A new synthetic strategy for 2-deoxy-D-ribose via palladium(II)-catalyzed cyclization of aldehyde

Article abstract of DOI:10.3987/COM-10-11988

We achieved a total synthesis of 2-deoxy-D-ribose through intramolecular Pd(II)-catalyzed cyclization of aldehyde via an unstable hemiacetal intermediate as a key step. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-11988

HETEROCYCLES, Vol. 81, No. 8, 2010
1891
HETEROCYCLES, Vol. 81, No. 8, 2010, pp. 1891 - 1902. © The Japan Institute of Heterocyclic Chemistry
Received, 8th June, 2010, Accepted, 24th June, 2010, Published online, 25th June, 2010
DOI: 10.3987/COM-10-11988
A NEW SYNTHETIC STRATEGY FOR 2-DEOXY-D-RIBOSE VIA
PALLADIUM(II)-CATALYZED CYCLIZATION OF ALDEHYDE
Masahiro Miyazawa,* Ken-ichiro Awasaguchi, Ikuyo Uoya, 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 – We achieved a total synthesis of 2-deoxy-D-ribose through
intramolecular Pd(II)-catalyzed cyclization of aldehyde via an unstable hemiacetal
intermediate as a key step.
INTRODUCTION
Carbohydrates are the most abundant organic compounds in nature, and 2-deoxy-D-ribose is a constituent
of DNA. 1-Substituted 2-deoxy-D-riboses also possess diverse biological activities.1 These compounds
have been constructed in a wide variety of ways.2 We previously developed a stereoselective construction
of polysubstituted heterocyclic compounds using palladium(II)-catalyzed intramolecular cyclization.3 We
have also reported cyclization via a hemiacetal intermediate using a palladium(II) catalyst and found a
stereoselective method for the construction of trisubstituted tetrahydropyran.4 We report here a synthesis
of 2-deoxy-D-ribose by using this methodology.
Oi-Pr
CHO
PdCl2(PhCN)2
O
i-PrOH, THF
Ph
OTHP
Ph
Scheme 1. Palladium(II)-catalyzed cyclization of the aldehyde
RESULTS AND DISCUSSION
Our retrosynthetic analysis of 2-deoxy-D-ribose (1) is shown in Scheme 2. 2-Deoxy-D-ribose would be
formed from the 4-vinylfuranoside 2. The construction of 2 could be achieved by palladium(II)-catalyzed
heterocyclization of the aldehyde 3 and benzyl alcohol. The aldehyde 3 can be easily prepared from
L-(-)-malic acid (4).

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HETEROCYCLES, Vol. 81, No. 8, 2010
OTHP
O
O
OH
OBn
O
HO2C
H
CO2H
HO
OH
HO
2-deoxy-D-ribose (1)
BnO
BnO
L-(-)-malic acid (4)
2
3
Scheme 2. Retorosynthetic analysis for 2-deoxy-D-ribose (4)
The synthesis of the key intermediate 3 is shown in Scheme 3. The benzylideneacetal 5 was prepared
according to the reported procedure in two steps from L-(-)-malic acid (4).5 Oxidation of 5 by Swern
oxidation followed by Horner-Wadsworth-Emmons reaction (triethyl phosphonoacetate, NaH) afforded
the (E)-ꢀ,ꢁ-unsaturated ester 6 in 78% yield. Reduction (DIBALH) of 6 followed by protection of the
resulting alcohol with DHP furnished the THP-ether 7. DIBALH reduction of 7 and oxidation of the
resulting primary alcohol with Dess-Martin periodinane gave the aldehyde 3.6
1) BH3•SMe2, B(OMe)3
THF, 0 oC to rt
1) (COCl)2, DMSO
-78 oC, then Et3N
EtO2C
HO
O
O
4
O
O
2) PhCH(OMe)2
2) (EtO)2P(O)CH2CO2Et
NaH, THF, -78 oC to rt
78% in 2 steps
Ph
p-TsOH, CH2Cl2, rt
Ph
5
85% in 2 steps
6
OTHP
1) DIBALH, toluene
0 oC to rt
1) DIBALH
OTHP
THF, -78 oC
CHO
O
O
2) DMP, CH2Cl2
0 oC to rt
2) DHP, p-TsOH
CH2Cl2, 0 oC to rt
88% in 2steps
OBn
Ph
3
78% in 2 steps
7
Scheme 3. Preparation of the aldehyde 3
We examined the cyclization of the aldehyde 3 with a variety of alcohols (Table 1). Initially, treatment of
the aldehyde 3 with 5 mol% of PdCl2(MeCN)2 catalyst and 5 equiv. of MeOH in THF at room
temperature furnished the cyclized products 2 as a 4.6 : 3.0 : 1.0 mixture of 2a : 2b : 2c in 40% isolated
yield (entry 1). When i-PrOH was used, the ratio of 4R-isomer : 4S-isomer (2a + 2b : 2c) was increased to
10.8 : 1 (entry 2). However, when t-BuOH was used, no reaction was observed (entry 3), and bezyl
alcohol was found to give the best result (entry 5). The ratio of 1R-isomer : 1S-isomer (2a + 2c : 2b) was
almost 1.8 : 1 in any reaction conditions. On the other hand, 4R-isomer formed in the predominance more
than 4S-isomer (4R-isomer : 4S-isomer = 6~11 : 1).

HETEROCYCLES, Vol. 81, No. 8, 2010
1893
Table 1. Pd(II)-catalyzed cyclization of the aldehyde 3
OTHP
O
O
O
1
ROH, PdCl2(MeCN)2
OR
OR
OR
4
O
+
+
H
THF, rt, 1 h
BnO
BnO
BnO
BnO
2a
2b
2c
3
ratio
alcohol
Pd(II)
(mol%)
yield
(%)
entry
1R,4R : 1S,4R : 1R,4S
2a : 2b : 2c
R
(eq.)
1
2
3
5
5
5
Me
i-Pr
t-Bu
5
5
5
40
41
-
4.6 : 3.0 : 1
6.7 : 4.1 : 1
-
4
5
6
7
5
5
Bn
Bn
Bn
Bn
5
3
2
3
51
55
37
45
4.5 : 3.1 : 1
5.2 : 3.8 : 1
3.8 : 2.6 : 1
3.7 : 2.5 : 1
5
10
a All reactions were conducted in THF (0.2M) under an argon atmosphere.
b Isolated yields. c The ratio was determined by 600 MHz 1H NMR spectra.
The stereochemistry of these diastereomers 2a~c could not be determined at this point. In order to
determine the relative stereochemistry, the cyclized products 2a~c were converted to the corresponding
primary alcohols 8a~c (Scheme 4). Our initial attempts to achieve double bond oxidation of the cyclized
products 2a~c by ozonolysis led to low yields of the desired aldehyde. After several attempts, we found
that oxidation of 2a~c proceeded smoothly in the presence of sodium periodate and a catalytic amount of
osmium tetroxide in dioxane / H2O to give the corresponding aldehydes. Treatment of these aldehydes
with NaBH4 in MeOH gave the primary alcohols 8a~c in moderate yield for the two-step sequence. The
alcohols 8a~c could be separated by silica gel column chromatography.
1) OsO4, NaIO4
HO
2,6-lutidine
O
O
OBn
OBn
dioxane-H2O, rt
2) NaBH4, MeOH
5 oC to rt
53% in 2 steps
BnO
2a, b, c
inseparable mixture
BnO
8a, b, c
separable diastereomer
Scheme 4. Transformation of 2 to the primary alcohols 8

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HETEROCYCLES, Vol. 81, No. 8, 2010
The relative stereochemistry of 8a~c was established by NOE experiments. For example, as shown in
Figure 1, NOE correlations were observed between the C-3 hydrogen and the C-2 ꢀ-hydrogen, and
between the C-2 ꢀ-hydrogen and the C-1 hydrogen.
H
H
H
H
H
H
O
O
OBn
O
OBn
4
1
OBn
1
4
4
HO
1
2
HO
HO
2
H
H
2
3
H
H
H
H
3
3
H
BnO
BnO
H
H
BnO
NOE
8a(1R,4R)
8b(1S,4R)
8c(1R,4S)
Figure 1. NOE correlations in the furanosides 8a-c
The stereochemistry of the cyclized products formed in the palladium-catalyzed cyclization depends on
various factors. A plausible mechanism for the cyclization of the aldehyde 3 is shown in Scheme 5.
Initially, the aldehyde 3 is converted into the alcohol 9 (step 1). The hemiacetal intermediate is formed by
1,2-addition of benzyl alcohol to the aldehyde 9 (step 2). The olefin and hydroxyl groups of the allylic
alcohol and hemiacetal coordinate with the palladium complex (step 3). The resulting complex may be
present as an equilibrium mixture of four forms (TS1, TS2, TS3, and TS4). TS1 and TS2 are favored
over TS3 and TS4 owing to the anomeric effect of the hemiacetal oxygen. On the other hand, TS2 and
TS4 are strongly destabilized by A1,3 strain. Because of these two factors, the overall mechanism can
account for the observed predominant formation of 2a and 2b.
H
O
H
OBn
O
OBn
OBn
OBn
Step 4.
cyclization
BnO
BnO
A1,3
Step 3.
coordination of
hemiacetal to Pd(II)
OH
Cl
OH
Pd
BnO
BnO
2c(1R,4S)
-PdCl(OH)
Pd
O
O
H
H
2a(1R,4R)
major product
H
Cl
ꢀ*c-o
no
TS2 : destabilzation by A1,3
TS1 : stabilization
by an anomeric effect
Step 2.
hemiacetal formation
THPO
H
HO
H
+BnOH
O
O
-BnOTHP
Product ratio
2a : 2b : 2c = 5.2 : 3.8 : 1
BnO
Step 1.
deprotection of THP group
BnO
3
9
Step 2.
hemiacetal formation
H
H
H
H
O
O
OBn
OBn
BnO
BnO
OH
Cl
Pd
OH
BnO
2b(1S,4R)
BnO
2d(1S,4S)
not obtained
O
Pd
O
BnO
TS3
BnO
H
A1,3
Cl
TS4
Scheme 5. Plausible mechanism of Pd(II)-catalyzed cyclization

HETEROCYCLES, Vol. 81, No. 8, 2010
1895
Finally, deprotection of all benzyl groups in 8a and 8b was conducted at an atmospheric pressure of
hydrogen in EtOH with palladium over charcoal (10%). After 58 h, 2-deoxy-D-ribose was obtained in
good yield. The product was easily purified by silica gel column chromatography. The product was
identical to an authentic sample of 2-deoxy-D-ribose in all respects, including the optical activity (Table
2).
Table 2. Specific optical rotation of synthetic 2-deoxy-D-ribose
O
O
OBn
OH
Pd/C, H2
EtOH, rt
HO
BnO
HO
HO
2-deoxy-D-ribose
8a : 97%
8b : 91%
8a (1R)
8b (1S)
20
2-deoxy-D-ribose
authentica
origin
c
solvent
[ꢀ]D
-36.3
-38.6
-37.4
MeOH
MeOH
MeOH
0.42
0.33
0.35
-
2a
synthetic
2b
a ALDRICH, purity >97%
In summary, we have developed an efficient synthesis of 2-deoxy-D-ribose via palladium(II)-catalyzed
cyclization. The synthesis involved 12 steps and proceeded in good overall yield from L-(-)malic acid.
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.
1
Optical rotations ([ꢀ]D) were determined with a JASCO P-1020 polarimeter. H 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,

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HETEROCYCLES, Vol. 81, No. 8, 2010
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 (ꢀ).
(S)-Butane-1,2,4-triol
To a solution of borane dimethyl sulfide complex (42.4 mL, 0.45 mol) and trimethyl borate (49.9 mL,
0.45 mol) was added a solution of L-(-)-malic acid (4) (20.0 g, 0.15 mol) in THF (100 mL) at 0 oC under
o
an argon atmosphere. The mixture was stirred at 0 C for 40 min, then warmed to rt and stirred for 7 h.
The reaction was quenched with MeOH and concentrated in vacuo. The residue was purified by silica gel
column chromatography (CH2Cl2-EtOH = 10:1 to 1:1, gradient) to afford (S)-butane-1,2,4-triol (16.1 g,
>99 %yield) as a colorless oil.ꢀꢀ
1
triol; colorless oil; [ꢁ]20 -29.4 (c 0.94, MeOH); H NMR (300 MHz, CD3OD) ꢀ 3.79-3.63 (m, 3H),
D
13
3.52-3.40 (m, 2H), 1.78-1.50 (m, 2H); C NMR (75 MHz, CD3OD) ꢀ 70.7, 67.5, 59.9, 37.1; IR (neat,
cm-1) 3341, 2940, 2884, 1421, 1060; MS (EI) m/z 76(5), 75(100), 61(9), 60(6), 58(20), 57(66), 55(5);
(DART) m/z 107 ([M+H]+); HRMS-DART calcd. for C4H11O3 ([M+H]+) 107.0708, found 107.0717.ꢀ
ꢀ
((2S,4S)-2-Phenyl-1,3-dioxan-4-yl)methanol (5)ꢀ
To a suspension of the triol (201 mg, 1.89 mmol) in CH2Cl2 (19 mL) was added benzaldehyde dimethyl
acetal (0.31 mL, 2.08 mmol) and p-toluenesulfonic acid (2 mg, 0.01 mmol) at rt under an argon
atmosphere, then the mixture was vigorously stirred at the same temperature for 24 h. The reaction was
quenched with Et3N and concentrated in vacuo. The residue was purified by silica gel column
chromatography
(hexane-AcOEt
=
10:1
to
1:1,
gradient)
to
afford
((2S,4S)-2-phenyl-1,3-dioxan-4-yl)methanol (5) (314 mg, 85% yield in 2 steps) as a white solid.
5; white solid; mp 58.0-60.0 oC; [ꢁ]20D 10.6 (c 0.59, CHCl3); 1H NMR (300 MHz, CDCl3) ꢀ 7.54-7.46 (m,
2H), 7.42-7.34 (m, 3H), 5.55 (s, 1H), 4.31 (ddd, J = 11.1, 5.2, 1.2 Hz, 1H), 4.09-3.94 (m, 2H), 3.77-3.61
13
(m, 2H), 2.00-1.86 (m, 1H), 1.46 (dtd, J = 13.1, 2.5, 1.4 Hz, 1H); C NMR (75 MHz, CDCl3) ꢀ 138.3,
129.0, 128.3(2C), 126.1(2C), 101.3, 77.5, 66.6, 65.7, 26.8; IR (KBr, cm-1) 3438, 2934, 2912, 1458, 1414,
1240, 1133, 1097, 1065, 1022, 969, 764, 704; MS (EI) m/z 194(M+, 16), 193(13), 163(14), 123(11),
122(12), 106(31), 105(84), 78(65), 77(100), 57(40), 51(27); (DART) m/z 195 ([M+H]+); HRMS-DART
calcd. for C11H15O3 ([M+H]+) 195.1021, found 195.0997.
(2S,4S)-2-Phenyl-1,3-dioxane-4-carbaldehyde
To a solution of dimethyl sulfoxide (1.1 mL, 15.4 mmol) in CH2Cl2 (15 mL) was added oxalyl chloride
(0.67 mL, 7.72 mmol) at -78 oC under an argon atmosphere. After stirring at the same temperature for 15
min, to the reaction mixture was added a solution of ((2S,4S)-2-phenyl-1,3-dioxan-4-yl)methanol (5)

HETEROCYCLES, Vol. 81, No. 8, 2010
1897
o
(1.00 g, 5.15 mmol) in CH2Cl2. The suspension was stirred at -78 C for 20 min, then the mixture was
o
added Et3N (3.2 mL, 23.2 mmol) at -78 C and warmed to rt. After stirring for 20 min, the reaction
mixture was poured into ice and 1 N HCl, and the aqueous phase was extracted with CHCl3 (x 2). The
combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, filtered, and
concentrated in vacuo to afford (2S,4S)-2-phenyl-1,3-dioxane-4-carbaldehyde (1.16 g) which was used
immediately without further purification. An aliquot was purified by silica gel column chromatography
(hexane-AcOEt = 3:1) to afford an analytical pure sample as a colorless oil.
1
aldehyde; colorless oil; [ꢀ]20 -63.2 (c 0.90, CHCl3); H NMR (300 MHz, CDCl3) ꢁ 9.74 (s,1H),
D
7.60-7.30 (m, 5H), 5.61 (s, 1H), 4.41-4.33 (m, 2H), 4.02 (td, J = 11.9, 2.8 Hz, 1H), 2.06-1.91(m, 1H),
13
1.81(dtd, J = 13.4, 3.0, 1.5 Hz, 1H); C NMR (75 MHz, CDCl3) ꢁ 200.6, 137.6, 129.2, 128.4(2C),
126.1(2C), 101.2, 80.4, 66.5, 25.9; IR (neat, cm-1) 3455, 2970, 2858, 1737, 1397, 1375, 1138, 1105, 996,
759, 700; MS (EI) m/z 192 (M+, 2), 191 (7), 163(100), 107(40), 105(64), 91(42), 79(66), 77(56), 57(22),
51(17); (DART) m/z 193 ([M+H]+); HRMS-DART calcd. for C11H13O3 ([M+H]+) 193.0865, found
193.0864.
(E)-Ethyl 3-((2S,4S)-2-phenyl-1,3-dioxan-4-yl)acrylate (6)
To a suspension of sodium hydride (60% in oil, 288 mg, 7.21 mmol) in THF (20 mL) was added triethyl
phosphonoacetate (1.55 mL, 7.72 mmol) at 0 oC under an argon atmosphere, then the mixture was stirred
at the same temperature for 30 min. After cooling to -78oC, to the solution was added a solution of the
crude (2S,4S)-2-phenyl-1,3-dioxane-4-carbaldehyde (1.16 g, < 5.15 mmol) in THF (5 mL) at -78oC, and
the mixture was gradually warmed to rt and stirred for 1 h. The reaction mixture was poured into
saturated aqueous NH4Cl solution, then the aqueous phase was extracted with hexane (x 3). The
combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (9% AcOEt in hexanes) to afford (E)-ethyl
3-((2S,4S)-2-phenyl-1,3-dioxan-4-yl)acrylate (6) (1.05 g, 78% yield in 2 steps) as a white solid.
6; white solid; mp 59.5-60.5 oC; [ꢀ]20D -25.5 (c 0.88, CHCl3); 1H NMR (300 MHz, CDCl3) ꢁ 7.53-7.48 (m,
2H), 7.40-7.33(m, 3H), 6.96 (dd, J = 15.5, 4.1 Hz, 1H), 6.14 (dd, J = 15.5, 1.9 Hz, 1H), 5.58 (s, 1H), 4.54
(dtt, J = 11.6, 2.1, 2.1 Hz, 1H), 4.30 (ddd, J = 11.6, 4.8, 1.1 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.01 (ddd,
J = 11.6, 11.6, 2.6 Hz, 1H), 1.98-1.83 (m,1H), 1.72-1.63 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3) ꢁ 166.3, 145.9, 138.1, 128.9, 128.2(2C), 126.0(2C), 120.1, 101.1, 75.2, 66.7, 60.4, 30.6,
14.1; IR (KBr, cm-1) 2977, 2952, 2872, 1721, 1664, 1397, 1366, 1298, 1280, 1174, 1139, 1020, 976, 698;
MS (EI) m/z 262 (M+, 3), 261(11), 217(2), 185(2), 140(12), 125(16), 106(40), 105(100), 97(28), 94(29),
77(42), 67(36), 55(20); (DART) m/z 263 ([M+H]+); HRMS-DART calcd. for C15H19O4 ([M+H]+)
263.1283, found 263.1306.

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HETEROCYCLES, Vol. 81, No. 8, 2010
(E)-3-((2S,4S)-2-Phenyl-1,3-dioxan-4-yl)prop-2-en-1-ol
To a solution of (E)-ethyl 3-((2S,4S)-2-phenyl-1,3-dioxan-4-yl)acrylate (6) (10.0 g, 38.1 mmol) in THF
(150 mL) was added dropwise diisobutylaluminum hydride (1.02 M in n-hexane, 112 mL, 114 mmol)
o
over a period of 30 min at -78 C under an argon atmosphere and the mixture was stirred at the same
temperature for 15 min. The reaction mixture was quenched with saturated aqueous Na2SO4 solution,
filtered through a pad of Celite® and the pad was washed with AcOEt. The filtrate was dried over MgSO4
and concentrated in vacuo. The residue was purified by silica gel column chromatography
(hexane-AcOEt = 3:1 to 1:1, gradient) to afford (E)-3-((2S,4S)-2-phenyl-1,3-dioxan-4-yl)prop-2-en-1-ol
(7.42 g, 88% yield) as a colorless oil.
1
allylic alcohol; colorless oil; [ꢀ]20 12.1 (c 0.67, CHCl3); H NMR (300 MHz, CDCl3) ꢁ 7.54-7.48 (m,
D
2H), 7.40-7.32(m, 3H), 5.97 (dtd, J = 15.5, 4.8, 1.0 Hz, 1H), 5.83 (dtd, J = 15.5, 3.4, 1.4 Hz, 1H), 5.58 (s,
1H), 4.45-4.37(m, 1H), 4.29 (ddd, J = 11.4, 5.2, 1.3 Hz, 1H), 4.21-4.13 (m, 2H), 4.06-3.95(m, 1H),
2.03-1.87(m, 1H), 1.66-1.56(m,1H); 13C NMR (75 MHz, CDCl3) ꢁ 138.4, 130.73, 130.71, 128.8,
128.2(2C), 126.1(2C), 101.2, 76.8, 66.8, 62.9, 31.3; IR (neat, cm-1): 3402, 2857, 1398, 1371, 1106, 1025,
977, 756, 700; MS (EI) m/z: 220 (M+, 1), 219(4), 163(4), 134(11), 106(59), 105(100), 77(59), 67(20),
55(19); (DART) m/z 221 ([M+H]+); HRMS-DART calcd. for C13H17O3 ([M+H]+) 221.1178, found
221.1185.
(2S,4S)-2-Phenyl-4-((E)-3-(tetrahydro-2H-pyran-2-yloxy)prop-1-enyl)-1,3-dioxane (7)
To a solution of (E)-3-((2S,4S)-2-phenyl-1,3-dioxan-4-yl)prop-2-en-1-ol (6.63 g, 30.1 mmol) and
p-toluenesulfonic acid (259 mg, 1.51 mmol) in CH2Cl2 (300 mL) was added 2H-dihydropyran (4.1 mL,
o
45.2 mmol) at 0 C under an argon atmosphere. After stirring for 5min at the same temperature, the
mixture was warmed to rt and stirred for 25 min. The reaction was quenched with saturated aqueous
NaHCO3 solution and the aqueous phase was extracted with AcOEt/ hexane (1/1 v/v). 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 = 10:1 to 1:1, gradient) to afford
(2S,4S)-2-phenyl-4-((E)-3-(tetrahydro-2H-pyran-2-yloxy)prop-1-enyl)-1,3-dioxane (7) (9.14 g, 99%
yield) as a colorless oil.
7; colorless oil; 1H NMR (300 MHz, CDCl3) ꢁ 7.55-7.47 (m, 2H), 7.41-7.29 (m, 3H), 5.98-5.80 (m, 2H),
5.57 (s, 1H), 4.64 (dd, J = 3.3, 3.3 Hz, 1H), 4.46-4.36 (m,1H), 4.34-4.22 (m, 2H), 4.08-3.74 (m, 2H), 3.87
(ddd, J = 11.2, 8.1, 3.4 Hz, 1H), 3.58-3.46 (m, 1H), 2.05-1.49 (m, 8H); IR (neat, cm-1) 2945, 2851, 1364,
1116, 1025, 980, 699; MS (EI) m/z 219(6), 203(11), 134(15), 106(58), 105(100), 85(71), 77(58), 55(40).ꢀ
ꢀ
(3S,E)-3-(Benzyloxy)-6-(tetrahydro-2H-pyran-2-yloxy)hex-4-en-1-ol

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1899
To a solution of (2S,4S)-2-phenyl-4-((E)-3-(tetrahydro-2H-pyran-2-yloxy)prop-1-enyl)-1,3-dioxane (7)
(8.54 g, 28.1 mmol) in toluene (128 mL) was added dropwise diisobutylaluminum hydride (1.01 M in
n-hexane, 139 mL, 140 mmol) at 0 oC over a period of 10 min under an argon atmosphere. After stirring
o
at 0 C for 2 h, the mixture was warmed up to rt and stirred for 1 h. The reaction was quenched with
saturated aqueous Na2SO4 solution, filtered through a pad of Celite® and the pad was washed with AcOEt
(x 2). The filtrate was separated and dried over MgSO4 and concentrated in vacuo. The residue was
purified by silica gel column chromatography (hexane-AcOEt = 3:1 to 1:1, gradient) to afford
(3S,E)-3-(benzyloxy)-6-(tetrahydro-2H-pyran-2-yloxy)hex-4-en-1-ol (6.93 g, 81% yield) as a colorless
oil.
1
alcohol; colorless oil; H NMR (300 MHz, CDCl3) ꢀ 7.39-7.26(m, 5H), 5.83 (dt, J = 15.5, 5.3 Hz, 1H),
5.75-5.65 (m, 1H), 4.70-4.59 (m, 2H), 4.37 (d, J = 12.0 Hz, 1H), 4.33-4.24 (m, 1H), 4.12-4.00 (m, 2H),
3.93-3.83 (m, 1H), 3.83-3.68 (m, 2H), 3.57-3.48 (m,1H), 1.98-1.48 (m, 8H); IR (neat, cm-1) 3436, 2942,
2868, 1119, 1076, 1038; MS (EI) m/z 177(3), 113(13), 107(11), 91(100), 85(23), 55(13); (DART) m/z
307 ([M+H]+); HRMS-DART calcd. for C18H27O4 ([M+H]+) 307.1909, found 307.1909.
(3S,E)-3-(Benzyloxy)-6-(tetrahydro-2H-pyran-2-yloxy)hex-4-enal (3)
To a solution of (3S,E)-3-(benzyloxy)-6-(tetrahydro-2H-pyran-2-yloxy) hex-4-en-1-ol (7) (2.00 g, 6.53
mmol) in CH2Cl2 (60 mL) was added Dess-Martin periodinane (5.54 g, 13.1 mmol) at 0 oC. The mixture
was warmed to rt and stirred for 1 h. After cooling, Dess-Martin periodinane (4.15 g, 9.78 mmol) was
added to the mixture at 0 oC, then the mixture was warmed up to rt and stirred for 1 h. The reaction was
quenched with saturated aqueous Na2S2O3 solution. To the mixture was added saturated aqueous NaHCO3
solution and the aqueous layer was extracted with AcOEt/ hexane (x 3). 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
=
5:1)
to
afford
(3S,E)-3-(benzyloxy)-6-(tetrahydro-2H-pyran-2-yloxy)hex-4-enal (3) (1.94 g, 97% yield) as a colorless
oil.
1
3; colorless oil; H NMR (300 MHz, CDCl3) ꢀ 9.79-9.74 (m, 1H), 7.38-7.25 (m, 5H), 5.95-5.84(m, 1H),
5.78-5.65 (m, 1H), 4.70-4.55 (m,2H), 4.45-4.25 (m, 3H), 4.04 (ddd, J = 13.4, 5.5, 1.3 Hz, 1H), 3.94-3.82
(m, 1H), 3.60-3.46 (m, 1H), 2.76 (dddd, J = 16.5, 8.3, 2.8, 1.3 Hz, 1H), 2.63-2.52 (m, 1H), 1.92-1.48 (m,
6H); IR (neat, cm-1) 2943, 2868, 1726, 1119, 1077, 1026; MS (EI) m/z 256(2), 248(3), 219(2), 159(6),
131(5), 108(35), 107(39), 91(100), 85(67), 79(44), 77(33), 67(26), 55(27); (DART) m/z 305 ([M+H]+);
HRMS-DART calcd. for C18H25O4 ([M+H]+) 305.1753, found 305.1764.
(3S)-3,5-Bis(benzyloxy)-2-vinyltetrahydrofuran (2)

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HETEROCYCLES, Vol. 81, No. 8, 2010
To a solution of (3S,E)-3-(benzyloxy)-6-(tetrahydro-2H-pyran-2-yloxy)hex-4-enal (3) (200 mg, 0.66
mmol) and BnOH (213 mg, 1.97 mmol) in THF (33 mL) was added PdCl2(MeCN)2 (9 mg, 0.033 mmol)
at rt under an argon atmosphere, then the mixture was stirred at the same temperature for 1 h. After
stirring, the 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 = 50:1 to 20:1, gradient) to afford (3S)-3,5-bis(benzyloxy)-2-vinyltetrahydrofuran (2)
(113 mg, 55% yield) as a colorless oil.
1
2 (diastereomer mixture); colorless oil; H NMR (600 MHz, CDCl3) ꢀ 7.38-7.24(m,10H), 6.10(ddd, J =
17.6, 10.3, 7.2 Hz, 0.1H), 5.94 (ddd, J = 17.2, 10.3, 7.0 Hz, 0.52H), 5.85 (ddd, J = 16.9, 10.4, 6.7 Hz,
0.38H), 5.38 (ddt, J = 17.2, 4.0, 1.3 Hz,0.9H), 5.44-5.30 (m, 0.3H), 5.32 (dd, J = 5.1, 2.2 Hz, 0.52H), 5.24
(dd, J = 5.7, 1.8 Hz, 0.38H), 5.21 (dt, J = 10.3, 1.3 Hz, 0.38H), 5.19 (dt, J = 10.3, 1.3 Hz, 0.52H), 4.77 (d,
J = 11.7 Hz, 0.1H), 4.59-4.47 (m, 4H), 4.17-4.10 (m, 0.62H), 3.84 (ddd, J = 8.1, 5.7, 4.0 Hz, 0.38H),
2.36-2.27 (m, 1H), 2.24-2.20 (m, 0.1H), 2.18-2.13 (m, 0.52H), 2.10 (ddd, J = 15.9, 4.0, 1.8 Hz, 0.38H);
MS (EI) m/z 254(3), 182(4), 163(5), 159(2), 108(9), 107(7), 91(100), 79(12), 77(8), 65(10), 51(4);
(DART) m/z 311 ([M+H]+); HRMS-DART calcd. for C20H23O3 ([M+H]+) 311.1647, found 311.1675.
((3S)-3,5-Bis(benzyloxy)tetrahydrofuran-2-yl)methanol (8)
To a solution of (3S)-3,5-bis(benzyloxy)-2-vinyltetrahydrofuran (2) (diastereomer mixture; 300 mg, 0.97
mmol) in 1,4-dioxane (9 mL) and H2O (5 mL) was added 2,6-lutidine (207 mg, 1.94 mmol), NaIO4 (414
mg, 1.94 mmol) and OsO4 (0.05 mol/L in tert-BuOH, 0.4 mL, 0.02 mmol), then the mixture was stirred at
rt for 16 h. The mixture was diluted with AcOEt and H2O, the aqueous phase was extracted with AcOEt
(x 1). The combined organic layers were washed with saturated aqueous Na2S2O3 solution and brine, dried
over MgSO4, filtered and concentrated in vacuo. The residue was diluted with MeOH (5 mL), to this
solution was added NaBH4 (73 mg, 1.94 mmol) at rt. After stirring at the same temperature for 30 min,
the mixture was quenched with saturated NH4Cl solution and concentrated in vacuo. The residue was
diluted with AcOEt and H2O, then the organic layer was separated and the aqueous layer was extracted
with AcOEt (x1). The combined organic layers were washed with 1 N HCl 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 ((3S)-3,5-bis(benzyloxy)tetrahydrofuran-2-yl)methanol (8) (304 mg, 53%
yield in 2 steps). Three diastereomers were separated in this step.
((2R,3S,5R)-3,5-Bis(benzyloxy)tetrahydrofuran-2-yl)methanol (8a); colorless oil; [ꢁ]20 -65.6 (c 1.60,
D
1
CHCl3); H NMR (300 MHz, CDCl3) ꢀ 7.38-7.26 (m, 10H), 5.36 (dd, J = 5.9, 2.1 Hz, 1H), 4.76 (d, J =
11.7 Hz, 1H), 4.53 (d, J = 11.7 Hz, 1H), 4.49 (s, 2H), 4.35-4.26 (m, 2H), 3.76 (dd, J = 12.0, 2.7 Hz, 1H),
3.64 (ddd, J = 12.0, 8.5, 3.9 Hz, 1H), 2.43 (ddd, J = 14.1, 6.9, 2.0 Hz, 1H), 2.23 (dt, J = 14.1, 5.3 Hz, 1H);

HETEROCYCLES, Vol. 81, No. 8, 2010
1901
13C NMR (75 MHz, CDCl3) ꢀ 137.7, 137.1, 128.53(2C), 128.46(2C), 128.0(2C), 127.9, 127.8, 127.7(2C),
104.0, 85.7, 79.0, 71.7, 70.0, 64.1, 40.2; IR (neat, cm-1) 3447, 2925, 2872, 1455, 1361, 1104, 1043, 1026,
698, 607; MS (EI) m/z 254(1), 207(7), 181(4), 163(2), 146(2), 108(32), 107(25), 91(100), 79(41), 77(26),
65(12), 51(12); (DART) m/z 315 ([M+H]+); HRMS-DART calcd. for C19H23O4 ([M+H]+) 315.1596, found
315.1608.
((2R,3S,5S)-3,5-Bis(benzyloxy)tetrahydrofuran-2-yl)methanol (8b); colorless oil; [ꢁ]20 -34.7 (c 0.33,
D
1
CHCl3); H NMR (300 MHz, CDCl3) ꢀ 7.39-7.27 (m, 10H), 5.39 (dd, J = 5.2, 1.9 Hz, 1H), 4.73 (d, J =
11.9 Hz, 1H), 4.59 (d, J = 11.7 Hz, 1H), 4.51-4.41 (m, 1H), 4.49 (d, J = 11.9 Hz, 1H), 4.42 (d, J = 11.7
Hz, 1H), 4.20 (dt, J = 5.8, 4.3 Hz, 1H), 4.00-3.85 (m, 2H), 2.29 (ddd, J = 13.4, 6.7, 1.9 Hz, 1H), 2.19 (ddd,
13
J = 13.4, 5.2, 5.2 Hz, 1H); C NMR (75 MHz, CDCl3) ꢀ 137.9, 137.4, 128.6(2C), 128.4(2C), 128.00,
127.97(3C), 127.7, 127.6, 102.2, 79.4, 79.0, 71.8, 69.3, 61.8, 39.6; IR (neat, cm-1) 3444, 2921, 2873, 1061,
1026, 737, 698; MS (EI) m/z 254(2), 207(3), 206(3), 182(3), 181(4),163(4), 149(3), 146(2), 108(34),
107(31), 91(100), 79(39), 77(29), 57(14); (DART) m/z 315 ([M+H]+); HRMS-DART calcd. for C19H23O4
([M+H]+) 315.1596, found 315.1607.
((2S,3S,5R)-3,5-Bis(benzyloxy)tetrahydrofuran-2-yl)methanol (8c); colorless oil; [ꢁ]20 162.4 (c 1.70,
D
1
CHCl3); H NMR (300 MHz, CDCl3) ꢀ 7.40-7.25 (m, 10H), 5.24 (dd, J = 5.3, 1.5 Hz, 1H), 4.81 (d, J =
12.4 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 4.54 (d, J = 12.4 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 4.20 (dd, J =
8.1, 4.0 Hz, 1H), 4.08-4.00 (m, 1H), 3.82 (dd, J = 11.9, 2.9 Hz, 1H), 3.61 (dd, J = 11.9, 2.9 Hz, 1H), 2.26
13
(ddd, J = 13.4, 8.3, 5.4 Hz, 1H), 2.12 (ddd, J = 14.1, 3.4, 1.7 Hz, 1H); C NMR (75 MHz, CDCl3) ꢀ
138.0(2C), 128.4(2C), 128.3(2C), 127.8(2C), 127.7(2C), 127.5(2C), 102.7, 82.9, 78.1, 71.7, 68.9, 62.6,
39.1; IR (neat, cm-1) 3445, 2920, 2872, 1454, 1360, 1207, 1113, 1043, 1027, 737, 698; MS (EI) m/z
207(11), 206(2), 10(21), 107(19), 91(100), 79(26), 77(18), 65(11), 51(10); (DART) m/z 315 ([M+H]+);
HRMS-DART calcd. for C19H23O4 ([M+H]+) 315.1596, found 315.1610.
2-Deoxy-D-ribose
To a solution of 8a (16 mg, 0.051 mmol) in EtOH (1 mL) was added Pd/C (2 mg) at rt, then the reaction
vessel was evacuated and back-filled with H2 (5x). After stirring for 58 h at rt, the mixture was filtered
over a pad of Celite®, which was washed with MeOH. The filtrate was concentrated in vacuo. The crude
material was purified by silica gel column chromatography (MeOH-CHCl3 = 1:3) to afford
2-deoxy-D-ribose (6.6 mg, 97% yield) as a colorless amorphous solid.
1
2-Deoxy-D-ribose; colorless amorphous solid; [ꢁ]20 -38.6 (c 0.33, MeOH); H NMR (300 MHz,
D
CD3OD) ꢀ difficult to assign the spectra; 13C NMR (75 MHz, CD3OD) the equilibrium mixture of
pyranose and furanose form and those epimer at C1; ꢀ 99.5, 99.4, 95.2, 93.1, 87.9, 86.7, 72.8, 72.5, 69.4,
69.2, 68.3, 66.6, 66.2, 64.5, 64.3, 63.2, 43.5, 43.1, 37.3, 36.6.

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HETEROCYCLES, Vol. 81, No. 8, 2010
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.
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