A novel free C-12 higher carbon sugar: asymmetric synthesis and reactivity with nucleophiles

Article abstract of DOI:10.1016/j.tetasy.2006.11.042

A novel C-12 higher carbon sugar, (1R)-(1,4:3,6-dianhydro-d-mannitol-2-yl)-1,4:3,6-dianhydro-d-fructose, was firstly synthesized via a convenient aldol reaction of 1,4:3,6-dianhydro-d-fructose without any protection and activation of functional groups. Th

Full text of DOI:10.1016/j.tetasy.2006.11.042

Tetrahedron: Asymmetry 17 (2006) 3230–3236
A novel free C-12 higher carbon sugar: asymmetric
synthesis and reactivity with nucleophiles
Hong-Min Liu,* Feng-Wu Liu, Xiao-Ping Song, Jing-Yu Zhang and Lin Yan
New Drug Research and Development Center, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, PR China
Received 5 October 2006; accepted 24 November 2006
Abstract—A novel C-12 higher carbon sugar, (1R)-(1,4:3,6-dianhydro-D-mannitol-2-yl)-1,4:3,6-dianhydro-D-fructose, was firstly synthe-
sized via a convenient aldol reaction of 1,4:3,6-dianhydro-D-fructose without any protection and activation of functional groups. The
reactivity of the novel higher sugar with nucleophiles was also studied, through which a series of oxazolidines and other derivatives
of the higher sugar were available. The study showed that the higher sugar possesses a highly reactive carbonyl group and a good stereo
controlling ability in the reaction.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
tetrahydroquinoline derivatives 1 via reaction of 1,4:3,6-
dianhydro-D-fructose 2, a useful building block, with ani-
lines in the presence of p-TsOH. From the structure of
compound 1, we noticed that the C-12 higher carbon sugar
skeleton was constructed through a simple dimerization of
the Schiff base derived from 1,4:3,6-dianhydro-D-fructose.
Thus, we pondered whether the free C-12 higher carbon
sugar 3 (as shown in Fig. 1) could be synthesized directly
from 1,4:3,6-dianhydro-D-fructose via a concise route.
Our interest in the synthesis of the target sugar molecule
and its derivatives stemmed from the potent bioactivity
and pharmaceutical application of 1,4:3,6-dianhydrohexi-
tol derivatives and the wide utilization of the special
V-shaped skeleton in asymmetric synthesis.10
Higher carbon sugars have been attracting the increasing
attention of organic chemists in the past decades due to
the fact that they can be used as non-metabolized analogues
of di- and oligosaccharides and are components of some
antibiotics1 and also that they are carbohydrate precursors
for higher carbon amino sugars. This class of compounds,
therefore, is interesting targets for developing new synthetic
methodologies. Several approaches toward higher carbon
sugars, including the Wittig reaction,2 Horner–Emmons
procedure,3 aldol condensation,4 radical addition,5 hetero-
Diels–Alder reaction,6 and enzymatic aldolization,7 have
been well documented. However most of these approaches
were limited by being complicated and having multi-steps,
or requiring separation of the product stereoisomers, or
activation of the starting monosaccharide, and in particu-
lar, requiring protection of functional groups. Accordingly,
development of simple, convenient, and protecting group
free synthetic methodology is a real challenge for organic
chemists.
Herein, we report a simple and convenient methodology
for asymmetric synthesis of the C-12 higher carbon sugar
and an investigation into its asymmetric reactivity with dif-
ferent nucleophiles. To our knowledge, this kind of higher
carbon sugar has not been reported in the literature.
2. Results and discussion
Thus, we are interested in designing a convenient approach
to new and special higher carbon sugars and the corre-
sponding amino derivatives that may have desired biol-
ogical activity. Following success in the stereoselective
synthesis of a C-10 higher sugar starting from D-xylose,8
we reported, in our previous paper,9 the synthesis of novel
In accordance with the literature11 and our previous exper-
imental data, the carbonyl group of keto-sugar 2 gave a hy-
drated carbonyl signal in the 13C NMR spectrum in D2O
(102.2 ppm) compared to the free carbonyl group
(213.3 ppm) in acetonitrile-d3, indicating that the carbonyl
group possesses a high reactivity toward nucleophiles.
Moreover, a methylene group a to a carbonyl group would
*
Corresponding author. E-mail: liuhm@zzu.edu.cn
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.042

H.-M. Liu et al. / Tetrahedron: Asymmetry 17 (2006) 3230–3236
3231
H
OH
O
HO
H
H
HO
O
H
H
OH
HO
O
H
H
H
O
O
O
HN
H
O
O
NH
O
O
OH
H
O
O
R
R
2
1
3
Figure 1.
be reactive due to the influence of the neighboring oxygen
atom and carbonyl group. Therefore, we attempted to use
different reagents and different reaction conditions to con-
struct the above-mentioned free C-12 sugar 3. When a solu-
tion of 2 in EtOH was treated with Et3N at reflux, a white
ambient temperature under catalyst-free conditions. Six
hours later, when the reaction was complete by TLC detec-
tion, the mixture was worked up to give product 4 in a yield
of 90%. HRMS and spectroscopic data suggested that com-
pound 4 is an oxazolidine derivative. The stereochemistry
for the newly formed stereogenic center at C-8 was estab-
lished as being of (R)-configuration by X-ray crystallo-
graphic analysis. The generality of this nucleophilic
addition was examined by replacement of 2-aminoethanol
with other vicinal amino alcohol analogues (VAA) in the
reaction. The results are outlined in Scheme 2 and Table 1.
1
precipitate was formed. Structural analysis by HRMS, H,
13C, and 2D NMR spectra confirmed that the precipitate is
the desired sugar product. The following single-crystal
X-ray analysis established the absolute configuration as de-
picted in Figure 2. From examination of the structure and
configuration we noted that, due to the stereo control of
the sugar rings, the ‘back to back’ aldol reaction between
the carbonyl group in one molecule and the methylene in
another molecule of 1,4:3,6-dianhydro-D-fructose afforded
the exo–exo combined product (Scheme 1).
The same absolute configurations at C-8 for the oxazoli-
dines 5 and 6 were also confirmed by X-ray crystallographic
analysis. Therefore we deduced that the formation of the
five-membered oxazolidine ring was highly stereoselective.
From entries 1 to 3, amino ethanol (VAA-1), 1-amino-3-
phenoxyl-isopropanol (VAA-2), and methyl L-threoninate
(VAA-3) were used in the reaction in sequence. With the
primary amine being changed to a secondary one, the in-
crease of steric hindrance of the substituent (R1) at the a
carbon resulted in a decrease of the reaction rate and yield.
Another reason for the poor yield of entries 3 and 4 could
also be explained by the diminished nucleophilicity of the
amino group due to the electron-drawing effect of methoxy-
carbonylmethenylmethyl group at the a carbon. When the
reaction was catalyzed with p-TsOH and heated at reflux,
the yield was improved (entry 4). In comparison with R1,
the steric hindrance of the substituent (R2) at the b carbon
gave slightly less influence on the reaction, which could be
observed from the good yields for entries 1, 2, 5, and 6.
The two amino alcohols (VAA-4 and 512) with bulky cyclic
groups, smoothly furnished the corresponding oxazolidines
(entries 5 and 6).
HO
H
HO
H
OH
O
H
H
O
Et3N, EtOH
Reflux
O
2
O
O
H
O
H
H
HO
O
O
3
2
Scheme 1. The highly stereoselective Aldol reaction of 2.
After the novel 12-carbon sugar 3 was synthesized success-
fully, we intended to investigate its reactivity with nucleo-
philes and the stereoselectivity of nucleophilic addition
reactions. Because chiral oxazolidines are important inter-
mediates used in numerous asymmetric transformations,
our first attempt was to treat 3 with 2-aminoethanol at
Figure 2. ORTEP diagram of compound 3.

3232
H.-M. Liu et al. / Tetrahedron: Asymmetry 17 (2006) 3230–3236
OH
O
HO
H
H
H
HO
OH
O
O
H
H
O
H2N
HO
R1
R2
O
8
+
O
O
H
H
O
H
HO
H
HO
HN
R1
4: R1 = R2 = H
5: R1 = H, R2 = CH2OC6H5
O
O
R2
3
VAA-1: R1 = R2 = H
VAA-2: R1 = H, R2 = CH2OC6H5
VAA-3: R1 = COOCH3, R2 = CH3 6: R1 = COOCH3, R2 = CH3
OH
H
H
HO
O
HO
O
H
O
8
O
H
H
O
∗
H
R1
HO
O
HN
O
H
∗
NH2
HO
O
R1
O
H
OH
7: R1 = H
8: R1 = CH3, *C:(R)
VAA-4: R1 = H
VAA-5: R1 = CH3, *C:(R)
Scheme 2. The reaction of 3 with various vicinal amino alcohols.
Table 1. Results for the reaction of 3 with 2-amino alcoholsa
Entry
VAA
Mol ratio (3:VAA)
Time (h)
Temperature (°C)
Product
Isolated yield (%)
1
2
3
4
5
6
VAA-1
VAA-2b
VAA-3
VAA-3c
VAA-4c
VAA-5c
1:1.2
1:2.4
1:1.2
1:1.2
1:1.2
1:1.2
6
12
48
12
12
12
rt
rt
rt
Reflux
Reflux
Reflux
4
5
6
6
7
8
90
78
31
43
86
75
a In MeOH.
b Racemate was used.
c In the presence of catalytic amount of p-TsOH.
The high stereoselectivity in the reaction could be explained
as follows. The amino group of the 2-amino alcohol con-
densed with the carbonyl group of the sugar to give an
imine intermediate. Then, an immediate five-membered
ring closure involving a nucleophilic attack of a hydroxyl
group to an imine double bond afforded the oxazolidine
derivative. The OH group attacked different diastereotopic
faces of the imine double bond and gave rise to the two
different configurations of the oxazolidine. Because of the
larger steric hindrance from the endo face than the exo face
with respect to the V-shaped molecule, the OH group
preferred to attack from the less hindered exo face, which
resulted in the (R)-isomer of oxazolidine. From the X-ray
crystallographical analysis of compounds 4, 5, and 6, we
noted that the intramolecular H-bond between N–H and
O(2) existed in each of them. Therefore, we could conclude
that both the stereocontrol of the V-shaped molecule and
the induction of an intramolecular H-bond should be
crucial to the highly stereoselective ring closure. Based on
the speciality of the reaction and in consideration of the
bulky tertiary hydroxyl groups in VAA-4 and 5, we could
deduce that compounds 7 and 8 have the same stereochem-
istry as 4, 5, and 6. This deduction was confirmed by the
NOE effect observed between protons H-9 and H-30 in
the NOESY spectrum of oxazolidine 7.
From the examination of the oxazolidine 5, we note that
the amino alcohol moiety in the molecule is the (R)-isomer,
which indicated that when the racemic VAA-2 was treated
with C-12 higher carbon sugar 3, only the (R)-isomer could
react with 3 to furnish the corresponding oxazolidine deriv-
ative 5. Based upon the characteristics of the reaction, the
racemic amino alcohol (VAA-2) was resolved with a suffi-
cient higher carbon sugar. The extension of this method
to the resolution of other synthetic chiral amino alcohols
and amino acids would be meaningful in organic synthesis
and drug development.
Being interested in the special biological property of amino
derivatives of higher carbon sugars,1d we attempted to syn-
thesize this class of derivatives via a Henry reaction. At
first, the reaction was conducted with compound 3 and
nitromethane in the presence of Et3N at reflux tempera-
ture,
(1S)-(1,4:3,6-dianhydro-D-mannitol-2-yl)-2-nitro-
methyl-1,4:3,6-dianhydro-D-glucitol 9 being obtained in
high yield. Product 9 was confirmed by HRMS, 1H

H.-M. Liu et al. / Tetrahedron: Asymmetry 17 (2006) 3230–3236
3233
NMR, and 13C NMR spectral analysis. The correlation
between the two protons of CH2NO2 and H-7 in the NOESY
spectrum reveals that the CH2NO2 and H-7 are on the
same side of the C(7)–C(8)–C(9) plane, which indicates that
C-8 possess the (R)-configuration. The solution of com-
pound 9 in CH3OH was hydrogenated in the presence of
Pd–C catalyst at 50 °C, leading to a novel amino alcohol:
(1S)-(1,4:3,6-dianhydro-D-mannitol-2-yl)-2-aminomethyl-
1,4:3,6-dianhydro-D-glucitol 10, as shown in Scheme 3.
However, the Henry reaction did not take place when
nitroethane was used in the reaction, which could be due
to the larger hindrance of nitroethane than nitromethane.
amino compounds and could be applied in organic synthe-
sis and asymmetric catalysis.
3. Conclusions
In summary, we have developed a simple and convenient
approach to a free C-12 higher carbon sugar and its amino
alcohol and lactone derivatives from a simple C-6 keto-
sugar. The notable features of the methodology are mild
reaction conditions, high stereoselectivity, high yields,
and operational simplicity. The addition reactions of the
novel higher sugar with the various nucleophiles show the
high stereocontrol effect and high reactivity of the sugar.
The selective reaction with (R)-amino alcohol provides a
new method for the resolution of racemic amino alcohols
and amino acids. The evaluation of the bioactivity and fur-
ther study on the applications of the novel compounds in
asymmetric synthesis are in progress.
Subsequently, dimethyl malonate, another nucleophile,
was allowed to react with the C-12 higher carbon sugar
and NaOMe, affording a new lactone derivative 11. The
structure was deduced from the [M+Na]+ peak at m/z
411.0885 in the HRMS spectrum and that only one methyl
signal was observed in the 1H NMR spectrum. It is obvious
that the nucleophilic addition first occurred and then was
followed by an intramolecular ester-exchange reaction.
From 1H NMR, 13C NMR, and DEPT-135 spectra we
note that only seven CH groups are present in the mole-
cule. A strong absorption at 1688 cmꢀ1 in the IR spec-
trum reveals the presence of one conjugated ester
carbonyl group in the lactone. In consideration of all the
above experimental data and the stereoselective feature of
the nucleophilic addition of this sugar, we can conclude
that the carbonyl group in the lactone ring exists in enolic
form. This reaction is designated in Scheme 4.
4. Experimental
4.1. General experimental methods
1H and 13C NMR spectra were acquired on Bruker
AVANCE DPX-400 spectrometer with chemical shift (d)
given in parts per million relative to tetramethylsilane as
an internal standard (d = 0.00 ppm). All assignments were
based upon the two-dimension NMR spectra. X-ray
diffraction experiment was made on a Rigaku RAXIS-
IV imaging plate with graphite monochromated Mo Ka
All these reactions of the higher carbon sugar 3 as
described above reveal that both the nucleophilic addition
and hydrogenation are highly stereoselective due to the
fixed stereochemistry of the sugar. Undoubtedly, the higher
sugar is an ideal chiral building block in asymmetric organic
chemistry. The compounds obtained, except for 11, are
amino sugars and are also chiral a,b- or a,c-amino alcohol
derivatives, which should be precursors to other biobased
˚
radiation (k = 0.71073 A). All data were collected at a
temperature of 291(2) K or 293(2) K and corrected for
Lorentz-polarization effects. Melting points were deter-
mined on WC-1 melting-point apparatus and are uncor-
rected. Infrared spectra were recorded on Nicolet IR200
instrument using KBr disks in the 400–4000 cmꢀ1 regions.
Optical rotation was detected on Perkin–Elmer 341 Polari-
HO
HO
H
HO
H
H
OH
OH
OH
O
O
H
H
O
H
H
O
O
O
a
b
O
O
O
H
H
O
O
H
H
HO
H
HO
O
H
HO
HO
H
H
HO
O
CH2NO2
CH2NH2
10
3
9
Scheme 3. Conversion of 3 to amino derivative 10. Reagents and conditions: (a) CH3NO2, Et3N, reflux; (b) CH3OH, H2, Pd–C, 50 °C.
HO
HO
HO
enolization
O
O
OH
OH
OH
O
O
O
CH2(COOCH3)2
CH3ONa
O
O
O
O
O
O
O
O
O
HO
OH
COOCH3
OH
COOCH3
O
O
HO
3
11
Scheme 4. Preparation of lactone derivative 11.

3234
H.-M. Liu et al. / Tetrahedron: Asymmetry 17 (2006) 3230–3236
20
meter. HRMS (high-resolution mass spectra) were taken
with a Q-Tof Micromass spectrometer.
Mp 121–123 °C, ½aꢁD ¼ þ58:0 (c 0.34, CHCl3); IR
(KBr): 3407, 3285, 2925, 2880, 1632, 1596, 1495 cmꢀ1; H
1
NMR (400 MHz, CDCl3): d 7.29 (m, 2H, H-3 and H-5,
Ph), 6.98 (t, 1H, J = 7.4 Hz, H-4, Ph), 6.92 (d, 2H,
J = 8.4 Hz, H-2 and H-6, Ph), 4.67 (t, 1H, J = 4.4 Hz,
H-10), 4.65 (d, 1H, J = 6.4 Hz, H-3), 4.45 (t, 1H,
J = 6.0 Hz, H-4), 4.39 (m, 1H, CHCH2OPh), 4.31 (dd,
1H, J = 6.0, 11.6 Hz, H-11), 4.26 (d, 1H, J = 4.4 Hz, H-
9), 4.18 (d, 1H, J = 10.6 Hz, H-1a), 4.14 (dd, 1H, J = 5.2,
9.6 Hz, H-5), 4.13 (d, 1H, J = 10.6 Hz, H-1b), 4.08 (dd,
1H, J = 5.6, 9.6 Hz, CHaHbO–Ph), 4.08 (s, 1H, H-7),
4.00 (dd, 1H, J = 6.4, 9.4 Hz, H-12a), 3.98 (dd, 1H,
J = 5.6, 9.6 Hz, CHaHbO–Ph), 3.93 (dd, 1H, J = 4.8,
9.4 Hz, H-6b), 3.85 (dd, 1H, J = 4.8, 9.4 Hz, H-6a), 3.64
(dd, 1H, J = 6.4, 9.4 Hz, H-12b), 3.30 (dd, 1H, J = 7.2,
12.0 Hz, HNCHaHbCH), 3.22 (dd, 1H, J = 4.0, 12.0 Hz,
HNCHaHbCH); 13C NMR (100 MHz, CDCl3): d 158.3
(C-1 Ph), 129.5 (C-3,5 Ph), 121.3 (C-4 Ph), 114.5 (C-2,6
Ph), 105.1 (C-8), 85.3 (C-9), 84.0 (C-3), 82.1 (C-7), 81.6
(C-4), 81.2 (C-10), 79.5 (C-2), 77.2 (C-1), 75.5
(CHCH2OPh), 75.3 (C-12), 73.7 (C-6), 72.7 (C-5), 70.8
(C-11), 68.5 (–CH2OPh), 47.3 (CHCH2NH); HRMS: calcd
for C21H27NO9: 437.1686. Found: 438.1767 [M+H]+.
4.2. (1R)-(1,4:3,6-Dianhydro-D-mannitol-2-yl)-1,4:3,6-di-
anhydro-D-fructose 3
A catalytic amount of Et3N was added to a solution of 2
(1.44 g, 10 mmol) in EtOH (20 mL) with stirring. The mix-
ture was heated and kept at refluxing temperature for 6 h,
followed by concentration under vacuumed pressure to
dryness. Recrystallization of the residue with absolute
EtOH furnished product 3 as a white solid (1.15 g, 80%).
20
Mp 190–191 °C, ½aꢁD ¼ þ173:4 (c 1.10, CH3OH). IR
1
(KBr): 3381, 1771 cmꢀ1; H NMR (400 MHz, DMSO-d6):
d 4.87 (dd, 1H, J = 4.8, 6.8 Hz, H-10), 4.39–4.41 (m, 2H,
H-3, H-4), 4.26 (d, 1H, J = 6.8 Hz, H-9), 4.10–4.15 (m,
2H, H-5, H-11), 3.92 (s, 1H, H-7), 3.95 (d, 1H,
J = 8.8 Hz, H-1a), 3.82 (dd, 1H, J = 4.8, 8.8 Hz, H-12a),
3.79 (m, 1H, H-6a), 3.54 (dd, 1H, J = 4.8, 8.8 Hz, H-
12b), 3.42 (d, 1H, J = 8.8 Hz, H-1b), 3.38 (m, 1H, H-6b);
13C NMR (100 MHz, DMSO-d6): d 212.8 (C-8), 83.2 (C-
2), 81.4 (C-4), 81.0 (C-7), 80.3 (C-10), 79.7 (C-3), 78.4
(C-9), 72.5 (C-12), 72.3 (C-1), 72.2 (C-5), 71.8 (C-6), 71.3
(C-11). HRMS: calcd for C12H16O8: 288.0845. Found:
289.0901 [M+H]+.
4.3.3. (2R,3R,3aS,6R,6aR,30R,30aS,60R,60aR,400S,500R)-Spiro-
[6,30,60-trihydroxy-octahydro[2,30]bi[furo[3,2-b]furan]-3,200-[400-
4.3. General procedures for the synthesis of oxazolidines 4–8
methoxycarbonyl-500-methyl-100,300-oxazolidine]
6. Separa-
tion by chromatography with elution of chloroform/meth-
To a solution of C-12 sugar 3 (1.44 g, 5 mmol) in ethanol
(20 mL), vicinal amino alcohol (6–12 mmol) was added (a
catalytic amount of p-TsOH was added as well if it was
necessary as indicated in Table 1). The mixture was stir-
red at the indicated temperature and time, followed by
concentration and purification by column chromatogra-
phy on silica gel or by recrystallization from isopropanol,
giving product oxazolidines as white solids (yields 31–
90%).
20
anol (7/1). Mp 98–100 °C, ½aꢁD ¼ þ77:0 (c 0.266, CH3OH);
IR (KBr): 3503, 3390, 3275, 2972, 2932, 2874, 1742 cmꢀ1
;
1H NMR (400 MHz, D2O): d 4.62 (d, 1H, J = 5.2 Hz, H-
3), 4.32 (t, 1H, J = 4.0 Hz, H-10), 4.13 (t, 1H, J = 5.2 Hz,
H-4), 4.08 (m, 1H, H-11), 4.06 (d, 1H, J = 4.0 Hz, H-9),
4.00 (m, 1H, H-5), 3.88 (d, 1H, J = 10.0 Hz, H-1a), 3.81
(s, 1H, H-7), 3.77 (m, 1H, H-12a), 3.77 (d, 1H,
J = 8.0 Hz, H-6a), 3.76 (m, 1H, CH3CHO), 3.74 (d, 1H,
J = 10.0 Hz, H-1b), 3.69 (s, 3H, CH3O), 3.54 (t, 1H,
J = 8.0 Hz, H-6b), 3.47 (dd, 1H, J = 8.8, 12.0 Hz,
NHCHCOO), 3.31 (t, 1H, J = 8.8 Hz, H-12b), 1.27 (d,
1H, J = 6.0 Hz, CH3CH); 13C NMR (100 MHz, D2O): d
104.5 (C-8), 85.2 (C-9), 85.2 (C-3), 81.0 (C-10), 80.7
(C-2), 80.7 (C-4), 80.4 (C-7), 76.4 (CH3CHO–), 74.9
(C-1), 72.6 (C-11), 72.0 (C-6), 71.2 (C-12), 71.2 (C-5),
65.2 (NHCHCOO), 52.4 (OCH3), 19.6 (CHCH3);
HRMS: calcd for C17H25NO10: 403.1478. Found:
404.1563 [M+H]+ and 426.1392 [M+Na]+, 442.1144
[M+K]+.
4.3.1. (2R,3R,3aS,6R,6aR,30R,30aS,60R,60aR)-Spiro[6,30,60-
trihydroxy-octahydro[2,30]bi[furo[3,2-b]furan]-3,200-[100,300-
oxazolidine] 4. Recrystallization from isopropanol. Mp
20
97–98 °C, ½aꢁD ¼ þ105:7 (c 1.06, CH3OH); IR (KBr):
1
3385, 3295, 2981, 2872, 1651 cmꢀ1; H NMR (400 MHz,
D2O): d 4.62 (d, 1H, J = 5.2 Hz, H-3), 4.57 (t, 1H,
J = 4.4 Hz, H-10), 4.33 (t, 1H, J = 5.2 Hz, H-4), 4.29 (m,
1H, H-11), 4.26 (d, 1H, J = 4.4 Hz, H-9), 4.25 (m, 1H,
H-5), 3.96 (dd, 1H, J = 6.4, 8.4 Hz, H-6a), 3.95 (s, 1H,
H-7), 3.91 (dd, 1H, J = 2.0, 8.8 Hz, H-12a), 3.90 (s, 2H,
H-1), 3.76 (m, 2H, HNCH2CH2O), 3.57 (t, 1H,
J = 8.4 Hz, H-6b), 3.47 (t, 1H, J = 8.8 Hz, H-12b), 3.15
(m, 1H, HNCHaHbCH2O), 2.98 (m, 1H, HNCHaHb-
CH2O); 13C NMR (100 MHz, D2O): d 103.7 (C-8), 85.5
(C-3), 84.5 (C-9), 82.2 (C-7), 81.1 (C-2), 81.1 (C-4), 81.0
(C-10), 74.7 (C-1), 72.0 (C-11), 71.1 (C-6), 70.8 (C-12),
70.7 (C-5), 66.2 (OCH2CH2NH), 44.4 (OCH2CH2NH);
HRMS: calcd for C14H21NO8: 331.1267. Found: 332.1341
[M+H]+, 354.1156 [M+Na]+.
4.3.4. (2R,3R,3aS,6R,6aR,30R,30aS,60R,60aR,500R,6000R,7000R,
8000S)-Dispiro[6,30,60-trihydroxy-octahydro[2,30]bi[furo[3,2-b]-
furan]-3,200-[100,300-oxazolidine]-500,3000-[6000-hydroxy-tetrahydro-
furo[3,2-b]furan] 7. Separation by chromatography with
elution of chloroform/methanol (7/1). Mp 112–114 °C,
20
½aꢁD ¼ þ140:9 (c 0.34, CH3OH), IR (KBr): 3428, 2945,
2877, 1413 cmꢀ1 1H NMR (400 MHz, D2O): d 4.66 (t,
;
1H, J = 4.6 Hz, H-4), 4.59 (d, 1H, J = 5.2 Hz, H-9), 4.51
(t, 1H, J = 4.5 Hz, H-40), 4.35 (m, 4H, H-3, H-5, H-10,
H-50), 4.25 (m, 1H, H-11), 4.25 (d, 1H, J = 4.0 Hz, H-30),
4.0 (s, 1H, H-7), 3.98 (dd, 1H, J = 6.2, 8.4 Hz, H-6a),
3.97 (d, 1H, J = 8.4 Hz, H-10a), 3.97 (d, 1H, J = 10.7 Hz,
H-1a), 3.95 (t, 1H, J = 8.4 Hz, H-6b), 3.81 (d, 1H,
4.3.2. (2R,3R,3aS,6R,6aR,30R,30aS,60R,60aR,500R)-Spiro-
[6,30,60-trihydroxy-octahydro[2,30]bi[furo[3,2-b]furan]-3,200-[500-
phenoxymethyl-100,300-oxazolidine] 5. Separation by chro-
matography with elution of chloroform/methanol (6/1).

H.-M. Liu et al. / Tetrahedron: Asymmetry 17 (2006) 3230–3236
3235
J = 10.7 Hz, H-1b), 3.76 (d, 1H, J = 8.8 Hz, H-12a), 3.73
(d, 1H, J = 8.4 Hz, H-10b), 3.54 (t, 1H, J = 8.8 Hz, H-
12b), 3.49 (t, 2H, J = 8.4 Hz, H-60), 3.01 (d, 1H,
J = 12.3 Hz, H-70b), 2.98 (d, 1H, J = 12.3 Hz, H-70a); 13C
NMR (100 MHz, D2O): d 104.7 (C-8), 88.3 (C-20), 86.0
(C-9), 84.9 (C-3), 84.4 (C-30), 82.4 (C-4), 81.7 (C-40), 81.2
(C-10), 81.1 (C-7), 81.0 (C-2), 74.8 (C-1), 72.2 (C-10), 72.1
(C-5), 71.9 (C-50), 71.8 (C-60), 70.9 (C-6), 70.9 (C-12),
70.8 (C-11), 51.9 (C-70); HRMS: calcd for C19H27NO11:
445.1584. Found: 446.1663 [M+H]+ and 468.1465
[M+Na]+.
C13H19NO10: 349.1009. Found: 350.1099 [M+H]+ and
372.0912 [M+Na]+.
4.5. (1S)-(1,4:3,6-Dianhydro-D-mannitol-2-yl)-2-amino-
methyl-1,4:3,6-dianhydro-D-glucitol or (2R,3R,3aS,6R,6aR,
30R,30aS,60R,60aR)-3-aminomethyl-3,6,30,60-tetrahydroxy-
octahydro[2,30]bi[furo[3,2-b]furan]) 10
Nitromethyl sugar 9 (1.05 g, 3 mmol) was dissolved in
EtOH (120 mL), to which 10% Pd–C catalyst (0.105 g,
10%) was added. The mixture was hydrogenated under
50 psi at 50 °C with shaking for 8 h. Subsequent filtration
and evaporation of the mixture gave allowed product 10
4.3.5. (2R,3R,3aS,6R,6aR,30R,30aS,60R,60aR,400R,500R,3000aS,
6000R,6000aR)-Dispiro[6,30,60-trihydroxy-octahydro[2,30]bi[furo-
[3,2-b]furan]-3,200-[400-methyl-100,300-oxazolidine]-500,3000-[6000-
hydroxy-tetrahydro-furo[3,2-b]furan] 8. Separation by
20
(0.85 g, 89%). Mp 76–78 °C, ½aꢁD ¼ þ86:5 (c 0.32,
CH3OH); IR (KBr): 3367, 2946, 2872 cmꢀ1 1H NMR
;
(400 MHz, D2O): d 4.66 (d, 1H, J = 4.4 Hz, H-3), 4.65 (t,
1H, J = 4.4 Hz, H-10), 4.32 (m, 1H, H-11), 4.31 (t, 1H,
J = 4.4 Hz, H-4), 4.28 (d, 1H, J = 4.4 Hz, H-9), 4.24 (m,
1H, H-5), 3.95 (s, 2H, H-1), 3.94 (m, 1H, H-6a), 3.87 (s,
1H, H-7), 3.85 (dd, 1H, J = 6.4, 9.2 Hz, H-12a), 3.58 (t,
1H, J = 8.4 Hz, H-6b), 3.52 (dd, 1H, J = 7.2, 9.2 Hz, H-
12b), 3.28 (s, 2H, CH2NH2); 13C NMR (100 MHz, D2O):
d 88.1 (C-9), 85.9 (C-3), 85.3 (C-7), 80.9 (C-10), 80.8 (C-
6), 80.4 (C-8), 79.7 (C-2), 74.7 (C-1), 71.9 (C-11), 71.8 (C-
6), 71.7 (C-12), 70.5 (C-5), 41.4 (CH2NH2). HRMS: calcd
for C13H21NO8: 319.1267. Found: 320.1341 [M+H]+ and
342.1175 [M+Na]+.
chromatography with elution of chloroform/methanol (7/
20
1). Mp 184–185 °C, ½aꢁD ¼ þ98:0 (c 0.22, CH3OH); IR
1
(KBr): 3422, 2945, 2879, 1643 cmꢀ1; H NMR (400 MHz,
D2O): d 4.65 (m, 1H, H-4), 4.64 (d, 1H, J = 5.2 Hz, H-9),
4.51 (t, 1H, J = 4.4 Hz, H-40), 4.39 (m, 1H, H-50), 4.37
(m, 3H, H-3, H-5, H-10), 4.30 (m, 1H, H-11), 4.28 (d,
1H, J = 4.0 Hz, H-30), 4.06 (d, 1H, J = 10.8 Hz, H-1a),
4.02 (s, 1H, H-7), 3.99 (d, 1H, J = 8.4 Hz, H-60a), 3.98
(dd, 1H, J = 6.8, 8.8 Hz, H-12a), 3.96 (dd, 1H, J = 6.8,
8.8 Hz, H-6a), 3.91 (d, 1H, J = 9.6 Hz, H-10a), 3.82 (d,
1H, J = 10.8 Hz, H-1b), 3.59 (d, 1H, J = 9.6 Hz, H-10b),
3.57 (t, 1H, J = 8.4 Hz, H-60b), 3.55 (t, 1H, J = 8.8 Hz,
H-12b), 3.51 (t, 1H, J = 8.8 Hz, H-6b), 3.30 (q, 1H,
J = 6.4 Hz, H-70), 1.19 (d, 3H, J = 6.8 Hz, H-80); 13C
NMR (100 MHz, D2O): d 103.1 (C-8), 89.8 (C-20), 86.1
(C-9), 85.0 (C-30), 84.0 (C-3), 81.2 (C-4), 80.8 (C-40),
80.6 (C-10), 80.5 (C-7), 80.4 (C-2), 74.1 (C-1), 71.9
(C-5), 71.8 (C-50), 71.2 (C-60), 70.7 (C-12), 70.6 (C-6),
70.6 (C-11), 68.8 (C-10), 57.2 (C-70), 11.98 (C-80); HRMS:
calcd for C20H29NO11: 459.1741. Found: 482.1638
[M+Na]+.
4.6. (2R,3R,3aS,6R,6aR,30R,30aS,60R,60aR)-Spiro[6000-
hydroxy-tetrahydro-furo[3,2-b]furan]-3000,2-[6,40,400-trihydr-
oxy-5-methoxycarbonyl-furo[200,300:40,50]furo[2,3-c]pyran-5-
ene] 11
C-12 Sugar 3 (118 mg, 0.41 mmol) was dissolved in MeOH
(5 mL), to which dimethyl malonate (70 mg, 0.55 mmol)
and 1 mL 0.55 M solution of NaOMe in methanol were
added. The mixture was stirred at room temperature for
12 h, followed by filtration, giving compound 11 as a
20
white solid (100 mg, 63%): mp 210–212 °C, ½aꢁD ¼ þ81:0
4.4. (1S)-(1,4:3,6-Dianhydro-D-mannitol-2-yl)-2-nitromethyl-
1,4:3,6-dianhydro-D-glucitol or (2R,3R,3aS,6R,6aR,30R,30aS,
60R,60aR)-3,6,30,60-tetrahydroxy-3-nitromethyl-octahydro-
[2,30]bi[furo[3,2-b]furan] 9
(c 0.218, H2O); IR (KBr): 3422, 2951, 2893, 1688,
1
1589, cmꢀ1; H NMR (400 MHz, DMSO-d6): d 4.83 (d,
1H, J = 4.8 Hz, H-3), 4.27 (m, 1H, H-4), 4.26 (m, 1H, H-
9), 4.07 (m, 1H, H-10), 4.03 (m, 2H, H-5, H-11), 4.00 (d,
1H, J = 8.8 Hz, H-1a), 3.80 (t, 1H, J = 7.6 Hz, H-12a),
3.69 (dd, 1H, J = 7.2, 8.0 Hz, H-6a), 3.60 (s, 1H, H-7),
3.56 (d, 1H, J = 8.8 Hz, H-1b), 3.43 (s, 3H, CH3), 3.39
(m, 1H, H-12b), 3.35 (m, 1H, H-6b); 13C NMR
(100 MHz, DMSO-d6): d 170.1 (C-15, C@O), 164.7 (C-
14), 88.1 (C-9), 83.3 (C-2), 82.0 (C-4), 81.0 (C-10), 80.5
(C-7), 79.4 (C-13), 79.3 (C-3), 73.7 (C-1), 73.1 (C-11),
72.7 (C-8), 72.4 (C-5), 71.5 (C-6), 71.1 (C-12), 49.0 (C-16,
CH3); HRMS: calcd for C16H20O11: 388.1006. Found:
411.0885 [M+Na]+, 427.0630 [M+K]+.
A mixture of 3 (1.44 g, 5 mmol), nitromethane (0.5 mL),
catalytic amount of Et3N, and EtOH (20 mL) was heated
at reflux temperature with stirring, After 1 h, the mixture
was evaporated, and then crystallized with EtOH, to afford
the compound
9
(1.66 g, 95%). Mp 160–162 °C,
20
½aꢁD ¼ þ92:9 (c 1.06, CH3OH); IR (KBr): 3405, 2942,
2849, 1554 cmꢀ1; H NMR (400 MHz, D2O): d 4.95 (d,
1
1H, J = 13.6 Hz, CH2NO2), 4.85 (d, 1H, J = 13.6 Hz,
CH2NO2), 4.60 (t, 1H, J = 4.0 Hz, H-10), 4.59 (d, 1H,
J = 5.4 Hz, H-3), 4.48 (d, 1H, J = 4.0 Hz, H-9), 4.31 (m,
1H, H-11), 4.26 (t, 1H, J = 5.4 Hz, H-4), 4.17 (m, 1H,
H-5), 3.91 (s, 2H, H-1), 3.89 (dd, 1H, J = 6.4, 8.8 Hz,
H-6a), 3.86 (dd, 1H, J = 6.8, 8.8 Hz, H-12a), 3.78 (s, 1H,
H-7), 3.50 (t, 1H, J = 8.8 Hz, H-6b), 3.45 (t, 1H,
J = 8.8 Hz, H-12b); 13C NMR (100 MHz, D2O): d 86.6
(C-9), 85.7 (C-3), 83.7 (C-7), 81.6 (C-8), 80.9 (C-10), 80.1
(C-4), 79.8 (C-2), 76.0 (CH2NO2), 74.1 (C-1), 71.6 (C-11),
71.1 (C-6), 70.5 (C-12), 70.1 (C-5). HRMS: calcd for
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary
publication numbers CCDC-622930, 622931, 622932, and
622933. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44(0) 1223 336033 or e-mail: deposit@
ccdc.cam.ac.uk].

3236
H.-M. Liu et al. / Tetrahedron: Asymmetry 17 (2006) 3230–3236
4. (a) Jarosz, S.; Fraser-Reid, B. Tetrahedron Lett. 1989, 30,
Acknowledgement
2359; (b) Haines, A. H.; Lamb, A. J. Carbohydr. Res. 2000,
325, 323–339.
5. Araki, Y.; Endo, T.; Arai, Y.; Tanji, M.; Ishido, Y.
Tetrahedron Lett. 1989, 30, 2829–2832.
6. Kim, K. S.; Cho, I. H.; Joo, Y. H.; Yoo, I. Y.; Song,
J. H.; Ko, J. H. Tetrahedron Lett. 1992, 33, 4029–
4032.
We gratefully acknowledge financial support from the
National Natural Science Foundation of PR China
(20572103).
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