Efficient and practical synthesis of l-hamamelose

Article abstract of DOI:10.1016/j.carres.2009.09.011

An efficient synthetic route of l-hamamelose was successfully accomplished starting from d-ribose. l-Hamamelose was synthesized in 42% overall yield with six reaction steps via a stereoselective Grignard reaction, a stereoselective crossed aldol reaction

Full text of DOI:10.1016/j.carres.2009.09.011

Carbohydrate Research 344 (2009) 2317–2321
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Efficient and practical synthesis of L-hamamelose
a
a
a
a
a
b
a
Won Hee Kim , Jin-Ah Kang , Hyung-Rock Lee , Ah-Young Park , Pusoon Chun , Boeun Lee , Jungsu Kim ,
a
c
a,
*
Jin-Ah Kim , Lak Shin Jeong , Hyung Ryong Moon
Laboratory of Medicinal Chemistry, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 609-735, Republic of Korea
College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
a
b
c
Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 May 2009
Received in revised form 10 September 2009
Accepted 12 September 2009
Available online 18 September 2009
An efficient synthetic route of L-hamamelose was successfully accomplished starting from D-ribose.
L-Hamamelose was synthesized in 42% overall yield with six reaction steps via a stereoselective Grignard
reaction, a stereoselective crossed aldol reaction and a controlled oxidative cleavage of the double bond
of a vinyl diol compound. During the oxidative cleavage of the double bond of the vinyl diol compound
with osmium tetroxide and NaIO , an over-oxidative cleavage of a-hydroxyl aldehyde generated from
4
ring opening of the first cleaved product, formyl lactol, did not occur, probably due to the stability of
the lactol form. A plausible mechanism for the stereoselective crossed aldol reaction was suggested.
Keywords:
L
-Hamamelose
The final target compound,
L-hamamelose can play a very important role as a chiral building block in syn-
Chiral building block
Crossed aldol reaction
Johnson–Lemieux oxidation
thesizing a wide variety of enantiopure compounds.
Ó 2009 Elsevier Ltd. All rights reserved.
1
. Introduction
and b-galactosidase and inhibitors of purine nucleoside phospho-
rylases and can serve as a substrate for the synthesis of precious
Branched-chain carbohydrates1–5 are components of many bio-
sugars. Recently, we have reported the efficient synthesis of
ose by using 2,3-isopropylidene- -hamamelofuranose as a starting
material. More recently, we found that an adenine nucleoside
with -hamamelose as its sugar exhibited potent inhibitory activ-
ity against HCV.
-Hamamelose can be obtained from a stereospecific isomeriza-
tion of -fructose using metal catalysts such as molybdene and
L-api-
logically active natural compounds, especially antibiotics and have
been an interesting subject of synthesis and biological evaluations.
In addition, they have attracted considerable attention of organic
chemists as a precursor of enantiomerically pure chiral building
D
1
7
D
1
8
block. 2-C-Methyl-
proved to be a good template for nucleosides that have anti-HCV
hepatitis C virus) activity.6
-Hamamelose (Fig. 1), a branched ri-
D-ribosyl sugar, an alkyl-branched carbohydrate
D
D
19,20
(
D
nickel.
lose and
compounds and
7–33%. Another methodology was reported to use the following
reactions: (i) an epoxidation of methyl 3,4-O-isopropylidene-b-D-
However, the reaction afforded a mixture of
-fructose which is very difficult to be separated into pure
-hamamelose was obtained in the ranges of
D-hamame-
bose at C-2 (2-C-hydroxymethyl ribose), has been widely found
in many plants and intensively studied due to its regulatory prop-
erty of ribulose bisphosphate carboxylase/oxygenase, which is
D
D
responsible for the assimilation of CO
2
during photosynthesis in
7
,8
higher plants, algae, and many photosynthetic bacteria. Hama-
pentopyranosidulose with diazomethane, (ii) an epoxide ring-
opening reaction with sodium hydroxide, and (iii) a deprotection
of isopropylidene group under acidic conditions, giving 13% yield
9
–12
melitannin,
galloyl ester of hamamelose, which is a major com-
ponent in the bark of Hamamelis virginiana L. was reported to be a
2
1
potent scavenger of ROS (reactive oxygen species) such as superox-
via six steps. This method was also unsatisfactory in terms of
1
3,14
ide anion radicals, hydroxyl radicals, and singlet oxygens.
C2-Hydroxymethylated aldoses including -hamamelose can be
D
converted via fragmentation of anomeric alkoxy radicals to unnat-
HO
OH
OH
R
R
OH
OH
HO
HO
ural ketoses which are available chiral substrates in the synthesis
O
O
O
of enantiomerically pure non-carbohydrate products.15 In addition,
D
-hamamelose has been used as a starting material for the synthe-
HO
OH
HO
OH
HO
OH
sis of inhibitors of powerful glycosidases16 such as b-glucosidase
Hamamelitannin
R = ester of 3,4,5-trihydroxy-
benzoic acid)
L-Hamamelose
D
-Hamamelose
(
*
Corresponding author. Tel.: +82 51 510 2815; fax: +82 51 513 6754.
E-mail address: mhr108@pusan.ac.kr (H.R. Moon).
Figure 1. Structures of D- and L-hamamelose and D-hamamelitannin.
0
008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.09.011

2
318
W. H. Kim et al. / Carbohydrate Research 344 (2009) 2317–2321
CHO
HO * CH OH
HO
H
o
1
80 rotation
HO
HO
OH
OH
OH
OH
2
in plane
O
HO
HO
H
H
*
H
HOH C
2
*
HO
OH
OH
CHO
L
-Hamamelose
H
H
OH
H
H
OH
OPg
H
H
OH
CHO
OH
H * OH
OPg
OPg
H
HOH C * OPg
H * OPg
CHO
H * OPg
2
CHO
H
OH
OH
H
OH
OH
I
II
III
D
-ribose
Scheme 1. Retrosynthetic analysis for the synthesis of
L
-hamamelose.
the overall yield and the number of reaction steps. The best
method was developed by Ho and gave excellent yields via an
HO
HO
HO
a
b
O
O
OH
H
OH
OH
OH
93%
81%
isopropylidenation of
deprotection of isopropylidene group.22 Unlike the synthetic meth-
od of -hamamelose, that of -hamamelose has not been studied
D-ribose, a crossed aldol reaction, and a
OH OH
O
O
O
O
D
L
D-ribose
1
2
much until now. The first synthesis of L-hamamelose was achieved
c 85%
by Burton et al. in 0.4% overall yield via eight steps.23 Later, the
TBDMSO
HO
HO
yield was largely improved to 13% by an alternative method devel-
O
4
O
6
1
O
d
HO
oped by the same authors.24 However, there was a defect that the
OH
3a
O
O
95%
3
O
O
method needed diazomethane with an explosive property. On the
O
O
other hand, due to the high cost of starting material,
impractical to apply Ho’s method for the synthesis of
lose. Although -hamamelose is a useful chiral synthon for the syn-
thesis of a wide variety of enantiopure products and is used as an
important starting material in the synthesis of potential
L
-ribose, it is
1
'
4
3
L
-hamame-
L
Scheme 2. Reagents and conditions: (a) acetone, c-H
CH @CHMgBr, THF, 0 °C, 3 h; (c) NaIO , CH Cl , H O, rt, 0.5 h; (d) 37% HCHO,
CO , MeOH, reflux, 36 h.
2 4
SO , rt, 2.5 h; (b)
2
4
2
2
2
K
2
3
glycosidase inhibitors like
D-hamamelose, there was no fur-
ther study to search for a better synthetic method. Therefore,
exploration of an efficient and simple synthetic approach to
0
been found in the reaction of TBDMS-protected compound 1 with
3
0
L
-hamamelose has been continuously required. Herein, we wish
to report a methodology for an efficient and mild synthesis of
-hamamelose.
vinylmagnesium bromide. This diastereoselectivity might be ex-
plained by a chelation model. As shown in Figure 2, magnesium
bromide might chelate with oxygens of the carbonyl and c-hydro-
L
xyl groups. Therefore, the ethenide anion might attack the carbonyl
carbon from the si face which was a less encumbered face, to give a
single stereoisomer 2. The newly generated stereochemistry re-
2
. Results and discussion
Retrosynthetic analysis (Scheme 1) shows that
L-hamamelose
flected L-stereochemistry of L-hamamelose. Oxidative cleavage of
could be synthesized from the key intermediate I via an oxidative
carbon–carbon bond cleavage of a double bond and a reduction.
Compound I could be derived from a stereoselective hydroxyme-
vicinal diols with sodium metaperiodate afforded an aldehyde,
which was rapidly equilibrated with the corresponding lactol
3
1,32
3,
of a hydroxymethyl group into a C-3a
fully accomplished using a method based on the reported proce-
a much more preferable form. Stereoselective introduction
thylation of II, which would be prepared from
D-ribose via a Grig-
a
position of 3 was success-
nard reaction.
2
2
Synthesis of the key intermediate 4 is shown in Scheme 2.
D-Ri-
dure. Stereoselective formation of 4, during the crossed aldol
bose was used as a starting material. Treatment of -ribose with
D
reaction, might be explained as follows. Potassium carbonate
anhydrous acetone in the presence of a catalytic amount of concen-
might abstract the a-hydrogen of c-hydroxy-aldehyde which
trated sulfuric acid yielded the corresponding 2,3-acetonide 1 in
formed from the ring-opening of lactol 3, to give an enolate. The
enolate might attack the carbonyl carbon of formaldehyde from
both sides of the enolate, giving a trans-product, in which the new-
ly formed hydroxymethyl group was on the opposite side of vinyl
group, and a cis-product, in which the hydroxymethyl group was
2
5–28
9
3% yield.
Grignard reaction of lactol 1 with vinylmagnesium
bromide exhibited a strong diastereoselective preference, giving a
2
9
ring-opened olefin 2
as a sole product. According to the
report of Chu and co-workers, the same diastereoselectivity has
Ethenide anion
Br
HO
HO
Mg
O
O
OH
OH
O
CH =CHMgBr
O
2
HO
Ethenide anion
O
O
O
O
Due to steric hindrance
O
O
1
Figure 2. Plausible mechanism produced a stereoselectivity.

W. H. Kim et al. / Carbohydrate Research 344 (2009) 2317–2321
2319
Table 2
HO
HO
TBSO
TBSO
TBSO
TBSO
OH
500 MHz 1H NMR chemical shifts (d, ppm) of anomeric protons of L-hamamelose in
O
O
O
a
b
D
2
O
69%
81%
O
O
O
O
O
O
a
-Furanose
b-Furanose
a-Pyranose
b-Pyranose
4
5α
5β
6α
6β
Chemical shift
5.10
5.03
4.95
4.65
b
71%
c
84%
In conclusion, we have developed a highly efficient synthetic
route to -hamamelose in 42% overall yield with six reaction steps
by using a stereoselective Grignard reaction, a stereoselective
crossed aldol reaction and a controlled oxidative cleavage of a dou-
O
HO
HO
OH
HO
HO
OH
L
HO
HO
d
O
O
OH
OH OH
98%
HO
OH
O
O
ble bond, starting from
stereoselective crossed aldol reaction was suggested. This work
will provide an easy access to the use of -hamamelose as a starting
material for the synthesis of powerful glycosidase inhibitors and a
precursor of enantiomerically pure chiral synthon for the synthesis
of various chiral compounds including natural products.
D-ribose. A plausible mechanism for the
L
-Hamamelose
7
L
Scheme 3. Reagents and conditions: (a) TBSCl, imidazole, CH
OsO , NaIO , acetone/H O (4:1), rt, 2 h; (ii) NaBH , MeOH, rt, 5 min; (c) n-Bu
THF, rt, overnight; (d) DOWEX 50WX4-100 ion-exchange resin, H O, reflux, 5 h.
2
Cl
2
, rt, 8 h; (b) (i) cat.
4
4
2
4
4
NF,
2
on the same side of vinyl group, respectively. Whereas the cis-
product could not be converted into a lactol, the trans-product
could be converted into a more stable lactol 4. The cis-product
inconvertible to a lactol might undergo a retro-aldol reaction,
going back to the enolate and formaldehyde which could re-partic-
ipate in the crossed aldol reaction. Repeat of the processes might
give 4 as a single diastereoisomer.
3
3
. Experimental
.1. General
Melting points are uncorrected. 1H and 13C NMR spectra were
recorded on Varian Unity INOVA 400 and Varian Unity AS 500
instruments. Chemical shifts are reported with reference to the
respective residual solvent or deuterated peaks (d
Conversion of 4 into L-hamamelose is depicted in Scheme 3. In
H C
3.30 and d
order to convert a vinyl group to a hydroxymethyl group, an oxi-
dative cleavage of the vinylic carbon–carbon double bond was em-
ployed. We were concerned about the second carbon–carbon
oxidative cleavage between the carbon of aldehyde generated by
the first oxidative cleavage reaction on the olefin and the adjacent
carbon (C-6). Therefore, two hydroxyl groups of 4 were first pro-
tected with TBSCl in order to prevent the second oxidative cleav-
4
9.0 for CD OD, d 7.27 and d 77.0 for CDCl ). Coupling constants
3
H
C
3
are reported in hertz. The abbreviations used are as follows: s (sin-
glet), d (doublet), m (multiplet), t (triplet), dd (doublet of doublet),
br s (broad singlet). All the reactions described below were per-
formed under argon or nitrogen atmosphere and were monitored
by TLC. All anhydrous solvents were distilled over CaH
zophenone prior to use.
2
or Na /ben-
age reaction, giving bis-silyl ethers 5
a
a
and 5b as an inseparable
and 5b was subjected to
(a stoichiometric amount of
and a catalytic amount of OsO ) to produce the correspond-
ing one-carbon-lessened aldehyde, which reacted with sodium
borohydride to afford alcohols 6 and 6b (two-step yield: 56%).
TBS groups of 6 and 6b mixture were removed with tetrabutyl-
ammonium fluoride to give 2,3-isopropylidene- -hamamelofura-
nose (7), which was easily converted to -hamamelose by
treatment with an acidic resin. However, the reaction steps to
the final -hamamelose seemed to be a little long. Therefore, a di-
mixture in 69% yield. The mixture of 5
3
.2. (ꢀ)-(3aR,4R/S,6R,6aR)-6-(Hydroxymethyl)-2,2-dimethyltetra-
a Johnson–Lemieux oxidation3
NaIO
3,34
hydrofuro[3,4-d][1,3]dioxol-4-ol (1)
4
4
To a stirred suspension of
tone (1.0 L) was added dropwise concd H
temperature and the reaction mixture was stirred at the same tem-
perature for 2.5 h. The mixture was neutralized with solid NaHCO
filtered, and evaporated under reduced pressure to give a colorless
syrup. The residue was purified by silica gel column chromatogra-
phy using hexane and ethyl acetate (1:2) as the eluent to afford 1
D
-ribose (80 g, 532.9 mmol) in ace-
a
2
SO (2.4 mL) at room
4
a
L
3
,
L
L
2
D
5
27
rect oxidative cleavage reaction without any protection of the
hydroxyl groups was attempted to reduce the reaction steps and
increase the overall yield. Judged from the yield of the reaction,
it seemed that the second cleavage occurred at a very slow rate,
contrary to our first expectation. This phenomenon might result
from a much greater stability of the first cleaved product, formyl
lactol, than that of the corresponding lactol ring-opened form. Fi-
as a colorless syrup (94.2 g, 93%): ½
aꢁ
ꢀ36.2 (c 1.45, acetone) lit.
1
ꢀ
37 (c 0.53, acetone); H NMR (400 MHz, CDCl
.75 (d, 1H, J 5.6 Hz, 3a-H), 4.51 (d, 1H, J 6.0 Hz, 6a-H), 4.33 (br t,
H, 6-H), 3.65 (m, 2H, HOCH ), 1.43 (s, 3H, CH ), 1.26 (s, 3H,
) d 112.4, 102.9, 87.8, 86.9, 81.8,
3
) d 5.34 (s, 1H, 4-H),
4
1
2
3
13
CH
6
C
3
); C NMR (100 MHz, CDCl
3.6, 26.5, 24.9; LRFABMS m/z 213 [M+Na] . Anal. Calcd for
: C, 50.52; H, 7.42. Found: C, 50.48; H, 7.36.
3
+
8 14 5
H O
nally,
4
L-hamamelose was obtained from D-ribose via six steps in
2% overall yield. 1H and C NMR data of
13
L-hamamelose
23,24
are
3
.3. (ꢀ)-(R)-1-((4R,5S)-5-((S)-1-Hydroxyallyl)-2,2-dimethyl-1,3-
depicted in Tables 1 and 2, respectively. To our best knowledge,
this approach is the most efficient and practical synthetic method
dioxolan-4-yl)ethane-1,2-diol (2)
of L-hamamelose.
To a stirred solution of acetonide 1 (1.018 g, 5.35 mmol) in THF
(
40 mL) was added dropwise vinylmagnesium bromide (24 mL,
2
4 mmol, 1.0 M solution in THF) at ꢀ78 °C, and the reaction mix-
Table 1
1
00 MHz 13C NMR chemical shifts (d, ppm) of L-hamamelose in D
2
O
ture was stirred at 0 °C for 3 h. After water (8 mL) was added to
the mixture at 0 °C, the resulting precipitate was removed through
a pad of Celite. The filtrate was extracted by ethyl acetate
0
C-1
97.4
C-2
C-2
C-3
C-4
C-5
a
-Furanose
b-Furanose
-Pyranose
b-Pyranose
78.0
81.1
75.6
75.1
60.8
62.5
60.3
63.0
69.9
71.2
67.2
66.2
81.3
82.2
68.6
68.4
62.5
63.0
67.2
63.0
(80 mL ꢂ 2), dried over anhydrous MgSO
4
, filtered, and evaporated
101.0
94.4
94.9
under reduced pressure to give an oil, which was purified by silica
gel column chromatography using hexane and ethyl acetate (1:2.5)
as the eluent to afford triol 2 (949 mg, 81%) as a white solid: mp
a

2
320
W. H. Kim et al. / Carbohydrate Research 344 (2009) 2317–2321
2
D
5
) lit.31,35 ꢀ31 (c 1.8, CHCl
1
7
3–74 °C; ½
a
ꢁ
ꢀ29.8 (c 1.23, CHCl
3
3
); H
3.6. tert-Butyl(((3aS,4S,6S,6aS)-4-(tert-butyldimethylsilyloxy)-
2,2-dimethyl-6-vinyltetrahydrofuro[3,4-d][1,3]dioxol-3a-yl)
NMR (CD
3
2
OD) d 5.97 (m, 1H, –CH@CH ), 5.31 (td, 1H, J 1.6, 17.2 Hz,
–
CH@CHH), 5.17 (td, 1H, J 1.6, 10.8 Hz, –CH@CHH), 4.24 (m, 1H, –
CHCH@CH ), 4.11 (dd, 1H, 5.6, 9.6 Hz, –CHCH(OH)CH@
CH ), 3.96 (dd, 1H, J 5.2, 9.6 Hz, –CHCH(OH)CH OH), 3.84 (m, 1H,
CH(OH)CH OH), 3.77 (dd, 1H, J 2.4, 11.2 Hz, –CHHOH), 3.59 (dd,
H, J 6.0, 11.2 Hz, –CHHOH), 1.35 (s, 3H, CH ), 1.28 (s, 3H, CH );
OD) d 138.2, 115.2, 108.7, 80.3, 77.4,
methoxy)dimethylsilane (5a) and tert-butyl(((3aS,4R,6S,6aS)-4-
(tert-butyldimethylsilyloxy)-2,2-dimethyl-6-vinyltetra
hydrofuro[3,4-d][1,3]dioxol-3a-yl)methoxy)dimethylsilane (5b)
2
J
2
2
–
1
2
3
3
To a stirred solution of 4 (132 mg, 0.61 mmol) and imidazole
(250 mg, 3.67 mmol) in CH Cl (5 mL) was added TBSCl (276 mg,
2 2
1
3
C NMR (100 MHz, CD
3
7
8
0.3, 70.0, 63.7, 27.0, 24.5. Anal. Calcd for C10
.31. Found: C, 54.97; H, 8.44.
H
18
O
5
: C, 55.03; H,
1.83 mmol) at 0 °C and the reaction mixture was stirred at room
temperature for 8 h. The reaction mixture was partitioned between
methylene chloride and water and the organic layer was dried over
4
anhydrous MgSO , filtered, and evaporated under reduced pressure.
3
.4. (–)-(3aS,4R/S,6S,6aS)-2,2-Dimethyl-6-vinyltetrahydrofuro
The resulting residue was purified by silica gel column chromatog-
raphy using hexane and ethyl acetate (90:1) as the eluent to give
[
3,4-d][1,3]dioxol-4-ol (3)
5
a
and 5b (189 mg, 69%) as an inseparable oily mixture: 1H NMR
To a stirred solution of triol 2 (2.75 g, 12.6 mmol) in methylene
(
500 MHz, CDCl
minor), 5.85 (ddd, 1H, J 6.5, 10.0, 17.0 Hz, –CH@CH
td, 1H, J 1.5, 17.0 Hz, –CH@CHaHb, major), 5.32 (s, 1H, anomeric
H, minor), 5.26 (td, 1H, J 1.5, 17.5 Hz, –CH@CHaHb, minor), 5.19
td, 1H, J 1.5, 10.0 Hz, –CH@CHaHb, major), 5.12 (td, 1H, J 1.5,
0.5 Hz, –CH@CHaHb, minor), 5.02 (s, 1H, anomeric H, major), 4.61
m, 1H, 6-H, major), 4.58 (qd, 1H, J 1.0, 7.0 Hz, 6-H, minor), 4.47 (s,
H, 6a-H, minor), 4.28 (d, 1H, J 3.5 Hz, 6a-H, major), 3.81 (d, 1 H, J
3
) d 5.94 (ddd, 1H, J 8.0, 11.0, 17.0 Hz, –CH@CH
2
,
chloride (47 mL) was added dropwise an aqueous solution of NaIO
29.1 mL, 18.92 mmol, 0.65 M solution) at 0 °C, and the reaction
4
2
, major), 5.35
(
(
mixture was stirred at room temperature for 30 min. After the
addition of water (30 mL), the mixture was extracted with methy-
(
1
(
1
lene chloride (100 mL ꢂ 2), dried over anhydrous MgSO
4
, filtered,
and evaporated under reduced pressure to give an oil, which was
purified by silica gel column chromatography using hexane and
ethyl acetate (2:1) as the eluent to give vinyl lactol 3 (2.00 g,
2
D
5
31
11.5 Hz, –CHaHbOTBS, minor), 3.78 (d, 1H, J 11.5 Hz, –CHaHbOTBS,
minor), 3.77 (d, 1H, J 10.5 Hz, –CHaHbOTBS, major), 3.57 (d, 1H, J
8
0
1
5%) as a colorless oil: ½
aꢁ
ꢀ10.5 (c 0.96, CHCl
3
) lit. ꢀ11.9 (c
1
.96, CHCl
0.4, 17.2 Hz, –CH@CH
), 5.47 (s, 1H, 4-H), 5.37 (td, 1H, J 1.6, 17.6 Hz, –CH@CHH),
.30–5.25 (m, 2H, –CH@CHH, 4-H), 5.20 (td, 1H, J 1.6, 10.8 Hz, –
CH@CHH), 5.15 (td, 1H, J 1.6, 10.0 Hz, –CH@CHH), 4.67–4.53 (m,
3 3
); H NMR (400 MHz, CDCl ) d 5.99 (ddd, 1H, J 7.6,
1
1.0 Hz, –CHaHbOTBS, major), 1.57 (s, 3H, CH
CH , minor), 1.43 (s, 3H, CH , minor), 1.40 (s, 3H, CH
s, 9H, t-butyl, major), 0.90 (s, 9H, t-butyl, minor), 0.89 (s, 9H, t-butyl,
major), 0.88 (s, 9H, t-butyl, minor), 0.13 (s, 6H, 2 ꢂ SiCH ), 0.11 (s,
3
, major), 1.50 (s, 3H,
2
), 5.77 (ddd, 1H, J 4.8, 10.8, 17.2 Hz, –
3
3
3
, major), 0.93
CH@CH
5
2
(
3
1
3
3
H, SiCH
3
), 0.10 (s, 3H, SiCH
) d 138.0, 136.1, 117.0, 116.8, 116.0, 113.5, 105.4,
8.0, 95.6, 93.1, 87.5, 86.4, 85.0, 82.8, 64.8, 62.8, 28.3, 27.8, 27.7,
7.3, 26.2, 26.1, 26.1, 25.8, 18.7, 18.6, 18.4, 18.0, ꢀ3.9, ꢀ4.5, ꢀ4.6,
3
), 0.06 (s, 6H, 2 ꢂ SiCH
3
); C NMR
6
(
3
1
8
5
H, 2 ꢂ 3a-H, 2 ꢂ 6-H, 2 ꢂ 6a-H), 3.94 (d, 1H, J 10.4 Hz, OH), 3.15
d, 1H, J 2.4 Hz, OH), 1.56 (s, 3H, CH ), 1.48 (s, 3H, CH ), 1.37 (s,
); C NMR (100 MHz, CDCl ) d 138.3,
34.8, 117.5, 117.3, 114.6, 112.7, 103.3, 96.4, 88.9, 86.3, 84.9,
4.0, 80.8, 79.3, 26.7, 26.4, 25.2, 25.2. Anal. Calcd for C
8.05; H, 7.58. Found: C, 58.47; H, 7.89.
(
100 MHz, CDCl
3
3
3
9
2
ꢀ
13
H, CH
3
), 1.31 (s, 3H, CH
3
3
+
5.1, ꢀ5.2, ꢀ5.4, ꢀ5.4; LRFABMS m/z 467 [M+Na] .
9 14 4
H O : C,
3
.7. ((3aS,4R,6R,6aS)-6-(tert-Butyldimethylsilyloxy)-6a-((tert-
butyldimethylsilyloxy)methyl)-2,2-dimethyltetrahydro
furo[3,4-d][1,3]dioxol-4-yl)methanol (6 ) and ((3aS,4S,6R,6aS)-
6-(tert-butyldimethylsilyloxy)-6a-((tert-butyldimethylsilyloxy)
methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)
methanol (6b)
3
.5. (ꢀ)-(3aS,4R/S,6S,6aS)-3a-Hydroxymethyl-2,2-dimethyl-6-
a
vinyl-tetrahydrofuro[3,4-d][1,3]-dioxol-4-ol (4)
To a stirred suspension of K CO (0.7 g) in MeOH (17 mL) was
2
3
added 37% aqueous formaldehyde (7 mL), and the solution was
stirred until the pH became 10. The supernatant clear solution
To a solution of 5a and 5b mixture (73.3 mg, 0.16 mmol) in ace-
(
10 mL) was added to vinyl lactol 3 (1.901 g, 10.21 mmol), and
tone/H O (4:1, 2 mL) were added a solution of osmium tetroxide
2
the reaction mixture was refluxed for 36 h. The mixture was parti-
2
(0.08 mL, 8 lmol, 0.1 M in H O) and an aqueous solution of NaIO4
tioned between water (5 mL) and ethyl acetate (80 mL ꢂ 2), and
(105.8 mg, 0.49 mmol) at 0 °C, successively and the reaction mix-
ture was stirred at room temperature for 2 h. The reaction mixture
was filtered through a pad of Celite, washed with acetone and
evaporated under reduced pressure to remove acetone. To the
resultant aqueous solution was added ethyl acetate and the organ-
ic layer was washed with aqueous sodium thiosulfate solution,
4
the organic layer was dried over anhydrous MgSO , filtered, and
evaporated in vacuo. The residue was purified by silica gel column
chromatography using hexane and ethyl acetate (1:1.5) as the elu-
2
D
5
ent to give diol 4 (2.096 g, 95%) as a colorless oil: ½
a
ꢁ
ꢀ22.5 (c 2.5,
1
CHCl
7.6 Hz, –CH@CH
CH@CH , major), 5.46 (s, 1H, 4-H, minor), 5.37 (td, 1H, J 1.2,
6.8 Hz, –CH@CHH, major), 5.29 (td, 1H, J 1.6, 17.2 Hz, –CH@CHH,
minor), 5.21 (td, 1H, J 1.2, 10.0 Hz, –CH@CHH, major), 5.16 (td, 1H, J
3
); H NMR (400 MHz, CDCl
3
) d 5.98 (ddd, 1H, J 7.6, 10.4,
1
2
, minor), 5.77 (ddd, 1H, J 4.8, 10.8, 17.6 Hz, –
dried over anhydrous MgSO , filtered, and evaporated under re-
4
2
duced pressure to give a crude aldehyde. To a solution of the alde-
1
hyde in methanol (2 mL) was added NaBH4 (6.2 mg, 0.16 mmol)
and the reaction mixture was stirred at room temperature for
5 min. The resulting precipitate was removed through a pad of Cel-
ite, and the filtrate was evaporated under reduced pressure. The
resulting residue was partitioned between aqueous sodium thio-
sulfate solution and ethyl acetate, and the organic layer was dried
1
4
.2, 10.8 Hz, –CH@CHH, minor), 5.07 (br s, 1H, 4-H, major), 4.64–
.61 (m, 2H, 6-H, major and minor), 4.50 (d, 1H, J 0.8 Hz, 6a-H, min-
or), 4.43 (d, 1H, J 1.2 Hz, 6a-H, major), 3.86 (d, 1H, J 12.4 Hz, –
CHHOH, minor), 3.81 (d, 1H, J 12.4 Hz, –CHHOH, minor), 3.72 (d,
1
H, J 11.6 Hz, –CHHOH, major), 3.65 (d, 1H, J 12.4 Hz, –CHHOH, ma-
jor), 1.58 (s, 3H, CH , major), 1.48 (s, 3H, CH , minor), 1.45 (s, 3H,
CH , major), 1.39 (s, 3H, CH
, minor); 13C NMR (100 MHz, CDCl
d 137.4, 134.6, 117.7, 117.3, 114.8, 113.7, 105.2, 97.6, 93.9, 90.9,
over anhydrous MgSO , filtered, and evaporated under reduced
pressure to give an oil, which was purified by silica gel column
4
3
3
3
3
3
)
chromatography using hexane and ethyl acetate (8:1) as the eluent
to give less polar material (37.2 mg, 50%) as a colorless oil and
more polar material (23.0 mg, 31%) as a colorless solid: less polar
8
8.2, 87.3, 85.5, 81.2, 63.8, 63.6, 28.0, 27.8, 27.5, 27.2; LRFABMS
+
+
25
D
1
m/z 199 [M+HꢀH
2
O] , 239 [M+Na] . Anal. Calcd for C10
H
16
O
5
: C,
material: ½
a
ꢁ
3 3
33.0 (c 1.8, CHCl ); H NMR (500 MHz, CDCl ) d
5
5.55; H, 7.46. Found: C, 55.26; H, 7.39.
5.33 (s, 1H, anomeric H), 4.65 (s, 1H, 3a-H), 430 (t, 1H, J 3.0 Hz,

W. H. Kim et al. / Carbohydrate Research 344 (2009) 2317–2321
2321
4
-H), 3.84 (d, 1H, J 11.5 Hz, –CHaHbOTBS), 3.76 (d, 1H, J 11.5 Hz, –
washed with methanol, and evaporated under reduced pressure to
give -hamamelose (988 mg, 98%) as a colorless oil: mp 109.4–
111.2 °C; ½
ꢀ6.6 (c 1.5, H
4.65 (each s, 1H, anomeric H); C NMR (100 MHz, D
CHaHbOTBS), 3.69 (td, 1H, J 2.5, 12.0 Hz, –CHaHbOH), 3.62 (td, 1H, J
L
2
D
5
22
3
3
0
3
8
.0, 11.0 Hz, –CHaHbOH), 3.04 (dd, 1H, J 3.5, 10.0 Hz, OH), 1.48 (s,
H, CH ), 1.45 (s, 3H, CH ), 0.91(s, 9H, t-butyl), 0.90 (s, 9H, t-butyl),
.16 (s, 3H, SiCH ), 0.14 (s, 3H, SiCH ), 0.08 (s, 3H, SiCH ), 0.07 (s,
); C NMR (100 MHz, CDCl ) d 113.7, 104.7, 96.3, 89.0,
4.1, 64.0, 62.6, 28.3, 28.2, 26.2, 25.7, 18.8, 18.1, ꢀ4.4, ꢀ5.1,
a
ꢁ
+5.8 (c 1.0, H
2
O) [in case of
O)]; H NMR (500 MHz, D O) d 5.10, 5.03, 4.95,
O) d 101.0,
D-hamamelose: lit.
1
3
3
2
2
1
3
3
3
3
2
1
3
H, SiCH
3
3
97.4, 94.9, 94.4, 82.2, 81.3, 81.1, 78.0, 75.6, 75.1, 71.2, 69.9, 68.6,
68.4, 67.2, 66.2, 65.4, 63.0, 62.5, 60.8, 60.3.
+
ꢀ
5.2; LRFABMS m/z 471 [M+Na] ; HRFABMS m/z calcd for
Si
[M]+ 448.2676, found 448.2683; more polar material:
mp 74.2–75.7 °C; ½
CDCl ) d 5.07 (s, 1H, anomeric H), 4.46 (d, 1H, J 3.5 Hz, 3a-H),
C
21
H
44
O
6
2
Acknowledgment
2
D
5
1
a
ꢁ
ꢀ25.3 (c 1.2, CHCl
3
); H NMR (500 MHz,
3
This work was supported for two years by Pusan National Uni-
versity Research Grant.
4
1
1
3
0
3
8
.27 (q, 1H, J 4.0 Hz, 4-H), 3.80 (m, 1H, –CHaHbOH), 3.79 (d, 1H, J
1.0 Hz, –CHaHbOTBS), 3.70 (m, 1H, –CHaHbOH), 3.66 (d, 1H, J
0.5 Hz, –CHaHbOTBS), 1.96 (dd, 1H, J 5.5, 6.5 Hz, OH), 1.56 (s,
Supplementary data
H, CH
3
), 1.40 (s, 3H, CH
), 0.12 (s, 3H, SiCH
); C NMR (100 MHz, CDCl
1.8, 65.1, 63.0, 27.6, 27.2, 26.1, 26.1, 18.6, 18.4, ꢀ4.5, ꢀ4.6,
3
), 0.92 (s, 9H, t-butyl), 0.90 (s, 9H, t-butyl),
), 0.08 (s, 3H, SiCH ), 0.07 (s,
) d 116.2, 98.5, 93.0, 82.7,
.13 (s, 3H, SiCH
H, SiCH
3
3
3
Supplementary data ( H and 13C NMR spectra of compounds 1, 2,
, 4, 5 , 5b, 6 , 6b, 7 and -hamamelose and COSY, HSQC and HMBC
spectra of -hamamelose) associated with this article can be found,
1
1
3
3
3
3
a
a
L
L
+
ꢀ
5.2, ꢀ5.4; LRFABMS m/z 471 [M+Na] ; HRFABMS m/z calcd for
in the online version, at doi:10.1016/j.carres. 2009.09.011.
+
C
21
H
44
O
6
Si
2
[M] 448.2676, found 448.2664.
References
3
.8. (ꢀ)-((3aS,4R/S,6S,6aS)-4-Hydroxy-2,2-dimethyltetrahydro-
furo[3,4-d][1,3]dioxole-3a,6-diyl)dimethanol (7)
1.
2.
3.
Pathak, T.; Bhattacharya, R. Carbohydr. Res. 2008, 343, 1980–1998.
Das, I.; Pal, T. K.; Suresh, C. G.; Pathak, T. J. Org. Chem. 2007, 72, 5523–5533.
Jones, N. A.; Nepogodiev, S. A.; MacDonald, C. J.; Hughes, D. L.; Field, R. A. J. Org.
Chem. 2005, 70, 8556–8559.
Method A (from 6 and 6b): To a stirred solution of 6
a
a and 6b
(
(
34 mg, 0.08 mmol) in THF (1.5 mL) was added 1 M TBAF solution
0.22 mL, 0.22 mmol, 1 M THF solution) at room temperature and
4.
Chapleur, Y.; Chretien, F. Prep. Carbohydr. Chem. 1997, 207–262.
5. Miyao, H.; Sakai, Y.; Takeshita, T.; Ito, Y.; Kinjo, J.; Nohara, T. Chem. Pharm. Bull.
1996, 44, 128–1231.
the reaction mixture was stirred at the same temperature overnight.
After the volatiles were evaporated, the residue was purified by silica
gel column chromatographyusing methylene chloride and methanol
6.
Eldrup, A. B.; Allerson, C. R.; Bennett, C. F.; Bera, S.; Bhat, B.; Bhat, N.;
Bosserman, M. R.; Brooks, J.; Burlein, C.; Carroll, S. S.; Cook, P. D.; Getty, K. L.;
MacCoss, M.; McMasters, D. R.; Olsen, D. B.; Prakash, T. P.; Prhavc, M.; Song, Q.;
Tomassini, J. E.; Xia, J. J. Med. Chem. 2004, 47, 2283–2295.
(20:1 to 15:1) as the eluent to give triol 7(14 mg, 84%) as a colorless oil.
7
8
9
.
.
.
Andralojc, P. J.; Keys, A. J.; Martindale, W.; Dawson, G. W.; Parry, M. A. J. J. Biol.
Chem. 1996, 271, 26803–26809.
Andralojc, P. J.; Keys, A. J.; Kossmann, J.; Parry, M. A. J. Proc. Natl. Acad. Sci. U.S.A.
2002, 99, 4742–4747.
Tourino, S.; Lizarraga, D.; Carreras, A.; Lorenzo, S.; Ugartondo, V.; Mitjans, M.;
Vinardell, M. P.; Julia, L.; Cascante, M.; Torres, J. L. Chem. Res. Toxicol. 2008, 21,
Method B (from 4): To a stirred solution of 4 (204 mg,
0
.94 mmol) in acetone and water (12.5 mL, 4/1) were added aque-
ous OsO solution (0.45 mL, 45 mol, 0.1 M solution in H O) and
NaIO (485 mg, 2.27 mmol) at room temperature, and the reaction
4
l
2
4
mixture was stirred at the same temperature. After 2 h, the reac-
tion mixture was filtered through a pad of Celite and the filtrate
was evaporated under reduced pressure to remove acetone. The
residue containing water was used to the next step without further
purification. To a solution of the resulting residue in methanol
6
96–704.
10. Masaki, H. Fragrance J. 1995, 23, 65–74.
1
1
1
1. Masaki, H.; Atsumi, T.; Sakurai, H. Biol. Pharm. Bull. 1995, 18, 59–63.
2. Masaki, H.; Atsumi, T.; Sakurai, H. Free Radical Res. 1995, 22, 419–430.
3. Masaki, H.; Atsumi, T.; Sakurai, H. J. Dermatol. Sci. 1995, 10, 25–34.
14. Roche, A. C.; Barzilay, M.; Midoux, P.; Junqua, S.; Sharron, N.; Monsigny, M. J.
Cell. Biochem. 1983, 22, 131–140.
5. de Armas, P.; Francisco, C. G.; Suarez, E. Tetrahedron Lett. 1993, 34, 7331–7334.
6. Bols, M. Tetrahedron Lett. 1996, 37, 2097–2100.
(
4
8 mL) was added portionwise NaBH (35 mg, 0.93 mmol) at room
1
1
temperature and the reaction mixture was stirred at the same tem-
perature. After 5 min, to the reaction mixture was added anhy-
17. Yun, M.; Moon, H. R.; Kim, H. O.; Choi, W. J.; Kim, Y.-C.; Park, C.-S.; Jeong, L. S.
drous Na
2
SO
4
and the solid was filtered through a pad of Celite.
Tetrahedron Lett. 2005, 46, 5903–5905.
8. Yoo, B. N.; Kim, H. O.; Moon, H. R.; Seol, S. K.; Jang, S. K.; Lee, K. M.; Jeong, L. S.
Bioorg. Med. Chem. Lett. 2006, 16, 4190–4194.
9. Yanagihara, R.; Osanai, S.; Yoshikawa, S. Chem. Lett. 1992, 89–90.
20. Hricoviniova-Bilikova, Z.; Hricovini, M.; Petrusova, M.; Serianni, A. S.; Petrus, L.
Carbohydr. Res. 1999, 319, 38–46.
1. Overend, W. G.; Williams, N. R. J. Chem. Soc. 1965, 3446–3448.
2. Ho, P.-T. Tetrahedron Lett. 1978, 19, 1623–1626.
23. Burton, J. S.; Overend, W. G.; Williams, N. R. Proc. Chem. Soc., London 1962, 181.
4. Burton, J. S.; Overend, W. G.; Williams, N. R. J. Chem. Soc. 1965, 3433–3445.
5. Rauter, A. P.; Ramoa-Ribeiro, F.; Fernandes, A. C.; Figueiredo, J. A. Tetrahedron
1
The filtrate was evaporated under reduced pressure to give a resi-
due, which was purified by silica gel column chromatography
using ethyl acetate only as the eluent to give triol 7 (148 mg,
1
2
D
5
1
7
(
1%) as a colorless oil: ½
500 MHz, CD OD) d 5.26 (s, 1H, anomeric H, major), 5.12 (s, 1H,
anomeric H, minor), 4.54 (s, 1H, 6a-H, major), 4.51 (d, 1H, J
a
ꢁ
ꢀ0.39 (c 0.94, CHCl
3
); H NMR
2
2
3
2
2
2
3
1
.0 Hz, 6a-H, minor), 4.15–4.11 (m, 2H, 6-H, major and minor),
.80 (d, 1H, J 12.0 Hz, HOCHHCquaternary, major), 3.74 (d, 1H, J
1
995, 51, 6529–6540.
26. Ewing, D. F.; Humble, R. W.; Mackenzie, G.; Raynor, A.; Shaw, G. Carbohydr. Res.
991, 218, 233–236.
2.0 Hz, HOCHHCquaternary, major), 3.71 (d, 1H, J 12.0 Hz,
1
HOCHHCquaternary, minor), 3.67 (d, 1H, J 12.0 Hz, HOCHHCquaternary
,
2
2
7. Kiso, M.; Hasegawa, A. Carbohydr. Res. 1976, 52, 95–101.
8. Acevedo, O. L.; Townsend, L. B. In Nucleic Acid Chemistry, Part Three: Improved
and New Synthetic Procedures, Methods and Techniques; Townsend, L. B., Tipson,
R. S., Eds.; Synthesis of 2,3-O-Isopropylidene-d-Ribose; John Wiley & Sons:
New York, 1986; pp 35–37.
minor), 3.65–3.58 (m, 4H, HOCH
2
CH–, major and minor), 1.55 (s,
3
1
1
3
H, CH
.42 (s, 3H, CH
07.7, 102.0, 98.8, 95.6, 91.0, 88.5, 87.0, 86.5, 66.9, 66.4, 66.0, 65.5,
3
, minor), 1.46 (s, 3H, CH
3
3
, major), 1.43 (s, 3H, CH , minor),
, major); 13C NMR (100 MHz, CD
3
3
OD) d 118.5, 117.1,
2
9. Redlich, H.; Sudau, W.; Szardenings, A. K.; Vollerthun, R. Carbohydr. Res. 1992,
+
1.0, 31.0, 30.3, 30.1; LRFABMS m/z 186 [Mꢀ2ꢂH
2
O] .
226, 57–78.
3
3
0. Jin, Y. H.;Wang, J.; Baker, R.;Huggins, J.; Chu,C.K. J. Org. Chem. 2003, 68, 9012–9018.
1. van Boggelen, M. P.; van Dommelen, G. F. G. A.; Jiang, S.; Singh, G. Tetrahedron
3
2
.9. (ꢀ)-(2R/S,3S,4S,5S)-3,5-Bis(hydroxymethyl)tetrahydrofuran-
1
997, 33, 16897–16910.
2. Moon, H. R.; Kim, H. O.; Lee, K. M.; Chun, M. W.; Kim, J. H.; Jeong, L. S. Org. Lett.
002, 4, 3501–3503.
,3,4-triol ( -hamamelose)
L
3
2
33. Pappo, R.; Allen, D. S.;Lemieux, R. U.;Johnson, W. S. J. Org. Chem.1956, 21, 478–492.
34. Evans, D. A.; Sims, C. L. Tetrahedron Lett. 1973, 14, 4691–4694.
35. Shing, T. K. M.; Elsley, D. A.; Gillhouley, J. G. J. Chem. Soc., Chem. Commun. 1989,
1280–1282.
2
To a solution of 7 (1.23 g, 5.59 mmol) in H O (35 mL) was added
DOWEX 50WX4-100 ion-exchange resin (700 mg) and the reaction
mixture was refluxed. After 5 h, the reaction mixture was filtered,