H each,
CH2–CO2H, J 3.2, 16.0Hz), 3.59–3.65 (m, 2H, H-2,
6a), 3.92 (dd, 1H, H-6b, J 3.6, 10.8Hz), 4.06–4.10 (m,
2H, H-1, 5), 4.18 (d, 1H, H-3, J 8.8Hz), 4.52 and
4.61 (d and d, 1H each, CH2Ph, J 12.0Hz), 4.55 and
4.90 (d and d, 1H each, CH2Ph, J 11.2Hz), 4.58
and 4.99 (d and d, 1H each, CH2Ph, J 11.2Hz), 7.23–
7.41 (m, 15H, 3 · Ph); 13C NMR (CDCl3): d 37.4 (C-
10), 67.6, 73.8, 74.1, 75.2, 75.7, 80.7, 82.4, 86.7, 127.9,
128.0, 128.3, 128.4, 128.5, 128.6, 128.7, 137.5, 137.6,
138.0, 175.9 (CO2H), 201.3 (C@O); HRFABMS: calcd
for C29H31O7 (M+H) m/z 491.2070; found m/z 491.2179.
13
3 · Ph); C NMR (CDCl3): d 21.3 (Ac), 31.1 (C-10),
61.5, 69.7, 69.9, 71.3, 74.1, 75.7, 76.0, 78.0, 82.0,
101.4 (CHPh), 126.6, 128.0, 128.3, 128.4, 128.6,
129.1, 138.1, 138.6 (2), 171.4 (C@O); HRFABMS:
calcd for C31H35O7 (M+H) m/z 519.2383; found m/z
519.2439.
3.11. C-(2,3,6-Tri-O-benzyl-a-D-galactopyranosyl)acetal-
dehyde (11)
3.9. 1-Acetoxy-2-(2,3,6-tri-O-benzyl-b-D-galactopyranos-
yl)ethane (9)
To a solution of 4 (1.0g, 2.11mmol) in CH2Cl2 (30mL)
was bubbled with O3 at ꢁ72ꢁC for 1h. The residue ob-
tained after removal of solvent was treated with Me2S
(2mL) overnight at room temperature. The solvent
was evaporated under vacuum, and the residue was sub-
jected to a column chromatography (1:2 EtOAc–hex-
anes) to afford 11 (0.82g, 82%): [a]D +30.7 (c 0.56,
CHCl3); 1H NMR (CDCl3): d 2.62 (d, 1H, 4-OH, J
2.0Hz), 2.63 (ddd, 1H, CH2–CHO, J 2.8, 8.4, 16.0Hz),
2.79 (ddd, 1H, CH2–CHO, J 1.2, 6.0, 16.0Hz), 3.61
(dd, 1H, H-3, J 3.2, 8.4Hz), 3.64 (dd, 1H, H-6a, J 8.0,
12.4Hz), 3.72–3.75 (m, 2H, H-5, 6b), 4.00 (dd, H-2, J
6.0, 8.8Hz), 4.12 (br s, 1H, H-4), 4.53 (s, 2H, CH2Ph),
4.58 (d, 1H, CH2Ph, J 11.6Hz), 4.67–4.73 (m, 4H, H-
1, 1.5 · CH2Ph), 7.25–7.35 (m, 15H, 3 · Ph), 9.68 (dd,
1H, CHO, J 1.6, 1.6Hz); 13C NMR (CDCl3): d 41.7
(C-10), 67.5, 69.4, 69.7, 70.9, 72.5, 73.9, 74.0, 75.1,
78.0, 128.0, 128.2, 128.7, 128.8, 138.0 (3), 200.2
(C@O); HRFABMS: calcd for C29H33O6 (M+H) m/z
477.2277; found m/z 477.2296.
˚
To a solution of 8 (0.2g, 0.386mmol), 3A molecular
sieves (0.5g), NaCNBH3 (0.25g, 3.97mmol), and a
few crystals of methyl orange in THF (10mL) was
added satd HCl–Et2O at 0ꢁC until a pink color per-
sisted. After 2h the reaction mixture was filtered, and
the filtrate was washed subsequently with water, aq
NaHCO3 and water, dried, and concentrated. Purifica-
tion by chromatography (1:1 EtOAc–hexanes) afforded
9 as an amorphous solid (0.1g, 50%): [a]D +2.0 (c 4.9,
1
CHCl3); H NMR (CDCl3): d 1.78 and 2.18 (m and
m, 1H each, CH2–CH2O), 2.01 (s, 3H, Ac), 2.61 (d,
1H, 4-OH, J 1.2Hz), 3.33 (ddd, 1H, H-1, J 2.0, 8.8,
9.2Hz), 3.51–3.57 (m, 3H, H-2, 3, 5), 3.67 (dd, 1H, H-
6a, J 5.6, 10.0Hz), 3.74 (dd, 1H, H-6b, J 6.0, 10.0Hz),
4.13 (br s, 1H, H-4), 4.15–4.30 (m, 2H, CH2OAc),
4.57 (s, 2H, CH2Ph), 4.65 and 4.92 (d and d, 1H each,
CH2Ph, J 10.8Hz), 4.66 and 4.74 (d and d, 1H each,
CH2Ph, J 11.2Hz), 7.28–7.35 (m, 15H, 3 · Ph); 13C
NMR (CDCl3):
d
21.2 (Ac), 31.2 (C-10), 61.3
(CH2OAc), 67.0 (C-4), 69.5 (C-6), 71.7 (CH2Ph), 73.9
(CH2Ph), 75.6 (CH2Ph), 76.2 (C-1), 76.7 (C-5), 78.3
(C-2), 83.2 (C-3), 128.0, 128.1, 128.2, 128.3, 128.6,
128.7, 137.9, 138.0, 138.2, 171.3 (Ac); HRFABMS:
calcd for C31H37O7 (M+H) m/z 521.2539; found m/z
521.2567.
3.12. C-(2,3,6-Tri-O-benzyl-b-D-galactopyranosyl)acetal-
dehyde (12)
A solution of 11 (0.5g) in 4% NaOMe (10mL) was kept
overnight at room temperature, diluted by the addition

W. Zou et al. / Carbohydrate Research 339 (2004) 2475–2485
2483
of EtOAc (50mL), washed with water, dried, and con-
centrated to a residue. Purification by chromatography
(1:2 EtOAc–hexanes) afforded 12 (0.34g, 68%): [a]D
1H, H-6b, J 2.0, 6.8, 12.8Hz), 3.89 and 4.00 (d and d,
1H each, CH2OBn, J 10.8Hz), 4.62 and 4.66 (d and d,
1H each, CH2Ph, J 12.0Hz), 4.73 (dm, 1H, H-7, J
9.6Hz), 4.84 (m, 1H, H-5), 4.87 (s, 2H, CH2Ph), 6.17
(d, 1H, H-4, J 5.2Hz), 7.27–7.36 (m, 10H, 2 · Ph); 13C
NMR (CDCl3): d 39.2 (C-6), 68.4 (C2OBn), 70.1
(CH2Ph), 71.7 (C-7), 73.5 (C-5), 74.2 (CH2Ph), 90.7
(C-1), 120.6 (C-4), 127.5, 127.9, 128.1, 128.2, 128.4,
128.6, 128.7, 135.8, 137.9, 149.9 (C-3), 190.9 (C-2);
HRFABMS: calcd for C22H22O5 (M) m/z 366.1467;
found m/z 366.1563. For 14-s (data extracted from a
1
+2.0 (c 0.26, CHCl3); H NMR (CDCl3): d 2.56 (br s,
1H, 4-OH), 2.60 (br dd, 1H, CH2–CHO, J 7.2,
16.0Hz), 2.73 (br d, 1H, CH2–CHO, J 16.0Hz), 3.53–
3.80 (m, 6H, H-1, 2, 3, 5, 6a, 6b), 4.15 (br s, 1H, H-4),
4.56 (s, 2H, CH2Ph), 4.58 and 4.91 (d and d, 1H each,
CH2Ph, J 10.4Hz), 4.67 and 4.75 (d and d, 1H each,
CH2Ph, J 11.6Hz), 7.25–7.35 (m, 15H, 3 · Ph), 9.70 (s,
13
1H, CHO); C NMR (CDCl3): d 46.5 (C-10), 67.1,
1
69.5, 71.8, 73.9, 74.7, 75.4, 77.1, 77.6, 83.2, 128.0,
128.1, 128.2, 128.3, 128.5, 128.7, 128.9, 137.7, 138.0
(2), 200.4 (C@O); HRFABMS: calcd for C29H33O6
(M+H) m/z 477.2277; found m/z 477.2366.
mixture of 14-r/14-s): H NMR (CDCl3): d 2.07 (ddd,
1H, H-6a, J 2.8, 7.6, 12.8Hz), 2.43 (dd, 1H, H-6b, J
7.6, 12.8Hz), 3.31 (d, 1H, 7-OH, J 6.8Hz), 4.00 and
4.14 (d and d, 1H each, CH2OBn, J 10.8Hz), 4.49 (m,
1H, H-7), 4.99 (m, 1H, H-5), 6.06 (d, 1H, H-4, J 5.2Hz).
3.13. C-(2,3,6-Tri-O-benzyl-b-D-xylo-hex-4-ulopyranos-
yl)acetaldehyde (13)
3.15. 3-Benzyloxy-1-benzyloxymethyl-7-hydroxy-
(1r,5s,7s)-8-oxabicyclo[3.2.1]-3-octen-2-one (15-s)
A solution of 12 (0.1g) in 2:1 Me2SO–Ac2O (2mL) was
kept overnight at room temperature. The solution was
diluted by the addition of EtOAc (30mL) and washed
subsequently with water, aq NaHCO3, and water dried,
and concentrated. Purification by chromatography (1:2
EtOAc–hexanes) afforded 13 as a syrup (80mg, 80%):
A solution of 13 (20mg) in 4% MeOH (2mL) or 1%
K2CO3–MeOH (2mL) were kept at room temperature
for 2days, at the end of which time TLC indicated com-
pletion of the reaction. The same workup as that for
compound 14 afforded 15-s/15-r as a syrup (>8:1,
12.0mg, 78%), [a]D +67 (c 0.2, CHCl3); for pure 15-s:
1
[a]D +25.2 (c 1.0, CHCl3); H NMR (CDCl3): d 2.60
1
(ddd, 1H, CH2–CH@O, J 2.4, 8.0, and 16.8Hz), 2.77
(ddd, 1H, CH2–CH@O, J 2.0, 4.4, and 16.8Hz), 3.57–
3.65 (m, 2H, H-2, 6a), 3.92 (dd, 1H, H-6b, J 4.0 and
10.8Hz), 4.08 (dd, 1H, H-5, J 4.0, 5.6Hz), 4.17
(m, 1H, H-1), 4.19 (d, 1H, H-3, J 8.4Hz), 4.52 and
4.58 (d and d, 1H each, CH2Ph, J 12.0Hz), 4.58
and 4.88 (d and d, 1H each, CH2Ph, J 12.0Hz),
4.58 and 4.99 (d and d, 1H each, CH2Ph, J 12.0Hz),
7.22–7.36 (m, 15H, 3 · Ph), 9.71 (dd, 1H, CHO, J 2.0,
2.0Hz);13C NMR (CDCl3): d 46.2 (C-10), 67.7, 73.9,
74.1, 74.4, 75.2, 80.6, 82.7, 86.7, 128.1, 128.3, 128.4,
128.5, 128.6, 128.8, 137.4, 138.0 (2), 199.4, 200.2; HRF-
ABMS: calcd for C29H31O6 (M+H) m/z 475.2121; found
m/z 475.2592.
[a]D +102 (c 0.7, CHCl3); H and 13C NMR spectra of
15-s were identical to those of compound 14-r.
3.16. 3-Benzyloxy-1-benzyloxymethyl-7-hydroxy-
(1s,3r,4s,5r,7r)-8-oxabicyclo[3.2.1]-octan-2-one (16)
A syrup with [a]D +30.0 (c 0.2, CHCl3); 1H NMR
(CDCl3): d 2.01 (d, 1H, 7-OH, J 2.1Hz), 2.22 (dd, 1H,
H-6a, J 3.6, 14.0Hz), 2.49 (m, 1H, H-6b), 3.52 and
4.01 (d and d, 1H each, CH2OBn, J 10.0Hz), 3.96 (dd,
1H, H-4, J 3.2, 8.8Hz), 4.38 (m, 1H, H-5), 4.45 (d,
1H, H-3, J 8.8Hz), 4.58–4.59 (m, 5H, H-7, 2 · CH2Ph),
4.78 (d, 1H, CH2Ph, J 11.6Hz), 5.04 (d, 1H, CH2Ph, J
11.6Hz), 7.29–7.44 (m, 15H, 3 · Ph); 13C NMR
(CDCl3): d 32.9 (C-6), 68.3 (C2OBn), 73.4, 74.3 (C-7),
74.4, 74.6, 76.3 (C-5), 83.5 (C-4), 84.7 (C-3), 86.6 (C-
1), 127.9, 128.0, 128.1, 128.4, 128.6, 128.8, 137.9,
138.4, 201.3 (C-2); HRFABMS: calcd for C29H29O6
(MꢁH) m/z 473.1964; found m/z 473.2393.
3.14. 3-Benzyloxy-1-benzyloxymethyl-7-hydroxy-
(1s,5r,7r)-8-oxabicyclo[3.2.1]-3-octen-2-one (14-r)
A solution of 6 (20mg, 0.042mmol) in 1% K2CO3–
MeOH (1mL) was kept at room temperature for 2days,
at the end of which time the starting material had disap-
peared as determined by TLC, and a major polar prod-
uct was indicated. The solution was diluted by the
addition of EtOAc (15mL), washed with water, dried,
and concentrated to a residue. Purification by chroma-
tography (1:2–1:1 EtOAc–hexanes gradient) afforded a
mixture of 14-r and 14-s as a syrup (>8:1, 11mg, 71%)
with [a]D ꢁ61 (c 0.6, CHCl3); for pure 14-r: [a]D ꢁ102
3.17. 1-C-(2,3-Di-O-benzyl-4,6-O-benzylidene-a-D-
galactopyranosyl)-2-propanol (18)
To a solution of 7 (0.6g, 1.27mmol) in Et2O (20mL) and
toluene (10mL) was added 3M MeMgBr in Et2O
(3.0mL, 9mmol) at ꢁ72ꢁC. The mixture was stirred
for 5h at room temperature and diluted by the addition
of 1:1 0.1M HCl–EtOAc (100mL). The organic phase
was washed with brine, dried, and concentrated to give
crystals. Recrystallization with EtOAc–hexanes gave
1
(c 0.2, CHCl3); H NMR (CDCl3): d 1.80 (dd, 1H, H-
6a, J 1.6, 12.8Hz), 1.85 (br s, 1H, 7-OH), 2.59 (ddd,

2484
W. Zou et al. / Carbohydrate Research 339 (2004) 2475–2485
18 (0.5g, 81%) as a mixture of two diastereoisomers in a
ratio of 3:2, which were separated by column chroma-
tography (1:1 EtOAc–hexanes). The major diastereo-
isomer with high Rf gave mp 131ꢁC; [a]D +86.5 (c
CH2C@O, J 7.2, 16.8Hz), 3.81 (dd, 1H, H-6a, J 4.0,
11.2Hz), 3.84 (dd, 1H, H-6b, J 6.0, 11.2Hz), 3.91 (dd,
1H, H-2, J 4.4, 5.6Hz), 4.24 (d, 1H, H-3, J 5.6Hz), 4.34
(dd, 1H, H-5, J 4.0, 6.0Hz), 4.39 and 4.68 (d and d, 1H
each, CH2Ph, J 11.6Hz), 4.48 and 4.81 (d and d, 1H each,
CH2Ph, J 11.6Hz), 4.52 and 4.56 (d and d, 1H each,
CH2Ph, J 11.6Hz), 4.63 (m, 1H, H-1), 7.26–7.37 (m,
15H, 3 · Ph); 13C NMR (CDCl3): d 30.8 (Me), 43.5 (C-
10), 68.4, 70.8, 73.2, 73.6, 73.7, 80.1, 80.4, 82.3, 128.0,
128.2, 128.3, 128.4, 128.6, 128.7, 137.3, 137.7, 138.0,
205.7 (C@O), 206.3 (C@O); HRFABMS: calcd for
C30H32O6 (M+H) m/z 488.2199; found m/z 488.2145.
1
0.43, CHCl3); H NMR (CDCl3): d 1.23 (d, 3H, CH-3,
J 6.4Hz), 1.82 (m, 2H, 10-CH2), 2.38 (d, 1H, 20-OH, J
4.8Hz), 3.47 (s, 1H, H-5), 3.74 (dd, 1H, H-3, J 3.2,
9.6Hz), 3.96 (m, 1H, 20-CH), 4.01 and 4.19 (d and d,
1H each, H-6a, 6b, J 12.0Hz), 4.22 (d, 1H, H-4, J
3.2Hz), 4.26 (dd, 1H, H-2, J 6.0, 10.0Hz), 4.51 (dt,
1H, H-1, J 6.4, 7.6Hz), 4.67 and 4.84 (d and d, 1H each,
CH2Ph, J 11.6Hz), 4.75 and 4.79 (d and d, 1H each,
CH2Ph, J 12.4Hz), 5.49 (s, 1H, CHPh), 7.26–7.55 (m,
15H, 3 · Ph);13C NMR (CDCl3): d 23.8 (Me), 34.7 (C-
10), 63.9 (C-5), 65.5 (C-20), 70.2 (C-6), 71.9 (CH2Ph),
72.8 (C-1), 74.2 (CH2Ph), 74.7 (C-4), 75.4 (C-2), 77.0
(C-3), 101.4 (CHPh), 126.5, 127.8, 127.9, 128.1, 128.3,
128.6, 129.1, 137.9, 138.7; HRFABMS: calcd for
C30H35O6 (M+H) m/z 491.2434; found m/z 491.2515.
3.20. 2-Benzyloxy-5-benzyloxymethyl-5-hydroxy-4-(2-
oxopropyl)-4,5-cis-cyclopent-2-enone (21)
A solution of 20 (60mg, 0.164mmol) in 4% NaOMe
(5mL) was stirred at room temperature for 2days. The
solution was diluted by the addition of EtOAc (30mL),
and washed with water, dried, and concentrated to a res-
idue. Purification by chromatography (1:1 EtOAc–hexa-
nes) afforded 21 as a syrup (31mg, 65%);1H NMR
(CDCl3): d 2.06 (s, 3H, COCH-3), 2.63 (dd, 1H,
CH2C@O, J 6.8, 18.0Hz), 2.96 (dd, 1H, CH2C@O, J
8.0, 18.0Hz), 3.21 (m, 1H, H-4), 3.36 (s, 1H, 5-OH),
3.40 (d, 1H, H-6a, J 9.6Hz), 3.51 (d, 1H, H-6b, J
9.6Hz), 4.42 and 4.46 (d and d, 1H each, 6-CH2Ph,
J 12.0Hz), 4.96 (s, 2H, 2-CH2Ph), 6.21 (d, 1H, H-3, J
2.4Hz), 7.26–7.37 (m, 10H, 2 · Ph); 13C NMR (CDCl3):
d 30.0 (O@CCH-3), 42.0 (C-4), 43.5 (CH2C@O), 71.7 (2-
CH2Ph), 72.6 (C-6), 74.1 (6-CH2Ph), 77.9 (C-5), 127.2,
127.7, 127.9, 128.0, 128.1, 128.2, 128.5, 128.7, 128.8,
129.3 (C-3), 135.6, 137.4, 154.6 (C-2), 201.0 (C-1),
208.5 (O@CCH-3); HRFABMS: calcd for C23H25O5
(M+H) m/z 381.1702; found m/z 381.1729.
3.18. 1-C-(2,3,6-Tri-O-benzyl-a-D-galactopyranosyl)-2-
propanol (19)
˚
To a solution of 18 (0.5g, 1.02mmol), 3A molecular
sieves (1.5g), NaCNBH3 (0.7g, 11.1mmol), and a few
crystals of methyl orange in THF (20mL) was added
satd HCl–Et2O at 0ꢁC until a pink color persisted.
Usual workup and purification by chromatography
(1:1 EtOAc–hexanes) afforded 19 as a syrup (0.3g,
60%). When the pure diastereoisomer with high Rf was
used as starting material, a single product was obtained
1
with [a]D +25.6 (c 5.6, CHCl3); H NMR (CDCl3): d
1.22 (d, 3H, CH-3, J 6.4Hz), 1.65 and 1.87 (ddd and
ddd, 1H each, 10-CH2), 2.51 (br s, 1H, 4-OH), 2.67 (br
s, 1H, 20-OH), 3.64–3.69 (m, 2H, H-3, 6a), 3.74 (dd,
1H, H-6b, J 6.8, 10.0Hz), 3.85 (m, 1H, H-5), 3.93 (dd,
1H, H-2, J 5.2, 8.4Hz), 3.97 (m, 1H, 20-CH), 4.06 (br
s, 1H, H-4), 4.34 (m, 1H, H-1), 4.53 and 4.57 (d and
d, 1H each, CH2Ph, J 12.0Hz), 4.61 and 4.70 (d
and d, 1H each, CH2Ph, J 11.6Hz), 4.64 and 4.71 (d
and d, 1H each, CH2Ph, J 12.0Hz), 7.26–7.36 (m,
15H, 3 · Ph); 13C NMR (CDCl3): d 23.4 (Me), 34.8
(C-10), 65.1 (C-20), 67.7 (C-4), 69.3 (C-6), 70.6 (C-1, 5),
72.7 (CH2Ph), 73.7 (CH2Ph), 73.8 (CH2Ph), 75.6 (C-2),
77.9 (C-3), 127.9, 128.0, 128.1, 128.5, 128.6, 128.7,
138.0 (2), 138.0; HRFABMS: calcd for C30H37O6
(M+H) m/z 493.2590; found m/z 493.2700.
Acknowledgements
This is NRCC publication No. 42493; this work was
supported in part by the National Research Council of
Canada (to W.Z.) and the National Science Council of
Taiwan (to S.W.). We are grateful to Ms. Lisa Morrison
for mass spectroscopic analyses and Mr. Nam Khieu for
assistance in NMR analysis.
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