Novel synthesis of methyl 4,6-O-benzylidenespiro[2-deoxy-α-d-arabino-hexopyranoside-2,2′-imidazolidine] and its homologue and sugar-γ-butyrolactam derivatives from methyl 4,6-O-benzylidene-α-d-arabino-hexopyranosid-2-ulose

Article abstract of DOI:10.1016/j.carres.2010.01.004

Novel methyl 4,6-O-benzylidenespiro[2-deoxy-α-d-arabino-hexopyranoside-2,2′-imidazolidine] and its homologue methyl 4,6-O-benzylidene-3′,4′,5′,6′-tetrahydro-1′H-spiro[2-deoxy-α-d-arabino-hexopyranoside-2,2′-pyrimidine] have been synthesized in good yields

Full text of DOI:10.1016/j.carres.2010.01.004

Carbohydrate Research 345 (2010) 839–843
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Novel synthesis of methyl 4,6-O-benzylidenespiro[2-deoxy-
pyranoside-2,20-imidazolidine] and its homologue and sugar-
derivatives from methyl 4,6-O-benzylidene- -D-arabino-hexopyranosid-2-ulose
a
-D-arabino-hexo-
c-butyrolactam
a
a
a
b,
Fuyi Zhang a, , Hong Liu , Yong-Feng Li , Hong-Min Liu
*
*
a Chemistry Department, The Key Lab of Chemical Biology and Organic Chemistry of Henan Province, Zhengzhou University, Zhengzhou 450052, PR China
b School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel methyl 4,6-O-benzylidenespiro[2-deoxy-a-D
-arabino-hexopyranoside-2,20-imidazolidine] and its
-arabino-hexopyrano-
side-2,20-pyrimidine] have been synthesized in good yields by reaction of methyl 4,6-O-benzylidene-
-arabino-hexopyranosid-2-ulose with 1,2-diaminoethane and 1,3-diaminopropane. The results are com-
pletely different from the reaction with arylamines or alkylamines. One-pot synthesis of novel (E)-methyl
4-[hydroxy (methoxy)methylene]-5-oxo-1-alkyl-(4,6-O-benzylidene-2-deoxy- -glucopyranosido)[3,2-
b]pyrrolidines has been achieved by the reaction of alkylamines with the butenolide-containing sugar,
derived from the aldol condensation of methyl 4,6-O-benzylidene- -arabino-hexopyranosid-2-ulose
homologue methyl 4,6-O-benzylidene-30,40,50,60-tetrahydro-10H-spiro[2-deoxy-
a-D
Received 2 November 2009
Received in revised form 29 December 2009
Accepted 6 January 2010
a
-
D
Available online 13 January 2010
a-D
Keywords:
Methyl 4,6-O-benzylidene-a-D-arabino-
hexopyranosid-2-ulose
Sugar-containing spiro-imidazolidine
Sugar-containing spiro-
a-D
with diethyl malonate. These sugar-
c
-butyrolactam derivatives are potential GABA receptor ligands.
Ó 2010 Elsevier Ltd. All rights reserved.
tetrahydropyrimidine
Sugar-c-butyrolactam derivative
Amino sugars and sugar–heterocyclic hybrids are of significant
importance for use as tools in glycobiology and the treatment of
many human diseases.1 Among them, sugar lactams are not only
important biological substances,2 but also are synthetic precursors
of imino sugars3 and structural components of natural products.4
Owing to their various biological properties and potential use,
there has been significant interest in the synthesis of these types
of compounds.5 We developed a convenient one-pot method for
the synthesis of new types of indole derivatives 2 and 3 by reaction
In continuation of our studies on the application of methyl 4,6-
O-benzylidene- -arabino-hexopyranosid-2-ulose, herein we re-
port the novel synthesis of sugar-containing spiro-imidazolidine
and its homologue as well as sugar- -butyrolactam derivatives.
In previous work, a compound containing a 2-substituted imidaz-
olidine moiety showed prostate antagonist activity.8 2-Disubsti-
tuted imidazolidine was used as a catalyst for the conversion of
an epoxide into the corresponding vicinal halohydrin with elemen-
tal halogen9 and for efficient conversion of an epoxide into a b-hy-
droxy thiocyanate with ammonium thiocyanate in high yields
under mild reaction conditions.10 Chiral imidazolidines were
shown to be efficient organocatalysts in the enantioselective addi-
a-D
c
of methyl 4,6-O-benzylidene-a-D-arabino-hexopyranosid-2-ulose
1 (Scheme 1) with arylamines.6 In order to synthesize N-alkyl
derivatives of allosamidin (a chitinase inhibitor), we developed an-
other method for the selective synthesis of N-alkyl-
D
-allosamines 7
tion reaction of nitroalkanes with a,b-unsaturated enones to pre-
by reaction of 1 with alkylamines followed by reduction.7 This
method offers attractive and important features: (1) the easily
available 1 undergoes a ‘carbonyl group transfer’ reaction to form
6 via the possible pathway shown in Scheme 1. The nucleophilic
addition of alkylamine to 1 generates intermediate 4. Dehydration
of 4 in weakly acidic medium produces enol intermediate 5, which
undergoes isomerization to give keto 6; (2) both steps for the syn-
pare functionalized precursors of different complex organic
molecules.11 Sugar-containing imidazolidine and its homologue
should be used as new water-soluble chiral catalysts for these
reactions, and these compounds are expected to possess biological
activities. 1,2-Diaminoethane was therefore employed to react
with 1 (Scheme 2) in the presence of NH4Cl at 60 °C. Sugar-contain-
ing spiro-imidazolidine 9 was obtained in 66% yield. The reactants
obviously undergo a condensation reaction to form intermediate 8,
followed by an intramolecular nucleophilic addition reaction. This
reaction was performed at different temperatures in various sol-
vents such as THF, DMF, CH2Cl2 and cyclohexane. No ‘carbonyl
group transfer’ product was formed. When 1,3-diaminopropane
was used to react with 1, the desired homologue 10 was produced
thesis of N-alkyl-D-allosamines show very high stereoselectivity.
* Corresponding authors. Tel./fax: +86 371 67763845.
E-mail addresses: zhangfy@zzu.edu.cn (F. Zhang), liuhm@zzu.edu.cn (H.-M. Liu).
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.01.004

840
F. Zhang et al. / Carbohydrate Research 345 (2010) 839–843
O
O
Ph
O
R1
R1
R2
OH
HN
N
NH
2 Ph
O
O
Ph
O
Ph
O
O
R3 NH2
OMe
O
H
O
O
R2
O
R2
HO
HO
H O
OMe
OMe
O
NH
NH
R3
H
1
R3
5
R1
4: R3 = Alkyl
2: R1 = OMe, R2 = H
3: R1 = R2 = Me
O
O
O
Ph
Ph
O
O
NaBH4
OMe
O
NH
NH
OMe
O
OH
R3
7
R3
6
Scheme 1. Synthesis of indole derivatives and N-alkyl-D-allosamines.
in 63% yield. However, under the same conditions, thiosemicarba-
zide gave the condensation product 11 in 72% yield. No analogue of
spiro-imidazolidine or ‘carbonyl group transfer’ product was
formed. The new compounds were characterized by spectroscopic
data. The high-resolution mass spectrum of compound 9 displayed
an [M+1] peak at m/z 323.1624, together with elemental analysis
indicating the formula to be C16H23N2O5. In the 1H NMR spectrum,
the proton that appeared as a singlet at d 4.44 was assigned to H-1.
The proton at d 4.21 (d, J 10.0 Hz) was coupled with that at d 3.73
(t, J 10.0 Hz). They were ascribed to H-3 and H-4. The four protons
at d 2.99–3.33, which appear as three multiplets, were assigned to
the protons of the imidazolidinyl group. This was also confirmed
by a DEPT spectrum showing two secondary carbons besides C-6.
The 13C NMR peak at d 101.2 was assigned to C-1. The signal at d
82.1 was ascribed to C-2. The two signals at d 71.1 and 80.7 were
assigned to C-3 and C-4. All the assignments were made on the ba-
sis of 2D NMR spectra.
O
O
Ph
NH2, NH4Cl, LiCl
O
COOMe
O
HO
R
O
O
Ph
OMe
OMe
O
R
N
O
CHCl3, 45−60 °C
OMe
O
12
O
H
13: R = n-Propyl
14: R = n-Butyl
: R = Isopentyl
15
16: R = Cyclohexyl
c-butyrolactam derivatives.
Scheme 3. Synthesis of sugar-
was then employed to react with 12 under various conditions to
generate sugar- -butyrolactam derivative 13. The temperature,
c
catalyst and solvent have an influence on the reaction (Table 1, en-
tries 1–6). The optimum temperature is 45 °C. Above 60 °C, TLC
indicates that the reaction is complicated and the yield decreases,
perhaps due to the cleavage of the benzylidene acetal in the
weakly acidic medium. The solvent CHCl3 is better than THF and
MeCN, and a 65% yield of 13 is attained by the use of CHCl3 in
the presence of NH4Cl and LiCl. The experiments were then per-
formed with other alkylamines such as n-butylamine, isopentyl-
amine and cyclohexylamine. The results are identical with that
of propylamine, and the optimized results are depicted in Table 1,
entries 7–9.
The different reaction patterns of methyl 4,6-O-benzylidene-
a-
D-arabino-hexopyranosid-2-ulose attracted our attempts to use it
for the synthesis of sugar-c-butyrolactam derivatives. c-Butyro-
lactams are of biological relevance as GABA receptor ligands.12
They have also been shown to possess anticonvulsant and antiox-
idant activity.13 Besides,
c-butyrolactams can be used as biosyn-
thetic precursors of GABA analogues and as key intermediates
for the synthesis of pyrrolidines.14 Consequently, fructose-fused
c
-butyrolactams have been synthesized, and their preliminary bio-
logical evaluation as GABA receptor ligands has been performed.2a
However, glucopyranoside- -butyrolactam and its derivatives
c
The new compounds were all characterized by spectroscopic
data. The high-resolution mass spectrum of compound 13 showed
an [MꢀMe] peak at m/z 406.1500, together with elemental
analysis, indicating its formula to be C21H27NO8. In the 1H NMR
remain unknown. Our synthesis began with the preparation of
compound 12 (Scheme 3) by reaction of 1 with diethyl malonate
in the presence of NaOMe as we formerly reported.15 Propylamine
H2N
O
H2N(CH2)n+1NH2,
CHCl3, NH4Cl
Ph
O
O
Ph
O
H2NNHCSNH2
Anhyd. THF,
O
n
O
O
Ph
HO
C
O
HO
O
Molecular sieve
60 °C, 63−66%
NH2
O
HO
HNN
OMe
OMe
MeOH, 50 °C, 72%
N
1
S
OMe
11
8
HN
n
O
Ph
: n = 1
9
: n = 2
10
O
O
HO
N
OMe
H
Scheme 2. Synthesis of sugar-containing spiro-imidazolidine and its homologue.

F. Zhang et al. / Carbohydrate Research 345 (2010) 839–843
841
Table 1
no-substituted derivatives have been conveniently achieved in
good yields under mild conditions. Novel sugar-containing spiro-
imidazolidine and its homologue spiro-tetrahydropyrimidine have
Synthesis of sugar-c-butyrolactam derivatives under various conditions
Entry Temperature
Time
(min)
Catalyst
Solvent Product Yield
(%)
(°C)
been easily synthesized. The one-pot synthesis of novel sugar-c-
butyrolactam derivatives, which are potential GABA receptor li-
gands, has also been accomplished, and the possible pathway for
their formation has been elucidated.
1
2
3
4
55
55
60
45
60
30
50
35
—
NH4Cl
LiCl
NH4Cl,
LiCl
CHCl3
CHCl3
CHCl3
CHCl3
13
13
13
13
38
46
45
65
1. Experimental
5
6
7
8
9
45
45
50
50
60
40
45
50
50
55
NH4Cl,
LiCl
NH4Cl,
LiCl
NH4Cl,
LiCl
NH4Cl,
LiCl
THF
13
13
14
15
16
53
50
62
63
60
MeCN
CHCl3
CHCl3
CHCl3
1.1. General methods
Melting points were measured in open capillary tubes or on a
WC-1 melting point apparatus and are uncorrected. Elemental
analyses were carried out on a MOD 1106 analyzer. Infrared spec-
tra were recorded on a Shimadzu IR-435 instrument using KBr
disks in the 400–4000 cmꢀ1 region. NMR spectra were recorded
with a Bruker DPX-400 spectrometer, and chemical shifts are given
as d values and are referenced to Me4Si as the internal reference or
to the residual solvent signal. Liquid secondary-ion mass spec-
trometry spectra were taken with a ZAB-2SE double-focusing mass
spectrometer. Thin-layer chromatography (TLC) was carried out on
glass plates coated with Silica Gel 60F254. The zones were detected
with UV light when possible, or by charring with 1:9 concd H2SO4–
EtOH followed by heating.
NH4Cl,
LiCl
spectrum, the proton at d 5.32 (d, J 4.4 Hz) was coupled with that at
d 4.09 (d, J 4.4 Hz). They are ascribed to H-1 and H-2, respectively.
The proton at d 4.64 (d, J 8.4 Hz) is assigned to H-4. These coupling
patterns indicate that no H-3 exists. The DEPT spectrum showed
three secondary carbon signals at d 69.5, 42.0 and 23.0, corre-
sponding to C-6 and those of propyl group. In the 13C NMR spec-
trum, the two signals at d 102.0 and 57.8 are ascribed to C-1 and
C-2. The peak at d 78.2 is ascribed to C-3. The three peaks displayed
at d 197.1, 170.7 and 168.1 as quaternary carbons were assigned to
1.2. General procedure for the synthesis of compounds 9 and 10
A mixture of methyl 4,6-O-benzylidene-a-D-arabino-hexopyr-
C@O, b- and
a-unsaturated carbons, respectively. All the assign-
anosid-2-ulose (1, 0.50 g, 1.78 mmol), 4 Å molecular sieves
(1.0 g), NH4Cl (0.0090 g, 0.18 mmol) and dry CHCl3 (15 mL) was
stirred at 60 °C. 1,2-Diaminoethane or 1,3-diaminopropane
(1.10 equiv) in 5 mL of dry CHCl3 was added dropwise for
10 min. The reaction was monitored by TLC. Then the molecular
sieves were filtered off. The filtrate was diluted with 15 mL of
CHCl3, washed with H2O (1 ꢁ 5 mL) and brine (1 ꢁ 5 mL), dried
over Na2SO4 and evaporated to dryness. The crude product was
recrystallized from EtOH to give 9 or 10 as a crystalline solid.
ments are based on 2D spectra.
The reactants for the formation of the product 13–16 undergo a
aminolysis, with subsequent rearrangement, followed by intramo-
lecular nucleophilic addition as the main steps in one pot, as
described in Scheme 4. The reaction sequence starts with a
NH4Cl–LiCl-catalyzed regioselective aminolysis of lactone 12 to
form intermediate 17, in which case, the five-membered ring is
opened and the amide is formed. Subsequent double-bond migra-
tion produces dienol intermediate 18. This is caused by the
electron-withdrawing ester and amide groups. In 18, an intramo-
lecular hydrogen bond is easily formed as a stable six-membered
ring between the enolic hydroxy and carbonyl group. The isomer-
ization of the enolic group in the sugar ring generates keto inter-
mediate 19. This is followed by an intramolecular nucleophilic
addition reaction to give the final products 13–16.
1.2.1. Methyl 4,6-O-benzylidenespiro[2-deoxy-a-D-arabino-
hexopyranoside-2,20-imidazolidine] (9)
Yield: 66%; mp 155–156 °C; Rf 0.55 (2:1 cyclohexane–EtOAc); IR
(KBr; cmꢀ1): 3324, 3300, 3096, 2960, 2921, 2868, 1458, 1405,
1153, 1095, 1068, 1042, 992, 981, 763, 704; 1H NMR (CDCl3,
400 MHz): d 7.51–7.49 (m, 2H, Ph), 7.38–7.35 (m, 3H, Ph), 5.55
(s, 1H, PhCH), 4.44 (s, 1H, H-1), 4.28 (dd, 1H, J6a,5 3.2 Hz, J6a,6b
In summary, several novel transformations of methyl 4,6-O-
benzylidene-
a-
D-arabino-hexopyranosid-2-ulose to different ami-
O
O
O
Ph
Ph
O
O
COOMe
O
O
HO
O
H
R NH2
O
Ph
Ph
O
OMe
O
O
OMe
OMe
H
H
O
H
OMe
R
N
R
N
OMe
12
O
O
O
H
17
18
O
O
O
O
Ph
O
O
HO
OMe
OMe
O
OMe
OMe
R
N
R
N
H
O
O
O
O
H
H
19
13-16
Scheme 4. A possible pathway for the formation of 13–16.

842
F. Zhang et al. / Carbohydrate Research 345 (2010) 839–843
8.8 Hz, H-6a), 4.21 (d, 1H, J3,4 10.0 Hz, H-3), 3.87–3.84 (m, 2H, H-5,
H-6b), 3.73 (t, 1H, J4,3 = J4,5 10.0 Hz, H-4), 3.44 (s, 3H, OMe), 3.33–
3.14 (m, 2H, NCHCHN), 3.04–2.99 (m, 2H, NCHCHN); 13C NMR
(CDCl3, 100 MHz): d 137.2, 129.2, 128.3, 126.4 (Ph), 102.0 (PhCH),
101.2 (C-1), 82.1 (C-2), 80.7 (C-4), 71.1 (C-3), 68.9 (C-6), 62.8 (C-
5), 55.5 (OMe), 46.3, 45.3 (NCH2CH2N); HRFABMS (m/z): [M+1]+
calcd for C16H23N2O5þ, 323.1607; found, 323.1624. Anal. Calcd for
C16H22N2O5: C, 59.61; H, 6.88; N, 8.69. Found: C, 59.60; H, 6.86;
N, 8.70.
1.4.1. (E)-Methyl 4-[hydroxy(methoxy)methylene]-5-oxo-1-
propyl-(4,6-O-benzylidene-2-deoxy-a-D-glucopyranosido)[3,2-
b]pyrrolidine (13)
Yield: 65%; mp 146–147 °C; Rf 0.45 (1:1 cyclohexane–EtOAc); IR
(KBr; cmꢀ1): 3409, 2963, 2918, 1741, 1674, 1522, 1130, 1020, 752,
699; 1H NMR (acetone-d6, 400 MHz): d 7.51–7.48 (m, 2H, Ph),
7.38–7.36 (m, 3H, Ph), 5.73 (s, 1H, PhCH), 5.32 (d, 1H, J1,2 4.4 Hz, H-
1), 4.64 (d, 1H, J4,5 8.4 Hz, H-4), 4.36 (dd, 1H, J6a,5 2.8 Hz, J6a,6b
8.4 Hz, H-6a), 4.09 (d, 1H, J2,1 4.4 Hz, H-2), 4.04–4.00 (m, 2H, H-5,
H-6b), 3.74 (s, 3H, OMe), 3.40 (s, 3H, C(1)-OMe), 3.23–3.16 (m, 2H,
NCH2), 1.55–1.49 (m, 2H, CH3CH2CH2N), 0.89 (t, 3H, J 7.2 Hz,
CH3CH2CH2N); 13C NMR (acetone-d6, 100 MHz): d 197.1 (C@O),
170.7 (C@C(OH)OMe), 168.1 (C@C(OH)OMe), 138.4, 129.6, 128.7,
127.1 (Ph), 103.0 (PhCH), 102.0 (C-1), 82.9 (C-4), 78.2 (C-3), 69.5
(C-6), 66.6 (C-5), 57.8 (C-2), 55.6 (C(1)OCH3), 53.2 (OCH3), 42.0
(NCH2CH2CH3), 23.0 (NCH2CH2CH3), 11.4 (NCH2CH2CH3); HRFABMS
(m/z): [MꢀMe]+ calcd for C20H24NO8þ, 406.1502; found, 406.1500;
[M+H2Oꢀ1]+ calcd for C21H28NO9þ, 438.1764; found, 438.1748.
Anal. Calcd for C21H27NO8: C, 59.85; H, 6.46; N, 3.32. Found: C,
59.86; H, 6.44; N, 3.33.
1.2.2. Methyl 4,6-O-benzylidene-30,40,50,60-tetrahydro-10
H-spiro[2-deoxy-a-D
-arabino-hexopyranoside-2,20-pyrimidine]
(10)
Yield: 63%; mp 142 °C (dec); Rf 0.65 (2:1 cyclohexane–EtOAc);
IR (KBr; cmꢀ1): 3338, 3292, 2923, 2889, 1459, 1118, 1096, 1064,
999, 748, 700; 1H NMR (CDCl3, 400 MHz): d 7.50–7.48 (m, 2H,
Ph), 7.35–7.33 (m, 3H, Ph), 5.54 (s, 1H, PhCH), 5.12 (s, 1H, H-1),
4.25 (dd, 1H, J6a,5 4.4 Hz, J6a,6b 10.0 Hz, H-6a), 3.94–3.87 (m, 2H,
H-4, H-6b), 3.82 (dt, 1H, J5,6a 4.4 Hz, J5,6b = J5,4 10.0 Hz, H-5), 3.67
(d, 1H, J3,4 10.0 Hz, H-3), 3.48 (s, 3H, OMe), 3.07–2.87 (m, 4H,
NCH2CH2CH2N), 1.63–1.47 (m, 2H, NCH2CH2CH2N); 13C NMR
(CDCl3, 100 MHz): d 137.3, 129.0, 128.2, 126.3 (Ph), 101.8 (PhCH),
96.7 (C-1), 78.2 (C-4), 72.0 (C-3), 71.1 (C-2), 68.8 (C-6), 62.7 (C-
5), 55.6 (OMe), 40.1, 40.0 (NCH2CH2CH2N), 25.8 (NCH2CH2CH2N);
HRFABMS (m/z): [M+1]+ calcd for C17H25N2O5þ, 337.1763; found,
337.1748. Anal. Calcd for C17H24N2O5: C, 60.70; H, 7.19; N, 8.33.
Found: C, 60.68; H, 7.18; N, 8.35.
1.4.2. (E)-Methyl 4-[hydroxy(methoxy)methylene]-5-oxo-1-
butyl-(4,6-O-benzylidene-2-deoxy-a-D-glucopyranosido)[3,2-
b]pyrrolidine (14)
Yield: 62%; mp 148–150 °C; Rf 0.50 (1:1 cyclohexane–EtOAc); IR
(KBr; cmꢀ1): 3464, 2958, 2923, 1743, 1679, 1520, 770, 704; 1H NMR
(acetone-d6, 400 MHz): d 7.37–7.35 (m, 2H, Ph), 7.34–7.23 (m, 3H,
Ph), 5.60 (s, 1H, PhCH), 5.18 (d, 1H, J1,2 4.4 Hz, H-1), 4.51 (d, 1H, J4,5
8.8 Hz, H-4), 4.23 (dd, 1H, J6a,5 2.8 Hz, J6a,6b 8.0 Hz, H-6a), 3.95 (d,
1H, J2,1 4.4 Hz, H-2), 3.91–3.87 (m, 2H, H-5, H-6b), 3.60 (s, 3H,
OMe), 3.27 (s, 3H, C(1)-OMe), 3.14–3.03 (m, 2H, CH2N), 1.40–1.33
(m, 2H, CH3CH2CH2CH2N), 1.26–1.19 (m, 2H, CH3CH2CH2CH2N),
0.77 (t, 3H, J 7.2 Hz, CH3CH2CH2CH2N); 13C NMR (acetone-d6,
100 MHz): d 197.2 (C@O), 170.7 (C@C(OH)OMe), 168.0 (C@C(OH)
OMe), 138.4, 129.7, 128.7, 127.1 (Ph), 102.9 (PhCH), 102.1 (C-1),
82.9 (C-4), 78.2 (C-3), 69.6 (C-6), 66.6 (C-5), 57.8 (C-2), 55.7
(C(1)OCH3), 53.2 (OCH3), 39.9 (NCH2CH2CH2CH3), 31.9 (NCH2
CH2CH2CH3), 20.4 (NCH2CH2CH2CH3), 13.9 (NCH2CH2CH2CH3);
HRFABMS (m/z): [MꢀMe]+ calcd for C21H26NO8+, 420.1658; found,
420.1700; [M+H2Oꢀ1]+ calcd for C22H30NO9þ, 452.1921; found,
452.1937. Anal. Calcd for C22H29NO8: C, 60.68; H, 6.71; N, 3.22.
Found: C, 60.66; H, 6.70; N, 3.21.
1.3. (E/Z)-Methyl 4,6-O-benzylidene-2-deoxy-2-(2-
carbamothioylhydrazono)-a-
D-arabino-hexopyranoside (11)
A mixture of methyl 4,6-O-benzylidene-
a
-D
-arabino-hexopyr-
anosid-2-ulose (1, 0.40 g, 1.42 mmol), NH4Cl (0.0070 g, 0.13 mmol)
and dry THF (15 mL) was heated to 50 °C with stirring. Thiosemi-
carbazide (0.13 g, 1.42 mmol) in anhyd MeOH (5 mL) was added
dropwise for 10 min. The reaction was monitored by TLC. Then
the mixture was evaporated to dryness. The residue was dissolved
in EtOAc (25 mL), washed with H2O (1 ꢁ 5 mL) and brine
(1 ꢁ 5 mL), dried over Na2SO4 and evaporated to dryness. The
crude product was recrystallized from MeOH to give 0.36 g of 11
(72%) as white solid. Mp 169–171 °C; Rf 0.60 (1:1 cyclohexane–
EtOAc); IR (KBr; cmꢀ1): 3434, 3313, 2937, 2882, 1600, 1499,
1452, 1404, 1089, 1055, 1030, 995, 947, 749, 696; 1H NMR (CDCl3,
400 MHz): d 7.51–7.49 (m, 2H, Ph), 7.41–7.39 (m, 3H, Ph), 5.56 (s,
1H, PhCH), 5.08 (d, 1H, J3,4 10.0 Hz, H-3), 4.90 (s, 1H, H-1), 4.34 (dd,
1H, J6a,5 4.8 Hz, J6a,6b 10.0 Hz, H-6a), 4.01 (dt, 1H, J5,6a 4.8 Hz,
J5,6b = J5,4 10.0 Hz, H-5), 3.81–3.73 (m, 2H, H-4, H-6b), 3.43 (s, 3H,
OMe); 13C NMR (CDCl3, 100 MHz): d 179.1 (C@S), 141.6 (C-2),
136.4, 129.5, 128.4, 126.2 (Ph), 102.2 (PhCH), 102.0 (C-1), 82.3
(C-4), 74.1 (C-3), 68.7 (C-6), 62.7 (C-5), 55.1 (OMe); HRFABMS
(m/z): [M+1]+ calcd for C15H20N3O5S+, 354.1124; found, 354.1120.
Anal. Calcd for C15H19N3O5S: C, 50.98; H, 5.42; N, 11.89. Found:
C, 50.97; H, 5.40; N, 11.88.
1.4.3. (E)-Methyl 4-[hydroxy(methoxy)methylene]-5-oxo-1-(3-
methylbutyl)-(4,6-O-benzylidene-2-deoxy-a-
glucopyranosido)[3,2-b]pyrrolidine (15)
D-
Yield: 63%; mp 134–135 °C; Rf 0.65 (1:1 cyclohexane–EtOAc); IR
(KBr; cmꢀ1): 3467, 3417, 2965, 2930, 1744, 1675, 1522, 1128,
1092, 700; 1H NMR (acetone-d6, 400 MHz): d 7.51–7.48 (m, 2H,
Ph), 7.39–7.36 (m, 3H, Ph), 5.73 (s, 1H, PhCH), 5.32 (d, 1H, J1,2
4.0 Hz, H-1), 4.65 (d, 1H, J4,5 9.2 Hz, H-4), 4.36 (dd, 1H, J6a,5
2.4 Hz, J6a,6b 8.0 Hz, H-6a), 4.08 (d, 1H, J2,1 4.0 Hz, H-2), 4.04–4.01
(m, 2H, H-5, H-6b), 3.74 (s, 3H, OMe), 3.39 (s, 3H, C(1)-OMe),
3.23–3.15, 3.04–2.97 (m, each 1H, NCH2), 1.64–1.59, 1.45–1.37
(m, each 1H, CH2CH(CH3)2), 1.19–1.11 (m, 1H, CH2CH(CH3)2),
0.90–0.87 (6H, m, CH2CH(CH3)2); 13C NMR (acetone-d6,
100 MHz): d 197.3 (C@O), 170.7 (C@C(OH)OMe), 168.1 (C@C(OH)
OMe), 138.4, 129.7, 128.7, 127.1 (Ph), 102.9 (PhCH), 102.1 (C-1),
82.9 (C-4), 78.2 (C-3), 69.5 (C-6), 66.6 (C-5), 57.8 (C-2), 55.7
(C(1)OCH3), 53.2 (OCH3), 45.8 (NCH2), 35.4 (CH2CH(CH3)2), 27.5
(CH2CH(CH3)2), 17.3, 11.4 (CH2CH(CH3)2); HRFABMS (m/z):
[M+H2Oꢀ1]+ calcd for C23H32NO9þ, 466.2077; found, 466.2076.
Anal. Calcd for C23H31NO8: C, 61.46; H, 6.95; N, 3.12. Found: C,
61.45; H, 6.93; N, 3.13.
1.4. General procedure for the synthesis of compounds 13–16
A
mixture of 12 (0.30 g, 0.83 mmol), LiCl (0.0017 g,
0.041 mmol), NH4Cl (0.0022 g, 0.041 mmol) and dry CHCl3
(20 mL) was heated to 45–60 °C (Table 1, entries 4, and 7–9) with
stirring, to which 1.0 equiv of alkylamine in dry CHCl3 (5 mL) was
added dropwise for 15 min with stirring. The reaction was moni-
tored by TLC. Then the solution was washed with H2O (1 ꢁ 5 mL)
and brine (1 ꢁ 5 mL), dried over Na2SO4 and evaporated to dryness.
The residues crystallized from EtOH to give 13–16 as white solids.

F. Zhang et al. / Carbohydrate Research 345 (2010) 839–843
843
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cyclohexyl-(4,6-O-benzylidene-2-deoxy-a-
glucopyranosido)[3,2-b]pyrrolidine (16)
D-
2. (a) Araujo, A. C.; Nicotra, F.; Costa, B.; Giagnoni, G.; Cipolla, L. Carbohydr. Res.
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1
637; H NMR (acetone-d6, 400 MHz): d 7.50–7.49 (m, 2H, Ph), 7.38–
7.36 (m, 3H, Ph), 5.73 (s, 1H, PhCH), 5.32 (d, 1H, J1,2 3.6 Hz, H-1), 4.66
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3H, C(1)-OMe), 1.92–1.85, 1.78–1.66, 1.58–1.55, 1.35–1.18 (m, 11H,
cyclohexyl-H); 13C NMR (acetone-d6, 100 MHz): d 197.7 (C@O),
170.6 (C@C(OH)OMe), 167.2 (C@C(OH)OMe), 138.3, 129.6, 128.7,
127.1 (Ph), 102.9 (PhCH), 102.0 (C-1), 82.9 (C-4), 77.8 (C-3), 69.6 (C-
6), 66.7 (C-5), 58.1 (C-2), 55.6 (C(1)OCH3), 53.2 (OCH3), 49.2, 32.8,
26.1, 25.2 (cyclohexyl-C); HRFABMS (m/z): [M+H2Oꢀ1]+ calcd for
C24H32NO9þ, 478.2077; found, 478.2032.
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We thank NNSF of China (No. 20972142), the State Key Labora-
tory of Bio-organic and Natural Products Chemistry, CAS (08417)
and NSF of Henan province (2009A150030) for financial support
and Dr. Bruno Bernet from ETH Zürich, Switzerland for naming
the compounds.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2010.01.004.
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