Synthesis of iminoalditol and N-alkyl iminoalditol derivatives of ribopyranosides

Article abstract of DOI:10.1016/j.carres.2008.08.005

Iminoalditol analogs of ribopyranosides were prepared by reduction of a vinylogous urethane intermediate formed from methyl 2-C-(5-O-methanesulfonyl-β-d-ribofuranosyl)acetate (1) by treatment with sodium azide in DMF at reflux. The N-alkylated analogs were synthesized either by N-alkylation of the corresponding parent iminoaldithol or, more efficiently, from the product of the reaction of 1 with various alkylamines. The latter process involves an S_N2 substitution at C-5 by the amine followed by an intramolecular hetero-Michael reaction under basic conditions. The 'aglycon' of the iminoalditol was also modified through amidation and esterification.

Full text of DOI:10.1016/j.carres.2008.08.005

Carbohydrate Research 343 (2008) 2887–2893
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of iminoalditol and N-alkyl iminoalditol derivatives
of ribopyranosides
a
b
c
a
An-Tai Wu a, , Pey-Jiuann Wu , Wei Zou , Jiun-Ly Chir , Yuan-Chun Chang ,
*
Shuan-Yi Tsai a, Chao-Qi Guo a, Wei-Shuan Chang a, Yu-Chi Hsieh a
a Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan
b Institute for Biological Sciences, National Research Council of Canada, 100 Sussex Drive, Ottawa, Ontario, Canada K1A 0R6
c Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 June 2008
Received in revised form 24 July 2008
Accepted 3 August 2008
Available online 9 August 2008
Iminoalditol analogs of ribopyranosides were prepared by reduction of a vinylogous urethane intermedi-
ate formed from methyl 2-C-(5-O-methanesulfonyl-b-D-ribofuranosyl)acetate (1) by treatment with
sodium azide in DMF at reflux. The N-alkylated analogs were synthesized either by N-alkylation of the
corresponding parent iminoaldithol or, more efficiently, from the product of the reaction of 1 with
various alkylamines. The latter process involves an SN2 substitution at C-5 by the amine followed by
an intramolecular hetero-Michael reaction under basic conditions. The ‘aglycon’ of the iminoalditol
was also modified through amidation and esterification.
Dedicated to Professor Yongzheng Hui
on the occasion of his 70th birthday
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Aza-C-glycoside
Iminoalditols
N-Alkylation
Amidation
Michael addition
1. Introduction
alternative method to iminoalditols via a vinylogous urethane
intermediate, and also report an efficient synthesis of N-alkylated
N-Alkylation of iminoalditols often results in better inhibitory
specificity against glycan-processing enzymes and improves bio-
availability.1 For example, N-hydroxyethyl 1-deoxynojirimycin
(Miglitol),1b and N-butyl 1-deoxynojirimycin (Miglustat)1a have
been used as therapeutics for the treatment of type II diabetes
and type I Gaucher disease, respectively. It has been suggested that
even better inhibition selectivity of iminoalditols could be
achieved by introducing additional interaction between the ‘agly-
con’ and the enzyme.2 By careful selection of the N-alkyl group
and aglycon, one might be able to tune the inhibitory activity of
an iminoalditol and its intracellular bioavailability.
One of the synthetic methods to iminoalditols uses 2-C-(azido-
glycosyl)acetates as intermediates, from which reduction of the
azido group to an amine is followed by an intramolecular hetero-
Michael addition leading to the product.3 The resultant iminoaldi-
tols can be further N-alkylated. However, this protocol may not
work well when intramolecular amidation between the amino
group and acetate ester takes place. In this paper, we describe an
iminoalditols by treatment of methyl 2-C-(5-O-methanesulfonyl-
b- -ribofuranosyl)acetate with amines, which involves an SN2 sub-
stitution of 5-O-methanesulfonyl group by an amine followed by
D
an intramolecular hetero-Michael addition.
2. Results and discussion
The key intermediate methyl 2-C-(5-O-methanesulfonyl-b-D-
ribofuranosyl)acetate (1) was prepared from readily available
2,3-O-isopropylidene ribofuranose4 by a Wittig reaction5 followed
by 5-O-mesylation.6 We treated 1 with sodium azide at 80 °C to
introduce a 5-azido group to obtain 2 in 86% yield. The product
was further converted by hydrogenation to amine 3 in 92% yield
(see Scheme 1). However, subsequent treatment with base pro-
duced desired iminoalditol 4 in only 35% yield. The reaction pro-
duced, as the major product, tricyclic lactam 5 in 63% yield,
which was not observed in the previous study.5 Apparently,
because of the cis relationship between the groups at C1 and C4
in 1, the spatial proximity between ester and 5-amino groups
favors the amidation leading to 5. In contrast, the less favored
b-elimination and intramolecular Michael addition thereafter
produced iminoalditol 4.
* Corresponding author. Fax: +886 4 7211 190.
E-mail address: antai@cc.ncue.edu.tw (A.-T. Wu).
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.08.005

2888
A.-T. Wu et al. / Carbohydrate Research 343 (2008) 2887–2893
O
O
MsO
OMe
N3
OMe
OMe
HO
OH
O
O
O
ref. 8
(a)
O
O
O
O
O
O
2
1
2,3-O-isopropylidene ribofuranose
(b)
(d)
O
H2N
O
NH
O
HO
O
OMe
O
O
O
6
3
(c)
ref. 7, 8
NH
O
HO
(e)
OMe
NH
HO
OH
O
O
O
O
4
7
or
O
O
NH
O
O
5
Scheme 1. Reagents and conditions: (a) NaN3, DMF, 80 °C, 86%; (b) H2/Pd/C, MeOH, 92%; (c) NaOMe, MeOH, 35% for 4, 63% for 5; (d) NaN3, DMF, reflux, 71%; (e) DIBALH,
CH2Cl2, 85%.
In a parallel experiment, we treated 1 with sodium azide in
DMF, which resulted in the isolation of vinylogous urethane 6 as
major product (71%) and azidoester 2 as minor product (10%)
(Scheme 1). The vinylogous urethane is produced following a
mechanism illustrated in Scheme 2. Initial sodium azide substitu-
tion at C-5 was followed by an intramolecular 1,3-dipolar cycload-
We reasoned that the intramolecular amidation from 3 to 5
might be suppressed if a secondary amine is used as the nucleo-
phile. This may allow b-elimination to compete more favorably
with amidation and consequently facilitate the hetero-Michael
addition. An additional advantage of this approach is the spontane-
ous formation of N-alkylated iminoalditol. As expected, treatment
of 1 with varies alkyl amines in the presence of triethylamine affor-
ded 5-N-alkyl-derivatives 9a–d in 72–84% yield (Scheme 3). Upon
further treatment with stronger base, these compounds gave the
respective N-alkylated iminoalditol (10a–d) in moderate yield.
Compounds 10b and 10d were obtained as a single b-anomer,
while 10a and 10c were obtained as a mixture of two isomers in
a ratio of ꢀ1:2.5 (a:b) according to NMR analysis. Reduction of
10a–c with DIBALH or LiAlH4 afforded alcohols 11a–c in 47–87%
yield.
dition of the azido group to an a,b-unsaturated ester, which led to
formation of a triazoline intermediate (8). Extrusion of nitrogen gas
and hydrogen atom migration in 8 afforded 6. This mechanism is
very similar to those described in literature.7,8 It is noteworthy that
triazoline was isolated in a similar reaction between azido group
and an unsaturated ester as only major product.9 Reduction of
the double bond of 6 gave iminoalditol 4 in 80% yield. Thus, this
method allows us to circumvent an undesired intramolecular ami-
dation and to use compound 1 as a substrate for the synthesis of
iminoalditol analogs or ribopyranosides. DIBALH reduction of the
ester was able to convert 4 to alcohol 7 in 85% yield.
We also attempted to introduce different ‘aglycons’ to the imi-
noalditols through modification of the ester. Thus, treatment of 4
-
N3
N
H
N
O
N
MeO2C
N
N
H
N
O
HO
N
OMe
NaN3
reflux
N
N
1
O
O
O
CO2Me
O
OH
O
O
8
- N2
O
NH
O
HO
O
OMe
6
Scheme 2.

A.-T. Wu et al. / Carbohydrate Research 343 (2008) 2887–2893
2889
O
R
RHN
OMe
N
HO
OMe
O
(b)
(a)
1
O
O
O
O
O
10a-d
9a-d
(β/α = 2.5/1 for 10a and 10c;
β form only for 10b and 10d)
(c)
R
N
MeO
b:
a:
R:
HO
OH
O
O
O
N
d:
c:
CH3(CH2)8CH2-
11a-c
Scheme 3. Reagents and conditions: (a) RNH2, Et3N, CH3CN, 72–84%; (b) NaOMe, MeOH, 37–59%; (c) DIBALH, CH2Cl2 or LiAlH4, THF, 47–87%.
NH
HO
NH
R
N
(b)
(b)
R
O
O
O
N
O
(a)
HO
HO
OMe
CO2H
O
13
O
O
O
OCH3
4 R = H
10b R = Ar
12a R = H
12b
R = Ar
(c)
N
H
N
HO
O
O
O
NH
O
HO
O
14
O
O
15
Scheme 4. Reagents and conditions: (a) NaOH, dioxane; (b) amines, Et3N, DEPC, DMF; (c) propagyl alcohol, DCC, DMAP, CH2Cl2.
and 10b with aqueous sodium hydroxide converted these esters to
acids 12a and 12b, which were then coupled with amines using
diethyl cyanophosphonate (DEPC) in DMF to give iminoalditol
amides 13 and 14, in 83% and 62% yield, respectively (Scheme 4).
In addition to amidation, we also prepared the alkynyl ester 15
in 66% yield from 12a and propargyl alcohol using N,N-dicyclo-
hexyl-carbodiimide (DCC) and catalytic amount of 4-dimethyl ami-
nopyridine (DMAP). Compound 15 as a substrate was tested for
Click reaction10 using a copper (I) catalyst in ethanol under reflux-
ing conditions, which produced triazole 16 in 47% yield (Scheme 5).
In summary, we report here an alternative method for the prep-
aration of iminoalditols via a vinylogous urethane intermediate. In
addition, a new efficient procedure to N-alkyl iminoalditols from 2-
with residual CHCl3, CHD2OD, or D2O as reference. Mass spectra
were recorded under fast atom bombardment (FAB) conditions.
3.2. Methyl 2-C-(5-azido-5-deoxy-2,3-di-O-isopropylidene-b-D-
ribofuranosyl)acetate (2)
A
mixture of 1 (2.39 g, 7.37 mmol) and NaN3 (1.44 g,
22.1 mmol) in DMF (60 mL) was stirred overnight at 80 °C. Upon
cooling to room temperature the reaction mixture was diluted by
the addition of Et2O (40 mL) and the solution was washed with
water and brine. Purification by chromatography (hexanes–EtOAc
9:1) gave 2 (1.72 g, 86%) as a yellow oil. 1H NMR (CDCl3) d: 4.52–
4.49 (m, 2H, H-2, H-3), 4.23–4.21 (m, 1H, H-1), 4.01 (q, 1H, H-4),
3.64 (s, 3H, CO2Me), 3.48 (dd, J = 13.2, 3.9 Hz, 1H, H-5a), 3.27 (dd,
J = 13.0, 4.5 Hz, 1H, H-5b), 2.64–2.59 (m, 2H, H-10a, H-10b), 1.51
(s, 3H, C(CH3)2), 1.27 (s, 3H, C(CH3)2); 13C NMR (CDCl3) d: 170.7
(C@O), 114.9 (C-iPr), 84.1 (C-3), 83.0 (C-2), 82.0 (C-4), 80.8 (C-1),
52.2 (C-5), 51.8 (CO2Me), 37.9 (C-10), 27.3 (C(CH3)2), 25.4
(C(CH3)2). FABMS m/z Calcd for C11H17N3O5 [M+H]+, 271.1168,
found 271.1168.
C-(5-O-methanesulfonyl-b-D-ribofuranosyl)acetate and amines, as
well as further derivatization was also described. This work may
provide an easy access to a large number of iminoalditol analogs.
3. Experimental
3.1. General methods
3.3. Methyl 2-C-(5-amino-5-deoxy-2,3-di-O-isopropylidene-b-
All reagents were obtained from commercial suppliers and were
used without further purification. CH2Cl2 was distilled over CaH2.
MeOH was distilled over magnesium and iodine. Analytical thin-
layer chromatography was performed using Silica Gel 60 F254
plates (Merck). The 1H and 13C NMR spectra were recorded on a
Bruker AM 300 spectrometer. Chemical shifts are given in ppm
D-ribofuranosyl)acetate (3)
A mixture of 2 (1.72 g, 6.34 mmol) and 10% Pd–C (0.17 g) in
MeOH (20 mL) was stirred under H2 atmosphere (balloon pressure)
for 40 min when the starting material was completely consumed.

2890
A.-T. Wu et al. / Carbohydrate Research 343 (2008) 2887–2893
OMe
O
O
O
O
NH
O
N
N
N
HO
O
NH
O
2
, Cu(0), CuSO4
HO
O
O
O
EtOH
O
O
16
15
Scheme 5.
The reaction mixture was filtered and the filtrate was concen-
trated. Purification by chromatography (CH2Cl2–MeOH 10:1) gave
3 (1.43 g, 92%) as a yellow oil. 1H NMR (CDCl3) d: 4.52–4.43 (m,
2H, H-2, H-3), 4.23–4.18 (m, 1H, H-1), 3.88 (q, 1H, H-4), 3.66 (s,
3H, CO2Me), 2.91–2.73 (m, 2H, H-5a, H-5b), 2.64–2.52 (m, 2H,
H-10a, H-10b), 1.50 (s, 3H, C(CH3)2), 1.34 (s, 3H, C(CH3)2); 13C
NMR (CDCl3) d: 170.9 (C@O), 114.7 (C-iPr), 85.5 (C-3), 84.2 (C-2),
82.4 (C-4), 80.3 (C-1), 51.8 (C-5), 44.0 (CO2Me), 38.1 (C-10), 27.4
(C(CH3)2), 25.5 (C(CH3)2). FABMS m/z Calcd for C11H20NO5
[M+H]+, 246.1341, found 246.1343.
d: 170.7 (C@O), 155.6 (C-1), 110.4 (C-iPr), 84.5 (C-10), 75.0 (C-2),
73.2 (C-3), 67.0 (C-4), 50.4 (CO2Me), 41.6 (C-5), 26.0 (C(CH3)2),
24.2 (C(CH3)2). FABMS m/z Calcd for C11H17NO5 [M], 243.1107,
found 243.1110.
3.6. 2-C-(5-Amino-5-deoxy-2,3-di-O-isopropylidene-b-D-
ribopyranosyl)ethanol (7)
To a solution of 4 (0.2 g, 0.815 mmol) in dry CH2Cl2 was added
1 M solution of DIBALH (2.45 mL, 3 equiv) at 0 °C. The reaction
mixture was stirred at the temperature for 1.5 h. MeOH (0.2 mL)
was added and the temperature was raised to room temperature.
Saturated NaCl (0.41 mL), Et2O (10.2 mL), and MgSO4 (1.07 g) were
added subsequently. The mixture was stirred for 1 h and then fil-
tered through Celite. The solvent was removed and the crude
was purified by chromatography (hexanes–EtOAc 1:1) to give 7
(0.15 g, 85%) as a yellow oil. 1H NMR (CDCl3) d: 4.69–4.66 (m,
1H, H-2), 4.60–4.57 (m, 1H, H-3), 4.21–4.09 (m, 2H, H-4, H-1),
3.78–3.75 (m, 2H, H-20a, H-20b), 3.39 (dd, J = 16.8, 9.9 Hz, 1H,
H-5a), 3.20 (dd, J = 12.9, 4.8 Hz, 1H, H-5b), 2.13 (br s, 1H, OH),
2.05–1.85 (m, 2H, H-10a, H-10b), 1.46 (s, 3H, C(CH3)2), 1.30 (s, 3H,
C(CH3)2); 13C NMR (CDCl3) d: 112.8 (C-iPr), 83.2 (C-3), 82.9 (C-4),
82.0 (C-2), 79.7 (C-1), 60.3 (C-20), 51.3 (C-5), 31.7 (C-10), 26.3
(C(CH3)2), 25.0 (C(CH3)2). FABMS m/z Calcd for C10H19NO4 [M],
217.1314, found 217.1323.
3.4. Methyl 2-C-(5-amino-5-deoxy-2,3-di-O-isopropylidene-b-
D-ribopyranosyl)acetate (4)
A solution of 3 (1.43 g, 5.96 mmol) in 2% NaOMe–MeOH (10 mL)
was stirred overnight and then neutralized by the addition of Dow-
ex 50WX8(H+) resin. The filtrate was concentrated to a residue.
Purification by chromatography (hexanes–EtOAc 12:1) gave 4
(0.51 g, 35%) as a yellow oil and tricyclic lactam 5 (0.80 g, 63%)
as a yellow oil. For 4: 1H NMR (CDCl3) d: 4.75 (dd, J = 6.0, 3.9 Hz,
1H, H-3), 4.59 (dd, J = 7.2, 1.2 Hz, 1H, H-2), 4.39–4.33 (m, 1H,
H-4), 4.16 (t, J = 10.8 Hz, 1H, H-1), 3.66 (s, 3H, CO2Me), 3.37 (dd,
J = 12.9, 6.6 Hz, 1H, H-10a), 3.22 (dd, J = 12.9, 4.8 Hz, 1H, H-10b),
2.72 (dd, J = 6.9, 3.3 Hz, 2H, H-5a, H-5b), 1.44 (s, 3H, C(CH3)2),
1.28 (s, 3H, C(CH3)2); 13C NMR (CDCl3) d: 171.3 (C@O), 113.0 (C-
iPr), 83.2 (C-2), 82.7 (C-1), 81.2 (C-3), 77.3 (C-4), 51.8 (CO2Me),
51.5 (C-10), 34.2 (C-5), 26.2 (C(CH3)2), 24.9 (C(CH3)2). FABMS m/z
Calcd for C11H19NO5 [M+H]+, 246.1341, found 246.1339.
3.7. Methyl 2-C-(5-allylamino-5-deoxy-2,3-di-O-
isopropylidene-b-D-ribofuranosyl)acetate (9a)
For 5: 1H NMR (CDCl3) d: 6.43 (br d, J = 5.7 Hz, NH), 4.78 (d,
J = 5.7 Hz, 1H, H-3), 4.63 (d, J = 5.7 Hz, 1H, H-2), 4.34 (d,
J = 3.9 Hz, 1H, H-4), 4.26 (q, 1H, H-1), 3.54 (d, J = 15.0 Hz, 1H,
H-5a0), 3.17–3.08 (m, 1H, H-5b0), 2.82 (dd, J = 16.5, 2.4 Hz, 1H,
CH2CO), 2.69–2.61 (m, 1H, CH2CO), 1.46 (s, 3H, C(CH3)2), 1.24 (s,
3H, C(CH3)2); 13C NMR (CDCl3) d: 176.0 (C@O), 112.0 (C-iPr), 83.9
(C-2), 82.9 (C-3), 82.4 (C-4), 79.2 (C-1), 46.3 (C-5), 43.7 (C-10),
26.0 (C(CH3)2), 24.3 (C(CH3)2). FABMS Calcd for C10H15NO4 [M],
m/z 213.1001, found 213.1005.
To a solution of 1 (3.89 g, 11.99 mmol) and triethylamine
(10 mL, 71.95 mmol) in dry CH3CN (40 mL) was added allylamine
(1.34 mL, 17.98 mmol), and the mixture was heated at reflux for
48 h. After cooling, the solvent was removed and the crude was
purified by chromatography (hexanes–EtOAc 1:2) to give 9a
(2.78 g, 81%) as a yellow oil. 1H NMR (CDCl3) d: 5.91–5.78 (m,
1H, @CH), 5.12 (dd, J = 17.1, 1.5 Hz, 2H, @CH2), 4.57–4.54 (m, 1H,
H-3), 4.48–4.44 (m, 1H, H-2), 4.21 (q, J = 4.8 Hz, 1H, H-1), 4.01 (q,
J = 6.0 Hz, 1H, H-4), 3.68 (s, 3H, CO2Me), 3.24 (d, J = 6.0 Hz, 2H,
CH2CH@), 2.87–2.52 (m, 4H, H-5a, H-5b, H-10a, H-10b), 1.50 (s,
3H, C(CH3)2), 1.28 (s, 3H, C(CH3)2); 13C NMR (CDCl3) d: 170.9
(C@O), 136.4 (@CH), 116.3 (@CH2), 114.7 (C-iPr), 84.2 (C-4), 83.5
(C-2), 82.9 (C-3), 80.5 (C-1), 52.3 (CH2CH@CH2), 51.8 (CO2Me),
50.7 (C-5), 38.2 (C-10), 27.4 (C(CH3)2), 25.5 (C(CH3)2). FABMS m/z
Calcd for C14H23NO5 [M], 285.1576, found 285.1580.
3.5. Methyl 2-C-(5-amino-5-deoxy-2,3-di-O-isopropylidene-b-
D-ribopyranosylidene)-acetate (6)
A
mixture of (0.12 g, 0.369 mmol) and NaN3 (72.1 mg,
1
1.11 mmol) in DMF (20 mL) was heated at reflux for 3 h. Upon
cooling to room temperature, the reaction mixture was diluted
by the addition of Et2O (20 mL), and the solution was washed with
water and brine. Purification by chromatography (hexanes–EtOAc
2:1) gave 6 (64 mg, 71%) as a white solid; mp: 135 °C; 1H NMR
(CDCl3) d: 8.26 (s, 1H, NH), 4.74 (s, 1H, H-10), 4.57 (d, J = 13.2 Hz,
1H, H-2), 4.48–4.44 (m, 1H, H-3), 3.75–3.67 (m, 1H, H-4), 3.60 (s,
3H, CO2Me), 3.27–3.14 (m, 2H, H-5a, 5b), 2.52 (d, J = 8.4 Hz, 1H,
OH), 1.50 (s, 3H, C(CH3)2), 1.39 (s, 3H, C(CH3)2); 13C NMR (CDCl3)
3.8. Methyl 2-C-[5-deoxy-2,3-di-O-isopropylidene-5-(4-
methoxybenzylamino)-b-D-ribofuranosyl]acetate (9b)
To
a solution of 1 (0.1 g, 0.31 mmol) and triethylamine
(0.042 mL, 0.31 mmol) in dry CH3CN (5 mL) was added 4-methoxy-

A.-T. Wu et al. / Carbohydrate Research 343 (2008) 2887–2893
2891
benzylamine (0.06 mL, 0.46 mmol), and the mixture was heated at
reflux for 48 h. After cooling, the solvent was removed and the
crude was purified by column chromatography (hexanes–EtOAc
1:1) which afforded 9b (0.092 g, 84%) as a yellow oil. 1H NMR
(CDCl3) d: 7.19 (d, J = 8.7 Hz, 2H, Ph), 6.83 (d, J = 8.7 Hz, 2H, Ph),
4.55 (dd, J = 6.9, 4.5 Hz, 1H, H-3), 4.44 (dd, J = 6.9, 4.8 Hz, 1H,
H-2), 4.23–4.17 (m, 1H, H-1), 4.03–3.99 (m, 1H, H-4), 3.83 (s, 3H,
OMe), 3.77 (d, J = 2.7 Hz, 2H, PhCH2), 3.65 (s, 3H, CO2Me), 2.85–
2.50 (m, 4H, H-5a, H-5b, H-10a, H-10b), 1.46 (s, 3H, C(CH3)2), 1.36
(s, 3H, C(CH3)2); 13C NMR (CDCl3) d: 170.8 (C@O), 158.6 (2Ph),
132.2 (Ph) , 129.3 (2Ph), 114.6 (C-iPr), 113.7 (2Ph), 84.2 (C-2),
83.6 (C-4), 82.9 (C-3), 80.4 (C-1), 55.2 (OMe), 53.2 (PhCH2),
51.8 (CO2Me), 50.6 (C-5), 38.1 (C-10), 27.4 (C(CH3)2), 25.5
(C(CH3)2). FABMS m/z Calcd for C19H27NO6 [M], 365.1838, found
365.1836.
J = 6.0, 3.9 Hz, 1H, H-2), 3.98 (dd, J = 5.4, 5.1 Hz, 1H, H-3), 3.65 (s,
4H, H-4, CO2Me), 3.24 (dd, J = 14.1, 4.6 Hz, 1H, CH2CH@), 3.13–
3.07 (m, 1H, H-1), 3.02 (d, J = 7.8 Hz, 1H, CH2CH@), 2.98–2.91 (m,
1H, H-5a), 2.71 (d, J = 6.6 Hz, 2H, H-10a, H-10b), 2.28 (d,
J = 12.3 Hz, 1H, H-5b), 1.54 (s, 3H, C(CH3)2), 1.28 (s, 3H, C(CH3)2);
13C NMR (CDCl3) d: 172.4 (C@O), 133.8 (@CH), 118.6 (@CHCH2),
108.9 (C-iPr), 74.3 (C-2), 74.1 (C-3), 65.0 (C-4), 56.2 (@CHCH2),
56.1 (C-1), 53.2 (C-5), 51.7 (CO2Me), 34.6 (C-10), 25.7 (C(CH3)2),
25.3 (C(CH3)2). FABMS m/z Calcd for C14H23NO5 [M], 285.1576,
found 285.1583.
For 10a–a
: 1H NMR (CDCl3) d: 5.82–5.68 (m, 1H, @CH), 5.15 (dd,
J = 17.7, 9.0 Hz, 2H, @CH2), 4.32 (dd, J = 4.5, 4.5 Hz, 1H, H-3), 4.00
(dd, J = 7.8, 5.1 Hz, 1H, H-2), 3.88 (br t, J = 5.1 Hz, 1H, H-4), 3.66
(s, 3H, CO2Me), 3.25 (dd, J = 13.9, 5.3 Hz, 1H, CH2CH@CH2), 2.96–
2.80 (m, 2H, CH2CH@CH2, H-1), 2.53 (dt, J = 10.5, 4.5 Hz, 2H,
H-10), 2.29 (t, J = 10.8 Hz, 2H, H-5a, H-5b), 1.50 (s, 3H, C(CH3)2),
1.34 (s, 3H, C(CH3)2); 13C NMR (CDCl3) d: 172.3 (C@O), 134.5
(@CH), 119.0 (@CHCH2), 109.4 (C-iPr), 77.4 (C-2), 74.6 (C-3), 66.1
(C-4), 59.4 (C-1), 55.9 (CH2CH@), 53.0 (C-10), 51.8 (CO2Me), 35.6
(C-5), 27.7 (C(CH3)2), 26.2 (C(CH3)2). FABMS m/z Calcd for
C14H23NO5 [M], 285.1576, found 285.1583.
3.9. Methyl 2-C-(5-deoxy-2,3-di-O-isopropylidene-5-
morpholinopropylamino-b-D-ribofuranosyl)acetate (9c)
To a solution of 1 (4.34 g, 13.37 mmol) and triethylamine
(5.65 mL, 3 equiv) in dry CH3CN (40 mL) was added N-(3-amino-
propyl)morpholine (2.5 mL, 1.2 equiv), and the mixture was heated
at reflux for 48 h. After cooling, the solvent was removed and the
crude was purified by column chromatography (EtOAc–MeOH
6:1) to give 9c (3.58 g, 72%) as a light yellow syrup. 1H NMR (CDCl3)
3.12. Methyl 2-C-[5-deoxy-2,3-di-O-isopropylidene-5-(4-
methoxybenzylamino)-b-D-ribopyranosyl]acetate (10b)
d
: 4.46–4.40 (m, 2H, H-2, H-3), 4.22–4.09 (m, 1H, H-4), 4.01–3.93
The same procedures as described above were used to obtain
10b (37%) as a semi-solid. 1H NMR (CDCl3) d: 7.03 (d, J = 8.4 Hz,
2H, Ph), 6.68 (d, J = 8.7 Hz, 2H, Ph), 4.22 (dd, J = 4.5, 4.5 Hz, 1H, H-
2), 3.95 (dd, J = 7.8, 5.1 Hz, 1H, H-3), 3.70 (d, J = 12.6 Hz, 2H, H-1,
PhCH2), 3.66 (s, 3H, OMe), 3.55 (s, 3H, CO2Me), 3.02 (d,
J = 12.6 Hz, 1H, PhCH2), 2.80–2.72 (m, 1H, H-4), 2.62–2.43 (m, 3H,
H-5a, H-10a, H-10b), 2.08–2.01 (m, 1H, H-5b), 1.36 (s, 3H, C(CH3)2),
1.24 (s, 3H, C(CH3)2); 13C NMR (CDCl3) d: 172.4 (C@O), 158.7 (Ph),
130.6 (Ph), 129.8 (2Ph), 113.7 (2Ph), 109.4 (C-iPr), 77.3 (C-3), 74.6
(C-2), 66.0 (C-1), 60.1 (C-4), 56.3 (PhCH2), 55.2 (OMe), 52.4 (C-5),
51.8 (CO2Me), 35.8 (C-10), 27.7 (C(CH3)2), 26.2 (C(CH3)2). FABMS
m/z Calcd for C19H27NO6 [M], 365.1838, found 365.1843.
(m, 1H, H-1), 3.80–3.54 (m, 7H, 2H-10a, 2H-10b, CO2Me), 2.80–
2.75 (m, 2H, H-6a, H-6b), 2.66–2.51 (m, 4H, H-5a, H-5b, H-8a, H-
8b), 2.36–2.28 (m, 6H, 2H-9a, 2H-9b, H-10a, H-10b), 1.62–1.58 (m,
2H, H-7a, H-7b), 1.45 (s, 3H, C(CH3)2), 1.25 (s, 3H, C(CH3)2); 13C
NMR (CDCl3) d: 170.6 (C@O), 114.6 (C-iPr), 84.0 (C-3), 83.3 (C-2),
82.8 (C-1), 80.3 (C-4), 66.7 (2C-10), 57.1 (C-10), 53.6 (2C-9), 51.6
(CO2Me), 51.4 (C-6), 48.4 (C-5), 38.0 (C-8), 26.17 (C-7), 27.2
(C(CH3)2), 25.4 (C(CH3)2). FABMS m/z calcd for C18H32N2O6 [M]
372.2260, found 372.2253.
3.10. Methyl 2-C-(5-decylamino-5-deoxy-2,3-di-O-
isopropylidene-b-D-ribofuranosyl)acetate (9d)
3.13. Methyl 2-C-(5-deoxy-2,3-di-O-isopropylidene-5-
To a solution of 1 (0.54 g, 1.66 mmol) and triethylamine
(0.7 mL, 3 equiv) in dry CH3CN (10 mL) was added decyl amine
(0.40 g, 1.5 equiv), and the mixture was heated at reflux for 24 h.
After cooling, the solvent was removed and the crude was purified
by column chromatography (CH2Cl2–MeOH 30:1) to give 9d
(0.50 g, 78%) as a colorless oil. 1H NMR (CDCl3) d: 4.48–4.36 (m,
2H, H-2, H-3), 4.13 (dd, J = 6.9, 4.8 Hz, 1H, H-1), 3.94 (td, J = 6.6,
4.2 Hz, 1H, H-4), 3.60 (s, 3H, CO2Me), 2.78–2.45 (m, 6H, H-10a,
H-10b, H-5a, H-5b H-6a, H-6b), 1.43 (s, 3H, C(CH3)2), 1.23 (s, 3H,
C(CH3)2), 1.22–1.15 (m, 16H), 0.78 (t, J = 6.9 Hz, 3H, CH3); 13C
NMR (CDCl3) d: 170.68 (C@O), 114.46 (C-iPr), 84.05, 83.43, 82.83,
80.27, 51.59 (CO2Me), 51.54, 49.93, 38.03, 31.71, 29.77, 29.42,
29.39 (2C), 29.14, 27.21, 27.12, 25.36 (C(CH3)2), 22.48 (C(CH3)2),
13.92. FABMS m/z Calcd for C21H40NO5 [M+H]+, 386.2906, found
386.2901.
morpholinopropylamino-b-D-ribopyranosyl)acetate (10c)
The same procedures as described above were used to obtain
10c–b (42%) as a light yellow syrup and 10c– (17%) as a yellow
a
syrup. For 10c–b: 1H NMR (CDCl3) d: 4.32 (dd, J = 4.8 Hz, 4.5 Hz,
1H, H-3), 3.95 (dd, J = 7.5, 5.1 Hz, 1H, H-2), 3.93–3.85 (m, 1H,
H-4), 3.71 (t, J = 4.5 Hz, 4H, 2H-10a, 2H-10b), 3.68 (s, 3H, CO2Me),
3.16 (br s, OH), 2.93–2.83 (m, 3H, H-1, H-6), 2.75–2.23 (m, 10H,
H-10a, H-10b, H-5a, H-5b, H-8a, H-8b, 2H-9a, 2H-9b), 1.68–1.55
(m, 2H, H-7a, H-7b), 1.52 (s, 3H, C(CH3)2), 1.47 (s, 3H, C(CH3)2);
13C NMR (CDCl3): d 172.34 (C@O), 109.38 (C-iPr), 77.35 (C-2),
74.39 (C-3), 66.68 (2C-10), 65.99 (C-4), 59.25 (C-1), 56.40 (C-5),
53.51 (2C-9), 52.51 (C-6), 51.78 (CO2Me), 50.30 (C-8), 35.62 (C-
10), 27.56 (C(CH3)2), 26.15 (C-7), 23.02 (C(CH3)2). FABMS m/z calcd
for C18H32N2O6 [M], 372.2260, found 372.2258.
For 10c–a:
1H NMR (CDCl3) d: 5.47 (br s, s, OH), 4.73–4.68 (d,
J = 6.0 Hz, 1H, H-3), 4.51–4.48 (d, J = 6.0 Hz, 1H, H-2), 4.26–4.19
(m, 2H, H-1, H-4), 3.67–3.65 (m, 7H, 2H-10a, 2H-10b, CO2Me),
2.82–2.64 (m, 6H, H-10a, H-10b, H-5a, H-5b, H-6a, H-6b), 2.42–
2.37 (m, 6H, H-8a, H-8b, 2H-9a, 2H-9b), 1.75–1.63 (m, 2H,
H-7a, H-7b), 1.43 (s, 3H, C(CH3)2), 1.26 (s, 3H, C(CH3)2); 13C
NMR (CDCl3): d 171.4 (C@O), 112.8 (C-iPr), 83.6 (C-2), 81.8
(C-1), 80.9 (C-3), 76.0 (C-4), 66.7 (2C-10), 57.4 (C-8), 53.5
(2C-9), 51.7 (CO2Me), 48.3 (C-6), 48.2 (C-10), 33.8 (C-5), 26.1
(C(CH3)2), 25.0 (C-7), 24.9 (C(CH3)2). FABMS m/z calcd for
C18H32N2O6 [M], 372.2260, found 372.2262.
3.11. Methyl 2-C-(5-allylamino-5-deoxy-2,3-di-O-
isopropylidene-b-D-ribopyranosyl)acetate (10a)
A solution of 9a (2.78 g, 9.74 mmol) in 2% NaOMe–MeOH
(20 mL) was stirred overnight and then neutralized by the addition
of Dowex 50WX8(H+) resin. The filtrate was concentrated to a res-
idue. Purification by chromatography (hexane–EtOAc 10:1) gave
10a–b (0.96 g, 35%) as a light yellow syrup and 10a–
a (0.41 g,
15%) as a light yellow syrup. For 10a–b: 1H NMR (CDCl3) d: 5.85–
5.71 (m, 1H, @CH), 5.16 (dd, J = 10.5, 6.3 Hz, 2H, @CH2), 4.26 (dd,

2892
A.-T. Wu et al. / Carbohydrate Research 343 (2008) 2887–2893
3.14. Methyl 2-C-(5-decylamino-5-deoxy-2,3-di-O-
isopropylidene-b- -ribopyranosyl)acetate (10d)
55.3 (OMe), 51.2 (C-5), 32.6 (C-10), 27.5 (C(CH3)2), 25.7 (C(CH3)2).
FABMS: m/z Calcd for C18H28NO5 [M+H]+, 338.1967, found
338.1962.
D
The same procedures as described above were used to obtain
10d (40%) as a colorless oil. 1H NMR (CDCl3) d: 4.31 (dd, J = 4.5,
4.5 Hz, 1H), 4.05–4.00 (m, 1H), 3.95 (br, OH, 1H), 3.65 (s, 3H),
3.00–2.85 (m, 2H), 2.61–2.37 (m, 6H), 1.50 (s, 3H), 1.33 (s, 3H),
1.30–1.10 (m, 16H), 0.84 (t, J = 6.6 Hz, 3H); 13C NMR (CDCl3) d:
172.21, 109.55, 77.17, 74.28, 59.20, 52.83, 52.32, 51.85, 35.38,
31.84, 29.55, 29.51 (2C), 29.40, 29.26, 27.53, 27.17, 26.11, 25.64,
22.64, 14.08. FABMS m/z Calcd for C21H40NO5 [M+H]+, 386.2906,
found 386.2901.
3.17. 2-C-(5-Deoxy-2,3-di-O-isopropylidene-5-
morpholinopropylamino-b-D-ribopyranosyl)ethanol (11c)
To a solution of 10c (0.25 g, 0.67 mmol) in dry CH2Cl2 (5 mL)
was added a 1 M solution of DIBALH (2.0 mL, 3 equiv) at 0 °C. Same
workup as above and purification by column chromatography
(EtOAc–MeOH 6:1) gave 11c (0.11 g, 47%) as a yellow syrup. 1H
NMR (CDCl3) d: 4.32 (dd, J = 5.1, 4.8 Hz, 1H, H-3), 4.04 (dd, J = 6.0,
6.0 Hz, 1H, H-2), 3.94–3.86 (m, 1H, H-4), 3.75–3.70 (m, 2H, H-20a,
H-20b), 3.65 (t, J = 4.8 Hz, 4H, 2H-10a, 2H-10b), 2.85 (br, s, OH),
2.80 (dd, J = 11.1, 4.5 Hz, 1H, H-5a), 2.74–2.65 (m, 2H, H-1,
H-10a), 2.59–2.50 (m, 1H, H-10b), 2.44–2.22 (m, 7H, H-5b, H-6a,
H-6b, 2H-9a, 2H-9b), 1.73–1.62 (m, 4H, H-7a, H-7b, H-8a, H-8b),
1.47 (s, 3H, C(CH3)2), 1.33 (s, 3H, C(CH3)2); 13C NMR (CDCl3) d:
109.1 (C-iPr), 77.2 (C-2), 74.1 (C-3), 66.7 (2C-10), 65.3 (C-4), 60.2
(C-20), 59.8 (C-1), 56.3 (C-6), 53.6 (2C-9), 51.7 (C-5), 51.3 (C-10),
32.7 (C-8), 27.4 (C(CH3)2), 25.6 (C(CH3)2), 23.0 (C-7). FABMS m/z
Calcd for C17H33N2O5 [M+H]+, 345.2389, found 345.2394.
3.15. 2-C-(5-Allylamino-5-deoxy-2,3-di-O-isopropylidene-b-D-
ribopyranosyl)ethanol (11a)
To a solution of 10a (0.84 g, 2.94 mmol) in dry CH2Cl2 was
added 1 M solution of DIBALH (8.83 mL, 3 equiv) at 0 °C. The reac-
tion mixture was stirred at the temperature for 1.5 h. MeOH
(0.86 mL) was added at 0 °C and was raised to room temperature.
Saturated NaCl (1.72 mL), Et2O (43.0 mL), and MgSO4 (4.5 g) were
added, and the mixture was stirred for 1 h and then filtered
through a Celite pad. The solvent was removed and the crude
mixture was purified by column chromatography (hexanes–
EtOAc) to give 11a (0.66 g, 87%) as a yellow oil. For 11a–b: 1H
NMR (CDCl3) d: 5.83–5.73 (m, 1H, @CH), 5.15 (dd, J = 17.7,
9.3 Hz, 2H, @CHCH2), 4.20 (dd, J = 6.0, 3.3 Hz, 1H, H-2), 3.96 (dd,
J = 5.7, 4.8 Hz, 1H, H-3), 3.79–3.67 (m, 3H, H-4, CH2OH), 3.32
(dd, J = 14.3, 5.2 Hz, 1H, @CHCH2), 3.08–2.91 (m, 2H, @CHCH2,
H-5a0), 2.73–2.68 (m, 1H, H-1), 2.24 (d, J = 1.5 Hz, 1H, H-5b0),
1.98–1.91 (m, 2H, H-10a, H-10b), 1.52 (s, 3H, C(CH3)2), 1.35 (s,
3H, C(CH3)2); 13C NMR (CDCl3) d: 133.5 (@CH), 118.6 (@CH2),
108.9 (C-iPr), 74.4 (C-3), 74.3 (C-2), 64.9 (C-4), 59.3 (C-20), 56.7
(C-1), 55.7 (CH2CH@), 53.4 (C-5), 32.0 (C-10), 25.7 (C(CH3)2),
25.3 (C(CH3)2). FABMS m/z Calcd for C13H23NO4 [M], 257.1627,
found 257.1630.
3.18. 2-C-(5-Amino-5-deoxy-2,3-di-O-isopropylidene-b-D-
ribopyranosyl)acetic acid (12a)
A mixture of 4 (0.23 g, 0.938 mmol) and aq NaOH (0.76 mL of a
1 M solution) in dioxane (2 mL) was stirred for 4 h. The solution
was acidified to pH 2 with 1 M HCl and extracted thoroughly with
EtOAc (6 ꢁ 5 mL). The combined organic phase was dried (MgSO4),
concentrated, and purified by column chromatography (hexane/
EtOAc, 1:2) to give 12a (0.16 g, 74%) as a yellow oil. 1H NMR
(CDCl3) d: 4.77 (dd, J = 6.0, 4.2 Hz, 1H, H-3), 4.62 (dd, J = 6.0,
1.5 Hz, 1H, H-2), 4.40–4.34 (m, 1H, H-4), 4.18 (t, J = 5.1 Hz, 1H,
H-1), 3.40 (dd, J = 12.9, 6.0 Hz, 1H, H-10a), 3.28 (dd, J = 12.9,
4.8 Hz, 1H, H-10b), 2.77 (dd, J = 6.6, 5.7 Hz, 2H, H-5a, H-5b), 1.46
(s, 3H, C(CH3)2), 1.31 (s, 3H, C(CH3)2); 13C NMR (CDCl3) d: 176.4
(C@O), 113.1 (C-iPr), 83.1 (C-2), 82.5 (C-1), 81.1 (C-3), 77.1 (C-4),
51.6 (C-10), 34.2 (C-5), 26.1 (C(CH3)2), 24.9 (C(CH3)2). FABMS m/z
Calcd for C10H18NO5 [M+H]+, 232.1185, found 232.1184.
For 11a–a
: 1H NMR (CDCl3) d: 5.82–5.68 (m, 1H, @CH), 5.12 (dd,
J = 18.9, 8.4 Hz, 2H, @CH2), 4.26 (dd, J = 4.5, 4.2 Hz, 1H, H-3), 3.97
(dd, J = 10.2, 4.8 Hz, 1H, H-2), 3.87–3.83 (m, 1H, H-4), 3.66 (t,
J = 6.0 Hz, 2H, H-20a, H-20b), 3.25 (dd, J = 13.9, 6.2 Hz, 1H, @CHCH2),
2.99 (dd, J = 13.5, 7.2 Hz, 1H, @CHCH2), 2.76 (dd, J = 11.4, 4.8 Hz,
1H, H-5a0), 2.56–2.50 (m, 1H, H-1), 2.31 (t, J = 11.1 Hz, 1H, H-5b0),
1.83–1.72 (m, 1H, H-10a), 1.66–1.56 (m, 1H, H-10b), 1.41 (s, 3H,
C(CH3)2), 1.26 (s, 3H, C(CH3)2); 13C NMR (CDCl3) d: 133.8 (@CH),
118.2 (@CH2), 108.9 (C-iPr), 76.9 (C-2), 74.4 (C-3), 65.0 (C-4),
59.9 (C-20), 59.4 (C-1), 55.8 (CH2CH=), 51.9 (C-5), 32.0 (C-10), 27.4
(C(CH3)2), 25.6 (C(CH3)2). FABMS m/z Calcd for C13H23NO4 [M],
257.1627, found 257.1622.
3.19. 2-C-[5-Deoxy-2,3-di-O-isopropylidene-5-(4-
methoxybenzylamino)-b-D-ribopyranosyl]acetic acid (12b)
A mixture of 10b (0.8 g, 2.19 mmol) and aq NaOH (1 M,
2.66 mL) in dioxane (8 mL) was stirred for 12 h. The solution was
acidified to pH 2 with 1 M HCl and extracted thoroughly with
EtOAc (6 ꢁ 5 mL). Purification by column chromatography afforded
12b (0.63 g, 82%) as a yellow oil. 1H NMR (CDCl3) d: 7.22 (d,
J = 8.4 Hz, 2H, Ph), 6.83 (d, J = 8.7 Hz, 2H, Ph), 4.33 (dd, J = 5.4,
4.5 Hz, 1H, H-3), 4.18–4.04 (m, 3H, H-2, H-4, PhCH2), 3.75 (s, 3H,
OMe), 3.66 (d, J = 12.9 Hz, 1H, PhCH2), 3.11 (dd, J = 11.7, 5.4 Hz,
1H, H-1), 2.84–2.56 (m, 4H, H-5a, H-5b, H-10a, H-10b), 1.47
(s, 3H, C(CH3)2), 1.39 (s, 3H, C(CH3)2); 13C NMR (CDCl3) d: 173.7
(C@O), 159.7 (Ph), 131.2 (2Ph), 125.6 (Ph), 114.3 (2Ph), 110.2 (C-
iPr), 75.6 (C-2), 73.4 (C-3), 64.1 (C-4), 58.4 (C-1), 57.8 (PhCH2),
55.3 (OMe), 48.4 (C-5), 33.6 (C-10), 27.3 (C(CH3)2), 25.4 (C(CH3)2),
FABMS m/z Calcd for C18H26NO6 [M+H]+, 352.1760, found
352.1757.
3.16. 2-C-(5-Deoxy-2,3-di-O-isopropylidene-5-(4-
methoxybenzyl)-b-D-ribopyranosyl)ethanol (11b)
To a solution of LAH (62.6 mg, 1.65 mmol) in dry THF (4 mL) un-
der N2 at 0 °C was added 10b (0.1 g, 0.27 mmol). The solution was
stirred for 2 h, and then acidified with 30% H2SO4. The precipitate
was filtered through a Celite pad and the filtrate was extracted
with CH2Cl2. Purification by column chromatography (EtOAc–hex-
anes–CH2Cl2 4:1:2) afforded 11b (52 mg, 57%) as a yellow oil. 1H
NMR (CDCl3) d: 7.16 (d, J = 8.4 Hz, 2H, Ph), 6.83 (d, J = 8.4 Hz, 2H,
Ph), 4.38 (dd, J = 5.1, 4.8 Hz, 1H, H-2), 4.20 (dd, J = 6.3, 6.0 Hz, 1H,
H-3), 3.96 (d, J = 12.9 Hz, 1H, PhCH2), 3.87–3.79 (m, 6H, OMe,
H-20a, H-20b, H-4), 3.41 (d, J = 12.6 Hz, 1H, PhCH2), 2.84–2.73
(m, 2H, H-1, H-5a), 2.58 (t, J = 5.4 Hz, 1H, H-5b), 2.17–2.13 (m,
2H, H-10a, H-10b), 1.40 (s, C(CH3)2), 1.26 (s, C(CH3)2); 13C NMR
(CDCl3) d: 158.9 (Ph), 130.3 (2Ph), 113.9 (3Ph), 109.3 (C-iPr), 77.3
(C-3), 74.1 (C-2), 65.4 (C-4), 60.8 (C-20), 60.3 (C-1), 57.5 (PhCH2),
3.20. N-Benzyl 2-C-(5-amino-5-deoxy-2,3-di-O-isopropylidene-
b-D
-ribopyranosyl)acetamide (13)
To a stirred solution of benzylamine (0.048 mL) and acid 12a
(0.102 g, 0.441 mmol) in DMF (73 mL), DEPC (0.1 mL, 1.5 equiv)
and Et3N (0.18 mL, 3 equiv) were added at 0 °C under an argon

A.-T. Wu et al. / Carbohydrate Research 343 (2008) 2887–2893
2893
atmosphere. The solution was warmed to room temperature and
3.23. 1,2,3-Triazole-linked aza-C-glycoside (16)
stirred for 24 h. The mixture was partitioned in EtOAc–H2O (1:1),
and the organic layer was washed with brine. The aqueous phase
was extracted with EtOAc (2 ꢁ 10 mL). The organic layers were
combined, dried, and concentrated. Purification by chromatogra-
phy (hexanes–EtOAc 1:1) gave 13 (0.117 g, 83%) as a colorless oil.
1H NMR (CDCl3) d: 7.30–7.19 (m, 5H, Ph), 4.66 (dd, J = 6.0, 3.9 Hz,
1H, H-3), 4.54 (d, J = 6.0 Hz, 1H, H-2), 4.48–4.30 (m, 2H, PhCH2),
4.37–4.30 (m, 1H, H-4), 4.14 (t, J = 5.8 Hz, 1H, H-1), 3.34 (dd,
J = 12.9, 6.9 Hz, 1H, H-10a), 3.17 (dd, J = 12.7, 4.9 Hz, 1H, H-10b),
2.60 (d, J = 6.3 Hz, 2H, H-5a, H-5b), 1.42 (s, 3H, C(CH3)2), 1.26 (s,
3H, C(CH3)2); 13C NMR (CDCl3) d: 170.1 (C@O), 138.2 (Ph), 128.5
(2Ph), 127.5 (2Ph), 127.3 (Ph), 112.8 (C-iPrC-iPr), 83.0 (C-2), 82.9
(C-1), 81.4 (C-3), 77.8 (C-4), 51.2 (C-10), 43.4 (PhCH2), 36.8 (C-5),
26.2 (C(CH3)2), 24.8 (C(CH3)2). FABMS m/z [M+H]+: Calcd for
C17H25N2O4, 321.1814, found 321.1807.
To a solution of 15 (0.213 g, 0.79 mmol) and 2 (0.236 g,
0.87 mmol) in ethanol (10 mL) were added copper turnings
(21.3 mg) and a copper sulfate solution (0.414 mL, 1 M). The mix-
ture was heated at reflux for 12 h when the reaction was complete
(monitored by TLC). The reaction mixture was filtered through Cel-
ite, and the filtrate was concentrated. Purification by column chro-
matography (hexanes–EtOAc, 1:3) afforded 16 (0.20 g, 47%) as a
yellow syrup. 1H NMR (CDCl3) d: 7.67 (s, 1H, ArH), 5.27 (d,
J = 12.9 Hz, 1H, ArCH2), 5.21 (d, J = 12.6 Hz, 1H, ArCH2), 4.76 (td,
J = 6.0, 4.2 Hz, 1H, H-3), 4.63–4.49 (m, 4H, H-2, H-4, H-50a, H-50b),
4.42–4.36 (m, 1H, H-1), 4.29–4.13 (m, 4H, H-10, H-20, H-30, H-40),
3.69 (s, 3H, CO2Me), 3.39 (dd, J = 12.9, 6.6 Hz, 1H, CH2CO2), 3.24
(dd, J = 12.9, 4.8 Hz, 1H, CH2CO2), 2.75 (dd, J = 6.7, 2.7 Hz, 2H,
H-5a, H-5b), 2.62 (dd, J = 15.9, 4.5 Hz, 1H, CH2CO2), 2.45 (dd,
J = 15.9, 6.6 Hz, 1H, CH2CO2), 1.49 (s, 3H, C(CH3)2), 1.44 (s, 3H,
C(CH3)2), 1.27 (s, 3H, C(CH3)2), 1.28 (s, 3H, C(CH3)2); 13C NMR
(CDCl3) d: 170.7 (C@O), 170.6 (C@O), 142.6 (Ar), 125.4 (C-ArH),
115.3 (C-iPr), 113.1 (C-iPr), 83.8, 83.2, 82.7, 82.1, 81.5, 81.2 (C-2,
C-4, C-10, C-20, C-30, C-40), 80.8 (C-3), 77.2 (C-1), 57.8 (ArCH2),
51.9 (CO2Me) , 51.7 (CH2CO2), 51.5 (C-50), 37.8 (CH2CO2), 34.5 (C-
5), 27.4 (C(CH3)2), 26.2 (C(CH3)2), 25.5 (C(CH3)2), 25.0 (C(CH3)2).
3.21. N-Allyl 2-C-[5-deoxy-2,3-di-O-isopropylidene-5-(4-
methoxybenzylamino)-b-D-ribopyranosyl acetamide (14)
To a solution of 12b (0.1 g, 0.28 mmol) in DMF were added allyl-
amine (0.02 mL, 1 mmol), DEPC (0.065 mL), and TEA (0.11 mL) at
0 °C under N2. The solution was warmed to room temperature
and stirred for 24 h. Same workup as above and purification by col-
umn chromatography (hexanes–EtOAc 1:1) afforded 14 (0.068 g,
62%) as a colorless syrup. 1H NMR (CDCl3) d: 7.12 (d, J = 8.4 Hz,
2H, Ph), 6.82 (d, J = 8.4 Hz, 2H, Ph) 5.89–5.76 (m, 1H, CH@), 5.23–
5.07 (m, 2H, CH2@), 4.38 (dd, J = 4.8, 4.5 Hz, 1H, H-3), 4.12–4.00
(m, 1H, H-2), 3.94–3.83 (m, 4H, CH2CH@, H-4, PhCH2), 3.81 (s,
3H, OMe), 3.22 (d, J = 12.9 Hz, 1H, PhCH2), 2.82–2.71 (m, 3H,
H-10a, H-5a, H-1), 2.56 (dd, J = 17.7, 6.0 Hz, 1H, H-10), 2.22 (t,
J = 11.0 Hz, 1H, H-5b), 1.48 (s, 3H, C(CH3)2), 1.40 (s, 3H, C(CH3)2);
13C NMR (CDCl3) d: 170.4 (C@O), 158.0 (Ph), 134.2 (CH@), 130.1
(2Ph), 129.3 (Ph), 116.6 (CH2@), 113.9 (2Ph), 109.8 (C-iPr), 77.2
(C-2), 74.5 (C-3), 65.6 (C-4), 60.2 (C-1), 56.0 (PhCH2), 55.3 (OMe),
51.7 (C-5), 41.8 (@CHCH2), 35.6 (C-10), 27.9 (C(CH3)2), 26.1
(C(CH3)2). FABMS m/z Calcd for C21H31N2O5 [M+H]+, 391.2233,
found 391.2243.
Acknowledgment
This work was supported by the National Science Council of
Taiwan.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2008.08.005.
References
1. (a) McCormack, P. L.; Goa, K. L. Drugs 2003, 63, 2427–2434; (b) Scott, L. J.;
Spencer, C. M. Drugs 2000, 59, 521–549; (c) Mellor, H. R.; Nolan, J.; Pickering, L.;
Wormald, M. R.; Platt, F. M.; Dwek, R. A.; Fleet, G. W. J.; Butters, T. D. Biochem. J.
2002, 366, 225–233.
2. (a) Wennekes, T.; van den Berg, R. J. B. H. N.; Donker, W.; van der Marel, G. A.;
Strijland, A.; Aerts, J. M. F. G.; Overkleeft, H. S. J. Org. Chem. 2007, 72, 1088–
1097; (b) Legler, C. Adv. Carbohydr. Chem. Biochem. 1990, 48, 319–384; (c)
Charnock, S. J.; Spurway, T. D.; Xie, H.; Beylot, M.-H.; Virden, R.; Warren, R. A. J.;
Hazlewood, G. P.; Gilbert, H. J. J. Biol. Chem. 1998, 273, 32187–32199.
3. Yi, T.; Wu, A. T.; Wu, S.-H.; Zou, W. Tetrahedron 2005, 61, 11716–11722.
4. Hughes, N. A.; Speakman, P. R. H. Carbohydr. Res. 1965, 1, 171–175.
5. (a) McDevitt, J. P., Jr.; Lansbury, P. T. J. Am. Chem. Soc. 1996, 118, 3818–3828; (b)
3.22. Propargyl 2-C-(5-amino-5-deoxy-2,3-di-O-
isopropylidene-b-D-ribopyranosyl)acetate (15)
To a stirred solution of acid 12a (0.279 g, 1.20 mmol) in dry
CH2Cl2 (20 mL), DMAP (0.147 g, 1.20 mmol), DCC (0.746 g,
3.61 mmol), and propargyl alcohol (0.091 mL, 1.56 mmol) were
added. The reaction mixture was then stirred overnight at room
temperature. The reaction mixture was filtered and the filtrate
washed with 1 M HCl, water, aq NaHCO3, and brine, dried and con-
centrated. Purification by chromatography (hexanes–EtOAc 6:1)
afforded 15 (0.213 g, 66%) as a yellow syrup. 1H NMR (CDCl3) d:
4.78 (dd, J = 6.0, 3.9 Hz, 1H, H-3), 4.69 (dd, J = 2.4, 1.8 Hz, 2H,
OCH2C„), 4.61 (dd, J = 6.0, 1.2 Hz, 1H, H-2), 4.43–4.37 (m, 1H,
H-4), 4.18 (td, J = 4.8, 1.2 Hz, 1H, H-1), 3.40 (dd, J = 12.9, 6.3 Hz,
1H, H-10a), 3.26 (dd, J = 13.0, 4.8 Hz, 1H, H-10b), 2.79 (dd, J = 6.7,
3.0 Hz, 2H, H-5a, H-5b), 2.46 (t, J = 2.4 Hz, 1H, C„CH), 1.46 (s,
3H, C(CH3)2), 1.31 (s, 3H, C(CH3)2); 13C NMR (CDCl3) d:
170.1(C@O), 113.1 (C-iPr), 83.2 (C-2), 82.6 (C-1), 81.2 (C-3), 77.2
(C-4), 75.0 (Cq, CH2C„CH), 52.1 (CH2, OCH2C„), 51.6 (C-10), 34.3
(C-5), 26.2 (C(CH3)2), 24.9 (C(CH3)2).
ˇ
´
´
´
Popsavin, V.; Grabez, S.; Popsavin, M.; Krstic, I.; Kojic, V.; Bogdanovic, G.;
Divjakovic´, V. Tetrahedron Lett. 2004, 45, 9409–9413; (c) Ohrui, H.; Jones, G. H.;
Moffatt, J. G.; Maddox, M. L.; Christensen, A. T.; Byram, S. K. J. Am. Chem. Soc.
1975, 97, 4602–4613.
6. van Well, R. M.; Overkleeft, H. S.; Overhand, M.; Carstenen, E. V.; van der Marel,
G. A.; Van Boom, J. H. Tetrahedron Lett. 2000, 41, 9331–9335.
7. Herdeis, C.; Schiffer, T. Tetrahedron 1996, 52, 14745–14756.
8. Carstensen, E. V.; Duynstee, H. I.; van der Marel, G. A.; van Boom, J. H.; Nielsen,
J.; Overkleeft, H. S.; Overhand, M. J. Carbohydr. Chem. 2003, 22, 241–252.
9. Krülle, T. M.; de la Fuente, C.; Pickering, L.; Aplin, R. T.; Tsitsanou, K. E.;
Zographos, S. E.; Oikonomakos, N. G.; Nash, R. J.; Griffiths, R. C.; Fleet, G. W. J.
Tetrahedron: Asymmetry 1997, 8, 3807–3820.
10. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2596–2599; (b) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org.
Chem. 2002, 67, 3057–3064; (c) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H.
Eur. J. Org. Chem. 2006, 51–68; (d) Lutz, J.-F. Angew. Chem., Int. Ed. 2007, 46,
1018–1025.