α-selective ribofuranosylation of alcohols with ribofuranosyl iodides and triphenylphosphine oxide

Article abstract of DOI:10.1021/jo500632h

Ribofuranosylation of a variety of alcohols with ribofuranosyl iodides in the presence of a base and triphenylphosphine oxide afforded the corresponding α-ribofuranosides with diastereoselectivities ≥ 99:1. This reaction can be carried out under mildly basic conditions and is thus compatible with acid-sensitive functional groups.

Full text of DOI:10.1021/jo500632h

Note
pubs.acs.org/joc
α‑Selective Ribofuranosylation of Alcohols with Ribofuranosyl
Iodides and Triphenylphosphine Oxide
Natsuhisa Oka,* Rin Kajino, Kaoru Takeuchi, Haruna Nagakawa, and Kaori Ando
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
S
* Supporting Information
ABSTRACT: Ribofuranosylation of a variety of alcohols with
ribofuranosyl iodides in the presence of a base and
triphenylphosphine oxide afforded the corresponding α-
ribofuranosides with diastereoselectivities ≥ 99:1. This
reaction can be carried out under mildly basic conditions
and is thus compatible with acid-sensitive functional groups.
α-Ribofuranosides are key components of various natural
products and biomolecules1,2 such as lampteroflavin1a,b and
poly(ADP)ribose.1c,d Because many such ribofuranosides have
intriguing biological activities, the stereocontrolled synthesis of
α-ribofuranosides has attracted much attention in recent
decades, and a variety of α-selective ribofuranosylation
reactions have been developed.3,4 Glycosyl donors such as
thioribofuranosides4a,b and ribofuranosyl imidates1b,4c are
activated by Lewis acids to generate active oxocarbenium
ions, which then react with nucleophiles to yield α-ribofurano-
sides preferentially.4 Various α-ribofuranosides, including
lampteroflavin1b and 2′-O-(α-D-ribofuranosyl)adenosine,4c
have been synthesized using such Lewis acid promoted
glycosylation reactions. However, the yield and α-selectivity
are highly dependent on the structure of the substrate.
Moreover, these methods are generally not applicable to the
synthesis of acid-sensitive molecules. Mukaiyama et al. have
also developed a series of efficient α-selective ribofuranosyla-
tion reactions5 wherein the β-face of the oxocarbenium ion
generated upon the activation of glycosyl donors is covered by
a perchlorate anion, inducing an α-selective nucleophilic
attack;5,6 however, the α-selectivity is still affected by the
structure of the substrates. Moreover, the explosive perchlorate
salts and heavy metal compounds such as toxic tin reagents5a−e
that are used in most of these reactions5a−i should be replaced
by less hazardous reagents. Furthermore, many of these
transformations rely on Lewis acids for the activation of the
glycosyl donors, and thus, their application to the synthesis of
acid-sensitive molecules is once again limited. Besides the acid-
catalyzed reactions, Schmidt et al.7 have developed the
anomeric O-alkylation of 2,3,5-protected ribofuranoses in the
presence of NaH, while Mukaiyama et al.8 reported the
condensation of a 2,3,5-protected ribofuranose with alcohols in
Under these circumstances, we developed a versatile, heavy-
metal-free α-selective ribofuranosylation of alcohols that can be
carried out under mildly basic conditions using glycosyl iodides
as the glycosyl donors. Glycosyl iodides have been extensively
used as glycosyl donors in the synthesis of pyranosides under
mildly basic conditions.9,10 In contrast, furanosyl iodides,11,12
particularly ribofuranosyl iodides,11 have not been studied in
depth and their properties as glycosyl donors have not yet been
fully explored. Thus, we investigated the synthesis of
ribofuranosyl iodides and their application to the ribofurano-
sylation of alcohols to develop a novel α-selective ribofur-
anosylation reaction.
The compound 1-O-trimethylsilyl-2,3,5-tri-O-benzyl-D-ribo-
furanose 15d was chosen as the starting material, and the
ribofuranosyl iodide 2 was synthesized via treatment of 1 with
TMSI at 0 °C. TLC monitoring of the reaction showed that
compound 1 was completely consumed within 0.5−1 h. Only
1
the crude form of 2 was characterized by H NMR analysis in
CDCl3 at low temperature, because the ribofuranosyl iodide 2
was unstable and decomposed even at 0 °C, albeit very slowly.
The signal attributable to the anomeric proton of the major
product appeared in the spectrum as a singlet at 6.61 ppm,13
indicating that the major product was the β-ribofuranosyl
iodide 2.
Ribofuranosylation reactions of alcohols using 2 were
conducted in one pot from 1. First, cyclopentanol was used
as the glycosyl acceptor to optimize the reaction conditions
(Table 1). It has been reported that glycosyl iodides react with
alcohols in the presence of tertiary amines, such as i-
Pr2NEt.9,10,12 As shown in entry 1, 2 reacted with cyclopentanol
in the presence of i-Pr2NEt to afford the corresponding
ribofuranoside 3a with excellent yield and α-selectivity. The α-
selectivity could be improved to >99:1 when 2 was treated with
cyclopentanol at −40 °C, though the reaction did not proceed
to completion even after 2 h (entry 2). The use of Et3N, 1,8-
bis(dimethylamino)naphthalene (DMAN), and 2,6-di-tert-
the presence of LiNTf2 and catalytic Ph3C+B(C6F5)4 , which
−
they proposed to work cooperatively to isomerize the resulting
ribofuranosides to the α-isomers. Both of these reactions afford
α-ribofuranosides with almost complete α-selectivity. However,
these methods have not been widely applied to the synthesis of
α-ribofuranosides.
Received: March 18, 2014
© XXXX American Chemical Society
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The Journal of Organic Chemistry
Note
Table 1. Ribofuranosylation of Cyclopentanol with
Ribofuranosyl Iodide 2
Table 2. Ribofuranosylation of Various Alcohols with
Ribofuranosyl Iodide 2
b
ab
,
entry
1
base
additive
time (h)
yield (%)
α-3a:β-3a
entry
ROH
additive
time (h)
3
yield (%)
c
c
i-Pr2NEt
i-Pr2NEt
Et3N
0.5
2
97
69
63
85
78
62
89
49
78
87
84
92
98:2
1
2
Ph(CH2)3OH
i-PrOH
TPPO
TPPO
TPPO
TPPO
TPPO
TBAI
TBAI
TBAI
TBAI
TBAI
0.5
0.5
0.5
1
3b
3c
3d
3e
3f
84 (99:1 )
a
c
c
2
>99:1
70 (99:1 )
c
c
3
4
5
6
7
0.5
0.5
0.5
0.5
0.5
2
97:3
3
c-C6H11OH
l-menthol
t-BuOH
88 (>99:1 )
c
c
DMAN
DTBMP
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
Et3N
95:5
4
84 (>99:1 )
c
c
87:13
5
2
71 (99:1 )
d
d
TBAI
83:17
6
Ph(CH2)3OH
i-PrOH
0.5
0.5
0.5
1
3b
3c
3d
3e
3f
55 (89:11 )
c
d
TPPO
TPPO
TPPO
TPPO
TPPO
TPPO
99:1
7
76 (87:13 )
a
c
d
8
99:1
8
c-C6H11OH
l-menthol
t-BuOH
80 (82:18 )
c
d
9
10
11
12
0.5
0.5
0.5
1
>99:1
9
67 (78:22 )
c
d
DMAN
DTBMP
>99:1
10
11
12
2
67 (90:10 )
c
c
96:4
Ph(CH2)3OH
t-BuOH
0.5
1
3b
3f
74 (97:3 )
d
c
55:45
91 (89:11 )
a
b
e
c
Reaction of 2 with cyclopentanol was carried out at −40 °C. Isolated
yield of 3a. Determined by HPLC. Determined by H NMR.
13
t-BuOH
2
3f
83 (>99:1 )
c
d
1
a
b
Isolated yield of 3a. d.r. (α-3:β-3) are given in parentheses.
c
d
e
Determined by HPLC. Determined by 1H NMR. DMAN was used
in place of i-Pr2NEt.
butyl-4-methylpyridine (DTBMP) gave comparable or lower α-
selectivities (entries 3−5). To further improve the α-selectivity,
tetrabutylammonium iodide (TBAI), which has been reported
to improve the α-selectivity of glycopyranosylations with
glycopyranosyl iodides,9,10 was employed as an additive.
However, both the α-selectivity and the yield of 3a decreased
under these conditions (entry 6). Subsequently, we tested
triphenylphosphine oxide (TPPO) as an additive, because
phosphine oxides have also been reported by Mukaiyama et al.
to improve the α-selectivity of glycopyranosylations using
glycopyranosyl iodides, with TPPO giving some of the best
results.9g We determined that α-3a was obtained with d.r. 99:1,
although in a slightly lower yield (entry 8). The addition of
TPPO at −40 °C did not improve the yield of α-3a (entry 2 vs
8). Neither the generation of 2 nor its reaction with
cyclopentanol proceeded at −78 °C (data not shown). TPPO
was found to suppress the generation of β-3a irrespective of the
base used (entries 1, 3−5 vs entries 7, 9−11). However, the
reaction in the absence of a base afforded 3a as a 55:45 mixture
of diastereomers, though the yield was still high (entry 12).
This result can be attributed to the anomerization of the
resultant α-3a by strongly acidic HI. The relatively low α/β
ratios in entries 5 and 11 may also be attributable to the weak
basicity of DTBMP.
Next, the scope of the reaction was investigated using 1°, 2°,
and 3° alcohols. As shown in Table 2, entries 1−5, the desired
α-ribofuranosides were obtained with d.r. ≥ 99:1 from alcohols
with various levels of steric hindrance. As in the case of
cyclopentanol (Table 1), the use of TBAI as an additive
resulted in the generation of diastereomixtures, although the α-
isomers were still generated preferentially (entries 6−10). We
conducted the ribofuranosylation of 3-phenylpropanol and t-
BuOH in the absence of TPPO, because the ribofuranosylation
of cyclopentanol in the absence of TPPO afforded α-3a with
excellent α-selectivity (Table 1, entry 1). When i-Pr2NEt was
used as the base, the α-selectivity decreased, particularly with t-
BuOH (entries 11 and 12). In contrast, only the α-
ribofuranoside was obtained from t-BuOH when DMAN was
used. These results show that, while ribofuranosylation is still
highly α-selective in the absence of TPPO, the α-selectivity is
dependent on both the glycosyl acceptor and the base. The
addition of TPPO suppressed the generation of the β-
ribofuranoside virtually completely under various reaction
conditions.
Next, the new method was applied to the synthesis of both
ribofuranosides bearing selected functional groups and
disaccharides (Figure 1). α-Ribofuranosides with a CC
bond, amino group, or trityl ether (α-3g−i) were obtained in
good yields under the same conditions as those used for the
synthesis of α-3a−f. The compatibility of the amino group and
the acid-sensitive trityl ether has demonstrated the advantage of
this base-promoted reaction. The method was also applicable to
the α-selective synthesis of disaccharides α-3j−o. For the
synthesis of α-3j−o, 1.5 molar equiv of 1 and TMSI relative to
the glycosyl acceptors were needed to achieve comparable
yields. The synthesis of α-3o required an extended reaction
time (4.5 h) due to the sterically hindered 2° hydroxy group of
1,2:5,6-di-O-isopropylidene-α-D-allofuranose. Notably, for all of
these reactions, the corresponding β-isomers could not be
1
detected in the crude mixtures by H NMR.
Next, we explored the possibility that the α-selective
ribofuranosylation reaction could be carried out without
TMSI and a base to expand the scope of substrates. Being
inspired by the studies in which glycopyranosyl iodides were
generated by the activation of glycosyl phosphites with
ammonium iodides,14 we were able to find that the
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Note
Scheme 2. Deprotection of α-Ribofuranosides α-3i,n
side reaction,13 which indicated the lability of the glycoside
bonds of α-ribofuranosides under acidic conditions. This result
shows that undesirable side reactions, such as the cleavage of
glycoside bonds and epimerization via the resultant oxocarbe-
nium ions, can also occur in acid-promoted ribofuranosylation
reactions, which are currently the major approach to α-
ribofuranosides. The new ribofuranosylation reaction described
in this paper is promoted under mildly basic conditions and
thus free from such side reactions. The results have also shown
that protecting groups other than those removed under acidic
conditions must be employed for the synthesis of α-
ribofuranosides as demonstrated by the deprotection of α-3i
and α-3n.
Figure 1. α-Ribofuranosides α-3g−o synthesized from ribofuranosyl
iodide 2.
A plausible reaction mechanism is given in Figure 2.
Although 2 exists mainly as the β-isomer (β-2) as determined
1
by H NMR analysis, it should be in equilibrium with the α-
ribofuranosyl iodide 4 could be generated by the activation of
the ribofuranosyl phosphite 5 with weakly acidic N,N-
diethylanilinium iodide. Subsequent addition of 3-butyn-1-ol
and TPPO gave the corresponding α-ribofuranoside (α-6) in
good yield with complete α-selectivity (Scheme 1). It is notable
isomer (α-2) due to repetitive nucleophilic attack of the iodide
ions generated by the decomposition of unstable 2 and the
progress of the reaction, as is observed for pyranosyl iodides,9,10
pyranosyl bromides,16 and ribofuranosyl bromides.17 The
stereocourse of the ribofuranosylation reaction of alcohols
with β-2 and α-2 without additive (α:β = 87:13 to > 99:1,
Table 1, entries 1−5, and Table 2, entries 11−13) can thus be
explained by the mechanism proposed by Guindon et al. for the
reaction of ribofuranosyl bromides with persilylated pyrimi-
dines (α-selectivity > 20:1).17 The reaction proceeds via the
inside attack18 of the alcohol in the “exploded” transition states
for both isomers,19 which adopt 5-membered envelop
conformations, to form staggered conformations20 of the
resultant ribofuranosides. In the absence of TPPO, TS2,
which leads to the formation of β-3, is likely to be destabilized
by the electronic and steric repulsions between the two eclipsed
electronegative groups at the 1- and 2-positions (I and OBn)
when compared to TS1, thereby resulting in the preferential
generation of α-3. It must be mentioned here that the results in
this study showed that the formation of the β-3 was dependent
on the reaction conditions and the structures of the substrates.
It is then expected that the addition of TBAI will accelerate the
exchange between β-2 and α-2, increasing the likelihood of α-2
reacting with the alcohol, resulting in a decrease in the α-
selectivity (α:β = 78:22−90:10; Table 1, entry 6, and Table 2,
entries 6−10). However, the observed improvement in α-
selectivity on the addition of TPPO irrespective of the reaction
conditions tested or the substrates (Table 1, entries 7−11;
Table 2, entries 1, 5) suggests that the reaction proceeds with
the intermediacy of β-9 or α-9,21,22 although 1H and 31P NMR
analyses of a solution of 2 and TPPO in CDCl3 could not
establish the formation of 9, indicating that the equilibrium is
likely to have shifted predominantly toward 2.13 The energy
difference between TS3 and TS4, which are formed from the
reaction of β-9 and α-9, respectively, with an alcohol, is likely to
Scheme 1. α-Selective Ribofuranosylation Using
Ribofuranosyl Phosphite 5 as Glycosyl Donor
that the silyl-protected glycosyl donor also afforded the
coresponding α-ribofuranoside with complete stereoselectivity,
indicating that functional groups incompatible with reductive
conditions to remove Bn groups (e.g., alkynyl group) can be
used.
Finally, three representative products (α-3i,m,n) were
selected for deprotection. Hydrogenolysis of compounds α-3i
and α-3n (H2 balloon, 10% Pd/C, EtOH, rt, 5 d) afforded the
corresponding fully deprotected ribofuranosides α-7 and α-8,
respectively, without any side reactions (Scheme 2). In
contrast, attempts to remove the isopropylidene group of
compound α-3m were not successful even with mildly acidic
conditions that have been used for the deprotection of acid-
sensitive molecules including other types of glycosides (AcOH/
H2O,15a PPTS/MeOH,15b,c TFA/CH2Cl2,15d Amberlyst (H+)/
MeOH15c). Cleavage of the α-glycoside bond was the major
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Note
Figure 2. Proposed reaction mechanism.
which was dried over MS4A prior to use, and dry i-Pr2NEt (0.0348
mL, 0.20 mmol) were successively added, and the mixture was kept
stirring for 30 min (for 3a−d), 1 h (for 3g), or 2 h (for 3f,h) at 0 °C.
The mixture was then diluted with CH2Cl2 (15 mL) and washed with
a saturated NaHCO3 aqueous solution (15 mL). The aqueous layer
was extracted with CH2Cl2 (2 × 15 mL), and the combined organic
layers were washed with a saturated NaCl aqueous solution (15 mL).
The aqueous layer was extracted with CH2Cl2 (5 mL), and the
combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was then purified
by silica gel column chromatography (silica gel 60N, spherical, neutral,
40−50 or 63-210 μm, hexane−AcOEt). In the cases of compounds
3a−d,f, all the fractions containing the desired α-ribofuranosides and
the trace amounts of minor β-ribofuranosides were collected together,
concentrated to dryness under reduced pressure, and analyzed by
HPLC.13
be larger than that between TS1 and TS2 due to the bulkiness
of TPPO, thus leading to the observed improvement in the α-
selectivity (α:β ≥ 99:1, Table 1, entry 3, and Table 2, entries
1−5). The generation of undesired active intermediate α-9 via
nucleophilic substitution of β-2 with TPPO may also be
hampered by the steric hindrance of the 2-O-benzyl group.
In conclusion, we developed a novel ribofuranosylation
reaction of alcohols with almost complete α-selectivity using
ribofuranosyl iodides and TPPO as the glycosyl donors and
additive, respectively. The novel acid-free and heavy-metal-free
reaction is advantageous for the synthesis of ribofuranoside
derivatives containing acid-sensitive functionalities and should
be applicable to the preparation of ribofuranoside derivatives
that are intended for use as therapeutic agents.
General Procedure B for Ribofuranosylation of Alcohols.
Synthesis of Compounds 3e,i by Ribofuranosylation of Solid
Alcohols in the Presence of TPPO. l-Menthol (0.0313 g, 0.20
mmol) or 5-triphenylmethoxy-1-pentanol23 (0.0693 g, 0.20 mmol)
and TPPO (0.0556 g, 0.20 mmol) were dried by repeated
coevaporation with dry toluene and dissolved in dry CH2Cl2 (1.0
mL). Dry i-Pr2NEt (0.0348 mL, 0.20 mmol) was added to the
solution. The resultant solution was then added dropwise at 0 °C to a
stirred mixture of the ribofuranosyl iodide 2, which was prepared in
advance from compound 1 (0.118 g, 0.24 mmol) and TMSI (0.0324
mL, 0.24 mmol) according to the general procedure A, and MS 4A
(0.2 g) in dry CH2Cl2 (2.0 mL). The resultant mixture was kept
stirring for 1 h (for 3e) or 2 h (for 3i) at the same temperature.
Aqueous workup and purification by silica gel column chromatography
were carried out as in the general procedure A to afford compounds
3e,i. In the case of compound 3e, all the fractions containing the
desired α-3e and the trace amount of minor β-3e were collected
together, concentrated to dryness under reduced pressure, and
analyzed by HPLC.13
General Procedure C for Ribofuranosylation of Alcohols.
Synthesis of Disaccharides 3j−o. The corresponding glycosyl
acceptor (0.20 mmol) and TPPO (0.0556 g, 0.20 mmol) were dried by
repeated coevaporation with dry toluene and dissolved in dry CH2Cl2
(1.0 mL). Dry i-Pr2NEt (0.0348 mL, 0.20 mmol) was added to the
solution. The resultant solution was then added dropwise at 0 °C to a
stirred mixture of the ribofuranosyl iodide 2, which was prepared in
advance from compound 1 (0.148 g, 0.30 mmol) and TMSI (0.0411
mL, 0.30 mmol) according to the general procedure A, and MS 4A
(0.2 g) in dry CH2Cl2 (2.0 mL). The resultant mixture was kept
stirring for 2 h (for 3j−n) or 4.5 h (for 3o) at the same temperature.
Aqueous workup as in the general procedure A and purification by
silica gel column chromatography (3k,n), PTLC (3j,m), or recycling
GPC (3l) were carried out to afford the disaccharides 3j−n.
EXPERIMENAL SECTION
■
General Methods. Commercially available reagents were used
without purification. Dry organic solvents were prepared by
appropriate procedures prior to use. The other organic solvents
were reagent grade and used as received. All reactions in dry solvents
were carried out under argon. Analytical thin-layer chromatography
(TLC) was performed on TLC plates precoated with silica gel 60 F254
.
Silica gel column chromatography was carried out using silica gel 60N
(spherical, neutral, 40−50 or 63−210 μm) or 3-aminopropyl-
functionalized NH silica gel. Preparative TLC (PTLC) was performed
on silica gel 60 F254 PLC glass plates (20 × 20 cm, 1 mm thickness).
Preparative recycling gel permeation chromatography (GPC) was
performed with JAIGEL-1H and −2H columns (CHCl3 as an eluent).
The 1H, 13C, and 31P spectra (400, 100, and 161.7 MHz) were
recorded at rt, except for the NMR spectra of crude 2 in the absence
and presence of TPPO, which were recorded at 4 °C. Tetramethylsi-
lane (TMS) was used as an internal standard for 1H NMR (0.0 ppm).
CDCl3 and CD3OD were used as internal standards for 13C NMR
(77.0 and 49.2 ppm, respectively). 85% H3PO4 was used as an external
standard for 31P NMR in CDCl3 (0.0 ppm). 1H NMR data are
reported as follows: chemical shift (multiplicity, coupling constants,
integration). Multiplicity is indicated as follows: s (singlet); d
(doublet); dd (doublet of doublets); dt (doublet of triplets); t
(triplet); q (quartet); m (multiplet). HPLC analyses were carried out
using a Mightysil Si60 column (5 μm, 4.6 × 150 mm).
General Procedure A for Ribofuranosylation of Alcohols.
Synthesis of Compounds 3a−d,f−h by Ribofuranosylation of
Liquid Alcohols in the Presence of TPPO. 1-O-Trimethylsilyl-
2,3,5-tri-O-Bn-D-ribofuranose 1 (0.118 g, 0.24 mmol) was dried by
repeated coevaporation with dry toluene and dissolved in dry CH2Cl2
(2.0 mL) under argon. MS 4A (0.2 g) was then added, and the mixture
was cooled to 0 °C. TMSI (0.0324 mL, 0.24 mmol) was slowly added
dropwise to the mixture while stirring, and the mixture was stirred for
1 h at the same temperature. A 0.20 M solution of TPPO, which was
dried by repeated coevaporation with dry toluene prior to use, in dry
CH2Cl2 (1.0 mL, 0.20 mmol), the substrate alcohol (0.20 mmol),
Cyclopentyl 2,3,5-Tri-O-benzyl-D-ribofuranoside (α-3a and
β-3a). [Table 1, entry 7] Ribofuranosylation of c-C5H11OH (0.0181
mL, 0.20 mmol) according to the general procedure A gave α-3a
(0.0872 g, 0.178 mmol, 89%, α:β = 99:1, colorless syrup). Conditions
D
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Note
for silica gel column chromatography: silica gel 60N, spherical, neutral,
63−210 μm, hexane−AcOEt (5:1, v/v).
mmol) according to the general procedure A gave α-3c (0.0647 g,
0.140 mmol, 70%, α:β = 99:1, pale yellow syrup). Conditions for silica
gel column chromatography: silica gel 60N, spherical, neutral, 40−50
μm, hexane−AcOEt (100:0 to 90:10, v/v).
[Table 1, entry 6] Ribofuranosylation of c-C5H11OH (0.0181 mL,
0.20 mmol) according to the general procedure A except for the use of
TBAI in place of TPPO gave a mixture of α-3a and β-3a (0.060 g,
0.123 mmol, 62%, α:β = 83:17, pale yellow syrup). Conditions for
silica gel column chromatography: silica gel 60N, spherical, neutral,
40−50 μm, hexane−AcOEt (100:0 to 90:10, v/v).
[Table 2, entry 7] Ribofuranosylation of i-PrOH (0.0358 mL, 0.47
mmol) according to the general procedure A except for the use of
TBAI in place of TPPO gave a mixture of α-3c and β-3c (0.165 g,
0.357 mmol, 76%, α:β = 87:13, pale yellow syrup). Conditions for
silica gel column chromatography: silica gel 60N, spherical, neutral,
40−50 μm, hexane−AcOEt (100:0 to 90:10, v/v).
Characterization Data of Cyclopentyl 2,3,5-Tri-O-benzyl-α-D-
1
ribofuranoside (α-3a). H NMR (400 MHz, CDCl3) δ 7.38−7.21
1H and 13C NMR spectra of α-3c and β-3c are consistent with those
in the literature.6b
(m, 15H), 5.09 (d, J = 4.3 Hz, 1H), 4.71 (d, J = 12.7 Hz, 1H), 4.70 (d,
J = 12.2 Hz, 1H), 4.61 (d, J = 12.4 Hz, 1H), 4.51 (d, J = 12.7 Hz, 1H),
4.50 (d, J = 12.4 Hz, 1H), 4.43 (d, J = 12.2 Hz, 1H), 4.26−4.20 (m,
2H), 3.84 (dd, J = 6.8, 4.5 Hz, 1H), 3.77 (dd, J = 6.8, 4.3 Hz, 1H), 3.48
(dd, J = 10.7, 3.6 Hz, 1H), 3.38 (dd, J = 10.7, 4.3 Hz, 1H), 1.86−1.71
(m, 6H), 1.55−1.25 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 138.5,
138.1, 138.0, 128.3, 128.3, 128.2, 128.0, 127.7, 127.6, 127.6, 127.5,
100.4, 80.7, 79.5, 76.7, 75.5, 73.3, 72.4, 72.1, 69.9, 33.4, 31.9, 23.6,
Cyclohexyl 2,3,5-Tri-O-benzyl-D-ribofuranoside (α-3d and β-
3d). [Table 2, entry 3] Ribofuranosylation of cyclohexanol (0.0211
mL, 0.20 mmol) according to the general procedure A gave α-3d
(0.0885 g, 0.176 mmol, 88%, α:β = >99:1, colorless syrup). Conditions
for silica gel column chromatography: silica gel 60N, spherical, neutral,
63−210 μm, hexane−AcOEt (100:0 to 90:10, v/v).
+
23.4. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C31H36NaO5
[Table 2, entry 8] Ribofuranosylation of cyclohexanol (0.0211 mL,
0.20 mmol) according to the general procedure A except for the use of
TBAI in place of TPPO gave a mixture of α-3d and β-3d (0.0799 g,
0.159 mmol, 80%, α:β = 82:18, pale yellow syrup). Conditions for
silica gel column chromatography: silica gel 60N, spherical, neutral,
40−50 μm, hexane−AcOEt (100:0 to 90:10, v/v).
511.2455; Found 511.2470.
Characterization Data of Cyclopentyl 2,3,5-Tri-O-benzyl-β-D-
1
ribofuranoside (β-3a). H NMR (400 MHz, CDCl3) δ 7.38−7.26
(m, 15H), 5.07 (d, J = 1.2 Hz, 1H), 4.65 (s, 2H), 4.58 (d, J = 12.4 Hz,
1H), 4.57 (d, J = 12.0 Hz, 1H), 4.54 (d, J = 12.4 Hz, 1H), 4.48 (d, J =
12.0 Hz, 1H), 4.31 (dt, J = 6.5, 4.0 Hz, 1H), 4.17 (m, 1H), 3.99 (dd, J
= 6.5, 4.9 Hz, 1H), 3.81 (dd, J = 4.9, 1.2 Hz, 1H), 3.60 (dd, J = 10.8,
4.0 Hz, 1H), 3.52 (dd, J = 10.8, 6.5 Hz, 1H), 1.68−1.48 (m, 8H). 13C
NMR (100 MHz, CDCl3) δ 138.3, 138.0, 137.9, 128.4, 128.3, 128.3,
127.9, 127.8, 127.7, 127.7, 127.6, 127.5, 104.0, 80.2, 80.1, 78.9, 78.7,
73.1, 72.3, 72.3, 71.7, 33.1, 31.6, 23.3, 23.2. HRMS (ESI-TOF) m/z:
1H NMR spectra of α-3d and β-3d are consistent with those in the
literature.24
l-Menthyl 2,3,5-Tri-O-benzyl-D-ribofuranoside (α-3e and β-
3e). [Table 2, entry 4] Ribofuranosylation of l-menthol (0.0313 g, 0.20
mmol) according to the general procedure B gave α-3e (0.0931 g,
0.167 mmol, 84%, α:β = >99:1, colorless syrup). Conditions for silica
gel column chromatography: silica gel 60N, spherical, neutral, 40−50
μm, hexane−AcOEt (7:1, v/v). [Table 2, entry 9] Ribofuranosylation
of l-menthol (0.0313 g, 0.20 mmol) according to the general
procedure B except for the use of TBAI in place of TPPO gave a
mixture of α-3e and β-3e (0.0747 g, 0.134 mmol, 67%, α:β = 78:22,
colorless syrup). Conditions for silica gel column chromatography:
silica gel 60N, spherical, neutral, 40−50 μm, hexane−AcOEt (7:1, v/
v).
+
[M + Na]+ Calcd for C31H36NaO5 511.2455; Found 511.2483.
3-Phenylpropyl 2,3,5-Tri-O-benzyl-D-ribofuranoside (α-3b
and β-3b). [Table 2, entry 1] Ribofuranosylation of 3-phenyl-1-
propanol (0.0272 mL, 0.20 mmol) according to the general procedure
A gave α-3b (0.090 g, 0.167 mmol, 84%, α:β = 99:1, pale yellow
syrup). Conditions for silica gel column chromatography: silica gel
60N, spherical, neutral, 40−50 μm, hexane−AcOEt (6:1, v/v).
[Table 2, entry 6] Ribofuranosylation of 3-phenyl-1-propanol
(0.0272 mL, 0.20 mmol) according to the general procedure A except
for the use of TBAI in place of TPPO gave a mixture of α-3b and β-3b
(0.059 g, 0.110 mmol, 55%, α:β = 89:11, pale yellow oil). Conditions
for silica gel column chromatography: silica gel 60N, spherical, neutral,
40−50 μm, hexane−AcOEt (6:1, v/v).
Characterization Data of l-Menthyl 2,3,5-Tri-O-benzyl-α-D-
ribofuranoside α-3e. 1H NMR (400 MHz, CDCl3) δ 7.36−7.21 (m,
15H), 5.16 (d, J = 4.2 Hz, 1H), 4.72 (d, J = 12.4 Hz, 1H), 4.68 (d, J =
12.4 Hz, 1H), 4.61 (d, J = 12.4 Hz, 1H), 4.55 (d, J = 12.4 Hz, 1H),
4.49 (d, J = 12.4 Hz, 1H), 4.43 (d, J = 12.4 Hz, 1H), 4.26 (q, J = 4.0
Hz, 1H), 3.84 (dd, J = 6.8, 4.0 Hz, 1H), 3.76 (dd, J = 6.8, 4.2 Hz, 1H),
3.46 (dd, J = 10.6, 4.0 Hz, 1H), 3.39 (dd, J = 10.6, 4.0 Hz, 1H), 3.41−
3.35 (m, 1H), 2.35 (m, 1H), 2.14 (m, 1H), 1.62 (m, 2H), 1.45−1.37
(m, 2H), 1.20 (q, J = 11.9 Hz, 1H), 1.00−0.80 (m, 2H), 0.90 (d, J =
7.2 Hz, 3H), 0.88 (d, J = 7.2 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ 138.6, 138.2, 138.0, 128.3, 128.3, 128.2,
128.0, 127.6, 127.6, 127.6, 127.5, 102.5, 81.1, 79.9, 77.9, 75.3, 73.4,
72.4, 72.1, 70.1, 48.1, 43.3, 34.3, 31.8, 24.9, 22.9, 22.3, 21.2, 15.9.
Characterization Data of 3-Phenylpropyl 2,3,5-Tri-O-benzyl-
α-D-ribofuranoside α-3b.5h 1H NMR (400 MHz, CDCl3) δ 7.37−
7.15 (m, 20H), 5.00 (d, J = 4.6 Hz, 1H), 4.71 (d, J = 12.6 Hz, 1H),
4.68 (d, J = 12.4 Hz, 1H), 4.65 (d, J = 12.4 Hz, 1H), 4.55 (d, J = 12.6
Hz, 1H), 4.49 (d, J = 12.4 Hz, 1H), 4.42 (d, J = 12.4 Hz, 1H), 4.26 (q,
J = 4.1 Hz, 1H), 3.86−3.76 (m, 3H), 3.56 (dt, J = 10.1, 7.2 Hz, 1H),
3.45 (dd, J = 10.8, 4.1 Hz, 1H), 3.37 (dd, J = 10.8, 4.1 Hz, 1H), 2.72
(dt, J = 7.2, 3.7 Hz, 2H), 2.00 (quintet, J = 7.2 Hz, 2H). 13C NMR
(100 MHz, CDCl3) δ 142.1, 138.3, 137.9, 128.4, 128.3, 128.2, 128.2,
128.0, 127.9, 127.7, 127.6, 127.5, 125.6, 101.4, 81.5, 77.5, 75.3, 73.4,
72.5, 72.2, 70.0, 67.7, 32.4, 31.3. HRMS (ESI-TOF) m/z: [M + Na]+
+
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C36H46NaO5
581.3237; Found 581.3219.
1H NMR spectrum of β-3e is consistent with that in the literature.25
tert-Butyl 2,3,5-Tri-O-benzyl-D-ribofuranoside (α-3f and β-
3f). [Table 2, entry 5] Ribofuranosylation of t-BuOH (0.0188 mL,
0.20 mmol) according to the general procedure A gave α-3f (0.0670 g,
0.141 mmol, 71%, α:β = 99:1, colorless syrup). Conditions for silica
gel column chromatography: silica gel 60N, spherical, neutral, 63−210
μm, hexane−AcOEt (100:0 to 90:10, v/v).
+
Calcd for C35H38NaO5 561.2611; Found 561.2609.
Characterization Data of 3-Phenylpropyl 2,3,5-Tri-O-benzyl-
β-D-ribofuranoside β-3b.5h 1H NMR (400 MHz, CDCl3) δ 7.37−
7.12 (m, 20H), 5.00 (s, 1H), 4.67 (d, J = 12.1 Hz, 1H), 4.63 (d, J =
12.1 Hz, 1H), 4.57 (d, J = 12.2 Hz, 1H), 4.54 (d, J = 12.4 Hz, 1H),
4.51 (d, J = 12.4 Hz, 1H), 4.47 (d, J = 12.2 Hz, 1H), 4.36−4.32 (m,
1H), 4.03 (dd, J = 7.1, 4.9 Hz, 1H), 3.87 (d, J = 4.9 Hz, 1H), 3.70 (dt,
J = 9.6, 6.4 Hz, 1H), 3.60 (dd, J = 10.8, 3.9 Hz, 1H), 3.50 (dd, J = 10.8,
6.2 Hz, 1H), 3.35 (dt, J = 9.6, 6.9 Hz, 1H), 2.59 (t, J = 7.3 Hz, 2H),
1.80 (quintet, J = 7.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 141.8,
138.2, 137.8, 128.4, 128.3, 128.3, 128.3, 127.9, 127.8, 127.7, 127.7,
127.6, 127.5, 125.7, 105.3, 80.3, 79.7, 78.5, 73.1, 72.3, 72.2, 71.4, 67.1,
32.2, 31.0. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
[Table 2, entry 10] Ribofuranosylation of t-BuOH (0.0188 mL, 0.20
mmol) according to the general procedure A except for the use of
TBAI in place of TPPO gave a mixture of α-3f and β-3f (0.0637 g,
0.134 mmol, 67%, α:β = 90:10, pale yellow syrup). Conditions for
silica gel column chromatography: silica gel 60N, spherical, neutral,
40−50 μm, hexane−AcOEt (100:0 to 90:10, v/v).
1H and 13C NMR spectra of α-3f and β-3f are consistent with the
data in the literature5a (only those of the anomeric positions are
reported).
+
C35H38NaO5 561.2611; Found 561.2624.
Isopropyl 2,3,5-Tri-O-benzyl-D-ribofuranoside (α-3c and β-
3c). [Table 2, entry 2] Ribofuranosylation of i-PrOH (0.0153 mL, 0.20
E
dx.doi.org/10.1021/jo500632h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
tert-Butyl 2,3,5-Tri-O-benzyl-α-D-ribofuranoside (α-3f). 1H
NMR (400 MHz, CDCl3) δ 7.39−7.22 (m, 15H), 5.32 (d, J = 4.1
Hz, 1H), 4.76 (d, J = 12.6 Hz, 1H), 4.70 (d, J = 12.6 Hz, 1H), 4.62 (d,
J = 12.6 Hz, 1H), 4.51 (d, J = 12.4 Hz, 1H), 4.50 (d, J = 12.6 Hz, 1H),
4.43 (d, J = 12.4 Hz, 1H), 4.27 (m, 1H), 3.88 (dd, J = 6.4, 5.2 Hz, 1H),
3.75 (dd, J = 6.4, 4.1 Hz, 1H), 3.51 (dd, J = 10.8, 3.5 Hz, 1H), 3.40
(dd, J = 10.8, 3.9 Hz, 1H), 1.32 (s, 9H). 13C NMR (100 MHz, CDCl3)
δ 138.5, 138.3, 138.1, 128.2, 128.2, 128.1, 127.9, 127.5, 127.4, 127.4,
96.3, 80.1, 77.1, 75.7, 74.8, 73.2, 72.3, 72.0, 69.8, 28.8. HRMS (ESI-
Methyl (2,3,5-Tri-O-benzyl-α-D-ribofuranosyl)-(1→6)-2,3,4-
tri-O-benzyl-α-D-glucopyranoside (α-3j). Ribofuranosylation of
methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (0.0929 g, 0.20 mmol)
according to the general procedure C gave α-3j (0.133 g, 0.153 mmol,
77%, colorless syrup). Purification was performed by PTLC (CH2Cl2−
MeOH (99:1, v/v)). 1H and 13C NMR spectra are consistent with the
data in the literature (only the signal corresponding to the anomeric
position is reported for 13C NMR).6,7 1H NMR (400 MHz, CDCl3) δ
7.38−7.17 (m, 30H), 5.15 (d, J = 3.6 Hz, 1H), 4.93 (d, J = 10.8 Hz,
1H), 4.81 (d, J = 10.8 Hz, 1H), 4.76 (m, 1H), 4.73 (s, 3H), 4.67 (d, J =
12.0 Hz, 1H), 4.62−4.56 (m, 3H), 4.50 (d, J = 12.0 Hz, 1H), 4.43 (d, J
= 11.4 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 4.23−4.20 (m, 1H), 4.15
(dd, J = 11.0, 3.0 Hz, 1H), 3.95 (t, J = 9.2 Hz, 1H), 3.90−3.86 (m,
2H), 3.78−3.65 (m, 3H), 3.49−3.38 (m, 3H), 3.33 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 139.1, 138.7, 138.3, 138.2, 138.0, 128.4, 128.3,
128.3, 128.2, 128.0, 127.9, 127.8, 127.6, 127.4, 127.4, 102.1, 98.1, 82.0,
81.4, 80.0, 77.8, 76.1, 75.5, 75.0, 73.4, 72.4, 72.4, 70.2, 69.8, 66.6, 55.1.
+
TOF) m/z: [M + Na]+ Calcd for C30H36NaO5 499.2455; Found
499.2481.
tert-Butyl 2,3,5-Tri-O-benzyl-β-D-ribofuranoside (β-3f). 1H
NMR (400 MHz, CDCl3) δ 7.37−7.26 (m, 15H), 5.27 (d, J = 2.0
Hz, 1H), 4.68 (s, 2H), 4.62−4.50 (m, 4H), 4.27 (q, J = 5.3 Hz, 1H),
3.97 (t, J = 5.3 Hz, 1H), 3.76 (dd, J = 5.3, 2.0 Hz, 1H), 3.61−3.54 (m,
2H), 1.19 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 138.4, 138.1,
138.0, 128.4, 128.3, 128.3, 127.9, 127.9, 127.7, 127.7, 127.5, 100.4,
81.0, 80.1, 78.4, 75.0, 73.2, 72.3, 72.2, 71.8, 28.8. HRMS (ESI-TOF)
+
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C54H58NaO10
+
m/z: [M + Na]+ Calcd for C30H36NaO5 499.2455; Found 499.2486.
889.3922; Found 889.3896.
2,3,5-Tri-O-benzyl-α-D-ribofuranosyl-(1→6)-1,2,3,4-tetra-O-
acetyl-β-D-glucopyranose (α-3k). Ribofuranosylation of 1,2,3,4-
tetra-O-acetyl-β-D-glucopyranose (0.0697 g, 0.20 mmol) according to
the general procedure C gave α-3k (0.0984 g, 0.131 mmol, 66%, white
powder). Purification was performed by silica gel column chromatog-
raphy (conditions: silica gel 60N, spherical, neutral, 63−210 μm,
4-Penten-1-yl 2,3,5-Tri-O-benzyl-α-D-ribofuranoside (α-3g).
Ribofuranosylation of 4-penten-1-ol (0.0203 mL, 0.20 mmol)
according to the general procedure A gave α-3g (0.0740 g, 0.151
mmol, 76%, pale yellow syrup). Conditions for silica gel column
chromatography: silica gel 60N, spherical, neutral, 40−50 μm,
hexane−AcOEt (6:1, v/v). 1H NMR (400 MHz, CDCl3) δ 7.37−
7.20 (m, 15H), 5.83 (m, 1H), 5.04−4.93 (m, 2H), 5.00 (d, J = 4.2 Hz,
1H), 4.70 (d, J = 12.4 Hz, 1H), 4.67 (d, J = 12.4 Hz, 1H), 4.63 (d, J =
12.4 Hz, 1H), 4.54 (d, J = 12.4 Hz, 1H), 4.49 (d, J = 12.2 Hz, 1H),
4.42 (d, J = 12.2 Hz, 1H), 4.23 (q, J = 4.0 Hz, 1H), 3.83 (dd, J = 6.9,
4.0 Hz, 1H), 3.77 (dd, J = 16.8, 6.8 Hz, 1H), 3.78 (dd, J = 6.9, 4.2 Hz,
1H), 3.54 (dt, J = 9.6, 6.8 Hz, 1H), 3.44 (dd, J = 10.4, 4.0 Hz, 1H),
3.37 (dd, J = 10.4, 4.0 Hz, 1H), 2.19−2.13 (m, 2H), 1.81−1.74 (m,
2H). 13C NMR (100 MHz, CDCl3) δ 138.4, 138.4, 138.0, 128.3, 128.3,
128.2, 128.1, 128.0, 127.7, 127.6, 127.5, 114.6, 101.4, 81.5, 77.5, 75.3,
73.4, 72.5, 72.2, 70.0, 67.7, 30.4, 28.8. HRMS (ESI-TOF) m/z: [M +
1
hexane−AcOEt (5:1 to 0:1, v/v)). H NMR (400 MHz, CDCl3) δ
7.39−7.21 (m, 15H), 5.72 (d, J = 8.4 Hz, 1H), 5.24 (t, J = 9.4 Hz, 1H),
5.11 (q, J = 9.4 Hz, 2H), 4.98 (d, J = 3.6 Hz, 1H), 4.66 (d, J = 12.0 Hz,
1H), 4.64 (d, J = 12.0 Hz, 1H), 4.60 (d, J = 12.4 Hz, 1H), 4.55 (d, J =
12.4 Hz, 1H), 4.49 (d, J = 12.4 Hz, 1H), 4.43 (d, J = 12.4 Hz, 1H),
4.24 (q, J = 4.0 Hz, 1H), 3.90−3.79 (m, 4H), 3.74 (dd, J = 11.4, 3.0
Hz, 1H), 3.46 (dd, J = 10.7, 4.0 Hz, 1H), 3.39 (dd, J = 10.7, 4.0 Hz,
1H), 2.03 (s, 3H), 2.02 (s, 3H), 1.99 (s, 3H), 1.97 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 170.3, 169.6, 169.3, 169.0, 138.5, 138.1, 128.4,
128.3, 128.2, 128.2, 127.8, 127.7, 127.6, 101.5, 91.8, 81.5, 77.7, 75.3,
73.8, 73.5, 73.2, 72.7, 72.1, 70.6, 70.0, 69.2, 66.2, 20.8, 20.7, 20.7, 20.7.
+
Na]+ Calcd for C31H36NaO5 511.2455; Found 511.2472.
+
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C40H46NaO14
2-(Methylphenylamino)ethyl 2,3,5-Tri-O-benzyl-α-D-ribofur-
anoside (α-3h). Ribofuranosylation of 2-(methylphenylamino)-
ethanol (0.0283 mL, 0.20 mmol) according to the general procedure
A gave α-3h (0.0854 g, 0.154 mmol, 77%, pale yellow syrup).
Conditions for silica gel column chromatography: silica gel 60N,
773.2780; Found 773.2817.
2,3,5-Tri-O-benzyl-α-D-ribofuranosyl-(1→6)-1,2:3,4-di-O-iso-
propylidene-α-D-galactopyranose (α-3l).4a Ribofuranosylation of
1,2:3,4-di-O-isopropylidene-α-D-galactopyranose (0.0521 g, 0.20
mmol) according to the general procedure C gave α-3l (0.120 g,
0.181 mmol, 91%, pale yellow syrup). Purification was performed by
1
spherical, neutral, 40−50 μm, hexane−AcOEt (6:1, v/v). H NMR
(400 MHz, CDCl3) δ 7.34−7.27 (m, 13H), 7.22−7.17 (m, 4H), 6.72
(d, J = 8.0 Hz, 2H), 6.67 (t, J = 7.4 Hz, 1H), 4.99 (d, J = 4.4 Hz, 1H),
4.69 (d, J = 12.4 Hz, 1H), 4.62 (s, 2H), 4.54 (d, J = 12.4 Hz, 1H), 4.49
(d, J = 12.0 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 4.22 (q, J = 4.0 Hz,
1H), 3.90−3.83 (m, 2H), 3.79−3.72 (m, 2H), 3.61 (m, 2H), 3.43 (dd,
J = 10.5, 4.0 Hz, 1H), 3.37 (dd, J = 10.5, 4.0 Hz, 1H), 2.96 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 149.2, 138.3, 137.9, 137.9, 129.1, 128.3,
128.3, 128.2, 128.1, 127.9, 127.8, 127.6, 127.6, 116.0, 112.0, 101.8,
81.8, 77.8, 75.3, 73.4, 72.5, 72.3, 70.0, 65.3, 52.3, 38.8. HRMS (ESI-
1
recycling GPC (CHCl3). H NMR (400 MHz, CDCl3) δ 7.37−7.20
(m, 15H), 5.51 (d, J = 5.0 Hz, 1H), 5.14 (d, J = 4.2 Hz, 1H), 4.73 (d, J
= 12.4 Hz, 2H), 4.62 (d, J = 12.4 Hz, 1H), 4.57 (dd, J = 8.0, 2.0 Hz,
1H), 4.55 (d, J = 12.4 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 4.42 (d, J =
12.0 Hz, 1H), 4.39 (dd, J = 8.0, 2.2 Hz, 1H), 4.29 (dd, J = 5.0, 2.2 Hz,
1H), 4.25 (q, J = 4.0 Hz, 1H), 4.13 (m, 1H), 3.89 (dd, J = 10.1, 5.4 Hz,
1H), 3.86 (dd, J = 6.9, 4.0 Hz, 1H), 3.80 (dd, J = 6.9, 4.2 Hz, 1H), 3.78
(dd, J = 10.1, 8.8 Hz, 1H), 3.46 (dd, J = 10.6, 4.0 Hz, 1H), 3.39 (dd, J
= 10.6, 4.0 Hz, 1H), 1.52 (s, 3H), 1.44 (s, 3H), 1.32 (s, 3H), 1.29 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 138.4, 138.0, 138.0, 128.3, 128.2,
128.0, 127.8, 127.7, 127.6, 127.5, 108.9, 108.5, 102.1, 96.3, 81.5, 77.5,
75.4, 73.4, 72.2, 72.1, 70.8, 70.6, 70.5, 69.8, 66.6, 65.8, 26.1, 26.0, 24.9,
+
TOF) m/z: [M + H]+ Calcd for C35H40NO5 554.2901; Found
554.2896.
5′-Triphenylmethoxypentyl 2,3,5-Tri-O-benzyl-α-D-ribofura-
noside (α-3i). Ribofuranosylation of 5-triphenylmethoxy-1-pentanol
(0.0693 g, 0.20 mmol) according to the general procedure B gave α-3i
(0.125 g, 0.167 mmol, 83%, colorless syrup). Conditions for silica gel
column chromatography: silica gel 60N, spherical, neutral, 63−210
μm, hexane−AcOEt (9:1 to 3:1, v/v). 1H NMR (400 MHz, CDCl3) δ
7.45−7.19 (m, 30H), 4.97 (d, J = 4.4 Hz, 1H), 4.66 (d, J = 12.4 Hz,
1H), 4.64 (d, J = 12.6 Hz, 1H), 4.60 (d, J = 12.6 Hz, 1H), 4.51 (d, J =
12.4 Hz, 1H), 4.48 (d, J = 12.4 Hz, 1H), 4.41 (d, J = 12.4 Hz, 1H),
4.20 (q, J = 4.0 Hz, 1H), 3.81 (dd, J = 6.8, 4.0 Hz, 1H), 3.77−3.70 (m,
2H), 3.50 (dt, J = 9.6, 6.8 Hz, 1H), 3.43 (dd, J = 10.6, 4.0 Hz, 1H),
3.35 (dd, J = 10.6, 4.0 Hz, 1H), 3.04 (t, J = 6.6 Hz, 2H), 1.69−1.61 (m,
4H), 1.47−1.39 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 144.5,
138.3, 138.0, 128.7, 128.3, 128.3, 128.2, 128.1, 128.0, 127.7, 127.6,
127.5, 126.8, 101.3, 86.3, 81.4, 77.4, 75.2, 73.4, 72.4, 72.1, 70.0, 68.3,
63.6, 29.9, 29.5, 22.9. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
+
24.4. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C38H46NaO10
685.2983; Found 685.2953.
Methyl (2,3,5-Tri-O-benzyl-α-D-ribofuranosyl)-(1→5)-2,3-O-
isopropylidene-β-D-ribofuranoside (α-3m).4a Ribofuranosylation
of methyl 2,3-O-isopropylidene-β-D-ribofuranoside (0.0408 g, 0.20
mmol) according to the general procedure C gave α-3m (0.0994 g,
0.164 mmol, 82%, colorless syrup). Purification was performed by
1
PTLC (hexane−AcOEt (2:1, v/v)). H NMR (400 MHz, CDCl3) δ
7.37−7.22 (m, 15H), 5.04 (d, J = 4.3 Hz, 1H), 4.94 (s, 1H), 4.87 (d, J
= 6.4 Hz, 1H), 4.69 (d, J = 12.4 Hz, 1H), 4.65 (s, 2H), 4.56−4.49 (m,
4H), 4.42 (d, J = 12.0 Hz, 1H), 4.30 (q, J = 3.6 Hz, 1H), 3.86 (dd, J =
6.6, 3.6 Hz, 1H), 3.81 (dd, J = 6.6, 4.3 Hz, 1H), 3.74 (dd, J = 10.8, 5.6
Hz, 1H), 3.66 (t, J = 10.8 Hz, 1H), 3.45 (dd, J = 10.6, 3.6 Hz, 1H),
3.38 (dd, J = 10.6, 3.6 Hz, 1H), 3.28 (s, 3H), 1.47 (s, 3H), 1.28 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 138.3, 137.9, 137.9, 128.3, 128.3,
+
C50H52NaO6 771.3656; Found 771.3651.
F
dx.doi.org/10.1021/jo500632h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
128.2, 128.1, 128.0, 127.8, 127.6, 127.6, 127.6, 112.0, 109.5, 102.2,
85.2, 85.1, 82.0, 81.7, 77.9, 75.4, 73.3, 72.5, 72.2, 69.9, 69.3, 54.7, 26.5,
Diethyl 2,3,5-Tris-O-tert-butyldimethylsilyl-D-ribofuranosyl
Phosphite (5). 2,3,5-Tris-O-tert-butyldimethylsilyl-D-ribofuranose27
(0.246 g, 0.50 mmol) was dried by repeated coevaporation with dry
toluene and dissolved in dry CH2Cl2 (5.0 mL) under argon. Dry Et3N
(0.209 mL, 1.5 mmol) and (EtO)2PCl (0.0865 mL, 0.60 mmol) were
added dropwise with stirring, and the mixture was allowed to stir for 1
h. The mixture was then treated with a saturated NaHCO3 aqueous
solution (15 mL). The aqueous layer was separated and extracted with
CH2Cl2 (3 × 15 mL). The organic layers were combined, dried over
Na2SO4, filtered, and concentrated under reduced pressure. Finally, the
residue was purified by silica gel column chromatography (conditions:
3-aminopropyl-functionalized NH silica gel, hexane−AcOEt (20:1 to
2:1, v/v) containing 3 vol % Et3N) to afford 5 (0.275 g, 0.45 mmol,
90%, α:β = 62:38) as a colorless syrup. 1H NMR (400 MHz, CDCl3) δ
5.46−5.40 (m, 1H), 4.20−3.63 (m, 9H), 1.28−1.21 (m, 6H), 0.93−
0.89 (m, 27H), 0.11−0.03 (m, 18H). 13C NMR (100 MHz, CDCl3) δ
100.6 (d, 2JPC = 17.0 Hz), 97.0 (d, 2JPC = 29.4 Hz), 87.0, 83.3, 77.5 (d,
+
24.9. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C35H42NaO9
629.2721; Found 629.2726.
Methyl 2,3-O-Benzylidene-β-D-ribofuranoside.26 AcCl (0.028
mL, 0.40 mmol) was added dropwise to dry MeOH (2.00 mL), and
the resultant solution was added dropwise a stirred mixture of D-ribose
(1.00 g, 6.67 mmol) and dry MeOH (13.0 mL) at rt under argon.
After stirring for 5 h, NaHCO3 (0.40 g, 4.8 mmol) was added to the
mixture, and the solid was filtered off and washed with MeOH (40
mL). The filtrate was then concentrated under reduced pressure. The
residue was dried by repeated coevaporation with dry pyridine and dry
toluene and dissolved in dry MeCN (60 mL) under argon.
Benzaldehyde dimethyl acetal (1.99 mL, 13.3 mmol) and PPTS
(0.335 g, 1.33 mmol) were added, and the resultant mixture was
stirred for 25 h at 90 °C. The mixture was allowed to cool to rt, and
Et3N (0.37 mL, 2.7 mmol) was added. The mixture was then diluted
with AcOEt (50 mL), washed successively with water (2 × 50 mL),
saturated NaHCO3 aqueous solutions (2 × 50 mL), and a saturated
NaCl aqueous solution (20 mL). The aqueous layers were combined
and extracted with AcOEt (20 mL). The organic layers were
combined, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was then purified by silica gel column
chromatography (silica gel 60N, spherical, neutral, 63−210 μm,
hexane−AcOEt (1:1, v/v)). The fractions containing the β-isomer
were collected and concentrated to dryness to afford the title
compound (1.25 g, 4.95 mmol, 74%, white solid) as a 96:4 mixture of
3
3JPC = 6.1 Hz), 74.1 (d, JPC = 9.4 Hz), 71.6, 71.1, 63.4, 63.2, 58.4 (d,
2JPC = 18.4 Hz), 58.1 (d, 2JPC = 10.8 Hz), 57.8 (d, 2JPC = 9.2 Hz), 26.0,
25.9, 25.9, 25.8, 25.8, 18.5, 18.4, 18.3, 18.1, 18.0, 16.8, 16.7, −4.3, −4.4,
−4.6, −4.8, −4.9, −5.3, −5.4, −5.5. 31P NMR (161.7 MHz, CDCl3) δ
+
138.9, 138.0. HRMS (ESI): m/z calcd for C27H61NaO7PSi3 [(M +
Na)+] 635.3355, found 635.3354.
3-Butyn-1-yl 2,3,5-Tris-O-tert-butyldimethylsilyl-α-D-ribofur-
anoside (α-6). Compound 5 (0.0613 g, 0.10 mmol) was dried by
repeated coevaporation with dry toluene and dissolved in dry CH2Cl2
(1.0 mL) under argon. MS 4A (0.2 g) was then added, and the mixture
was cooled to 0 °C. A solution of N,N-diethylanilinium iodide (0.0277
g, 0.10 mmol) in dry CH2Cl2 (2.0 mL) was added dropwise, and the
mixture was allowed to stir for 10 min. A solution of 3-butyn-1-ol (7.5
μL, 0.10 mmol) and TPPO (0.0278 g, 0.10 mmol) in dry CH2Cl2 (1.0
mL) was then added, and the mixture was stirred for 1 h. The mixture
was then treated with a saturated NaHCO3 aqueous solution (15 mL).
The aqueous layer was separated and extracted with CH2Cl2 (3 × 15
mL). The organic layers were combined, washed with a saturated NaCl
aqueous solution (10 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was dissolved in
Et2O (20 mL) and then washed with 0.1 M HCl aqueous solutions (2
× 15 mL) and a saturated NaCl aqueous solution (10 mL). The
organic layer was dried over Na2SO4, filtered, and concentrated under
reduced pressure. Finally, the residue was purified by PTLC (hexane−
AcOEt (10:1, v/v)) to afford α-6 (0.0454 g, 0.083 mmol, 83%) as a
1
the endo- and exo-isomers. The H NMR spectrum is consistent with
that in the literature.26b,c 1H NMR (400 MHz, CDCl3) δ 7.52−7.47
(m, 2H), 7.41−7.38 (m, 3H), 5.77 (s, 1H), 5.13 (s, 1H), 4.92 (d, J =
6.0 Hz, 1H), 4.70 (d, J = 6.0 Hz, 1H), 4.61 (t, J = 2.8 Hz, 1H), 3.77−
3.63 (m, 2H), 3.47 (s, 3H), 3.26 (dd, J = 10.4, 2.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 135.9, 129.8, 128.4, 126.9, 109.6, 105.8, 88.1,
86.3, 82.5, 63.9, 55.5. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
+
C13H16NaO5 275.0890; Found 275.0889.
Methyl (2,3,5-Tri-O-benzyl-α-D-ribofuranosyl)-(1→5)-2,3-O-
benzylidene-β-D-ribofuranoside (α-3n). Ribofuranosylation of
methyl 2,3-O-benzylidene-β-D-ribofuranoside (0.0505 g, 0.20 mmol)
according to the general procedure C gave α-3n (0.108 g, 0.165 mmol,
83%, white solid). Purification was performed by silica gel column
chromatography (conditions: silica gel 60N, spherical, neutral, 63−210
μm, hexane−AcOEt (2:1, v/v)). 1H NMR (400 MHz, CDCl3) δ
7.51−7.17 (m, 20H), 5.70 (s, 1H), 5.08 (s, 1H), 5.05 (d, J = 4.0 Hz,
1H), 4.97 (d, J = 6.4 Hz, 1H), 4.74−4.63 (m, 5H), 4.53 (d, J = 12.4
Hz, 1H), 4.48 (d, J = 12.2 Hz, 1H), 4.39 (d, J = 12.2 Hz, 1H), 4.30 (q,
J = 3.6 Hz, 1H), 3.86−3.70 (m, 4H), 3.43 (dd, J = 10.6, 3.8 Hz, 1H),
3.35 (dd, J = 10.6, 3.8 Hz, 1H), 3.31 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 138.2, 137.8, 137.8, 136.2, 129.6, 128.2, 128.1, 128.0, 127.9,
127.7, 127.5, 127.5, 126.9, 109.1, 105.8, 102.1, 85.7, 84.8, 82.7, 81.7,
77.9, 75.4, 73.2, 72.5, 72.2, 69.9, 69.0, 54.7. HRMS (ESI-TOF) m/z:
1
colorless syrup. H NMR (400 MHz, CDCl3) δ 4.91 (d, J = 4.4 Hz,
1H), 4.07 (dd, J = 5.4, 3.4 Hz, 1H), 4.02−3.98 (m, 2H), 3.84 (dt, J =
9.4, 7.4 Hz, 1H), 3.68 (dd, J = 11.4, 3.0 Hz, 1H), 3.65 (dd, J = 11.4, 3.0
Hz, 1H), 3.59 (dt, J = 9.4, 7.4 Hz, 1H), 2.48 (dt, J = 7.4, 2.6 Hz, 1H),
1.92 (t, J = 2.6 Hz, 1H), 0.91 (s, 9H), 0.89 (s, 9H), 0.89 (s, 9H), 0.09
(s, 3H), 0.07 (s, 3H), 0.07 (s, 3H), 0.06 (s, 6H), 0.05 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 102.5, 85.2, 81.5, 73.9, 71.4, 69.0, 65.9,
62.9, 26.0, 25.9, 25.9, 20.1, 18.4, 18.3, 18.1, −4.4, −4.5, −4.6, −4.9,
−5.3, −5.5. HRMS (ESI): m/z calcd for C27H56NaO5Si3+ [(M + Na)+]
567.3328, found 567.3308.
+
[M + Na]+ Calcd for C39H42NaO9 677.2721; Found 677.2723.
2,3,5-Tri-O-benzyl-α-D-ribofuranosyl-(1→3)-1,2:5,6-di-O-iso-
propylidene-α-D-allofuranose (α-3o). Ribofuranosylation of
1,2:5,6-di-O-isopropylidene-α-D-allofuranose (0.0521 g, 0.20 mmol)
according to the general procedure C with an extended reaction time
(4.5 h) gave α-3o (0.0986 g, 0.149 mmol, 75%, colorless syrup).
Purification was performed by silica gel column chromatography
(conditions: silica gel 60N, spherical, neutral, 63−210 μm, hexane−
5′-Hydroxypentyl α-D-Ribofuranoside (α-7). A mixture of
compound α-3i (0.0375 g, 0.050 mmol), 10% Pd/C (2.5 mg), and
dry EtOH (0.50 mL) was stirred under H2 (balloon) for 5 days at rt.
The mixture was then filtered, and the filtrate was concentrated under
reduced pressure. The residue was dissolved in H2O (20 mL) and
washed with Et2O (20 mL). The organic layer was extracted with H2O
(3 × 20 mL). The aqueous layers were combined and lyophilized to
afford α-7 (0.0107 g, 0.045 mmol, 91%) as a colorless syrup. 1H NMR
(400 MHz, CD3OD) δ 4.96 (d, J = 4.4 Hz, 1H), 3.99−3.96 (m, 2H),
3.93−3.91 (m, 1H), 3.77 (dt, J = 9.6, 6.6 Hz, 1H), 3.66 (dd, J = 12.0,
3.6 Hz, 1H), 3.59 (dd, J = 12.0, 4.4 Hz, 1H), 3.56 (t, J = 6.6 Hz, 2H),
3.50 (dt, J = 9.6, 6.4 Hz, 1H), 1.65 (m, 2H), 1.60−1.53 (m, 2H),
1.48−1.40 (m, 2H). 13C NMR (100 MHz, CD3OD) δ 103.7, 86.5,
73.2, 71.5, 69.4, 63.4, 63.0, 33.5, 30.6, 23.6. HRMS (ESI-TOF) m/z:
1
AcOEt (5:1 to 1:1, v/v)). H NMR (400 MHz, CDCl3) δ 7.40−7.19
(m, 15H), 5.88 (d, J = 4.1 Hz, 1H), 5.30 (d, J = 3.6 Hz, 1H), 4.88 (d, J
= 12.2 Hz, 1H), 4.77 (t, J = 4.1 Hz, 1H), 4.73 (d, J = 12.2 Hz, 1H),
4.66 (d, J = 12.2 Hz, 1H), 4.56 (d, J = 12.2 Hz, 1H), 4.53−4.40 (m,
5H), 4.30 (dd, J = 8.2, 7.0 Hz, 1H), 4.25 (dd, J = 8.8, 2.0 Hz, 1H),
3.89−3.84 (m, 3H), 3.46 (dd, J = 10.6, 3.6 Hz, 1H), 3.39 (dd, J = 10.6
Hz, 4.0 Hz, 1H), 1.51 (s, 3H), 1.48 (s, 3H), 1.37 (s, 3H), 1.35 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 138.3, 138.2, 137.9, 128.3, 128.3,
128.1, 128.0, 127.8, 127.6, 127.5, 127.4, 112.7, 109.4, 104.4, 98.4, 82.0,
78.2, 77.6, 76.9, 75.7, 73.8, 73.3, 72.2, 71.7, 71.5, 69.9, 63.9, 26.8, 25.9,
+
[M + Na]+ Calcd for C10H20NaO6 259.1152; Found 259.1176.
Methyl α-D-Ribofuranosyl-(1→5)-β-D-ribofuranoside (α-8). A
mixture of compound α-3n (0.0613 g, 0.0936 mmol), 10% Pd/C (4.7
mg), and dry EtOH (1.00 mL) was stirred under H2 (balloon) for 5
+
24.7. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C38H46NaO10
685.2983; Found 685.3017.
G
dx.doi.org/10.1021/jo500632h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
days at rt. The mixture was then filtered, and the filtrate was
concentrated under reduced pressure. The residue was dissolved in
H2O (40 mL) and washed with Et2O (40 mL). The organic layer was
extracted with H2O (3 × 20 mL). The aqueous layers were combined
and lyophilized to afford α-8 (0.0231 g, 0.0780 mmol, 83%) as a white
solid. 1H NMR (400 MHz, CD3OD) δ 5.03 (d, J = 4.4 Hz, 1H), 4.76
(s, 1H), 4.17−4.14 (m, 1H), 4.10−3.99 (m, 3H), 3.95−3.91 (m, 2H),
3.85 (dd, J = 10.4, 5.6 Hz, 1H), 3.68−3.58 (m, 3H), 3.35 (s, 3H). 13C
NMR (100 MHz, CD3OD) δ 110.4, 103.8, 87.0, 83.0, 76.3, 73.6, 73.5,
71.6, 70.3, 63.4, 63.4, 55.8. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
S. Chem. Lett. 1991, 20, 981. (d) Mukaiyama, T.; Matsubara, K. Chem.
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+
for C11H20NaO9 319.1000; Found 319.1007.
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ASSOCIATED CONTENT
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* Supporting Information
HPLC profiles and NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: oka@gifu-u.ac.jp (N.O.). Tel/Fax: (+81) 58-293-
2564.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Toshiyasu Inuzuka (Gifu Univ.) for his
assistance with the low-temperature NMR analysis. We also
thank Prof. Toshiaki Murai and Prof. Fumitoshi Shibahara
(Gifu Univ.) for providing access to a recycling GPC system.
This research was financially supported by A-STEP from JST
and a grant from the Toukai Foundation for Technology
̌ ́
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