A novel pentose synthesis via palladium(II)-catalyzed cyclization of an unstable hemiacetal

Article abstract of DOI:10.3987/COM-10-12001

PdCl₂(PhCN)₂ (5 mol%)-catalyzed cyclization of a hemiacetal derived from (E,2S,3R)-2,3-isopropylidenedioxy-6-(tetrahydro-2H- pyran-2-yl)-4-hexenal and methanol gave substituted furanoside in moderate yield, exclusively via 5-exo-mode cyclization, without the need for a reoxidant. New stereogenic centers at C1 and C4 on the tetrahydrofuran ring showed preferential 1R and 4R stereochemistry due to anomeric effect (n _oσ^*_c-o) and A^1,2 strain, respectively. This methodology was applied to stereocontrolled synthesis of pentoses: D-ribose and L-lyxose. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-12001

HETEROCYCLES, Vol. 81, No. 9, 2010
2105
HETEROCYCLES, Vol. 81, No. 9, 2010, pp. 2105 - 2121. © The Japan Institute of Heterocyclic Chemistry
Received, 25th June, 2010, Accepted, 15th July, 2010, Published online, 15th July, 2010
DOI: 10.3987/COM-10-12001
A NOVEL PENTOSE SYNTHESIS VIA PALLADIUM(II)-CATALYZED
CYCLIZATION OF AN UNSTABLE HEMIACETAL
Ken-ichiro Awasaguchi, Masahiro Miyazawa,* Ikuyo Uoya, Koichi Inoue,
Koji Nakamura, Hajime Yokoyama, and Yoshiro Hirai*
Graduate School of Science and Technology, University of Toyama, 3190 Gofuku,
Toyama 930-8555, Japan; E-mail: miyazawa@sci.u-toyama.ac.jp
Abstract – PdCl2(PhCN)2 (5 mol%)-catalyzed cyclization of a hemiacetal derived
from (E,2S,3R)-2,3-isopropylidenedioxy-6-(tetrahydro-2H-pyran-2-yl)-4-hexenal
and methanol gave substituted furanoside in moderate yield, exclusively via
5-exo-mode cyclization, without the need for a reoxidant. New stereogenic centers
at C1 and C4 on the tetrahydrofuran ring showed preferential 1R and 4R
stereochemistry due to anomeric effect (no-!*c-o) and A1,2 strain, respectively. This
methodology was applied to stereocontrolled synthesis of pentoses: D-ribose and
L-lyxose.
INTRODUCTION
Substituted tetrahydrofuran moieties are often found in natural products, biologically active compounds
and drugs such as antivirals.1 Therefore, the stereocontrolled synthesis of substituted tetrahydrofuran
derivatives has received considerable attention. Among reported methods, intramolecular cyclization of
!-olefin-palladium complex is a powerful tool for the construction of heterocycles.2 However, because
the Pd(II) catalyst is reduced to Pd(0) at the end of the reaction, most of these methods require a reoxidant
such as O2/CuCl2 or 1,4-benzoquinone (BQ) to transform Pd(0) to Pd(II) and regenerate the catalyst.
Recently, Kawai and co-workers have reported palladium(II)-catalyzed stereospecific synthesis of
2,6-substituted tetrahydropyrans from olefinic alcohol,3 and we have reported stereoselective synthesis of
2,4,6-trisubstituted tetrahydropyrans from olefinic hemiacetal without a reoxidant.4 To the best of our
knowledge, however, there have been few reports on the construction of a tetrahydrofuran ring by
palladium(II)-catalyzed cyclization without a reoxidant.5 As a continuation of our work, we focus here on
tetrahydrofuran. Herein, we present a novel strategy for stereocontrolled tetrahydrofuran ring construction

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HETEROCYCLES, Vol. 81, No. 9, 2010
with palladium(II) catalyst via hemiacetal as a nucleophile and its application in syntheses of D-ribose
and L-lyxose.6
RESULTS AND DISCUSSION
Our synthetic plan to attain a substituted tetrahydrofuran ring by palladium(II)-catalyzed cyclization is
outlined in Scheme 1. The unstable hemiacetal 2 derived from aldehyde 1 and alcohol (R’OH) reacts as a
nucleophile with the olefin moiety activated by palladium(II) catalyst to give the substituted furanoside 3.
OH
OH
O
Pd(II)
R'OH
OR'
O
HO
H
OR'
R
R
R
1
2
3
Scheme 1. Synthetic plan for furanoside 3 by Pd(II)-catalyzed cyclization via
unstable hemiacetal 2
Our retrosynthetic analysis for D-ribose is illustrated in Scheme 2. We envisioned that the pentose would
be obtained by transformation of 4-vinylfuranoside (4), and the tetrahydrofuran ring would be constructed
by palladium(II)-catalyzed cyclization of the hemiacetal derived from aldehyde 5. Aldehyde 5 would be
readily prepared by side chain elongation of acetate 6, followed by oxidation of the resulting alcohol.
Optically active acetate 6 was to be synthesized by asymmetric acetylation of meso-diol 7 using lipase.
Finally, meso-diol 7 would be readily available from the simple achiral cis-2-butene-1,4-diol (8).
OTHP
O
OMe
H
4
O
OH
O
HO
O
O
O
O
HO
OH
4R : D-ribose
4S : L-lyxose
4
5
6
HO
OH
AcO
OH
HO
OH
O
O
O
O
8
7
Scheme 2. Retrosynthesis of furanose
Our synthesis commenced with the benzoylation of cis-2-butene-1,4-diol (8), followed by
dihydroxylation with a catalytic amount of osmium tetroxide and N-methylmorpholine N-oxide at room

HETEROCYCLES, Vol. 81, No. 9, 2010
2107
temperature to afford the diol 9 (Scheme 3). Protection of 9 in the presence of 2,2-dimethoxypropane as
its acetonide followed by methanolysis of the resulting dibenzoate afforded the meso-diol 7 as a key
intermediate. The meso-diol 7 was subjected to asymmetric acetylation with lipase AK Amano 20 in vinyl
acetate to give almost optically pure acetate 6.7 The enantiopurity was confirmed by NMR analysis of
both MPA esters of 6 and was determined to be >98% by 1H NMR. Protection of the hydroxyl group of 6
in the presence of tert-butyldimethylsilyl chloride, followed by methanolysis of the resulting TBS ether
gave the alcohol 10. Swern oxidation of the alcohol 10 and Horner-Wadsworth-Emmons reaction of the
resulting aldehyde afforded the ",#-unsaturated ester 11. Reduction of the ester 11 with DIBALH,
followed by protection of the resulting alcohol in the presence of dihydropyran gave 12. Finally, removal
of the TBS group in 12 using tetra-n-butylammonium fluoride and oxidation of the resulting alcohol
under Ley’s condition in the presence of N-methylmorpholine N-oxide, MS 4A and a catalytic amount of
tetra-n-propylammonium perruthenate afforded the aldehyde 5 in 62% yield over 13 steps from the
simple achiral olefin 8.
1) 2,2-dimethoxypropane
1) BzCl, pyridine
p-TsOH, CH2Cl2, 40 oC
CH2Cl2, rt
BzO
OBz
Lipase AK Amano 20
8
7
2) OsO4, NMO
H2O-acetone, rt
vinyl acetate, rt
90%, >98%ee
HO
OH
2) K2CO3, MeOH, rt
96% in 2 steps
9
94% in 2 steps
EtO2C
1) (COCl)2, DMSO
1) TBSCl, imidazole
DMF, rt
HO
OTBS
CH2Cl2, -78 oC, then Et3N
OTBS
6
O
O
O
O
O
2) K2CO3, MeOH, rt
98% in 2 steps
2) (EtO)2P(O)CH2CO2Et
NaH, THF, -78 oC to rt
10
11
94% in 2 steps
OTHP
O
OTHP
1) TBAF
1) DIBALH
THF, 0 oC
H
THF, 5 oC to rt
OTBS
2) TPAP, NMO, MS 4A
CH2Cl2, 5 oC
2) DHP, p-TsOH
O
O
O
CH2Cl2, 0 oC
87% in 2 steps
5
12
96% in 2 steps
Scheme 3. Synthesis of aldehyde 5
With the requisite aldehyde 5 in hand, we next focused on palladium(II)-catalyzed cyclization (Table 1).
On the basis of our previous study, the cyclization was conducted in tetrahydrofuran and PdCl2(PhCN)2
was used as a Pd(II) catalyst.4 When the aldehyde 5 was treated with 5 mol% of PdCl2(PhCN)2 and 5
equivalents of methanol in THF at room temperature, the cyclization proceeded smoothly and the

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HETEROCYCLES, Vol. 81, No. 9, 2010
cycloadduct 4 was isolated as two diastereomers in 65% yield (entry 1). The stereochemistry of these
diastereomers 4A and 4B was established by means of NOE experiments, and (1R,4R) and
(1R,4S)-configurations were assigned, respectively, as shown in Figure 1. Then we investigated the
effects of temperature, amounts of alcohol and Pd(II) catalyst, and additive. When the cyclization was run
o
at 0 C, the reaction was slower and the Pd(II) catalyst was deactivated and precipitated as palladium
black before the substrate 5 was completely consumed. In contrast, when the reaction was conducted at
o
50 C, the substrate 5 was consumed completely in 1 h. Under these conditions (entries 2 and 3), the
cycloadduct 4 was obtained in lower yield. When the cyclization was performed in the presence of 20
equivalents of methanol, the yield of the cycloadduct 4 was not improved (entry 4). Meanwhile, when the
reaction was conducted in the presence of 20 mol% of Pd(II) catalyst or 5 mol% of Pd(II) catalyst, 20
mol% of 1,4-benzoquinone (BQ) as reoxidant and 20 equivalents of methanol, the yield andꢀselectivity
were much lower (entries 5 and 6, respectively).
Table 1. Pd(II)-catalyzed cyclization of hemiacetal derived from 5a
OTHP
O
4
1
PdCl2(PhCN)2
MeOH
OMe
H
O
O
O
THF
O
O
5
4
yieldb
(%)
temp.
(oC)
ratioc
4R:4S
Pd(II)
(mol%)
MeOH additive
time
(h)
entry
(eq.)
(mol%)
5
5+5d
5
5
5
5
-
rt
0
65
57
53
1
2
3
4
5
6
2
4
1
2
3.0:1
2.4:1
3.5:1
3.4:1
-
-
50
rt
5
-
-
64
50
44
20
5
rt
rt
1.5:1
1.1:1
20
5
2
2
20
BQ(20)
a All reactions were conducted in THF (0.02M) under an argon atmosphere.
b Isolated yields.
c The ratio was determined from 600 MHz 1H NMR spectra.
d 5 mol% of Pd(II) catalyst was added twice at 0 min and 2 h.
Although the selectivity of the cyclization was seemingly low under the conditions of entries 5 and 6, this
result was not due toꢀlow selectivity of the cyclization, but reflected more rapid decomposition of the
cycloadduct 4A having (1R,4R)-configuration, as compared with 4B having (1R,4S)-configuration.

HETEROCYCLES, Vol. 81, No. 9, 2010
2109
H
H
H
O
H
O
H
O
1
4
1
4
O
O
OMe
OMe
H
H
H
H
O
4A(1R,4R)
4B(1R,4S)
Figure 1. NOE experiment of 4
We then focused on the further transformation of 4A and 4B into D-ribose and L-lyxose, respectively
(Scheme 4). Ozonolysis of the major cycloadduct 4A followed by in situ reduction with sodium
borohydride afforded the alcohol 13A in 72% yield. Protection of the hydroxyl group of 13A in the
presence of benzyl bromide and a catalytic amount of tetra-n-hexylammonium iodide gave 14A in 97%
yield. Removal of the acetal groups of 14A in the presence of IR-120H, a strong acid ion-exchange resin,
in water afforded the triol 15A in 82% yield.8 Finally, deprotection of the benzyl group in 15A by
hydrogenolysis with Pd/C in ethanol furnished D-ribose in 99% yield. Similarly, 4B was transformed into
L-lyxose in 58% yield over 4 steps.
O
O
4
OMe
OMe
NaH, THF, 5 oC,
O3, MeOH, -78 oC,
then NaBH4, 0 oC
HO
O
O
O
O
then BnBr, n-Hex4NI
5 oC to rt
13A : 4R (72%)
13B : 4S (85%)
4A : 4R
4B : 4S
O
BnO
OMe
O
4
OH
BnO
O
OH
IR-120H
Pd/C, H2
EtOH, rt
HO
O
O
H2O, rt
HO
OH
HO
OH
4R : D-ribose (99%)
4S : L-lyxose (99%)
14A : 4R (97%)
14B : 4S (93%)
15A : 4R (82%)
15B : 4S (74%)
Scheme 4. Syntheses of D-ribose and L-lyxose
A plausible mechanism for the Pd(II)-catalyzed cyclization of hemiacetal derived from the aldehyde 5 is
illustrated in Scheme 5. First of all, deprotection of the tetrahydropyranyl group with methanol in the
presence of the palladium(II) catalyst, which behaves as a Lewis acid, gives the allylic alcohol 16 (Step 1).
Then, the hemiacetal intermediate is formed by the reaction of aldehyde and methanol (Step 2). Pd
!-complex is formed by coordination of PdCl2Ln with the allylic alcohol, and one of the !-faces of the

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HETEROCYCLES, Vol. 81, No. 9, 2010
olefin may be preferentially recognized with the assistance of the adjacent hydroxyl group of the
hemiacetal (Step 3). This complex may be present in equilibrium with four complexes (TS1, TS2, TS3
and TS4) owing to the formation of hemiacetal having other stereochemistry and coordination of PdCl2Ln
with the other !-face of the olefin. Although the conformations TS1 and TS2 are stabilized by anomeric
effect (no-!$c-o), the conformations TS3 and TS4 are not. In addition to this, although the conformations
TS2 and TS4 are destabilized by A1,2 strain, the conformations TS1 and TS2 are not. Therefore, the
cyclization of the hemiacetal derived from aldehyde 4 proceeds preferentially through the preferred
conformation TS1. A syn-attack of the hydroxyl group in the hemiacetal on the electrophilic sp2 carbon in
TS1 occurs intramolecularly from the same side of the Pd-complex in a 5-exo-trigonal fashion to give a
%-Pd complex, followed by syn-elimination of PdCl(OH)Ln to afford furanoside 4A having
(1R,4R)-configuration. In the catalytic cycle, PdCl(OH)Ln may catalyze the reaction by itself or
regenerate PdCl2Ln with chloride ion. For this reason, this Pd(II)-catalyzed cyclization proceeds very
smoothly in the absence of any reoxidant.
Step 3.
coordination of
hemiacetal to Pd(II)
H
O
O
A1,2
OMe
OMe
OMe
H
H
OMe
O
O
Step 4.
cyclization
H
H
O
OH
Cl
OH
O Pd
Cl
O
O
O
O
O
Pd
H
!*c-o
O
no
H
-PdCl(OH)
4A (1R,4R)
major product
4B (1R,4S)
minor product
TS2: destabilization by A1,2
TS1: stabilization
by an anomeric effect
Step 2.
hemiacetal formation
Step 1.
deprotection of THP group
HO
H
THPO
H
O
O
product ratio; 4A : 4B = 3 : 1
in Table 1 entry 1
+MeOH
O
O
O
O
-MeOTHP
16
5
Step 2.
hemiacetal formation
O
O
H
H H
OMe
OMe
H
H
H
H
O
O
O
O
Cl
OH
OH
Pd
O
O
O
O
O Pd
Cl
MeO
O
MeO
TS3
TS4
4C (1S,4R)
not obtained
4D (1S,4S)
not obtained
Scheme 5. Plausible mechanism of Pd(II)-catalyzed cyclization

HETEROCYCLES, Vol. 81, No. 9, 2010
2111
In conclusion, we have developed a novel method for tetrahydrofuran ring construction by means of
PdCl2(PhCN)2-catalyzed cyclization of hemiacetal as a nucleophile, without the need for a reoxidant. This
cyclization proceeds under mild conditions, affording the substituted furanoside, which was used for the
synthesis of pentose. Further application of this methodology to the synthesis of other sugars and natural
products is in progress.
EXPERIMENTAL
General Remarks: All moisture sensitive reactions were carried out under an argon atmosphere.
Anhydrous solvents were obtained as follows: tetrahydrofuran (THF) and dichloromethane were
purchased from Kanto Chemical Co., Ltd.; N,N-dimethylformamide (DMF) and dimethyl sulfoxide
(DMSO) was distilled from CaH2. Triethylamine was distilled from KOH. Column chromatography was
performed with Silica gel 60N and Fuji BW-820. Analytical thin layer chromatography (TLC) was
conducted on precoated TLC plates (silica gel 60F254, Merck) visualized under UV light and stained with
either phosphomolybdic acid or p-anisaldehyde. Melting points were determined with Yanaco micro
melting point apparatus and were uncorrected. IR spectra were measured with a JASCO Model
FT/IR-6100 spectrometer. Mass spectra (MS) and high resolution mass spectra (HRMS) were recorded at
a JEOL JMS-700 or JMS-T100TD spectrometer. Elemental analyses were performed on a Yanaco MT-5.
Optical rotations (["]D) were determined with a JASCO P-1020 polarimeter. 1H NMR spectra were
recorded at 300 MHz with a JEOL JNM-ECX 300 spectrometer or 600 MHz with a JEOL JNM-ECP 600
using tetramethylsilane (TMS) as the internal standard (0.00 ppm). Chemical shifts were reported in ppm
(&) downfield from TMS. The following abbreviations were used to explain the multiplicities: s = singlet,
d = doublet, t = triplet, m = multiplet. 13C NMR spectra were recorded at 75 MHz with a JEOL JNM-ECX
300 spectrometer with chemical shifts reported in ppm (&).
cis-1,4-Dibenzoyloxy-2-butene
To a solution of diol 8 (10.0 g, 114 mmol) and pyridine (26.9 g, 340 mmol) in CH2Cl2 (200 mL) was
added benzoyl chloride (36.7 g, 261 mmol) at 0 oC under an argon atmosphere. The mixture was stirred at
the same temperature for 10 min and warmed up to rt. After stirring at the same temperature for 6 h, the
reaction was quenched with aqueous HCl and ice cooled water. The resulting mixture was extracted with
AcOEt (x 3). The combined organic layers were washed with 5% HCl, water, saturated aqueous NaHCO3
solution and brine, dried over MgSO4, and concentrated in vacuo. The resulting solid was recrystallized
o
1
from n-hexane to afford the dibenzoate (33.6 g, > 99% yield) as colorless plates. mp 59.0-60.0 C; H
NMR (300 MHz, CDCl3) & 8.07-8.04 (m, 4H), 7.56 (tt, J = 11.4, 7.4 Hz, 2H), 7.46-7.41 (m, 4H), 5.96
13
(ddd, J = 5.3, 4.0, 1.1 Hz, 2H), 5.01 (dd, J = 4.0, 1.1 Hz, 4H); C NMR (75 MHz, CDCl3) & 166.3(2C),

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HETEROCYCLES, Vol. 81, No. 9, 2010
133.1(2C), 130.0(2C), 129.7(6C), 128.4(4C), 60.6(2C); IR (KBr, cm-1) 1714, 1267, 708; MS (EI) m/z 175
(12), 149 (7), 105 (100), 77 (28); (DART) m/z 297 ([M+H]+); HRMS-DART calcd. for C18H17O4
([M+H]+) 297.1127, found 297.1155.; Anal. Calcd. for C18H16O4 : C, 72.96, H, 5.44; Found : C, 72.86, H,
5.53.
(2R*,3S*)-1,4-Dibenzoyloxybutane-2,3-diol (9)
To a solution of the dibenzoate (5.00 g, 16.9 mmol) and N-methylmorpholine N-oxide (50% in water,
4.55 mL, 21.9 mmol) in acetone (60 mL) and water (20 mL) was added OsO4 (0.05 mol/ L in t-BuOH,
1.01mL, 0.051 mmol) at rt. The mixture was stirred at the same temperature for 18 h. The precipitate was
filtered, and washed with a minimum quantity of acetone. To the filtrate was added saturated aqueous
Na2S2O3 solution (50 mL) at rt and the quenched mixture was stirred until the organic phase was cleared.
The resulting mixture was concentrated in vacuo. The precipitate was filtered, and washed with a
minimum quantity of acetone and water. The filtrate was extracted with Et2O until the white solid was
dissolved. The combined organic layers were washed with 10% HCl (x 2), water, saturated aqueous
NaHCO3 solution and brine, dried over MgSO4, and concentrated in vacuo to afford the diol 9 as white
solid (5.25 g, 95% yield), which was used for next step without further purification. An aliquot was
o
1
crystallized from AcOEt to give an analytical pure sample. colorless needles; mp 153.0-154.0 C; H
NMR (300 MHz, CDCl3) & 8.09-8.05 (m, 4H), 7.59 (tt, J = 7.4, 1.6 Hz, 2H), 7.48-7.43 (m, 4H), 4.65-4.64
(m, 4H), 4.01-3.99 (m, 2H), 2.95 (d, J = 4.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) & 167.5(2C), 133.4(2C),
129.8(4C), 129.5(2C), 128.5(4C), 70.7(2C), 66.2(2C); IR (KBr, cm-1) 3473, 1693, 1285, 1129, 710; MS
(EI) m/z 269 (7), 227 (5), 195 (13), 177 (9), 165 (63), 123 (29), 105 (100), 75 (79); (DART) m/z 331
([M+H]+); HRMS-DART calcd. for C18H19O6 ([M+H]+) 331.1182, found 331.1185.; Anal. Calcd. for
C18H18O6 : C, 65.45, H, 5.49; Found : C, 65.55, H, 5.57.
(2R*,3S*)-1,4-Dibenzoyloxy-2,3-isopropylidenedioxybutane
To a solution of the diol 9 (400 mg, 1.21 mmol) and p-toluenesulfonic acid (2.1 mg, 0.0121 mmol) in
CH2Cl2 (4 mL) was added 2,2-dimethoxypropane (1.48 mL, 12.1 mmol). The reaction mixture was stirred
at 40 oC for 3 h. After stirring, the mixture was cooled with ice bath and the reaction was quenched with
saturated aqueous NaHCO3 solution. The organic layer was separated and the aqueous phase was
extracted with AcOEt (x 2). The combined organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo to afford the acetonide protected dibenzoate as white solid (440 mg,
98% yield). An aliquot was recrystallized from hexane to give an analytical pure sample. colorless
o
needles; mp 107.0-108.0 C; H NMR (300 MHz, CDCl3) & 8.08-8.03 (m, 4H), 7.56 (tt, J = 7.4, 1.5 Hz,
1
13
2H), 7.47-7.39 (m, 4H), 4.64-4.56 (m, 4H), 4.53-4.45 (m, 2H), 1.52 (s, 3H), 1.42 (s, 3H); C NMR (75
MHz, CDCl3) & 166.2(2C), 133.2(2C), 129.8(4C), 129.7(2C), 128.4(4C), 109.5, 74.8(2C), 62.9(2C), 27.7,

HETEROCYCLES, Vol. 81, No. 9, 2010
2113
25.4; IR (KBr, cm-1) 1714, 1270, 1116, 1082, 711; MS (EI) m/z 356 (39), 355 (89), 235 (36), 178 (28),
177 (93), 126 (52), 105 (100), 77 (73); (DART) m/z 371 ([M+H]+); HRMS-DART calcd. for C21H23O6
([M+H]+) 371.1495, found 371.1497.; Anal. Calcd. for C21H22O6 : C, 68.10, H, 5.99; Found : C, 68.04, H,
6.14.
(2R*,3S*)-2,3-Isopropylidenedioxybutane-1,4-diol (7)
A mixture of the acetonide protected dibenzoate (89.7 g, 242 mmol) and K2CO3 (1.67 g, 12.1 mmol) in
MeOH (242 mL) was stirred at rt for 15 h. The reaction was quenched with 6N HCl. After stirring for 5
min, the mixture was concentrated in vacuo. The residue was purified by silica gel column
chromatography (hexane-AcOEt = 4:1 to AcOEt, gradient) to afford the diol 7 (38.5 g, 98% yield) as a
white solid. mp 35.5-37.0 oC; 1H NMR (300 MHz, CDCl3) & 4.33-4.27 (m, 2H), 3.85-3.74 (m, 4H), 2.46 (t,
J = 4.6 Hz, 2H), 1.48 (s, 3H), 1.38 (s, 3H); 13C NMR (75 MHz, CDCl3) & 108.4, 76.8(2C), 60.9(2C), 27.6,
25.1; IR (KBr, cm-1) 3401, 2988, 2938, 1382, 1218, 1049; MS (EI) m/z 149 (100), 137 (12), 123 (16), 111
(27), 97 (38), 83 (59), 71 (82), 57 (86); (DART) m/z 163 ([M+H]+); HRMS-DART calcd. for C7H15O4
([M+H]+) 163.0970, found 163.0982.
(2S,3R)-4-Acetoxy-2,3-isopropylidenedioxybutanol (6)
A suspension of the diol 5 (406 mg, 2.50 mmol) and Lipase AK Amano 20 (56 mg) in vinyl acetate (0.51
mL, 5.51 mmol) was stirred at rt for 9.5 h under an argon atmosphere. The mixture was diluted with
AcOEt and filtered through a pad of Celite®. The filtrate was concentrated in vacuo. The residue was
purified by silica gel column chromatography (hexane-AcOEt = 3:2) to afford the acetate 6 (463 mg, 90%
yield, >98% ee) as a colorless oil. The enantiopurity of 6 was confirmed by NMR analysis of both MPA
esters. ["]20D 18.3 (c 0.40, CHCl3); 1H NMR (300 MHz, CDCl3) & 4.39 (td, J = 6.9, 4.9 Hz, 1H), 4.33-4.27
(m, 2H), 4.14 (dd, J = 11.7, 7.2 Hz, 1H), 3.80-3.66 (m ,2H), 2.10 (s, 3H), 1.87 (t, J = 6.2 Hz, 1H), 1.50 (s,
3H), 1.39 (s, 3H); 13C NMR (75 MHz, CDCl3) & 170.1, 109.0, 76.9, 74.6, 63.0, 60.9, 27.6, 25.1, 20.9; IR
(neat, cm-1) 3476, 2988, 2938, 1742, 1373, 1240, 1167; MS (EI) m/z 189 (58), 173 (12), 131 (46), 129
(63), 115 (100), 113 (14), 87 (19), 85 (8), 73 (11), 69 (46), 59 (85); (DART) m/z 205 ([M+H]+);
HRMS-DART calcd. for C9H17O5 ([M+H]+) 205.1076, found 205.1069.
(2R, 3S)-4-(tert-Butyldimethylsilyl)oxy-2,3-isopropylidenedioxybutyl acetate
To a solution of the acetate 6 (1.02 g, 4.99 mmol) in N,N-dimethylformamide (5 mL) were added
o
imidazole (815 mg, 12.0 mmol) and t-butyldimethylsilyl chloride (902 mg, 5.99 mmol) at 0 C under an
argon atmosphere. The reaction mixture was stirred at rt for 1.5 h. The reaction mixture was diluted with
Et2O, and washed with water. The aqueous layer was extracted with diethyl ether (x 1). The combined
organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude

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was purified by silica gel column chromatography (hexane-AcOEt = 9:1) to afford the TBS ether (1.58 g,
1
99% yield) as a colorless oil. ["]20 32.7 (c 0.95, CHCl3); H NMR (300 MHz, CDCl3) & 4.47 (dd, J =
D
11.6, 3.1 Hz, 1H), 4.38 (ddd, J = 8.2, 6.3, 2.9 Hz, 1H), 4.20 (dd, J = 6.3, 6.2 Hz, 1H), 4.10 (dd, J = 11.6,
8.2 Hz, 1H), 3.67 (d, J = 6.2 Hz, 2H), 2.10 (s, 3H), 1.46 (s, 3H), 1.37 (s, 3H), 0.90 (s, 9H), 0.074 (s, 3H),
13
0.071 (s, 3H); C NMR (75 MHz, CDCl3) & 170.9. 109.0, 76.8, 75.4, 63.6, 61.5, 27.8, 25.8(3C), 25.3,
21.0, 18.2, -5.5(2C); IR (neat, cm-1) 2987, 2955, 2932, 2858, 1746, 1372, 1250, 1091, 838, 778; MS (EI)
m/z 303 (64), 245 (15), 243 (14), 203 (92), 143 (100), 117 (96), 115 (67), 75 (85), 73 (77); (DART) m/z
319 ([M+H]+); HRMS-DART calcd. for C15H31O5Si ([M+H]+) 319.1941, found 319.1939.
(2R, 3S)-4-(tert-Butyldimethylsilyl)oxy-2,3-isopropylidenedioxybutanol (10)
To a suspension of the TBS ether (37.6 g, 118 mmol) and K2CO3 (1.63 g, 11.8 mmol) in MeOH (190 mL)
was stirred at rt for 3 h. The reaction was quenched with water and the solvent was concentrated in vacuo.
The residue was diluted with AcOEt and water. The organic layer was separated and the aqueous phase
was extracted with AcOEt (x 2). The combined organic layers were washed with brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-AcOEt
= 4:1) to afford the alcohol 10 (32.3 g, 99% yield) as a colorless oil. ["] 20D 3.9 (c 0.85, CHCl3); 1H NMR
(300 MHz, CDCl3) & 4.35 (dt, J = 6.8, 5.8 Hz, 1H), 4.23 (ddd, J = 8.9, 5.9, 4.1 Hz, 1H), 3.87-3.72 (m, 3H),
3.68 (dd, J = 10.7, 4.1 Hz, 1H), 3.01 (dd, J = 8.3, 5.8 Hz, 1H), 1.42 (s, 3H), 1.36 (s, 3H), 0.90 (s, 9H),
13
0.109 (s, 3H), 0.108 (s, 3H); C NMR (75 MHz, CDCl3) & 108.4, 77.4, 76.9, 61.6, 60.8, 27.8, 25.8(3C),
25.2, 18.2, -5.52, -5.58; IR (neat, cm-1) 3490, 2986, 2954, 2931, 2885, 2858, 1254, 1218, 1085, 1057, 837,
778; MS (EI) m/z 261 (16), 161 (71), 131 (96), 117 (89), 75 (100), 73 (78), 59 (51); (DART) m/z 277
([M+H]+); HRMS-DART calcd. for C13H29O4Si ([M+H]+) 277.1835, found 277.1830.
Ethy (E,4R,5S)-6-(tert-Butyldimethylsilyl)oxy-4,5-isopropylidenedioxy-2-hexenoate (11)
To a solution of dimethyl sulfoxide (10.0 mL, 141 mmol) in CH2Cl2 (200 mL) was added oxalyl chloride
o
(6.1 mL, 70.5 mmol) at -78 C under an argon atmosphere. After stirring for 20 min, to the reaction
mixture was added a solution of the alcohol 10 (13.0 g, 47.0 mmol) in CH2Cl2 (20 mL). The suspension
was stirred at the same temperature for 30 min. To the mixture was added Et3N (29.5 mL, 212 mmol) at
o
-78 C, the suspension was warmed to rt and stirred at the same temperature for 30 min. The reaction
mixture was poured into ice cooled water and 10% HCl, and the aqueous phase was extracted with CHCl3
(x 1). The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine,
filtered, and concentrated in vacuo to afford aldehyde (12.9 g) as a yellow color oil, which was
immediately used for the next reaction without further purification. To a suspension of sodium hydride
(60% in oil, 2.63 g, 65.8 mmol) in THF (250 mL) was added triethyl phosphonoacetate (14.1 mL, 70.5
mmol) at 0oC under an argon atmosphere. The mixture was stirred at the same temperature for 30 min. To

HETEROCYCLES, Vol. 81, No. 9, 2010
2115
the mixture was added a solution of aldehyde (12.9 g, 47 mmol) in THF (30 mL) at -78oC, the mixture
was stirred at the same temperature for 10 min and warmed to rt. After stirring at the same temperature
for 10 min, the reaction mixture was diluted with AcOEt and poured into saturated aqueous NH4Cl
solution. The aqueous phase was extracted with AcOEt (x 2). The combined organic layers were washed
with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column
chromatography (hexane-AcOEt = 20:1) to afford the ",#-unsaturated ester 11 (15.2 g, 94% yield in 2
steps) as a colorless oil. ["]20D 7.8 (c 0.74, CHCl3); 1H NMR (300 MHz, CDCl3) & 6.99 (dd, J = 15.8, 5.2
Hz, 1H), 6.12 (dd, J =15.8, 1.5 Hz, 1H), 4.81 (ddd, J = 6.9, 5.2, 1.5 Hz, 1H), 4.29 (ddd, J = 8.0, 6.9, 4.6
Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.63 (dd, J = 10.1, 4.6 Hz, 1H), 3.53 (dd, J = 10.1, 8.0 Hz, 1H), 1.49 (s,
3H), 1.38 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 0.88 (s, 9H), 0.042 (s, 3H), 0.036 (s, 3H); 13C NMR (75 MHz,
CDCl3) & 166.0, 143.1, 122.3, 109.2, 78.3, 76.6, 61.8, 60.4, 27.6, 25.8(3C), 25.2, 18.2, 14.3, -5.6(2C); IR
(neat, cm-1) 2985, 2955, 2931, 2886, 2858, 1724, 1257, 1162, 1097, 839, 778; MS (EI) m/z 344 (M+, 7),
343 (28), 127 (100), 117 (86), 89 (54), 75 (68), 73 (72); (DART) m/z 345 ([M+H]+); HRMS-DART calcd.
for C17H33O5Si ([M+H]+) 345.2097, found 345.2105.
(E,4R,5S)-6-(tert-Butyldimethylsilyl)oxy-4,5-isopropylidenedioxy-2-hexenol
To a solution of the ester 11 (1.10 g, 3.20 mmol) in THF (16 mL) was added DIBALH (0.98 M in
o
n-hexane, 6.6 mL, 6.4 mmol) at 0 C under an argon atmosphere. The mixture was stirred at the same
temperature for 1.5 h. The reaction was quenched sequentially with methanol, ice cooled water and 10%
HCl. The aqueous phase was extracted with AcOEt (x 3), the combined organic layers were washed with
saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by silica gel column chromatography (hexane-AcOEt = 3:1) to afford the alcohol
(0.98 g, 99% yield) as a colorless oil. ["]20D 8.1 (c 0.72, CHCl3); 1H NMR (300 MHz, CDCl3) & 5.97 (dt, J
= 15.5, 5.2 Hz, 1H), 5.80 (dd, J = 15.5, 7.3 Hz, 1H), 4.67 (dd, J = 7.3, 6.3 Hz, 1H), 4.22-4.16 (m, 3H),
3.61 (d, J = 6.3 Hz, 2H), 1.47 (s, 3H), 1.37 (s, 3H), 1.31 (t, J = 6.2 Hz, 1H), 0.88 (s, 9H), 0.06 (s, 3H),
13
0.05 (s, 3H); C NMR (75 MHz, CDCl3) & 133.0, 126.7, 108.6, 78.5, 77.9, 63.0, 62.2, 27.9, 25.9(3C),
25.4, 18.3, -5.4(2C); IR (neat, cm-1) 3424, 2954, 2930, 2857, 1253, 1100, 838, 777; MS (EI) m/z 302 (M+,
3), 301(10), 201(13), 187(31), 169(26), 157(19), 117(62), 89(36), 75(100), 73(56), 59(29) ; (DART) m/z
303 ([M+H]+); HRMS-DART calcd. for C15H31O4Si ([M+H]+) 303.1992, found 303.1994.
(E,4R,5S)-6-(tert-Butyldimethylsilyl)oxy-4,5-isopropylidenedioxy-1-(tetrahydropyran-2-yl)oxy-2-
hexene (12)
To a solution of the alcohol (8.30 g, 27.4 mmol) in CH2Cl2 (125 mL) were added p-toluenesulfonic acid
o
(240 mg, 1.37 mmol) and 2H-dihydropyran (3.8 mL, 41.2 mmol) at 0 C under an argon atmosphere.
After stirring at the same temperature for 1 h, the reaction mixture was diluted with CHCl3 and the

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HETEROCYCLES, Vol. 81, No. 9, 2010
reaction was quenched with saturated aqueous NaHCO3 solution. The aqueous phase was extracted with
CHCl3 (x 2), and the combined organic layers were washed with brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-AcOEt =
20:1) to afford the THP ether 12 (10.3 g, 97% yield as diastereomer mixtures) as a colorless oil. 1H NMR
(300 MHz, CDCl3) & 5.90 (dt, J = 15.9, 5.1 Hz, 1H), 5.79 (dd, J = 15.9, 6.2 Hz, 1H), 4.68-4.65 (m, 2H),
4.29-4.23 (m, 1H), 4.18 (dd, J = 12.5, 6.2 Hz, 1H), 3.99 (dt, J = 12.5, 5.4 Hz, 1H), 3.89-3.82 (m, 1H),
3.61 (d, J = 5.4 Hz, 2H), 3.54-3.47 (m, 1H), 1.81 - 1.67 (m, 6H), 1.47 (s, 3H), 1.37 (s, 3H), 0.88 (s, 9H),
0.054 (s, 3H), 0.049 (s, 3H); IR (neat, cm-1) 2936, 2857, 1119, 1097, 1079, 1026, 837, 777.
(E,2S,3R)-2,3-Isopropylidenedioxy-6-(tetrahydro-2H-pyran-2-yl)oxy-4-hexenol
To a solution of the THP ether 12 (21.0 g, 54.3 mmol) in THF (200 mL) was added tetra-n-butyl-
o
ammonium fluoride (1.0 M in THF, 81.5 mL, 81.5 mmol) at 5 C under an argon atmosphere. The
reaction mixture was stirred at the same temperature for 10 min, and then warmed to rt. After stirring at
the same temperature for 2 h, the mixture was diluted with Et2O, and washed with water. The aqueous
phase was extracted with Et2O (x 5). The combined organic layers were washed with brine, dried over
MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column
chromatography (hexane-AcOEt = 7:3 to 1:1, gradient) to afford the alcohol (14.1 g, 95% yield) as a
1
colorless oil. H NMR (300 MHz, CDCl3) & 6.01-5.92 (m, 1H), 5.83-5.74 (m, 1H), 4.70 (t, J = 6.9 Hz,
1H), 4.63 (d, J = 2.1 Hz, 1H), 4.23 (dt, J = 13.0, 6.0 Hz, 2H), 4.05 (dt, J = 13.4, 6.5 Hz, 1H), 3.89-3.82 (m,
1H), 3.60-3.57 (m, 2H), 3.54-3.47 (m, 1H), 2.05-1.53 (m, 7H), 1.51 (s, 3H), 1.39 (s, 3H); IR (neat, cm-1)
3419, 2943, 2873, 1714, 1372, 1218, 1123, 1074, 1035, 975, 756; MS (DART) m/z 273 ([M+H]+);
HRMS-DART calcd. for C14H25O5 ([M+H]+) 273.1702, found 273.1702.
(E,2S,3R)-2,3-Isopropylidenedioxy-6-(tetrahydro-2H-pyran-2-yl)-4-hexenal (5)
To a suspension of the alcohol (1.05 g, 3.86 mmol) and MS 4A (2.00 g) in CH2Cl2 (50 mL) was added
N-methylmorphorine N-oxide (905 mg, 7.71 mmol), then the mixture was stirred for 1 h at rt. To the
mixture was added tetra-n-propylammnomium perruthenate (67 mg, 1.93 mmol) at 5 oC, and the mixture
was stirred at the same temperature for 40 min. The mixture was diluted with CH2Cl2, filtered through a
pad of Celite® and the pad was washed with CH2Cl2. The filtrate was washed with saturated aqueous
Na2S2O3 solution, 1N HCl and brine, dried over MgSO4 and concentrated in vacuo. The residue was
purified by silica gel column chromatography (hexane-AcOEt = 1:1) to afford the aldehyde 5 (960 mg,
92% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3) & 9.57 (d, J = 3.1 Hz, 1H), 6.01 (dt, J = 15.3, 5.2
Hz, 1H), 5.67 (dddd, J = 15.3, 7.4, 2.9, 1.5 Hz, 1H), 4.89 (t, J = 7.2 Hz, 1H), 4.62-4.59 (m, 1H), 4.41 (dd,
J = 7.4, 2.9 Hz, 1H), 4.30-3.78 (m, 3H), 3.55-3.45 (m, 1H), 1.88-1.35 (m, 6H), 1.63 (s, 3H), 1.44 (s, 3H);
IR (neat, cm-1) 2984, 2940, 2871, 1736, 1382, 1218, 1119, 1068, 1025, 973, 870; MS (DART) m/z 271

HETEROCYCLES, Vol. 81, No. 9, 2010
2117
([M+H]+); HRMS-DART calcd. for C14H23O5 ([M+H]+) 271.1546, found 273.1545.
(3R,4R)-3,4-Isopropylidenedioxy-5-methoxy-2-vinyltetrahydrofuran (4)
To a solution of the aldehyde 5 (200 mg, 0.740 mmol) and MeOH (119 mg, 3.70 mmol) in THF (37 mL)
was added PdCl2(PhCN)2 (14 mg, 0.037 mmol) at rt under an argon atmosphere, then the mixture was
stirred at the same temperature for 2 h. The reaction mixture was filtered through a pad of Florisil®, the
pad was washed with AcOEt, and the filtrate was concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexane-AcOEt = 10:1) to afford the olefin 4 (104 mg, 70% yield) as a
colorless oil. (2R,3R,4R,5R)-4A;colorless oil; ["]20D -52.6 (c 0.84, CHCl3); 1H NMR (300 MHz, CDCl3) &
5.88 (ddd, J = 17.9, 10.0, 8.0 Hz, 1H), 5.27 (ddd, J =17.9, 1.3, 1.2 Hz, 1H), 5.16 (ddd, J =10.0, 1.3, 1.2
Hz, 1H), 4.99 (s, 1H), 4.631 (d, J = 8.0 Hz, 1H), 4.626 (s, 2H), 3.35 (s, 3H), 1.50 (s, 3H), 1.32 (s, 3H); 13C
NMR (75 MHz, CDCl3) & 137.6, 117.3, 112.3, 109.3, 88.4, 85.5, 84.6, 54.6, 26.5, 25.0; IR (neat, cm-1)
2988, 2938, 2833, 1373, 1210, 1105, 1057, 1031, 868; MS (EI) m/z 280 (7), 279 (16), 243 (7), 225 (5),
205 (10), 185 (18), 169 (26), 167 (29), 165 (24), 149 (100), 111 (31); (DART) m/z 201 ([M+H]+);
HRMS-DART calcd. for C10H17O4 ([M+H]+) 201.1127, found 201.1129. (2S,3R,4R,5R)-4B; colorless oil;
1
["]20 -24.6 (c 0.83, CHCl3); H NMR (300 MHz, CDCl3) & 6.00 (ddd, J = 17.5, 10.3, 7.3 Hz, 1H),
D
5.45-5.38 (m, 1H), 5.37-5.32 (m, 1H), 4.92 (s, 1H), 4.68 (dd, J = 5.8, 3.7 Hz, 1H), 4.58 (d, J = 5.8 Hz,
1H), 4.39 (dd, J = 7.3, 3.7 Hz, 1H), 3.35 (s, 3H), 1.47 (s, 3H), 1.32 (s, 3H); 13C NMR (75 MHz, CDCl3) &
132.3, 119.1, 112.6, 107.2, 85.3, 81.5, 81.1, 54.7, 26.1, 24.9; IR (neat, cm-1) 2989, 2937, 1373, 1211,
1104, 1021, 758; MS (EI) m/z : 279 (21), 243 (3), 239 (2), 205 (3), 185 (27), 167 (29), 149 (100), 125
(13), 111 (14); (DART) m/z 201 ([M+H]+); HRMS-DART calcd. for C10H17O4 ([M+H]+) 201.1127, found
201.1123.
((2R,3R,4R,5R)-(3,4-Isopropylidenedioxy-5-methoxy-2-tetrahydrofuranyl))methanol (13A)
A gas of O3 was bubbled into a solution of the olefin 4A (300 mg, 1.50 mmol) in MeOH (10 mL) at -78
oC for 30 min, then O2 was bubbled into the reaction mixture until the blue color solution was cleared. To
the reaction mixture was added NaBH4 (85 mg, 2.25 mmol) at 0oC and the mixture was stirred at rt for 22
h. The mixture was concentrated in vacuo, the residue was diluted with AcOEt and quenched with 1N
HCl. The aqueous phase was extracted with AcOEt. The combined organic layers were washed with
saturated aqueous NaHCO3 solution and brine, dried over MgSO4, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (hexane- AcOEt = 3:1) to afford the alcohol 13A (220
mg, 72% yield) as a colorless oil. ["]20D -72.2 (c 1.02, CHCl3); 1H NMR (300 MHz, CDCl3) & 4.98 (s, 1H),
4.84 (d, J = 5.8 Hz, 1H), 4.59 (d, J = 5.8 Hz, 1H), 4.44 (dd, J = 3.1, 2.7 Hz, 1H), 3.70 (ddd, J = 14.3, 2.7,
2.7 Hz, 1H), 3.61 (ddd, J = 14.3, 10.3, 3.1 Hz, 1H), 3.44 (s, 3H), 3.23 (dd, J = 10.3, 2.7 Hz, 1H), 1.49 (s,
3H), 1.32 (s, 3H); 13C NMR (75 MHz, CDCl3) & 112.1, 109.9, 88.3, 85.8, 81.4, 63.9, 55.5, 26.3, 24.6; IR

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HETEROCYCLES, Vol. 81, No. 9, 2010
(neat, cm-1) 3447, 2988, 2941, 1383, 1374, 1211, 1093, 1044, 871; MS (EI) m/z 259 (2), 203 (2), 201 (4),
189 (91), 173 (100), 157 (55), 129 (29), 115 (36), 113 (82); (DART) m/z 205 ([M+H]+); HRMS-DART
calcd. for C9H17O5 ([M+H]+) 205.1076, found 205.1080.
((2S,3R,4R,5R)-(3,4-Isopropylidenedioxy-5-methoxy-2-tetrahydrofuranyl))methanol (13B)
A gas of O3 was bubbled into a solution of the olefin 4B (150 mg, 0.75 mmol) in MeOH (8 mL) at -78oC
for 30 min, then O2 was bubbled into a reaction mixture until the blue color solution was cleared. To the
reaction mixture was added NaBH4 (43 mg, 1.12 mmol) at 0 oC and the mixture was warmed to rt. After
stirring at the same temperature for 21 h, the mixture was concentrated in vacuo. The residue was diluted
with AcOEt and 1N HCl. The aqueous phase was extracted with AcOEt (x 3). The combined organic
layers were washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4 and
concentrated in vacuo. The crude oil was purified by silica gel column chromatography (hexane-AcOEt =
4:1 to 2:1, gradient) to afford the alcohol 13B (153 mg, < 85% yield) as an inseparable mixture which
was colorless oil. 13C NMR (75 MHz, CDCl3) & 112.7, 107.0, 85.2, 80.4, 79.2, 61.1, 54.7, 25.9, 24.5.
(2R,3R,4R,5R)-2-Benzyloxymethyl-3,4-isopropylidenedioxy-5-methoxytetrahydrofuran (14A)
To a solution of the alcohol 13A (1.00 g, 4.90 mmol) in THF (50 mL) was added NaH (235 mg, 5.39
mmol) at 5oC, then the mixture was stirred at rt for 1 h. To a suspension were added a solution of benzyl
bromide (1.17 g, 6.86 mmol) and tetra-n-hexylammonium iodide (236 mg, 0.49 mmol) at 5oC, then the
mixture was stirred at rt for 4.5 h. The reaction mixture was cooled with ice bath and the reaction was
quenched with saturated aqueous NH4Cl solution. The aqueous phase was extracted with AcOEt (x 2).
The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in
vacuo. The crude oil was purified by silica gel column chromatography (hexane-AcOEt = 15:1) to afford
the benzyl ether 14A (1.40 g, 97% yield) as a yellow oil. ["]20D -52.2 (c 1.94, CHCl3); 1H NMR (300 MHz,
CDCl3) & 7.36-7.28 (m, 5H), 4.96 (s, 1H), 4.68 (dd, J = 5.8, 1.0 Hz, 1H), 4.57 (d, J = 5.8 Hz, 1H), 4.56 (s,
2H), 4.38 (ddd, J = 8.8, 7.8, 1.0 Hz, 1H), 3.53 (dd, J = 8.8, 6.5 Hz, 1H), 3.46 (dd, J = 7.8, 1.0 Hz, 1H),
3.29 (s, 3H), 1.49 (s, 3H), 1.32 (s, 3H); 13C NMR (75 MHz, CDCl3) & 138.0, 128.4(3C), 127.7(2C), 112.4,
109.3, 85.19, 85.18, 82.2, 73.3, 71.1, 54.8, 26.5, 25.0; IR (neat, cm-1) 2988, 2938, 2862, 1455, 1382, 1373,
1211, 1109, 1062, 871, 739, 699; MS (EI) m/z 279 (26), 248 (31), 247 (100), 173 (36), 157 (26), 115 (30),
113 (33), 107 (42); (DART) m/z 295 ([M+H]+); HRMS-DART calcd. for C16H23O5 ([M+H]+) 295.1546,
found 295.1548.
(2S,3R,4R,5R)-2-Benzyloxymethyl-3,4-isopropylidenedioxy-5-methoxytetrahydrofuran (14B)
To a solution of the alcohol 13B (180 mg, 0.88 mmol) in THF (8.8 mL) was added NaH (64 mg, 1.59
mmol) at rt, then the mixture was stirred at the same temperature for 30 min. To a suspension were added

HETEROCYCLES, Vol. 81, No. 9, 2010
2119
a THF solution of benzyl bromide (316 mg, 1.85 mmol) and tetra-n-hexylammonium iodide (42 mg, 0.09
mmol) at rt, then the mixture was stirred at the same temperature for 23 h. The reaction was quenched
with saturated NH4Cl solution, then the aqueous phase was extracted with AcOEt (x 2). The combined
organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude
oil was purified by silica gel column chromatography (hexane-AcOEt = 10:1) to afford the benzyl ether
1
14B (242 mg, 93% yield) as a yellow oil. ["]20 - 31.9 (c 0.72, CHCl3); H NMR (300 MHz, CDCl3) &
D
7.38-7.26 (m, 5H), 4.92 (s, 1H), 4.72 (dd, J = 5.8, 3.8 Hz, 1H), 4.67 (d, J = 12.0 Hz, 1H), 4.55 (d, J =12.0
Hz, 1H), 4.55 (d, J = 5.8 Hz,1H), 4.17 (ddd, J = 7.1, 4.2, 3.8 Hz, 1H), 3.83 (dd, J = 10.3, 4.2 Hz, 1H),
13
3.70 (dd, J = 10.5, 7.1 Hz, 1H), 3.34 (s, 3H), 1.43 (s, 3H), 1.30 (s, 3H); C NMR (75 MHz, CDCl3) &
138.2, 128.4(2C), 127.8(2C), 127.6, 112.6, 107.3, 84.9, 80.0, 79.0, 73.5, 68.3, 54.7, 26.1, 24.9; IR (neat,
cm-1) : 2989, 2936, 1455, 1373, 1210, 1102, 874, 739, 698; MS (EI) m/z 279 (10), 178 (18), 145 (9), 107
(20), 92 (23), 91 (100), 87 (22), 77 (15), 55 (15); (DART) m/z 295 ([M+H]+); HRMS-DART calcd. for
C16H23O5 ([M+H]+) 295.1546, found 295.1544.
5-O-Benzyl-D-ribose (15A)
To a suspension of the benzyl ether 14A (260 mg, 0.88 mmol) in water (8.8 mL) was added Amberlite
IR-120H (2.00 g) at rt, then the mixture was stirred at rt for 28 h. The mixture was saturated with NaCl
and AcOEt was added to the mixture. After vigorously stirring for 5 min, the mixture was filtered and the
aqueous phase was extracted with AcOEt (x 3). The combined organic layers were washed with brine,
dried over MgSO4, filtered and concentrated in vacuo. The crude oil was purified by silica gel column
chromatography (hexane-AcOEt = 1:10) to afford the triol 15A (173 mg, 82% yield) as a white solid.
["]20D 38.2 (c 0.86, CHCl3); 1H NMR (300 MHz, CD3OD) & 7.38-7.23 (m, 5H), 5.23 (d, J = 3.6 Hz, 0.3H),
5.12 (s, 0.7H), 4.58 (s, 1.4H), 4.54 (s, 0.6H), 4.14-4.07 (m, 1H), 4.03-3.93 (m, 1.4H), 3.81 (dd, J = 4.8,1.0
13
Hz, 0.6H), 3.69 (dd, J = 10.5, 3.6 Hz, 0.6H), 3.63-3.52 (m, 1.4H); C NMR (75 MHz, CD3OD) & major
epimer : 139.6, 129.4(2C), 128.9(2C), 128.8, 103.3, 82.8, 77.0, 74.4, 73.3, 72.8; minor epimer : 139.6,
129.4(2C), 128.69, 128.66(2C), 98.0, 83.4, 74.4, 72.43, 72.38, 71.6; IR (KBr, cm-1) 3421, 3309, 2937,
2867, 1456, 1246, 1128, 1091, 1051, 1010, 948, 933, 844, 743, 698; MS (EI) m/z 222 (6), 149 (5), 131 (7),
107 (41), 92 (47), 91 (100), 73 (19), 65 (25); (DART) m/z 241 ([M+H]+); HRMS-DART calcd. for
C12H17O5 ([M+H]+) 241.1076, found 241.1167.
5-O-Benzyl-L-lyxose (15B)
To a suspension of the benzyl ether 14B (200 mg, 0.68 mmol) in water (5.1 mL) and 1,4-dioxane (5.1
mL) was added Amberlite IR-120H (2.00 g) at rt, then the mixture was stirred at rt for 106 h. The reaction
mixture was filtered, the residue was washed with 1,4-dioxane and the filtrate was concentrated in vacuo.
The crude oil was purified by silica gel column chromatography (hexane-AcOEt = 1:9) to afford the triol

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HETEROCYCLES, Vol. 81, No. 9, 2010
15B (121 mg, 74 % yield) as a colorless oil. ["]20D -36.9 (c 0.53, CHCl3); 1H NMR (300 MHz, CD3OD) &
7.28-7.12 (m, 5H), 5.08 (d, J = 3.2 Hz, 0.65H), 5.01 (d, J = 4.7 Hz, 0.35H), 4.48-4.43 (m, 2H), 4.25-4.16
(m, 1.65H), 3.90 (t, J = 4.8 Hz, 0.35H), 3.81 (dd, J = 4.3, 3.2 Hz, 0.65H), 3.72 (dd, J = 10.0, 4.7 Hz,
13
0.35H), 3.64 (dd, J = 10.7, 4.3 Hz, 0.65H), 3.63-3.47 (m, 0.7H), 3.53 (dd, J = 10.7, 6.2 Hz, 0.65H) C
NMR (75 MHz, CD3OD) & major epimer : 139.6, 129.4(2C), 129.0(2C), 128.7, 103.0, 80.0, 78.6, 74.4,
72.6, 70.5; minor epimer : 139.5, 128.94(2C), 128.91, 128.87, 128.7, 97.6, 80.5, 74.3, 73.5, 72.1, 71.4; IR
(neat, cm-1): 3388, 2926, 2870, 2514, 1076, 1027, 742, 699; MS (EI) m/z: 178 (3), 149 (4), 108 (9), 107
(23), 92 (13), 91 (100), 79 (10), 77 (11), 65 (10); (DART) m/z 241 ([M+H]+); HRMS-DART calcd. for
C12H17O5 ([M+H]+) 241.1076, found 241.1079.
D-Ribose
To a solution of the triol 15A (50 mg, 0.21 mmol) in EtOH (2.1 mL) was added Pd/C (5 mg), then the
reaction vessel was evacuated and back-filled with H2 (x 5). After stirring at rt for 51 h, the mixture was
filtered through a pad of Celite® and the pad was washed with MeOH. The filtrate was concentrated in
vacuo. The crude material was purified by silica gel column chromatography (MeOH) to afford D-ribose
1
(31 mg, >99 % yield) as a colorless amorphous solid. ["]20 -23.5 (c 1.50, MeOH); H NMR (300 MHz,
D
CD3OD) & 4.91 (d, J = 4.8 Hz, 0.8H), 4.76 (d, J = 2.1 Hz, 0.2H), 3.91 (dd, J = 3.1, 2.7 Hz, 0.8H),
3.88-3.52 (m, 2.4H), 3.83 (dd, J = 8.4, 2.7 Hz, 0.8H), 3.49 (d, J = 3.1 Hz, 0.2H), 3.46-3.43 (m, 0.8H); 13C
NMR (75 MHz, CD3OD) & major epimer : 96.0, 73.3, 70.2, 69.2, 64.6; minor epimer : 95.3, 72.1, 71.3,
69.0, 64.6; MS (EI) m/z: 149 (1), 119 (5), 101 (5), 86 (18), 73 (100), 71 (21), 61 (19), 60 (58), 57 (15).
L-Lyxose
To a suspension of the triol 15B (36 mg, 0.15 mmol) in EtOH (2.5 mL) was added Pd/C (5 mg), then the
reaction vessel was evacuated and back-filled with H2 (x 5). After stirring for 19.5 h at rt, the mixture was
filtered over a pad of Celite® and the pad was washed with EtOH. The filtrate was concentrated in vacuo.
The crude material was purified by silica gel column chromatography (MeOH) to afford L-lyxose (23 mg,
>99 % yield) as a colorless amorphous solid. ["]20D 8.6 (c 1.13, MeOH); 1H NMR (300 MHz, CD3OD) &
4.83 (d, J = 3.4 Hz, 0.8H), 4.71 (br s, 0.2H), 3.88 (dd, J = 11.9, 3.6 Hz, 0.2H), 3.72-3.47(m, 5.6H), 3.14
13
(dd, J = 11.7, 6.9 Hz, 0.2H); C NMR (75 MHz, CD3OD) & major epimer : 96.0, 72.5, 72.2, 69.2, 64.3;
minor epimer : 96.0, 74.4, 70.1, 69.3, 64.1; MS (EI) m/z: 149 (1), 119 (6), 101 (6), 91 (7), 86 (8), 73 (100),
71 (21), 61 (28), 60 (63), 57 (16).
ACKNOWLEDGEMENTS
This study was financially supported by a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science, and Technology of Japan.

HETEROCYCLES, Vol. 81, No. 9, 2010
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