Synthesis and biological evaluation of ether bridged bicyclic iminosugar derivatives

Article abstract of DOI:10.1016/j.carres.2009.05.029

Bicyclic iminosugar derivatives with an ether bridge bearing different substituents on C-2 and the nitrogen atom have been synthesized from a C-glycoside bearing an isopropylidene acetal. The activities of these compounds were investigated against several

Full text of DOI:10.1016/j.carres.2009.05.029

Carbohydrate Research 344 (2009) 1639–1645
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis and biological evaluation of ether bridged bicyclic
iminosugar derivatives
Jiun-Ly Chir a, Pey-Jiuann Wu b, Wei Zou c, Milan Bhasin c, Wei-Fu Juang b, Chao-Qi Guo b, An-Tai Wu b,
*
a Biotechnology Center in Southern Taiwan, Academia Sinica, 2F., No. 22, Lane 31, Sec. 1, Huandong Rd., Sinshih Township, Tainan County 744, Taiwan
b Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan
c Institute for Biological Sciences, National Research Council of Canada, 100 Sussex Drive, Ottawa, Ontario, Canada K1A 0R6
a r t i c l e i n f o
a b s t r a c t
Article history:
Bicyclic iminosugar derivatives with an ether bridge bearing different substituents on C-2 and the nitro-
gen atom have been synthesized from a C-glycoside bearing an isopropylidene acetal. The activities of
these compounds were investigated against several glycosidase enzymes and showed moderate inhibi-
tion and activation.
Received 23 March 2009
Received in revised form 25 May 2009
Accepted 31 May 2009
Available online 6 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Bicyclic
Iminosugar
Ether bridge
C-Glycoside
Glycosidase
1. Introduction
report the syntheses of various ether bridged bicyclic iminosugars
(5a, 5b, 6a, 6b, and 22) and their biological evaluation.
N-Alkylated iminosugars have been clinically applied as potent
glycosidase inhibitors for the treatment of diabetes and glycosi-
dase-deficiency diseases.1 For example, N-hydroxyethyl 1-deoxy-
OH
H
N
R
N
H
N
HN
R1
N
R
(Miglitol)2
and
N-butyl
1-deoxynojirimycin
O
nojirimycin
(Miglustat)3 have been used in the treatment of type II diabetes
and type I Gaucher’s disease, respectively. Previous studies suggest
that even better selectivity of inhibition may be achieved by mod-
ification of the iminosugars, including alteration of the alkyl chain
length, saturation, hydroxylation, and ring hydroxyl residues.4,5
Recently, researchers have focused considerable effort on the prep-
aration of bicyclic iminosugars6–8 and bridge bicyclic iminosugar
derivatives9,10 for glycosidase inhibition.
O
O
O
O
R
HO
OH
HO
OH
HO
6a R1 = H
6b R1 = allyl
OH
HO
OH
1 R = hydroxyalkyl
or benzyloxyalkyl
2 R = Bz, BnCO
3
4
5a R = H
5b R = allyl
2. Results and discussion
The N-substituted derivatives of 8-oxa-3-azabicyclo-[3,2,1]oc-
tanes 1 and 2 are types of an ether bridged bicycle azasugar, and
they exhibit analgesic and anti-inflammatory activities in mice
and rats.11–14 In addition, [2,2,2]-bicyclic iminosugar analogue 3,
which lacks both the 2- and 6-hydroxyl groups, shows weak inhi-
bition of several glycosidase enzymes.15 Fuentes and co-workers
synthesized related derivatives of ether bridged bicyclic iminosug-
ars 4,16 prompting us to synthesize other ether bridged bicyclic
iminosugar analogues for the current study. Recently, we described
the preparation of N-alkylated iminosugar derivatives.17 Now, we
The synthetic route to the ether bridged bicyclic iminosugars 5a
and 5b started with the conversion of C-glycoside 78 to azido-C-
glycoside 8 by mesylation and azido substitution (Scheme 1).18
Compound 8 was further converted to an amine by hydrogenation
and subsequently treated with base to promote intramolecular
amidation between the amino group and the ester. This process
produced ether bridged bicyclic iminosugar 9 (63%) as a major
product, together with aza-C-glycoside 1017 (35%). An allyl func-
tionality was introduced by treatment of 7 with O-iodoxybenzoic
acid (IBX) to afford an aldehyde intermediate. The aldehyde was
in turn subjected to BF3ꢀOEt2-induced allylation at a low tempera-
ture,19 leading to a diastereomeric mixture of allyl alcohol in
* Corresponding author. Fax: +886 4 7211 190.
E-mail address: antai@cc.ncue.edu.tw (A.-T. Wu).
a
ꢁ1:1 ratio. Subsequent mesylation and azido substitution
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.05.029

1640
J.-L. Chir et al. / Carbohydrate Research 344 (2009) 1639–1645
O
O
NH
O
H
N
HO
OMe
N3
OMe
(b)
+
O
O
R
O
O
(a)
O
10
O
O
O
O
9
8
H
N
HO
OMe
(f)
O
(e)
5a
5b
O
O
O
H
O
O
N
N3
OMe
(d)
5
6
O
O
2
1
O
O
(c), (a)
8
O
7
O
O
O
13a R = H
13b R = allyl
11
12
Scheme 1. Synthesis of ether bridged bicyclic iminosugars 5a and 5b. Reagents and conditions: (a) MsCl, TEA, CH2Cl2; NaN3, DMF; (b) H2/Pd/C, MeOH; NaOMe, MeOH; (c) IBX,
CH3CN; allylTMS, BF3ꢀOEt2, CH2Cl2; (d) PPh3, CH3CN; NaOMe, MeOH; (e) BH3/THF or LAH/THF; (f) 80% HOAc.
converted this allyl alcohol to the corresponding desired diastereo-
meric mixture, allyl-azido-C-glycoside 11 in a ꢁ1:1 ratio. Reduc-
tion of 11 with triphenylphosphine (PPh3) in CH3CN afforded the
corresponding amine (92%) as a diastereomeric mixture in a ratio
of ꢁ2:1.
chloride derivative 16 (62%) instead of the mesyl derivative. The di-
rect substitution of the chloride derivative 16 was carried out with
4-methyloxylbenzylamine in DMF to afford 17 (36%). Treating
chloride derivative 16 with 1,3-diaminopropane in DMF did not
yield the product 19, but instead produced dimethylamine-substi-
tuted 18 (42%) (see Scheme 3). This implies that dimethylformam-
ide is not stable in the presence of 1,3-diaminopropane, but
hydrolyzes to formic acid and dimethylamine. This ‘in situ’ reaction
produces dimethylamine, which can further act as a nucleophile in
an SN2 reaction. Dimethylamine is a colorless gas produced by the
catalytic reaction of CH3OH and ammonia at elevated temperatures
and high pressure.23 Thus, using 1,3-diaminopropane in DMF is a
good approach to synthesize dimethylamine derivatives. Neverthe-
less, the desired product 19 (68%) was obtained when 16 was re-
acted under nitrogen with a large excess of 1,3-diaminopropane.
In addition to N-alkylated derivatives, we attempted to intro-
duce a sugar triazole to the bicyclic iminosugar via a Click reac-
tion24,25 (Scheme 4). Compound 13a served as the starting
material for the synthesis of 22. Compound 13a underwent alkyl-
ation by treatment with propargyl bromide to afford alkyne 20
(71%). Compound 20 was treated with a copper(I) catalyst and
The intramolecular amidation of the amine and ester was exam-
ined under basic conditions (2% NaOCH3 in CH3OH) and was totally
stereoselective, producing a lactam 12 (73%) as a single diastereo-
mer with the S-configuration at C-2 as indicated by NMR analysis.
The higher conversion of 12 compared with 9 is probably due to
the presence of an allyl group in the lactam ring. Next, 9 was re-
duced with BH3ꢀTHF20,21 and 12 was reduced with lithium alumi-
num hydride (LAH) to afford isopropylidenenated amines 13a
(96%) and 13b (81%), respectively. Finally, the reaction of 13a
and 13b with 80% acetic acid at 100 °C produced the O-unpro-
tected target compounds 5a (67%) and 5b (59%), respectively. The
products were obtained as ammonium acetates after filtration and
removal of acetic acid and were fairly pure. Free amines were ob-
tained by dissolving the ammonium salt in organic solvent fol-
lowed by washing with NaHCO3.
N-Alkyl bicyclic iminosugar derivatives 6a and 6b were easily
prepared using isopropylidene lactams 9 and 12 as key intermedi-
ates (Scheme 2), and the following reaction sequences: (a) treat-
ment of 9 and 12 with ethyl bromoacetate22 produces 14a (68%)
and 14b (83%), respectively; (b) subsequent reduction of 14a/b
with LAH afforded alcohols 15a (92%) and 15b (95%), respectively;
(c) deprotection of 15a/b with 80% acetic acid at 100 °C gave the
products 6a and 6b. After filtration and removal of the solvent,
the acetate salts 6a and 6b were washed with NaHCO3 to afford
the respective free amines 6a (63%) and 6b (53%) as single
products.
azido-C-glycoside
8
in ethanol under refluxing conditions,26
producing sugar triazole bicyclic iminosugar 21 (55%) with
1,4-regioselectivity. Further deprotection of 21 with 80% acetic
acid at 100 °C produced 22 (58%). All products were characterized
by 1H, 13C, and COSY NMR spectroscopies, as well as mass
spectrometry.
Due to the low yields of 16, 17, 18, and 19, we did not evaluate
their biological activities. The compounds 5a, 5b, 6a, 6b, and 22
N-Alkyl bicyclic iminosugar derivatives 17, 18, and 19 were
then prepared from 15a by standard mesylation in the presence
of triethylamine or pyridine. This process produced an unexpected
HN
O
O
N
O
OMe
HO
(b)
(c)
Cl
17
HO
EtO
N
N
HO
N
O
O
O
N
O
(a)
O
H
N
O
O
R
O
R
N
R
N
R
N
O
O
O
O
O
(c)
18
(a)
(b)
O
O
O
(d)
H
N
O
O
O
15a
16
O
N
(CH2)3NH2
O
O
O
HO
OH
O
O
19
9 R = H
12 R = allyl
14a R = H
6a R = H
15a R = H
14b R = allyl
6b R = allyl
15b R = allyl
Scheme 3. Synthesis of ether bridged bicyclic iminosugar derivatives 17–19.
Reagents and conditions: (a) MsCl, TEA; (b) 4-methyloxylbenzylamine, Et3N, DMF;
(c) 1,3-diaminopropane, Et3N, DMF; (d) 1,3-diaminopropane, Et3N.
Scheme 2. Synthesis of ether bridged bicyclic iminosugars 6a and 6b. Reagents and
conditions: (a) BrCH2CO2Et, KOtBu, THF; (b) LAH, THF; (c) 80% HOAc.

J.-L. Chir et al. / Carbohydrate Research 344 (2009) 1639–1645
O
1641
CH3OH 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 with
Bruker AM 300 (300 MHz) spectrometers. Chemical shifts are ex-
pressed in ppm with residual CHCl3 or CD3OD as reference. Low-
and high-resolution mass spectra were recorded under fast atom
bombardment (FAB) or electron spray interface (ESI) conditions.
N
N
N
OMe
N
O
(a)
(b)
O
N
13a
O
O
O
O
O
21
(c)
O
O
20
O
3.2. Enzyme assays
N
N
N
OMe
O
The enzyme assays were performed with a procedure previ-
ously reported in the literature.27,28 Briefly, the glycosidases and
the compounds we synthesized (5a, 5b, 6a, 6b, and 22) were
pre-incubated at room temperature for 5 min before the addition
of the appropriate p-nitrophenyl glycosides substrates at the opti-
mum pH for each enzyme. The microtiter plate was incubated at
37 °C for 10 min, and the reaction was terminated by addition of
0.5 M Na2CO3. The released p-nitrophenol was measured spectro-
photometrically at 400 nm using a microtiter plate reader.
N
HO
OH
O
22
HO
OH
Scheme 4. Synthesis of ether bridged bicyclic iminosugar derivative 22. Reagents
and conditions: (a) propagyl bromide, Et3N, CH3CN, reflux; (b) 8, Cu(0), CuSO4,
EtOH, reflux; (c) 80% HOAc.
were assayed27,2829 for their inhibitory activity toward 10
commercially available glycosidases (see Table 1). None of these
compounds showed significant inhibitory activity against
nosidase (jack bean), -glucosidase (baker’s yeast), b-glucosidase
(almonds), -galactosidase (coffee bean and guar seed), and b-
3.3. (1R,6S,7S,8S)-7,8-Isopropylidene-7-methyl-9-oxa-3-
azabicyclo[4.2.1]nonan-4-one (9)
a-man-
a
a
A mixture of 8 (1.72 g, 6.35 mmol) and 10% Pd–C (0.17 g) in
CH3OH (20 mL) was stirred under H2 atmosphere (balloon pres-
sure) for 40 min when the starting material was completely con-
sumed. The reaction mixture was filtered and the filtrate was
concentrated. Purification by chromatography (DCM–CH3OH,
10:1) gave amine (1.44 g, 92%) as a yellow oil. The solution of
amine (1.44 g, 5.85 mmol) in 2% NaOCH3–CH3OH (10 mL) was stir-
red overnight and then neutralized by the addition of Dowex
50WX8 (H+) resin. The filtrate was concentrated to a residue. Puri-
fication by chromatography (hexanes–EtOAc 12:1) gave tricyclic
lactams 9 (0.79 g, 63%) and 10 (0.50 g, 35%) as a yellow oil. For 9,
1H NMR (CDCl3) d: 6.43 (s, 1H, NH), 4.79 (d, J = 5.7 Hz, 1H, H-8),
4.63 (d, J = 6.0 Hz, 1H, H-7), 4.35 (d, J = 3.6 Hz, 1H, H-1), 4.26 (q,
J = 2.4 Hz, 1H, H-6), 3.55 (d, J = 15.0 Hz,1H, H-2a), 3.17–3.08 (m,
1H, H-2b), 2.83 (dd, J = 16.2, 2.4 Hz, 1H, H-5a), 2.70–2.62 (m, 1H,
H-5b), 1.47 (s, 3H, C(CH3)3), 1.25 (s, 3H, C(CH3)3); 13C NMR (CDCl3):
d 176.0 (C@O), 112.0 (C(CH3)2), 83.9 (C-7), 82.9 (C-8), 82.4 (C-1),
79.2 (C-6), 46.3 (C-2), 43.7 (C-5), 26.0 (C(CH3)2), 24.3 (C(CH3)2);
ESIMS: calcd for C10H15NO4 [M]+, m/z 213.1001; found m/z
213.1005.
galactosidase (Escherichia coli) at a concentration of 1 mM. When
screened against b-galactosidase from Aspergillus oryzae, only 6a
(41%) and 22 (36%) show moderate inhibitory activity. On the other
hand, 6a (48%) showed moderate inhibitory activity toward bovine
liver b-galactosidase. Interestingly, compounds 5b (+26%) and 6b
(+47%), which both contain an allyl group in the bridge ring,
showed moderate activation activity of a-galactosidase (Aspergillus
niger). These results show that structural variations in these com-
pounds, such as the absence or presence of the N-ethylenehydroxyl
group and the C-2 allyl substituent group of ether bridge bicyclic
iminosugars, can affect the activities (inhibition or activation) of
glycosidase enzymes.
In conclusion, we have synthesized different substituted ether
bridge bicyclic iminosugars from C-glycoside 7 and have evaluated
them against a variety of glycosidases derived from different
sources. Although the compounds displayed weak to moderate ef-
fects (inhibition or activation), further modification may lead to
more potent glycosidase inhibitors or activators.
3. Experimental
3.4. Methyl 2-C-(5-azido-5-allyl-2,3-di-O-isopropylidene-5-
3.1. General methods
deoxy-b-D-ribofuranosyl)acetate (11)
All reagents were obtained from commercial suppliers and were
used without further purification. DCM was distilled over CaH2.
To a solution of 7 (0.4 g, 1.63 mmol) in CH3CN (150 mL) was
added IBX (1.37 g, 3 equiv), and the mixture was stirred at 80 °C
Table 1
Activity of glycosidases against compounds 5a, 5b, 6a, 6b, and 22
Enzyme
-Galactosidase
Origin
5a
5b
6a
6b
22
a
Coffee bean
A. niger
Guar seed
—
—
—
—
+26%
—
—
25%
—
—
+47%
—
—
—
—
b-Galactosidase
A. oryzae
E. coli
—
—
—
—
41%
—
—
—
36%
—
Bovine liver
K. lactis
20%
15%
35%
—
48%
—
34%
—
—
—
a
-Mannosidase
-Glucosidase
Jack bean
Baker0s yeast
Almonds
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
a
b-Glucosidase
Percentage inhibition or activation (+) at 1 mM concentration. (ꢂ) = no inhibition at 1 mM concentration.

1642
J.-L. Chir et al. / Carbohydrate Research 344 (2009) 1639–1645
for 1.5 h. Upon cooling to room temperature the reaction mixture
was diluted by the addition of benzene (40 mL) and then the sol-
vent was removed to afford the crude aldehyde. Without further
purification, to a solution of the above crude aldehyde (0.276 g,
1.13 mmol) in CH2Cl2 (10 mL) at ꢂ78 °C under nitrogen were
added allyltrimethylsilane (0.22 mL, 1.2 equiv) and BF3ꢀOEt2
(0.07 mL, 0.5 equiv) and the temperature was raised to ꢂ20 °C
and was further stirred overnight. The reaction mixture was added
to H2O and extracted with EtOAc. The organic layers were com-
bined, washed with brine, and dried with MgSO4. Purification by
chromatography (hexanes–EtOAc 4:1) gave allyl alcohol (0.39 g,
83%) as a yellow oil. The allyl alcohol underwent mesylation, azido
substitution7, and was purified by chromatography (hexanes–
EtOAc 1:6) to obtain compound 11 (1:1 mixture of anomers) in
86% yield; 1H NMR (CDCl3) d: 5.86–5.72 (m, 1H, CH@), 5.21–5.06
(m, 2H, @CH2), 4.65–4.43 (m, 2H), 4.26–4.20 (m, 1H), 3.95–3.90
(m, 1H), 3.67 (s, 3H, CO2 CH3), 2.68–2.60 (m, 2H), 2.41 (t,
J = 6.0 Hz, 1H), 1.50 (s, 3H, C(CH3)2), 1.28 (s, 3H, C(CH3)2); 13C
NMR (CDCl3) d: 170.8 (C@O), 133.3 (C-7), 133.2 (C-7), 118.63 (C-
8), 118.60 (C-8), 114.8 (C(CH3)2), 85.7 (C-4), 85.5 (C-4), 84.0 (2C-
3), 82.4 (C-2), 80.7 (2C-1), 80.4 (C-2), 62.6 (C-5), 62.0 (C-5), 51.8
(CO2CH3), 51.7 (CO2CH3), 38.0 (C-10), 37.9 (C-10), 35.2 (C-6), 34.5
(C-6), 27.4 (2 C(CH3)2), 25.5 (2 C(CH3)2).
C(CH3)2); 13C NMR (CDCl3) d: 111.1 (C(CH3)2), 89.2 (C-7), 86.2 (C-
8), 84.8 (C-1), 84.3 (C-6), 55.0 (C-2), 46.8 (C-4), 34.7 (C-5), 26.4
(C(CH3)2), 24.7 (C(CH3)2); ESIMS: calcd for C10H17NO3 [M]+, m/z
199.1208; found m/z 199.1205.
3.7. (1R,6S,7S,8S)-2-Allyl-7,8-isopropylidene-9-oxa-3-
azabicyclo[4.2.1]nonane (13b)
To a solution of LAH (60 mg, 1.58 mmol) in dry THF (10 mL) un-
der N2 at 0 °C was added 12 (0.2 g, 0.79 mmol) and stirred for 2 h,
and then acidified with aq ammonium chloride. The resulting pre-
cipitate was filtered through a Celite pad and the filtrate was ex-
tracted with CH2Cl2. Purification by column chromatography
(hexanes–EtOAc 4:1) afforded 13b (0.153 g, 81%) as a yellow oil.
1H NMR (CDCl3) d: 5.76–5.65 (m, 1H, CH@), 5.10–5.04 (m, 2H,
@CH2), 4.61 (d, J = 6.3 Hz, 1H), 4.55 (d, J = 6.0 Hz, 1H, H-8), 4.41
(d, J = 7.2 Hz, 1H, H-7), 4.13 (s, 1H, H-1), 3.01–2.92 (m, 1H, H-4a),
2.80 (t, J = 7.5 Hz, 1H, H-2), 2.47–2.35 (m, 2H, H-4b, CH2CH@),
2.26–2.17 (m, 1H, CH2CH@), 1.88–1.82 (m, 1H, H-5a), 1.73–1.64
(m, 1H, H-5b), 1.46 (s, 3H, C(CH3)2), 1.28 (s, 3H, C(CH3)2); 13C
NMR (CDCl3) d: 135.0 (CH@), 117.8 (@CH2), 111.5 (C(CH3)2), 88.7
(C-1), 87.7 (C-7), 87.0 (C-6), 84.4 (C-8), 59.4 (C-2), 39.6 (C-4),
36.4 (CH2CH@), 35.3 (C-5), 26.4 (C(CH3)2), 24.8 (C(CH3)2); FABMS:
calcd for C13H22NO3 [M+H]+, m/z 240.1600; found m/z 240.1596.
3.5. (1R,6S,7S,8S)-2-Allyl-7,8-isopropylidene-9-oxa-3-
azabicyclo[4.2.1]nonan-4-one (12)
3.8. (1R,6S,7S,8S)-9-Oxa-3-azabicyclo[4.2.1]nonane-7,8-diol (5a)
To a solution of 11 (0.15 g, 0.48 mmol) in CH3CN (50 mL) was
added PPh3 (0.139 g, 1.1 equiv), and the mixture was stirred at
80 °C for 12 h. The solvent was removed under reduced pressure
affording the crude residue. Purification by column chromatogra-
phy (hexanes–EtOAc 1:1) gave amine (0.125 g, 92%) as a yellow
oil. The solution of amine (0.125 g, 0.44 mmol) in 2% NaOCH3–
CH3OH (10 mL) was stirred overnight and then neutralized by
the addition of Dowex 50WX8(H+) resin. The filtrate was concen-
trated to a residue. Purification by chromatography (hexanes–
EtOAc 2:1) obtained 12 (88.7 mg, 73%) as a yellow oil. 1H NMR
(CDCl3, 300 MHz) d: 6.29 (d, J = 5.4 Hz, 1H, NH), 5.77–5.68 (m,
1H, CH@), 5.17–5.11 (m, 2H, @CH2), 4.75 (d, J = 5.7 Hz, 1H, H-8),
4.60 (d, J = 6.0 Hz, 1H, H-7), 4.35 (d, J = 2.7 Hz, 1H, H-1), 4.28 (t,
J = 3.6 Hz, 1H, H-6), 3.08–3.05 (m, 1H, H-2), 2.85 (dd, J = 16.3,
3 Hz, 1H, H-5a), 2.66 (dd, J = 27.0, 3.3 Hz, 1H, H-5b), 2.50–2.42
(m, 2H, CH2CH@), 1.47 (s, 3H, C(CH3)2), 1.29 (s, 3H, C(CH3)2); 13C
NMR (CDCl3) d: 174.62 (C@O), 133.27 (CH), 119.09 (@CH2),
112.12 (C(CH3)2), 84.43 (C-1), 83.94 (C-8), 83.43 (C-7) 79.57 (C-
6), 55.83 (C-2) 43.16 (C-5), 37.01 (CH2CH@), 26.00 (C(CH3)2),
24.29 (C(CH3)2); FABMS: calcd for C13H20NO4 [M+H]+, m/z
254.1392; found m/z 254.1402.
Compound 13a (95 mg, 0.48 mmol) was dissolved in AcOH–H2O
(9.0 mL:3.0 mL) and stirred at 100 °C for 6 h. After removal of the
solvents under reduced pressure, the solid residue was coevaporat-
ed with CH3OH–toluene (1:1 v/v, 10 mL) to yield the crude diol
(salt form of 5a). The amine form was obtained by dissolving the
salt in dichloromethane followed by washing with aqueous sodium
bicarbonate. The organic phase was dried and concentrated to give
syrup. Purification by chromatography (EtOAc–CH3OH, 8:1) gave
5a (51 mg, 67%) as a white oil. [
a]
+16.3 (c 1.0, CH3OH); 1H
D
NMR (CD3OD) d: 4.13–4.02 (m, 4H), 2.88–2.80 (m, 2H), 2.76–2.67
(m, 2H), 1.95–1.85 (m, 1H), 1.62–1.52 (m, 1H); 13C NMR (CD3OD)
d: 88.0, 85.5, 79.4, 75.5, 53.1, 46.4, 34.7; FABMS: calcd for
C7H14NO3 [M+H]+, m/z 160.0974; found m/z 160.0980.
3.9. (1R,6S,7S,8S)-2-Allyl-9-oxa-3-azabicyclo[4.2.1]nonane-7,8-
diol (5b)
The same procedures as described above were used to obtain 5b
(59%) as a yellow oil. [a]
+20.5 (c 1.0. CHCl3); 1H NMR (CDCl3) d:
D
5.78–5.66 (m, 1H, CH@), 5.13–5.08 (m, 2H, @CH2), 4.32 (d,
J = 5.7 Hz, 1H, H-8), 4.28 (d, J = 7.5 Hz, 1H, H-7), 4.09 (d,
J = 5.4 Hz, 1H, H-6), 3.92 (s, 1H, H-1), 3.09–ꢂ3.00 (m, 1H, H-4a),
2.91 (t, J = 6.6 Hz, 1H, H-2), 2.61–2.53 (m, 1H, H-4b), 2.47–2.38
(m, 1H, CH2CH@), 2.31–2.24 (m, 1H, CH2CH@), 2.00–1.89 (m, 1H,
H-5a), 1.71–1.56 (m, 1H, H-5b); FABMS: calcd for C10H18NO3
(M+H), m/z 200.1287; found m/z 200.1288.
3.6. (1R,6S,7S,8S)-7,8-Isopropylidene-9-oxa-3-
azabicyclo[4.2.1]nonane (13a)
To a solution of 9 (1.61 g, 7.55 mmol) in distilled THF (40 mL)
was added BH3ꢀTHF (1.5 M in THF, 25.0 mL, 22.65 mmol), and the
mixture was stirred at 65 °C overnight. A few drops of EtOH were
added after cooling the solution, then the solvent was removed,
and the residue diluted with EtOH (40 mL) and heated at reflux
for 48 h. After evaporation, the residue was partitioned between
CH2Cl2–NaOH (1 M in H2O). The aqueous layer was extracted with
CH2Cl2 (2 ꢃ 10 mL), and the combined organic layers were dried
over MgSO4 and concentrated. Purification by column chromatog-
raphy (hexanes–EtOAc 4:1) afforded 13a (1.45 g, 96%) as a color-
less oil. 1H NMR (CDCl3) d: 4.56 (s, 2H, H-7, H-8), 4.34 (d,
J = 8.4 Hz, 1H, H-6), 4.27 (t, J = 2.4 Hz, 1H, H-1), 2.98–2.84 (m, 2H,
H-4a, H-2a), 2.69–2.55 (m, 2H, H-2b, H-4b), 1.95–1.85 (m, 1H, H-
5a), 1.74–1.64 (m, 1H, H-5b), 1.43 (s, 3H, C(CH3)2), 1.24 (s, 3H,
3.10. Ethyl 2-((1R,6S,7S,8S)-7,8-isopropylidene-4-oxo-9-oxa-3-
azabicyclo-[4.2.1]nonan-3-yl)acetate (14a)
To a solution of 9 (0.27 g, 1.27 mmol) in dry THF (20 mL) was
added potassium tert-butoxide (0.29 g, 2 equiv) and ethyl bromo-
acetate (0.18 mL, 1.7 mmol). The reaction mixture was stirred at
room temperature for 4 h. After removal of the solvent under re-
duced pressure, the residue was dissolved in ether, washed with
aq NaHCO3, and dried over MgSO4. Purification by chromatography
(hexanes–EtOAc 8:1) led to 14a as an orange syrup (0.26 g, 68%).
1H NMR (CDCl3) d: 4.93 (d, J = 5.7 Hz, 1H, H-8), 4.54 (d,
J = 5.7 Hz,1H, H-7), 4.29 (d, J = 4.5 Hz, 1H, H-1), 4.21 (t, J = 3.3 Hz,

J.-L. Chir et al. / Carbohydrate Research 344 (2009) 1639–1645
1643
1H, H-6), 4.10 (q, J = 7.2 Hz, 2H, OCH2), 3.99 (d, J = 7.5 Hz, 2H,
N–CH2), 3.81 (d, J = 7.5 Hz, 1H, H-2a), 3.13 (dd, J = 15.3, 4.8 Hz,
1H, H-2b), 2.77 (dd, J = 3.6, 0.6 Hz, 2H, H-5a, H-5b), 1.40 (s, 3H,
C(CH3)2), 1.23 (s, 3H, C(CH3)2), 1.19 (t, J = 7.2 Hz, 3H, OCH2CH3);
13C NMR (CDCl3) d: 173.0 (C@O), 168.7 (C@O), 111.7 (C(CH3)2),
83.4 (C-7), 82.4 (C-8), 81.5 (C-1), 78.6 (C-6), 61.2 (OCH2), 54.6
(C-2), 51.5 (NCH2), 43.8 (C-5), 25.8 (C(CH3)2), 24.2 (C(CH3)2), 14.0
(OCH2CH3); FABMS: calcd for C14H22NO6 [M+H]+, m/z 300.1447;
found m/z 300.1454.
d: 135.46 (CH@), 117.95 (@CH2), 111.67 (C(CH3)2), 89.35 (C-1),
86.67 (C-6), 85.67 (C-7), 84.00 (C-8), 66.03 (C-2), 59.29 (CH2OH),
59.01 (N–CH2), 44.22 (C-4), 33.93 (C-5), 29.40 (CH2CH@), 26.47
(C(CH3)2), 24.73 (C(CH3)2); FABMS: calcd for C15H26NO4 [M+H]+,
m/z 284.1862; found m/z 284.1869.
3.14. (1R,6S,7S,8S)-3-(2-Hydroxyethyl)-9-oxa-3-
azabicyclo[4.2.1]nonane-7,8-diol (6a)
Compound 15a (0.11 g, 0.45 mmol) was dissolved in AcOH–H2O
(5.4 mL/1.8 mL) and reacted at 100 °C for 6 h. After removal of the
solvents under reduced pressure, the solid residue was coevaporat-
ed with CH3OH–toluene (1:1 v/v, 5 mL) to yield the crude diol.
Purification by chromatography (CH2Cl2–CH3OH 2:1) gave 6a
3.11. Ethyl 2-((1R,6S,7S,8S)-2-Allyl-7,8-7,8-isopropylidene-4-
oxo-9-oxa-3-azabicyclo[4.2.1]nonan-3-yl)acetate (14b)
The same procedures as described above were used to obtained
14b (83%) as a yellow syrup. 1H NMR (CDCl3) d: 5.74–5.69 (m, 1H,
CH@), 5.27 (d, J = 6.0 Hz, 1H, H-8), 5.19–5.12 (m, 2H, @CH2), 4.63
(d, J = 6.0 Hz, 1H, H-7), 4.54 (d, J = 17.1 Hz, 1H, N–CH02), 4.37 (d,
J = 3.6 Hz, 1H, H-1), 4.29 (dd, J = 4.2, 2.7 Hz, 1H, H-6), 4.18 (q,
J = 6.9 Hz, 2H, CO2CH2), 3.46 (d, J = 17.1 Hz, 1H, N–CH2), 3.23–
3.16 (m, 1H, H-2), 2.92–2.75 (m, 2H, H-5a, H-5b), 2.57–2.40 (m,
2H, CH2CH@), 1.48 (s, 3H, C(CH3)2), 1.32 (s, 3H, C(CH3)2), 1.28 (t,
J = 6.9 Hz, 2H, OCH2); 13C NMR (CDCl3) d: 171.8 (C@O), 169.1
(C@O), 133.2 (@CH), 119.4 (CH2@), 111.9 (C(CH3)2), 83.6 (C-1),
83.1 (C-8), 83.0 (C-7), 79.1 (C-6), 64.6 (C-2), 61.3 (CO2CH2), 52.1
(NCH2), 43.4 (C-5), 35.2 (CH2CH@), 26.0 (C(CH3)2), 24.5 (C(CH3)2),
14.2 (CH3); FABMS: calcd for C17H26NO6 (M+H), m/z 340.1760;
found m/z 340.1766.
(58 mg, 63%) as a colorless syrup. [
a]
+51.4 (c 1.0, CHCl3); 1H
D
NMR (CDCl3) d: 4.28–4.19 (m, 3H), 3.62–3.49 (m, 2H), 2.79–2.48
(m, 7H), 2.06–1.96 (m, 1H), 1.76–1.65 (m, 1H); 13C NMR (CDCl3)
d: 86.3, 84.2, 79.6, 74.5, 61.0, 60.8, 59.1, 53.3, 33.3; FABMS: calcd
for C9H18NO4 [M+H]+, m/z 204.1236; found m/z 204.1228.
3.15. (1R,6S,7S,8S)-2-Allyl-3-(2-hydroxyethyl)-9-oxa-3-
azabicyclo[4.2.1]nonane-7,8-diol (6b)
The same procedures as described above were used to obtained
6b (53%) as a yellow syrup. [a]
D +1.9 (c 1.0, CHCl3); 1H NMR (CDCl3)
d: 5.82–5.68 (m, 1H, @CH), 5.14–5.04 (m, 2H, CH2@), 4.32 (dd,
J = 5.7, 6.0 Hz, 1H, H-8), 4.25 (d, J = 8.7 Hz, 1H, H-6), 4.12 (d,
J = 5.1 Hz, 1H, H-7), 3.75 (br s, 1H, OH), 4.06 (s, 1H, H-1), 3.54–
3.50 (m, 2H, CH2OH), 3.03–2.93 (m, 1H, H-4), 2.77–2.62 (m, 3H,
NCH2, H-2), 2.51–2.22 (m, 5H, CH2CH@, H-4b, 2OH), 1.99–1.89
(m, 1H, H-5a), 1.63–1.52 (m, 1H, H-5b); 13C NMR (CDCl3) d:
135.7 (CH@), 117.7 (@CH2), 87.3 (C-1), 83.9 (C-6), 79.2 (C-7),
74.9 (C-8), 65.0 (C-2), 59.6 (CH2OH), 58.5 (NCH2), 44.3 (C-4), 33.5
(C-5), 29.5 (CH2CH@); FABMS: calcd for C12H22NO4 [M+H]+, m/z
244.1549; found m/z 244.1541.
3.12. (1R,6S,7S,8S)-3-(2-Hydroxyethyl)-7,8-isopropylidene-9-
oxa-3-azabicyclo[4.2.1]nonane (15a)
To a solution of 14a (1.74 g, 5.82 mmol) in dry CH2Cl2 (20 mL)
was added a 1 M solution of DIBAL (18.3 mL, 3 equiv) at 0 °C. The
reaction mixture was stirred at 0 °C for 1.5 h. CH3OH (1.8 mL)
was added at 0 °C and the temperature was raised to room temper-
ature. Saturated NaCl (3.6 mL) was added and the mixture was di-
luted with Et2O (89 mL). MgSO4 (9.4 g) was added, and the mixture
was stirred for 1 h and then filtered through a Celite pad. The sol-
vent was removed and the crude mixture was purified by column
chromatography (hexanes–EtOAc 4:1) to give 15a (1.30 g, 92%) as a
yellow oil. 1H NMR (CDCl3): d 4.58 (d, J = 6.0 Hz, 1H, H-8), 4.53 (d,
J = 6.0 Hz, 1H, H-7), 4.38 (d, J = 8.7 Hz, 1H, H-6), 4.30 (t, J = 2.1 Hz,
1H, H-1), 3.60–3.48 (m, 2H, CH2OH), 2.75–2.49 (m, 6H, H-2a, H-
2b, H-4a, H-4b, N–CH2), 2.02–1.92 (m, 1H, H-5a), 1.76–1.65 (m,
1H, H-5b), 1.47 (s, 3H, C(CH3)2), 1.29 (s, 3H, C(CH3)2); 13C NMR
(CDCl3) d: 111.6 (C(CH3)2), 89.2 (C-7), 85.0 (C-1), 84.5 (C-8), 83.9
(C-6), 61.7 (C-2), 61.1 (N–CH2), 59.0 (CH2OH), 53.6 (C-4), 33.3 (C-
5), 26.4 (C(CH3)2), 24.7 (C(CH3)2); ESIMS: calcd for C12H21NO4
[M]+, m/z 243.1471; found m/z 243.1476.
3.16. (1R,6S,7S,8S)-3-(2-Chloroethyl)-7,8-isopropylidene-9-oxa-
3-azabicyclo[4.2.1]nonane (16)
To a solution of 15a (1.38 g, 5.68 mmol) in dry CH2Cl2 (10 mL) at
0 °C under argon atmosphere were added dry triethylamine
(1.58 mL, 11.34 mmol) and methanesulfonyl chloride (0.57 mL,
7.37 mmol). The solution was stirred at room temperature for
4 h, and then neutralized by the addition of aq NaHCO3. The mix-
ture was diluted with water and extracted with CH2Cl2
(3 ꢃ 10 mL). The organic phase was washed with brine, dried over
MgSO4, and the solvent was removed under reduced pressure to
give a residue, which upon column chromatography (hexanes–
EtOAc 10:1), yielded 16 (0.92 g, 62%) as an oil. 1H NMR (CDCl3) d:
4.66 (d, J = 11.1 Hz, 1H, H-8), 4.61 (d, J = 2.4 Hz, 1H, H-7), 4.35 (d,
J = 8.4 Hz, 1H, H-6), 4.27 (t, J = 2.1 Hz, 1H, H-1), 3.46 (t, J = 6.3 Hz,
2H, CH2Cl), 2.80–2.52 (m, 6H, N–CH2, H-2a, H-2b, H-4a, H-4b),
1.95–1.85 (m, 1H, H-5a), 1.78–1.67(m, 1H, H-5b), 1.46 (s, 3H,
C(CH3)2), 1.28 (s, 3H, C(CH3)2); 13C NMR (CDCl3) d: 111.4
(C(CH3)2), 89.1 (C-7), 85.2 (C-1), 84.8 (C-8), 84.3 (C-6), 61.7 (C-2),
61.1 (N–CH2), 53.9 (C-4), 42.4 (CH2Cl), 33.5 (C-5), 26.5 (C(CH3)2),
24.8 (C(CH3)2); ESIMS: calcd for C12H20ClNO3 [M]+, m/z 261.1132;
found m/z 261.1133.
3.13. (1R,6S,7S,8S)-2-Allyl-3-(2-hydroxyethyl)-7,8-
isopropylidene-9-oxa-3-azabicyclo[4.2.1]nonane (15b)
To a solution of LAH (46 mg, 1.2 mmol) in dry THF (4 mL) under
N2 at 0 °C was added 14b (0.2 g, 0.59 mmol). The solution was stir-
red at 0 °C for 2 h, and then acidified with aq ammonium chloride.
The precipitate was filtered through a Celite pad and the filtrate
was extracted with CH2Cl2. The solvent was removed and the crude
mixture was purified by column chromatography (hexanes–EtOAc
4:1) to afford 15b (0.16 g, 95%) as a yellow oil. 1H NMR (CDCl3) d:
5.82–5.69 (m, 1H, @CH), 5.08 (m, 2H, @CH2), 4.61 (d, J = 6.0, 1H, H-
8), 4.54 (d, J = 6.3, 1H, H-7), 4.40 (d, J = 9.0 Hz, 1H, H-6), 4.24 (s, 1H,
H-1), 3.54–3.50 (m, 2H, CH2OH), 3.03–2.93 (m, 1H, H-4a), 2.71 (t,
J = 6.0 Hz, 2H, N–CH2), 2.73–2.44 (m, 2H, H-2, @CH2), 2.37–2.26
(m, 2H, H-4b, @CH2), 1.99–1.90 (m, 1H, H-5a), 1.73–1.62 (m, 1H,
H-5b), 1.47 (s, 3H, C(CH3)2), 1.29 (s, 3H, C(CH3)2); 13C NMR (CDCl3)
3.17. (1R,6S,7S,8S)-3-(2-(4-Methoxybenzylamino)ethyl)-7,8-
isopropylidene-9-oxa-3-azabicyclo[4.2.1]nonane (17)
To a solution of 16 (50 mg, 0.19 mmol) in DMF (5 mL) was
added 4-methyloxylbenzylamine (0.03 mL, 0.25 mmol) and trieth-
ylamine (0.08 mL, 0.57 mmol) and the reaction mixture was heated
at reflux overnight. After cooling, the solvent was removed under

1644
J.-L. Chir et al. / Carbohydrate Research 344 (2009) 1639–1645
reduced pressure and the crude mixture was purified by column
chromatography (hexanes–EtOAc 1:3) to give 17 (25 mg, 36%) as
a yellow oil. 1H NMR (CDCl3) d: 7.17 (d, J = 8.4 Hz, 2H, Ph), 6.83
(d, J = 8.7 Hz, 2H, Ph), 5.00 (s, 1H, NH), 4.55 (s, 2H, H-7, H-8),
4.34–4.25 (m, 4H, H-6, H-1, PhCH2), 4.14–4.06 (m, 2H, N–CH2),
3.76 (s, 3H, OCH3), 2.73–2.47 (m, 6H, NCH2CH2, H-2a, H-2b, H-4a,
H-4b), 1.92–1.83 (m, 1H, H-5a), 1.76–1.65 (m, 1H, H-5b), 1.46 (s,
3H, C(CH3)2), 1.26 (s, 3H, C(CH3)2); 13C NMR (CDCl3) d: 159.0
(Ph), 156.3 (Ph), 130.4 (Ph), 128.9 (Ph), 114.0 (2Ph), 111.3
(C(CH3)2), 89.1 (C-8), 85.1 (C-7), 84.7 (C-1), 84.2 (C-6), 62.9
(N–CH2), 62.1 (C-2), 58.6 (NCH2CH2), 55.2 (OCH3), 54.1 (C-4),
44.6 (PhCH2), 33.4 (C-5), 26.5 (C(CH3)2), 24.8 (C(CH3)2); ESIMS:
calcd for C20H30N2O4 [M]+, m/z 362.2206; found m/z 326.2214.
49.0 (NCH2), 32.8 (C-5), 26.4 (C(CH3)2), 24.8 (C(CH3)2); ESIMS: calcd
for C13H19NO3 [M]+, m/z 237.1365; found m/z 237.1362.
3.21. Methyl 2-(5-((5-((7,8-dimethylmethylenedioxy-9-oxa-3-
azabicyclo[4.2.1]nonan-3-yl)methyl)-1H-1,2,3-triazol-1-
yl)methyl)-3,4-isopropyliden-tetrahydrofuran-2-yl)acetate 21
To
a solution of 20 (86 mg, 0.36 mmol) and 8 (0.10 g,
1.1 equiv) in 10 mL of EtOH were added copper turnings
(8.6 mg) and saturated Cu(SO4)2 solution (0.18 mL, 1 M) and the
reaction mixture was heated at reflux for 12 h. After completion
of the reaction, the reaction mixture was filtered through Celite.
The Celite pad was washed with CHCl3 and the solvent was re-
moved under reduced pressure. The residue was purified by col-
umn chromatography (hexanes–EtOAc 1:2) over silica gel to
afford 21 (0.10 g, 55%) as a colorless oil. 1H NMR (CDCl3) d:
7.47 (s, 1H, ArH), 4.61–4.47 (m, 4H, H-2, H-3, H-20 H-30), 4.34–
4.15 (m, 6H, CH2CO2, H-4, H-40 H-1 H-10), 3.71 (s, 2H, N–CH2),
3.66 (s, 3H, CO2CH3), 2.80–2.69 (m, 2H, H-5a, H-5b), 2.61 (dd,
J = 15.7, 4.5 Hz, 1H, H-6a), 2.46–2.34 (m, 3H, H-6b, H-50a, H-50b),
1.93–1.84 (m, 1H, H-7a), 1.71–1.61 (m, 1H, H-7b), 1.47 (s, 3H,
C(CH3)2), 1.43 (s, 3H, C(CH3)2), 1.26 (d, J = 2.1 Hz, 6H, 2C(CH3)2);
13C NMR (CDCl3) d: 170.4 (C@O), 145.0 (Ar), 123.7 (ArH), 115.3
(C(CH3)2), 111.4 (C(CH3)2), 89.1, 84.9, 84.7, 84.0, 83.8, 82.3, 81.6,
80.7 (C-1, C-2, C-3, C-4, C-10, C-20 C-30 C-40), 61.2 (C-5), 54.8 (N–
CH2), 53.3 (C-50), 51.8 (CO2CH3), 51.5 (CH2CO2), 37.9 (C-6), 33.1
(C-7), 27.3 (C(CH3)2), 26.5 (C(CH3)2), 25.4 (C(CH3)2), 24.9
(C(CH3)2); ESIMS: calcd for C24H36N4O8 [M]+, m/z 508.2533; found
m/z 508.2536.
3.18. (1R,6S,7S,8S)-3-(2-(Dimethylamino)ethyl)-7,8-
isopropylidene-9-oxa-3-azabicyclo[4.2.1]nonane (18)
To a solution of 16 (42 mg, 0.16 mmol) in DMF (5 mL) was
added triethylamine (0.07 mL, 0.48 mmol) and 1,3-diaminopro-
pane (0.02 mL, 0.21 mmol) and the reaction mixture was heated
at reflux overnight. After cooling, the solvent was removed under
reduced pressure and the crude mixture was purified by column
chromatography (EtOAc–CH3OH, 14:1) to give 18 (18 mg, 42%) as
a yellow oil. 1H NMR (CDCl3) d: 4.58 (d, J = 6.0 Hz, 1H, H-8), 4.56
(d, J = 3.6 Hz, 1H, H-7), 4.33 (d, J = 8.7 Hz, 1H, H-6), 4.26 (bt,
J = 1.8 Hz, 1H, H-1), 2.71–2.29 (m, 8H, H-2a, H-2b, H-4a, H-4b,
NCH2CH2), 2.20 (s, 6H, 2NCH3), 1.94–1.85 (m, 1H, H-5a),
1.74–1.63 (m, 1H, H-5b), 1.46 (s, 3H, C(CH3)2), 1.28 (s, 3H,
C(CH3)2); 13C NMR (CDCl3) d: 111.3 (C(CH3)2), 89.1 (C-7), 85.2
(C-1), 84.8 (C-8), 84.2 (C-6), 62.1 (C-2), 58.2 (NCH2CH2), 57.9
(NCH2CH2), 54.2 (C-4), 45.9 (2NCH3), 33.5 (C-5), 26.5 (C(CH3)2),
24.9 (C(CH3)2); ESIMS: calcd for C14H26N2O3 [M]+, m/z 270.1943;
found m/z 270.1952.
3.22. Methyl 2-(5-((5-((7,8-Dihydroxy-9-oxa-3-
azabicyclo[4.2.1]nonan-3-yl)methyl)-1H-1,2,3-triazol-1-
yl)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)acetate 22
3.19. (1R,6S,7S,8S)-3-(2-(Dimethylamino)ethyl)-7,8-isopropyl-
idene-7-methyl-9-oxa-3-azabicyclo[4.2.1]nonane (19)
Compound 21 (0.10 g, 0.20 mmol) was dissolved in AcOH–H2O
(12.0 mL:4.0 mL) and heated at 100 °C for 6 h. After removal of
the solvents under reduced pressure, the solid residue was
coevaporated with CH3OH–toluene (1:1 v/v, 10 mL) to yield the
crude diol. The crude mixture was purified by column chromatog-
raphy (EtOAc–CH3OH, 4:1) to give 22 (50 mg, 58%) as a white so-
A solution of 16 (0.20 g, 0.77 mmol) in 1,3-diaminopropane
(15 mL) was heated at reflux overnight. After cooling, the solvent
was removed under reduced pressure and the crude mixture was
purified by column chromatography (EtOAc–CH3OH, 1:1) to give
19 (0.16 g, 68%) as a yellow oil. 1H NMR (CDCl3) d: 4.51 (s, 2H,
H-7, H-8), 4.31 (d, J = 8.4 Hz, 1H, H-6), 4.25 (t, J = 1.8 Hz, H-1),
2.77–2.53 (m, 12H), 2.06 (s, 3H, 3NH), 1.93–1.85 (m, 1H, H-5),
1.64–1.59 (m, 3H, H-5, H-4), 1.43 (s, 3H, C(CH3)2), 1.25 (s, 3H,
C(CH3)2); 13C NMR (CDCl3) d: 111.4 (C(CH3)2), 89.2 (C-8), 85.1
(C-1), 84.7 (C-7), 84.0 (C-6), 62.0 (C-2), 59.1, 53.7, 48.0, 47.7,
40.5, 33.5 (C-5), 33.1 (C-4), 26.4 (C(CH3)2), 24.8 (C(CH3)2).
lid. [a]
+17.0 (c 1.0, CH3OH); 1H NMR (CD3OD) d: 7.78 (s, 1H),
D
4.65–4.43 (m, 2H), 4.20 (dd, J = 6.0, 1.8 Hz, 1H), 4.08–3.83 (m,
5H), 3.78 (t, J = 5.7 Hz, 1H), 3.65 (s, 2H), 3.59 (s, 3H), 3.42 (t,
J = 5.4 Hz, 1H), 3.23–3.21 (m, 1H), 2.78–2.67 (m, 2H), 2.50 (dd,
J = 15.6, 4.8 Hz, 1H), 2.42–2.23 (m, 2H), 1.88–1.78 (m, 1H),
1.68–1.57 (m, 1H); 13C NMR (CD3OD) d: 172.9, 146.1, 126.3,
87.6, 85.7, 82.9, 81.3, 80.1, 75.4, 73.0, 61.3, 55.1, 54.0, 53.0,
52.3, 39.4, 34.1; FABMS: calcd for C18H29N4O8 [M+H]+, m/z
429.1985; found m/z 429.1982.
3.20. (1R,6S,7S,8S)-7,8-Isopropylidene-3-(prop-2-ynyl)-9-oxa-3-
azabicyclo[4.2.1]nonane (20)
Acknowledgment
To a solution of 13a (93 mg, 0.46 mmol) in CH3CN (10 mL) were
added triethylamine (0.19 mL, 1.40 mmol) and propargyl bromide
(0.06 mL, 0.70 mmol) and the reaction mixture was heated at re-
flux for 10 h. After removal of the solvent, the residue was dis-
solved in ether, washed with aq NaHCO3, and dried over MgSO4.
Chromatographic separation (hexanes–EtOAc 12:1) led to 20
This work was supported by the National Science Council of
Taiwan.
Supplementary data
(77 mg, 71%) as
a
yellow oil. 1H NMR (CDCl3) d: 4.56 (d,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2009.05.029.
J = 6.0 Hz, 1H, H-8), 4.53 (d, J = 6.3 Hz, 1H, H-7), 4.32 (d,
J = 8.4 Hz, 1H, H-6), 4.26 (t, J = 2.1 Hz, 1H, H-1), 3.25 (t, J = 2.7 Hz,
2H, N–CH2), 2.70–2.61 (m, 2H, H-2a, H-2b), 2.55–2.45 (m, 2H, H-
4a, H-4b), 2.17 (t, J = 2.4 Hz, 1H, „CH), 1.94–1.84 (m, 1H, H-5a),
1.74–1.63 (m, 1H, H-5b), 1.43 (s, 3H, C(CH3)2), 1.25 (s, 3H,
C(CH3)2); 13C NMR (CDCl3): d 111.4 (C(CH3)2), 89.0 (C-7), 84.7 (C-
1, C-8), 84.0 (C-6), 79.1 (C„), 72.5 („CH), 60.7 (C-2), 53.1 (C-4),
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