Synthesis and structure determination of some sugar amino acids related to alanine and 6-deoxymannojirimycin

Article abstract of DOI:10.1016/S0008-6215(01)00109-4

(5′R)-5′-Methyl-5′-[methyl (4S)-2,3-O-isopropylidene-β-L-erythrofuranosid-4-C-yl]-imidazolidin- 2′,4′-dione was synthesised starting from methyl 6-deoxy-2,3-O-isopropylidene-α-D-lyxo-hexofuranosid-5-ulose applying the Bucherer-Bergs reaction. Its 5′-R configuration was confirmed by X-ray crystallography. Corresponding α-amino acid-methyl (5R)-5-amino-5-C-carboxy-5,6-dideoxy-α-D-lyxo-hexofuranoside (alternative name: 2-[methyl (4S)-2,3-O-isopropylidene-β-L-erythrofuranosid-4-C-yl]-D-alanine) was obtained from the above hydantoin by acid hydrolysis of the isopropylidene group followed by basic hydrolysis of the hydantoin ring. Total deprotection afforded 5-C-carboxy-6-deoxymannojirimycin. Analogously, methyl (5S)-5-amino-5-C-carboxy-5,6-dideoxy-α-L-lyxo-hexofuranoside and 5-C-carboxy-6-deoxy-L-mannojirimycin were prepared from the corresponding (5′S)-5′-methyl-5′-[methyl (4R)-2,3-O-isopropylidene-β-D-erythrofuranosid-4-C-yl]-imidazolidin- 2′,4′-dione starting from methyl 6-deoxy-2,3-O-isopropylidene-α-L-lyxo-hexofuranosid-5-ulose.

Full text of DOI:10.1016/S0008-6215(01)00109-4

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Carbohydrate Research 332 (2001) 351–361
Synthesis and structure determination of some sugar
amino acids related to alanine and
6-deoxymannojirimycin
a,
a
a
b
c
&
Miroslav Koo´sˇ, * Bohumil Steiner, Ju´lia Micˇova´, Vratislav Langer, Maria´n Dur´ık,
Dalma Gyepesova´c
aInstitute of Chemistry, Slo6ak Academy of Sciences, Du´bra6ska´ cesta 9, SK-84238 Bratisla6a, Slo6ak Republic
bDepartment of Inorganic En6ironmental Chemistry, Chalmers Uni6ersity of Technology,
SE-41296 Gothenburg, Sweden
cInstitute of Inorganic Chemistry, Slo6ak Academy of Sciences, SK-84236 Bratisla6a, Slo6ak Republic
Received 18 January 2001; accepted 19 April 2001
Dedicated to Professor Dr Peter Ko¨ll on the occasion of his 60th birthday
Abstract
(5%R)-5%-Methyl-5%-[methyl (4S)-2,3-O-isopropylidene-b-
synthesised starting from methyl 6-deoxy-2,3-O-isopropylidene-a-
Bucherer–Bergs reaction. Its 5%-R configuration was confirmed by X-ray crystallography. Corresponding a-amino
acid–methyl (5R)-5-amino-5-C-carboxy-5,6-dideoxy-a- -lyxo-hexofuranoside (alternative name: 2-[methyl (4S)-2,3-
O-isopropylidene-b- -erythrofuranosid-4-C-yl]- -alanine) was obtained from the above hydantoin by acid hydrolysis
of the isopropylidene group followed by basic hydrolysis of the hydantoin ring. Total deprotection afforded
5-C-carboxy-6-deoxymannojirimycin. Analogously, methyl (5S)-5-amino-5-C-carboxy-5,6-dideoxy-a- -lyxo-hexo-
furanoside and 5-C-carboxy-6-deoxy- -mannojirimycin were prepared from the corresponding (5%S)-5%-methyl-5%-
[methyl (4R)-2,3-O-isopropylidene-b- -erythrofuranosid-4-C-yl]-imidazolidin-2%,4%-dione starting from methyl
6-deoxy-2,3-O-isopropylidene-a- -lyxo-hexofuranosid-5-ulose. © 2001 Published by Elsevier Science Ltd.
L
-erythrofuranosid-4-C-yl]-imidazolidin-2%,4%-dione was
D
-lyxo-hexofuranosid-5-ulose applying the
D
L
D
L
L
D
L
Keywords: Sugar amino acids; Hydantoins, Alanine; 6-Deoxymannojirimycin; Methyl 2,3-O-isopropylidene-hexofuranosid-5-
uloses; X-ray analysis
1. Introduction
curring.1–5 Due to their responsibility for
recognition in biological events,4 there is
growing interest in the use of synthetic gly-
copeptides as model compounds. In this re-
spect, many O- and N-linked glycoproteins
have been synthesised and studied inten-
sively.6–26 Besides these mostly anomerically
linked carbohydrate–amino acid conjugates,
some analogs linked through CꢀC bonds have
also been described.1,3,27–35
Glycoconjugates of lipids and proteins rep-
resent a very important group of organic com-
pounds, especially with respect to their
biological activity. Some a-amino acids
derived from carbohydrates are naturally oc-
* Corresponding author. Fax: +421-7-59410222.
E-mail address: chemmiro@savba.sk (M. Koo´sˇ).
0008-6215/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0008-6215(01)00109-4

352
M. Koo´sˇ et al. / Carbohydrate Research 332 (2001) 351–361
In this paper, we present the synthesis and
(based on the analysis of NMR spectra) in
favour of the hydantoin (2) having R configu-
ration at C-5 and the isolation and purifica-
tion of the isomer with S configuration at C-5
(3) is rather difficult. In fact, we were able to
isolate only ca. 4% of pure 3. Acid hydrolysis
of the 2,3-O-isopropylidene group (to increase
the solubility of the product 4 in water) and
subsequent basic hydrolysis of the hydantoin
afforded the desired amino acid 5. The C-5
and C-6 atoms of a saccharide moiety repre-
sent in this case the a- and b-carbon atoms of
alanine, as well.
structure determination of some model com-
pounds having C-2-linked amino acid at-
tached to a hexose backbone in the C-5
position. Alanine derivatives branched at the
C-2 atom are obtained from suitably O-pro-
tected 6-deoxy-hexofuranos-5-ulose. Further
studies on analogous hexofuranos-5-uloses, 6-
deoxy-6-isopropyl-hexofuranos-5-uloses and
6-deoxy-6-phenyl-hexofuranos-5-uloses afford-
ing glycoconjugates of serine, leucine and
phenylalanine, respectively, are in progress.
Because of the obvious difficulties in unam-
biguous establishing the configuration at C-5
(R versus S) by NMR methods, suitable crys-
tals of compound 2 were subjected to X-ray
analysis. This confirmed 5-R configuration of
2. There are two independent molecules (A
and B) of the compound 2 and four water
molecules in the asymmetric unit, which is
equal in this case to the unit cell. Fig. 1 shows
molecule A of compound 2 and the number-
ing scheme adopted for both molecules A and
B. The H-positions (with the exception for
water molecules) have been put at calculated
positions and were, during refinement, riding
on their respective pivot atoms. The relevant
crystallographic data for 2 are given in Table
1. The bond lengths and bond angles are listed
in Table 2. A list of selected torsion angles is
given in Table 3. The final positional parame-
ters for compound 2 are summarised in Table
4.
2. Results and discussion
Although a lot of sugar hydantoins (either
as a final compound or precursor of the final
amino acid) have been prepared,24,28–31,36–39
the Bucherer–Bergs reaction has been applied
only several times to
a
carbohydrate
derivative.28,29,36
Recently, we have described40 the synthesis
of two sugar amino acids via corresponding
hydantoin derivatives starting from methyl 6-
deoxy-2,3-O-isopropylidene-a- -lyxo-hexopy-
L
ranosid-4-ulose. Application of the Bucherer–
Bergs reaction to methyl 6-deoxy-2,3-O-iso-
propylidene-a-
(1)41 (prepared from methyl 2,3-O-isopropyli-
dene-a-
-lyxo-pentodialdo-1,4-furanoside42,43
D
-lyxo-hexofuranosid-5-ulose
D
by the Grignard reaction with methylmagne-
sium iodide and subsequent oxidation of the
reaction product with pyridinium dichromate)
led to the formation of the corresponding
hydantoin derivative 2 (Scheme 1). The
stereoselectivity of this reaction is about 85%
The presence of a 1,3-dioxolane ring fused
to a furanose ring at the 2,3-position and the
a-glycosidic methyl group imposes some con-
Scheme 1.

M. Koo´sˇ et al. / Carbohydrate Research 332 (2001) 351–361
353
Analysis of the molecular packing in the
unit cell revealed several hydrogen bonds. In
addition to weak intramolecular hydrogen
bonds between N-1ꢀH and O-3 (in both inde-
pendent molecules A and B), there are two
strong hydrogen bonds, each one involving
the N-1ꢀH of one of the two independent
molecules and the O-5 of the carbonyl group
at C-2 (C-12 in the ZORTEP plot) of the hy-
dantoin ring of the other molecule. Four
molecules of water present in the cell unit take
Table 1
Crystallographic and experimental data for compound 2 a
Empirical formula
Formula weight
C12H18N2O6·2 H2O
322.32
Temperature, T (K)
183(2)
,
Wavelength, u (A)
Crystal system
Space group
0.71073
triclinic
P1
Unit cell dimensions
,
a (A)
8.04030 (10)
9.10680 (10)
11.5856 (2)
92.7080(10)
108.8510(10)
92.2050 (10)
800.618 (19)
2
Fig. 1. ZORTEP plot and atomic numbering of molecule A of
,
b (A)
(5%R)-5%-methyl-5%-[methyl (4S)-2,3-O-isopropylidene-b-
throfuranosid-4-C-yl]-imidazolidin-2%,4%-dione (2).
L-ery-
,
c (A)
h (°)
i (°)
k (°)
formational rigidity on 2. The values of rele-
vant torsion angles [C-1ꢀC-2ꢀC-3ꢀC-4=
6.9(2)°, O-4ꢀC-1ꢀC-2ꢀC-3=16.6(2)°, C-2ꢀC-
3ꢀC-4ꢀO-4= −28.0(2)° for molecule A and
C-1ꢀC-2ꢀC-3ꢀC-4=3.6(2)°, O-4ꢀC-1ꢀC-2ꢀC-
3=21.6(2)°, C-2ꢀC-3ꢀC-4ꢀO-4= −27.5(1)°
for molecule B] and puckering parameters
3
,
Unit-cell volume V (A )
Formula units per unit cell, Z
Dcalcd (g/cm3)
1.337
Mo Ka
0.113
Radiation
Absorption coefficient, v
(mm−1
)
F(000)
Crystal size (mm)
344
0.70 (max)
0.10 (min)
Siemens SMART CCD
1.86–32.72
,
[Q=0.359(2) A, €=348.7(3)° for molecule A
,
and Q=0.390(2) A, €=354.5(2)° for
Diffractometer
q Range (°)
5
molecule B] indicate slightly deformed E con-
formation of the furanoside ring where C-1,
C-2, C-3, C-4 atoms lie almost in a plane.
Analogously, the puckering parameters Q=
Range of h
Range of k
Range of l
Scan mode
Reflections
Independent reflections
Refinement method
−12“11
−13“13
−16“17
ꢀ
,
0.314(2) A, €=134.3(3)° for molecule A and
14106
,
Q=0.328(2) A, €=139.9(3)° for molecule B
10353 (Rint=0.0179)
Full-matrix least-squares
on F2
10353/15/473
1.010
R1=0.0447,
wR2=0.1128
R1=0.0536,
wR2=0.1204
0.237 and −0.445
and the relevant torsion angles O-2ꢀC-2ꢀC-
3ꢀO-3, C-2ꢀC-3ꢀO-3ꢀC-8, C-8ꢀO-2ꢀC-2ꢀC-3
of 5.5(2), −24.8(2), 16.1(2)° for molecule A
and 2.4(2), −23.4(1), 19.6(2)° for molecule B,
respectively, are indicative of E3 form for five-
membered 1,3-dioxolane ring with O-2, C-2,
C-3, O-3 atoms approximately in a plane. The
five-membered hydantoin rings are almost pla-
nar as all relevant torsion angles are close to
zero.
Data/restraints/parameters
Goodness-of-fit (all)
Final R indices [I\2|(I)]
R indices (all data)
Largest difference peak and
3
,
hole (e/A )
a Standard deviations in parentheses.

354
M. Koo´sˇ et al. / Carbohydrate Research 332 (2001) 351–361
Table 2
a
,
Bond lengths (A) and bond angles (°) for compound 2
,
Bond lengths (A)
O-1AꢀC-1A
O-1AꢀC-7A
O-2AꢀC-2A
O-2AꢀC-8A
O-3AꢀC-3A
O-3AꢀC-8A
O-4AꢀC-1A
O-4AꢀC-4A
O-5AꢀC-12A
O-6AꢀC-11A
N-1AꢀC-12A
N-1AꢀC-5A
N-2AꢀC-11A
N-2AꢀC-12A
C-1AꢀC-2A
C-2AꢀC-3A
C-3AꢀC-4A
C-4AꢀC-5A
C-5AꢀC-6A
C-5AꢀC-11A
C-8AꢀC-9A
C-8AꢀC-10A
1.401(2)
1.435(3)
1.420(2)
1.431(2)
1.424(2)
1.444(2)
1.4301(19)
1.4348(19)
1.2287(18)
1.224(2)
1.3410(19)
1.4581(19)
1.361(2)
1.4014(19)
1.532(2)
1.553(2)
1.530(2)
1.538(2)
1.531(2)
1.536(2)
1.509(3)
1.522(3)
O-1BꢀC-1B
O-1BꢀC-7B
O-2BꢀC-2B
O-2BꢀC-8B
O-3BꢀC-3B
O-3BꢀC-8B
O-4BꢀC-1B
O-4BꢀC-4B
O-5BꢀC-12B
O-6BꢀC-11B
N-1BꢀC-12B
N-1BꢀC-5B
N-2BꢀC-11B
N-2BꢀC-12B
C-1BꢀC-2B
C-2BꢀC-3B
C-3BꢀC-4B
C-4BꢀC-5B
C-5BꢀC-6B
C-5BꢀC-11B
C-8BꢀC-9B
C-8BꢀC-10B
1.416(2)
1.435(2)
1.4259(19)
1.433(2)
1.4297(18)
1.4371(18)
1.4197(18)
1.4362(18)
1.2315(19)
1.2230(19)
1.3406(19)
1.4554(18)
1.356(2)
1.4018(19)
1.536(2)
1.559(2)
1.527(2)
1.5314(19)
1.533(2)
1.538(2)
1.503(3)
1.530(3)
Bond angles (°)
C-1AꢀO-1AꢀC-7A
C-2AꢀO-2AꢀC-8A
C-3AꢀO-3AꢀC-8A
C-1AꢀO-4AꢀC-4A
C-12AꢀN-1AꢀC-5A
C-11AꢀN-2AꢀC-12A
O-1AꢀC-1AꢀO-4A
O-1AꢀC-1AꢀC-2A
O-4AꢀC-1AꢀC-2A
O-2AꢀC-2AꢀC-1A
O-2AꢀC-2AꢀC-3A
C-1AꢀC-2AꢀC-3A
O-3AꢀC-3AꢀC-4A
O-3AꢀC-3AꢀC-2A
C-4AꢀC-3AꢀC-2A
O-4AꢀC-4AꢀC-3A
O-4AꢀC-4AꢀC-5A
C-3AꢀC-4AꢀC-5A
N-1AꢀC-5AꢀC-6A
N-1AꢀC-5AꢀC-4A
C-6AꢀC-5AꢀC-4A
N-1AꢀC-5AꢀC-11A
C-6AꢀC-5AꢀC-11A
C-4AꢀC-5AꢀC-11A
O-2AꢀC-8AꢀO-3A
O-2AꢀC-8AꢀC-9A
O-3AꢀC-8AꢀC-9A
O-2AꢀC-8AꢀC-10A
O-3AꢀC-8AꢀC-10A
C-9AꢀC-8AꢀC-10A
O-6AꢀC-11AꢀN-2A
O-6AꢀC-11AꢀC-5A
N-2AꢀC-11AꢀC-5A
O-5AꢀC-12AꢀN-1A
O-5AꢀC-12AꢀN-2A
N-1AꢀC-12AꢀN-2A
112.65(15)
108.35(14)
107.27(12)
106.42(11)
112.56(12)
110.99(13)
112.11(14)
107.45(14)
105.66(12)
109.69(15)
104.90(13)
104.72(13)
111.95(12)
103.82(13)
103.03(13)
104.95(12)
108.41(11)
118.46(12)
112.60(12)
113.27(12)
111.67(12)
100.79(12)
110.67(13)
107.17(12)
103.79(13)
108.57(18)
109.27(15)
110.38(17)
110.35(18)
113.97(18)
127.02(15)
125.53(15)
107.45(12)
127.74(14)
124.11(14)
108.14(12)
C-1BꢀO-1BꢀC-7B
C-2BꢀO-2BꢀC-8B
C-3BꢀO-3BꢀC-8B
C-1BꢀO-4BꢀC-4B
C-12BꢀN-1BꢀC-5B
C-11BꢀN-2BꢀC-12B
O-1BꢀC-1BꢀO-4B
O-1BꢀC-1BꢀC-2B
O-4BꢀC-1BꢀC-2B
O-2BꢀC-2BꢀC-1B
O-2BꢀC-2BꢀC-3B
C-1BꢀC-2BꢀC-3B
O-3BꢀC-3BꢀC-4B
O-3BꢀC-3BꢀC-2B
C-4BꢀC-3BꢀC-2B
O-4BꢀC-4BꢀC-3B
O-4BꢀC-4BꢀC-5B
C-3BꢀC-4BꢀC-5B
N-1BꢀC-5BꢀC-4B
N-1BꢀC-5BꢀC-6B
C-4BꢀC-5BꢀC-6B
N-1BꢀC-5BꢀC-11B
C-4BꢀC-5BꢀC-11B
C-6BꢀC-5BꢀC-11B
O-3BꢀC-8BꢀO-2B
O-3BꢀC-8BꢀC-9B
O-2BꢀC-8BꢀC-9B
O-3BꢀC-8BꢀC-10B
O-2BꢀC-8BꢀC-10B
C-9BꢀC-8BꢀC-10B
O-6BꢀC-11BꢀN-2B
O-6BꢀC-11BꢀC-5B
N-2BꢀC-11BꢀC-5B
O-5BꢀC-12BꢀN-1B
O-5BꢀC-12BꢀN-2B
N-1BꢀC-12BꢀN-2B
112.54(14)
107.56(12)
106.73(11)
105.18(11)
112.33(12)
110.92(13)
110.99(13)
107.22(13)
105.12(12)
109.58(13)
104.31(12)
103.97(12)
111.14(12)
104.23(11)
102.75(12)
104.88(11)
107.43(11)
119.73(12)
113.56(11)
112.68(13)
111.94(12)
100.92(12)
105.85(12)
111.12(12)
104.14(12)
109.33(13)
108.76(15)
109.95(15)
110.86(14)
113.39(16)
127.23(15)
125.33(15)
107.43(12)
127.76(14)
123.90(14)
108.34(13)
a Standard deviations in parentheses.

M. Koo´sˇ et al. / Carbohydrate Research 332 (2001) 351–361
355
Table 4
part in additional hydrogen bonds, gluing thus
the dimers of 2 into an infinite 2-dimensional
array (see Table 5 and Fig. 2), approximately
in the mean plane of both hydantoin rings
(dihedral angle between the mean planes
defined by the hydantoin rings is 21.55(9)°).
Identically to compounds 4 and 5 prepared
from 2, the derivatives 6 and 7 with 5S
configuration were also prepared from hydan-
toin 3.
Atomic coordinates (×104) and equivalent isotropic displace-
2
3
a
,
ment parameters (A ×10 ) for compound 2
Atom
X
y
z
Ueq
O-1A
O-2A
O-3A
O-4A
O-5A
O-6A
N-1A
H-1A
N-2A
H-2A
C-1A
10881.1(18) 3668.2(15) 11240.2(11) 33.2(3)
8685.6(19) 622.8(17)
10747.2(16) 328.4(14)
9282.6(14) 39.1(3)
8358.6(11) 29.3(2)
10833.3(16) 3531.4(13) 9200.3(11) 27.2(2)
10311.0(15) 4108.3(12) 5453.6(10) 26.3(2)
14631.2(18) 5240.1(15) 9124.4(12) 34.3(3)
11618.2(17) 2692.4(14) 7067.5(11) 22.5(2)
The same reaction steps as in the case of
preparation of 5 were also applied to methyl
11029
1848
6773
44(7)
12454.6(18) 5067.5(14) 7234.0(12) 23.2(2)
6-deoxy-2,3-O-isopropylidene-a- -lyxo-hexo-
L
12475
10023(2)
5993
3043.8(19) 10057.5(15) 28.1(3)
3260 9785 23(5)
1380.1(19) 10089.8(16) 29.5(3)
1039 10938 46(7)
1097.0(17) 9498.6(14) 25.0(3)
524 10020 30(5)
2652.7(17) 9333.4(14) 22.8(3)
3010 10104 29(5)
7051
55(8)
furanosid-5-ulose (8)44,45 (prepared by oxida-
tion of methyl 6-deoxy-2,3-O-isopropyli-
H-1A1 8749
C-2A
H-2A1 10549
dene-a-
L
-mannofuranoside46) giving the major
10232(2)
(5S)-amino acid 12 and minor (5R)-amino
acid 14 as final products (Scheme 2). The
configuration at C-5 in this series (compounds
9, 11 and 12) was determined on the basis of
following facts: (a) configuration at C-1, C-2,
C-3A
H-3A
C-4A
H-4A
C-5A
C-6A
H-6A1 14233
H-6A2 15524
H-6A3 15005
11680(2)
12647
12320(2)
13271
12996.8(19) 2892.1(16) 8253.3(13) 21.1(2)
14582(2)
1979(2)
930
8323.1(15) 28.4(3)
C-3 and C-4 is known (a- -lyxo) and did not
L
1
change; (b) identical H and 13C NMR spec-
tral data with those given for compounds 2, 4
and 5; (c) the same values but reverse signs of
the specific rotation as those observed for 2, 4
and 5. These facts clearly indicate that
configuration at C-5 in 9, 11 and 12 must be
S. The same relationship was observed in the
series of compounds 10, 13 and 14 in compari-
son with 3, 6 and 7.
8277
26(5)
2238
9097
29(5)
2186
7640
40(6)
C-7A
10729(4)
5231(2)
5716
5589
11334(2)
10885
12196
10987
47.6(5)
74(11)
72(10)
60(9)
H-7A1 11416
H-7A2 11177
H-7A3 9490
C-8A
C-9A
H-9A1 6666
H-9A2 8107
H-9A3 7553
C-10A 9627(4)
H-10A 10572
H-10B 10012
H-10C 8579
C-11A 13494(2)
5455
9190(3)
7753(3)
−389(2)
−527(3)
−939
−1179
448
8488.9(18) 34.1(4)
7265(2)
7362
45.8(5)
64(9)
6699
55(8)
6937
44(7)
−1846(2)
−1674
−2514
−2289
9077(3)
9863
8537
51.3(6)
71(10)
67(9)
Table 3
Selected torsion angles (°) for compound 2 a
9210
92(13)
4543.3(17) 8291.6(14) 23.9(3)
Torsion angle
Molecule A
Molecule B
C-12A 11347.3(19) 3936.8(16) 6475.2(13) 21.2(3)
O-1B
O-2B
O-3B
O-4B
O-5B
O-6B
N-1B
H-1B
N-2B
H-2B
C-1B
H-1B1 3176
C-2B
H-2B1 2136
C-3B
H-3B
C-4B
1765.8(16) 500.4(13)
4169.5(16) 3420.8(14) 5372.2(11) 29.0(2)
6123.7(14) 3825.5(12) 4370.8(10) 24.6(2)
4836.9(14) 629.8(12)
10302.3(15) 54.0(13)
5965.7(19) −1109.7(15) 1877.5(12) 35.8(3)
3249.0(12) 28.5(2)
C-1ꢀC-2ꢀC-3ꢀC-4
O-4ꢀC-1ꢀC-2ꢀC-3
C-2ꢀC-3ꢀC-4ꢀO-4
C-3ꢀC-4ꢀO-4ꢀC-1
C-4ꢀO-4ꢀC-1ꢀC-2
O-2ꢀC-2ꢀC-3ꢀO-3
C-2ꢀC-3ꢀO-3ꢀC-8
C-3ꢀO-3ꢀC-8ꢀO-2
O-3ꢀC-8ꢀO-2ꢀC-2
C-8ꢀO-2ꢀC-2ꢀC-3
C-11ꢀC-5ꢀN-1ꢀC-12
C-5ꢀN-1ꢀC-12ꢀN-2
N-1ꢀC-12ꢀN-2ꢀC-11
C-12ꢀN-2ꢀC-11ꢀC-5
N-2ꢀC-11ꢀC-5ꢀN-1
6.9(2)
16.6(2)
−28.0(2)
40.4(2)
−35.6(2)
5.5(2)
−24.8(2)
35.1(2)
−31.4(2)
16.1(2)
1.6(2)
3.6(2)
21.6(2)
−27.5(1)
43.1(1)
−40.4(1)
2.4(2)
−23.4(1)
36.0(2)
−34.6(2)
19.6(2)
0.4(2)
4059.5(10) 24.7(2)
5532.3(11) 27.4(2)
8312.7(16) 1481.9(14) 4220.6(11) 21.8(2)
8632
2340
4632
35(6)
8194.2(17) −921.9(14) 3740.8(12) 23.9(2)
8433
3252(2)
−1855
1071.1(18) 4228.0(15) 25.2(3)
775 5031 30(5)
2753.4(17) 4176.2(14) 24.8(3)
3139 3773 33(6)
3813
32(6)
−2.6(2)
2.7(2)
−1.7(2)
0.1(2)
−1.8(2)
2.6(2)
−2.3(2)
1.2(2)
3319(2)
4640.5(19) 3069.3(16) 3474.2(13) 22.1(3)
4130 3652 2745 46(7)
5079.0(19) 1526.0(16) 3132.7(13) 20.5(2)
a Standard deviations in parentheses.

356
M. Koo´sˇ et al. / Carbohydrate Research 332 (2001) 351–361
Table 4 (Continued)
standard Me4Si) were recorded on a Bruker
Avance DPX 300 instrument operating at
300.13 and 75.46 MHz working frequencies,
respectively. For the assignments of signals,
1D NOESY and C–H heterocorrelated exper-
iments were used. The quaternary carbon
atoms were identified on the basis of a semi-
slective INEPT experiment and a 1D INADE-
QUATE pulse sequence technique. The EI
and CI (using pyridine as a reactive gas) mass
spectra (70 eV) were obtained on a Finnigan
MAT SSQ 710 instrument. Specific rotations
were determined on a Perkin–Elmer 241 po-
larimeter (10-cm cell). Microanalyses were
performed on a Fisons EA 1108 analyser.
Melting points were determined with a
Boetius PHMK 05 microscope. All reactions
were monitored by TLC on Silica Gel plates
(E. Merck) using the following solvents: 3:2
EtOAc–hexane (eluent A), 5:1 CHCl3–MeOH
(eluent B), 1:3 CHCl3–MeOH (eluent C). Vi-
sualisation was affected with iodine vapour or
H2SO4. Column chromatography was per-
formed as flash chromatography on Silica Gel
60 (E. Merck, 230–400 mesh) with the same
eluents.
Atom
X
y
z
Ueq
H-4B
C-5B
C-6B
H-6B1 7152
H-6B2 6453
H-6B3 8490
4185
1175
2334
25(5)
6909.1(19) 1266.2(16) 3050.8(13) 20.5(2)
7285(2)
2132(2)
3182
1783
2051.0(16) 29.2(3)
2201
1252
2060
3045(2)
2737
2444
3815
43(7)
41(6)
69(10)
38.5(4)
41(7)
30(6)
45(7)
1984
C-7B
1753(3)
−1067(2)
−1312
−1426
−1534
4476.4(18) 5292.1(15) 27.1(3)
4618(2)
3653
4979
5313
5941(2)
6613
6379
H-7B1 2716
H-7B2 627
H-7B3 1908
C-8B
C-9B
H-9B1 7440
H-9B2 6503
H-9B3 7887
5490(2)
6958(3)
6495.0(18) 37.8(4)
6688
7139
644
4888(2)
4761
5522
4123
76(11)
55(8)
41(7)
40.9(4)
45(7)
63(9)
41(7)
C-10B
4690(3)
H-10D 5588
H-10E 4264
H-10F 3706
C-11B
C-12B
Ow-1
Hw-11 15420(60)
Hw-12 14900(60)
Ow-2
Hw-21 5520(50)
Hw-22 5550(50)
Ow-3
Hw-31 13080(50)
Hw-32 11790(40)
Ow-4
5769
6935(2)
9063.3(19) 224.8(16)
14751(4)
−401.2(17) 2784.2(14) 23.6(3)
4599.6(14) 21.5(3)
8363(3)
8730(50)
7280(40)
−4267.7(19) 1752.3(15) 60.8(6)
−3240(30) 1630(30)
−4550(40) 1000(30)
8025.4(17) 6845.9(15) 46.8(4)
8340(40)
8570(40)
−3836.6(15) 3731.7(15) 41.5(3)
9222(2)
10080(30)
9290(40)
90.9(10)
95(13)
99(14)
5669(3)
77(11)
61(9)
X-ray techniques.—Crystal and experimen-
tal data for compound 2 are listed in Table 1.
The structure was solved by direct methods
and refined by a full-matrix least-squares tech-
12555(2)
7600(30)
6500(30)
69(10)
67(10)
8911(2)
nique. The crystallographic computations
Hw-41 7990(40)
Hw-42 9180(40)
−4120(40) 3300(30)
−4400(30) 4290(30)
73(11)
55(8)
47
were performed with Bruker SHELXTL
.
The
a Standard deviations in parentheses.
ZORTEP program48 was used for the molecular
graphics drawing.
Finally, total deprotection of 5 afforded
5-C-carboxy-6-deoxymannojirimycin
(15)
(5%R)-5%-Methyl-5%-[methyl (4S)-2,3-O-iso-
which was isolated as corresponding hydro-
propylidene-i- -erythrofuranosid-4-C-yl]-imi-
L
gensulfite adduct 16. Analogously, 5-C-car-
dazolidin-2%,4%-dione (2).—To a solution of 5-
ulose 1 (6.49 g, 30 mmol) in 50% aq EtOH (50
mL), was added NaCN (2.94 g, 60 mmol) and
(NH4)2CO3 (13.45 g, 140 mmol) and the mix-
ture was stirred at 60 °C for 6 h. Ethanol was
then evaporated and after cooling to rt, the
first portion (3.24 g) of 2 crystallised from the
aqueous solution. This was filtered off, and
boxy-6-deoxy- -mannojirimycin (17) and its
L
hydrogensulfite adduct 18 were obtained from
amino acid 12.
3. Experimental
General methods.—1H and 13C NMR spec-
tra (in CDCl3 unless specified other, internal

M. Koo´sˇ et al. / Carbohydrate Research 332 (2001) 351–361
357
Table 5
Hydrogen bond geometry in compound 2 a
,
,
,
XꢀH···Y
Symmetry code
XꢀH (A)
H···Y (A)
X···Y (A)
XꢀH···Y (°)
N-1AꢀH-1A···O-3A
N-1AꢀH-1A···O-5B
N-1BꢀH-1B···O-3B
N-1BꢀH-1B···O-5A
N-2AꢀH-2A···Ow-3
N-2BꢀH-2B···Ow-4
Ow-1ꢀHw-11···O-6B
Ow-1ꢀHw-12···O-6A
Ow-2ꢀHw-21···O-6B
Ow-2ꢀHw-22···O-6A
Ow-3ꢀHw-31···Ow-1
Ow-3ꢀHw-32···O-5B
Ow-4ꢀHw-41···Ow-2
Ow-4ꢀHw-42···O-5A
0.8803
0.8803
0.8798
0.8798
0.8796
0.8802
1.00(3)
1.00(4)
0.96(3)
0.87(3)
0.87(3)
0.82(3)
0.77(3)
0.82(3)
2.4137
2.0588
2.4173
2.0443
1.8785
1.8638
1.98(3)
1.86(4)
1.95(3)
2.05(3)
1.92(3)
1.98(4)
2.12(3)
1.99(3)
2.8684(18)
2.8706(17)
2.8522(17)
2.8707(17)
2.754(2)
2.7380(19)
2.921(3)
2.838(3)
2.870(2)
2.893(2)
2.744(3)
2.784(2)
112.51
152.91
110.90
156.07
173.56
171.85
156(4)
166(4)
160(3)
162(4)
157(4)
168(3)
159(3)
165(3)
1+x, 1+y, 1+z
−1+x, −1+y, −1+z
x, 1+y, z
2.860(3)
2.7952(19)
x, −1+y, z
a Standard deviations in parentheses.
Fig. 2. Crystal packing and hydrogen bonds of compound 2.
portion (2.14 g) of 2. The combined portions
of 2 were recrystallised from EtOAc–hexane
affording white crystals (5.23 g, 61%) with mp
179–180 °C. Recrystallisation from water af-
forded 2 as a dihydrate having mp 205–
the aqueous solution concentrated under di-
minished pressure and the residue chro-
matographed on a column of silica gel with
eluent A. The fractions having Rf 0.35 were
collected and evaporated to give a further

358
M. Koo´sˇ et al. / Carbohydrate Research 332 (2001) 351–361
Scheme 2.
207 °C; [h]D +151° (c 1, CHCl3), +145° (c 1,
CIMS: m/z 366 [M+80]+. Anal. Calcd for
C12H18N2O6: C, 50.30; H, 6.34; N, 9.79.
Found: 50.22; H, 6.39; N, 9.72.
1
MeOH); NMR: H (300 MHz, CDCl3): l 9.03
(bs, 1 H, NH), 6.02 (bs, 1 H, NH), 4.91 (s, 1
H, H-1), 4.84 (dd, 1 H, J2,3 5.8, J3,4 3.4 Hz,
H-3), 4.57 (d, 1 H, H-2), 4.12 (d, 1 H, H-4),
3.25 (s, 3 H, OCH3), 1.53 and 1.31 (2 s, each
3 H, Me2C), 1.52 (s, 3 H, H-6); 13C (75.5
MHz, CDCl3): l 176.0 (CO at C-4 of hydan-
toin), 156.8 (CO at C-2 of hydantoin), 113.1
(CMe2), 106.6 (C-1), 84.6 (C-2), 79.5 (C-4),
79.1 (C-3), 63.4 (C-5), 54.6 (OCH3), 25.7 and
24.1 [(CH3)2C], 20.2 (C-6); EIMS (70 eV): m/z
271 [M−Me]+, 255, 211, 197, 173 (100%),
168, 125, 115, 113, 96, 87, 85, 71, 59, 43, 42.
CIMS: m/z 366 [M+80]+. Anal. Calcd for
C12H18N2O6·2 H2O: C, 44.70; H, 6.88; N, 8.69.
Found: C, 44.59; H, 6.93, N, 8.62.
(5%R)-5%-Methyl-5%-[methyl
(4S)-i- -ery-
L
throfuranosid-4-C-yl]-imidazolidin-2%,4%-dione
(4).—A suspension of hydantoin 2 (2.86 g, 10
mmol, Rf 0.87 in solvent B) in diluted AcOH
(70%, 50 mL) was heated at 80 °C for 75 min.
The reaction mixture became clear during the
first 15 min. The solvent was evaporated to
dryness under diminished pressure and co-
evaporated twice with toluene. The residual
white solid was dissolved in EtOAc (30 mL),
treated with charcoal, filtered and the solvent
was evaporated. Recrystallisation from
EtOAc–hexane afforded pure 4 (Rf 0.50, sol-
vent B) as white crystals (1.57 g, 64%); mp
188–190 °C; [h]D +150° (c 1, water), +179°
(5%S)-5%-Methyl-5%-[methyl (4S)-2,3-O-iso-
1
propylidene - i -
L
- erythrofuranosid - 4 - C - yl]-
(c 1, MeOH); NMR: H (300 MHz, D2O): l
imidazolidin-2%,4%-dione (3).—The fractions
having Rf 0.30 from the above column chro-
matography were collected and evaporated.
Fractional crystallisation of the product from
EtOAc–hexane gave pure 3 (343 mg, 4%
yield); mp 156–158 °C; [h]D +6° (c 1,
5.04 (d, 1 H, J1,2 4.6 Hz, H-1), 4.53 (dd, 1 H,
J2,3 4.6, J3,4 3.7 Hz, H-3), 4.41 (d, 1 H, H-4),
4.16 (t, 1 H, H-2), 3.48 (s, 3 H, OCH3), 1.56
(s, 3 H, H-6); 13C (75.5 MHz, D2O): l 180.5
(CO at C-4 of hydantoin), 159.6 (CO at C-2 of
hydantoin), 109.2 (C-1), 81.5 (C-4), 76.5 (C-2),
71.4 (C-3), 65.3 (C-5), 57.2 (OCH3), 19.4 (C-
6); EIMS (70 eV): m/z 247 [M+1]+, 215, 133,
114 (100%), 113, 87, 73, 45, 42. Anal. Calcd
for C9H14N2O6: C, 43.90; H, 5.73; N, 11.40.
Found: C, 43.84; H, 5.78; N, 11.31.
1
CHCl3); NMR: H (300 MHz, CDCl3): l 9.04
(bs, 1 H, NH), 6.16 (bs, 1 H, NH), 4.99 (s, 1
H, H-1), 4.75 (dd, 1 H, J2,3 5.9, J3,4 3.8 Hz,
H-3), 4.56 (d, 1 H, H-2), 4.00 (d, 1 H, H-4),
3.34 (s, 3 H, OCH3), 1.62 and 1.24 (2 s, each
3 H, Me2C), 1.43 (s, 3 H, H-6); 13C (75.5
MHz, CDCl3): l 176.0 (CO at C-4 of hydan-
toin), 157.1 (CO at C-2 of hydantoin), 113.1
(CMe2), 106.3 (C-1), 84.7 (C-2), 79.7 (C-4),
79.3 (C-3), 62.6 (C-5), 54.7 (OCH3), 24.3 and
24.0 [(CH3)2C], 25.3 (C-6); EIMS (70 eV): m/z
271 [M−Me]+, 255, 211, 197, 173 (100%),
168, 125, 115, 113, 96, 87, 85, 71, 59, 43, 42.
Methyl
(5R)-5-amino-5-C-carboxy-5,6-
-lyxo-hexofuranoside (5).—A mix-
dideoxy-h-
D
ture of hydantoin 4 (1.23 g, 5 mmol), barium
hydroxide octahydrate (4.73 g, 15 mmol) and
water (50 mL) was heated under reflux for 6 h.
Carbon dioxide gas was then passed into the
hot mixture. The separated barium carbonate
was removed by filtration and washed with

M. Koo´sˇ et al. / Carbohydrate Research 332 (2001) 351–361
359
3.25 (s, 3 H, OCH3), 1.38 (s, 3 H, H-6); 13C
(75.5 MHz, D2O): l 176.1 (CO), 108.0 (C-1),
82.8 (C-4), 77.3 (C-2), 70.7 (C-3), 66.6 (C-5),
56.2 (OCH3), 18.9 (C-6); EIMS (70 eV): m/z
176 [M−COOH]+, 144, 116, 102, 87, 86
(100%), 74, 73, 57, 44, 43, 42. Anal. Calcd for
C8H15NO6: C, 43.40; H, 6.83; N, 6.33. Found:
C, 43.44; H, 6.90; N, 6.37.
hot water. Carbon dioxide gas was again
passed into the hot solution and after cooling
to rt, another portion of barium carbonate
separated. Filtration and decolourising with
charcoal gave a clear solution. Water was
evaporated under diminished pressure and the
residual solid was purified on a short column
of silica gel (eluent C). Fractions with Rf 0.39
(eluent C) were collected and evaporated to
afford 5 (420 mg, 38%). Analytical sample
(white needles) was obtained by recrystallisa-
tion from water–methanol; mp (dec) 190 °C;
(5%S)-5%-Methyl-5%-[methyl (4R)-2,3-O-iso-
propylidene - i -
D
- erythrofuranosid - 4 - C - yl]-
imidazolidin-2%,4%-dione (9).—Starting from 8
(6.49 g, 30 mmol), and application of the same
reaction procedure as described for the prepa-
ration of 2 afforded 9 (5.06 g, 59%); mp
208–209 °C; [h]D −151° (c 1, CHCl3), −145°
(c 1, MeOH); NMR and mass spectra were
identical with those reported for compound 2.
Anal. Calcd for C12H18N2O6: C, 50.30; H,
6.34; N, 9.79. Found: 50.19; H, 6.40; N, 9.73.
(5%R)-5%-Methyl-5%-[methyl (4R)-2,3-O-iso-
1
[h]D +93° (c 1, water); NMR: H (300 MHz,
D2O): l 4.99 (d, 1 H, J1,2 4.5 Hz, H-1), 4.51
(d, 1 H, J3,4 3.3 Hz, H-4), 4.49 (dd, 1 H, J2,3
4.5 Hz, H-3), 4.14 (t, 1 H, H-2), 3.41 (s, 3 H,
OCH3), 1.54 (s, 3 H, H-6); 13C (75.5 MHz,
D2O): l 175.7 (CO), 108.9 (C-1), 80.6 (C-4),
77.1 (C-2), 72.1 (C-3), 62.8 (C-5), 56.9
(OCH3), 18.8 (C-6); EIMS (70 eV): m/z 176
[M−COOH]+, 144, 116, 102, 87, 86 (100%),
74, 73, 57, 44, 43, 42. Anal. Calcd for
C8H15NO6: C, 43.40; H, 6.83; N, 6.33. Found:
C, 43.47; H, 6.88; N, 6.37.
propylidene - i -
D
- erythrofuranosid - 4 - C - yl]-
(10).—Fractional
imidazolidin-2%,4%-dione
crystallisation (from EtOAc–hexane) of the
product, obtained from column chromatogra-
phy (Rf 0.30, eluent A) of the crude product
from the mother liquor (after exhaustive re-
covery of 9) from above preparation of 9,
afforded pure 10 (377 mg, 4.4% yield); mp
158–160 °C; [h]D −6° (c 1, CHCl3); NMR
and mass spectra were identical with those
reported for compound 3. Anal. Calcd for
C12H18N2O6: C, 50.30; H, 6.34; N, 9.79.
Found: 50.23; H, 6.38; N, 9.84.
(5%S)-5%-Methyl-5%-[methyl
(4S)-i- -ery-
L
throfuranosid-4-C-yl]-imidazolidin-2%,4%-dione
(6).—Starting from 3 (572 mg, 2 mmol), and
application of the same reaction procedure as
described for the preparation of 4 afforded 6
(335 mg, 68%); mp 238–239 °C; [h]D +19° (c
1, MeOH); NMR: 1H (300 MHz, D2O): l 4.82
(s, 1 H, H-1), 4.33 (dd, 1 H, J2,3 4.6, J3,4 7.6
Hz, H-3), 4.16 (d, 1 H, H-4), 4.01 (t, 1 H,
H-2), 3.29 (s, 3 H, OCH3), 1.46 (s, 3 H, H-6);
13C (75.5 MHz, D2O): l 180.4 (CO at C-4 of
hydantoin), 159.8 (CO at C-2 of hydantoin),
108.4 (C-1), 83.9 (C-4), 75.2 (C-2), 71.7 (C-3),
66.1 (C-5), 55.8 (OCH3), 18.2 (C-6); EIMS (70
eV): m/z 247 [M+1]+, 215, 133, 114 (100%),
113, 87, 73, 45, 42. Anal. Calcd for
C9H14N2O6: C, 43.90; H, 5.73; N, 11.40.
Found: C, 43.80; H, 5.79; N, 11.35.
(5%S)-5%-Methyl-5%-[methyl
(4R)-i- -ery-
D
throfuranosid-4-C-yl]-imidazolidin-2%,4%-dione
(11).—Starting from 9 (2.86 g, 10 mmol), and
application of the same reaction procedure as
described for the preparation of 4 afforded 11
(1.62 g, 66%); mp 184–186 °C; [h]D −150° (c
1, water), −179° (c 1, MeOH); NMR and
mass spectra were identical with those re-
ported for compound 4. Anal. Calcd for
C9H14N2O6: C, 43.90; H, 5.73; N, 11.40.
Found: C, 43.98; H, 5.78; N, 11.32.
Methyl
dideoxy-h-
(5S)-5-amino-5-C-carboxy-5,6-
-lyxo-hexofuranoside (7).—Start-
D
Methyl
dideoxy-h-
(5S)-5-amino-5-C-carboxy-5,6-
-lyxo-hexofuranoside (12).—Start-
ing from 6 (246 mg, 1 mmol), and application
of the same reaction procedure as described
for the preparation of 5 afforded 7 (91 mg,
41%); mp (dec) 196 °C; [h]D +12° (c 1, wa-
L
ing from 11 (1.23 g, 5 mmol), and application
of the same reaction procedure as described
for the preparation of 5 afforded 12 (442 mg,
40%); mp (dec) 193 °C; [h]D −93° (c 1, wa-
ter); NMR and mass spectra were identical
with those reported for compound 5. Anal.
1
ter); NMR: H (300 MHz, D2O): l 4.88 (s, 1
H, H-1), 4.24 (dd, 1 H, J2,3 4.6, J3,4 7.7 Hz,
H-3), 4.10 (d, 1 H, H-4), 3.98 (t, 1 H, H-2),

360
M. Koo´sˇ et al. / Carbohydrate Research 332 (2001) 351–361
Calcd for C8H15NO6: C, 43.40; H, 6.83; N,
6.33. Found: C, 43.42; H, 6.86; N, 6.31.
Acknowledgements
(5%R)-5%-Methyl-5%-[methyl (4R)-i- -ery-
D
The authors thank K. Paule, G. Kosˇicky´,
A. Karovicˇova´, A. Kanska´, and Dr V. Pa¨to-
prsty´ (Institute of Chemistry) for microanaly-
ses, optical rotation, NMR, and mass spectral
measurements. Financial support of this work
by the Scientific Grant Agency (VEGA, Slo-
vak Academy of Sciences, Grant No. 2/7144/
20) is gratefully appreciated.
throfuranosid-4-C-yl]-imidazolidin-2%,4%-dione
(13).—Starting from 10 (572 mg, 2 mmol),
and application of the same reaction proce-
dure as described for the preparation of 4
afforded 13 (320 mg, 65%); mp 240–241 °C;
[h]D −19° (c 1, MeOH). NMR and mass
spectra were identical with those reported for
compound 6. Anal. Calcd for C9H14N2O6: C,
43.90; H, 5.73; N, 11.40. Found: C, 43.82; H,
5.79; N, 11.38.
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