Synthesis of a novel N-O-interglycosidic disaccharide

Article abstract of DOI:10.1016/S0008-6215(03)00270-2

The carbohydrate subunits carrying an N-O-interglycosidic bond play a very important role in the biological activity of the enediyne antibiotics. Condensation of O-(α- and β-D-glucopyranosyl)hydroxylamine (5a and 5b) with the hex-3-ulopyranoside (6) furnished methyl 4,6-O-benzylidene-2,3-dideoxy-3-(2,3,4,6-tetra-O-benzyl-α-D- glucopyranosyloxy)imino-α- and β-D-erythro-hexopyranoside (7a and 7b). Stereoselective reduction of the C=N bond of 7a and 7b with sodium cyanoborohydride resulted in the formation of the required protected N-O-interglycosidic disaccharides (8a and 8b). Finally, catalytic hydrogenation of 8a afforded methyl 2,3-dideoxy-3-(α-D-glucopyranosyloxy)amino-α-D-ribo- hexopyranoside (9a). Under similar conditions the β anomer 8b underwent decomposition.

Full text of DOI:10.1016/S0008-6215(03)00270-2

Carbohydrate Research 338 (2003) 1787ꢀ1792
/
www.elsevier.com/locate/carres
Note
Synthesis of a novel Nꢀ
/
O-interglycosidic disaccharide
Miklo´s Hornya´k, Ferenc Sztaricskai,* Istva´n F. Pelyva´s, Gyula Batta
Research Group of Antibiotics of the Hungarian Academy of Sciences, and Department of Pharmaceutical Chemistry, University of Debrecen,
P.O. Box 70, Debrecen H-4010, Hungary
Received 14 March 2003; accepted 20 May 2003
Abstract
The carbohydrate subunits carrying an Nꢀ
enediyne antibiotics. Condensation of O-(a- and b-
furnished methyl 4,6-O-benzylidene-2,3-dideoxy-3-(2,3,4,6-tetra-O-benzyl-a-
pyranoside (7a and 7b). Stereoselective reduction of the CÄN bond of 7a and 7b with sodium cyanoborohydride resulted in the
formation of the required protected NꢀO-interglycosidic disaccharides (8a and 8b). Finally, catalytic hydrogenation of 8a afforded
methyl 2,3-dideoxy-3-(a- -glucopyranosyloxy)amino-a- -ribo-hexopyranoside (9a). Under similar conditions the b anomer 8b
underwent decomposition.
# 2003 Elsevier Ltd. All rights reserved.
/
O-interglycosidic bond play a very important role in the biological activity of the
-glucopyranosyl)hydroxylamine (5a and 5b) with the hex-3-ulopyranoside (6)
-glucopyranosyloxy)imino-a- and b- -erythro-hexo-
D
D
D
/
/
D
D
Keywords: Nꢀ
O-interglycosidic disaccharide; Synthesis; 1H and 13C NMR
/
The enediyne antibiotics1 calicheamycin (1) and esper-
amycin (2) (Fig. 1) exert their antibacterial and anti-
tumor activity2 via DNA splitting,3ꢀ5 thus causing
apoptosis of the cells. In some cases the biological
target interglycosidic linkage is developed via O-glyco-
sylation of N-hydroyaminosugar derivatives; (ii) glycu-
lose derivatives of sugars are condensed with an O-
glycosylhydroxylamine. Nevertheless, in the latter reac-
tion, theoretically four isomers (syn- and anti- as well as
a- and b-) are produced (Fig. 2).
activity of the enediyne antibiotics is 2ꢀ4000-fold
/
higher6 than that of adriamycin, a drug nowadays
extensively used in clinical practice.
During the stereoselective reduction of the CÄ
/N bond
It was assumed7 that the Nꢀ
O-interglycosidic moiety
/
in Ia a mixture of only two components IIa can be
d
b
ꢀ
ꢀ
and its conformation play an important role in the
activity of these antibiotics. No such type of interglyco-
sidic bond has been elucidated thus far in any other
compounds of natural origin.
formed. The situation is further simplified when the
starting material is an O-glycosylhydroxylamine deriva-
tive having fixed and known anomeric configuration.
The present paper reports the use of such a synthetic
strategy.
The known10 crystalline phthaloyl glycosides 4a and
4b, synthesized from 2,3,4,6-tetra-O-benzyl-D
-glucose11
Recently, we reported the first definitive synthesis8 of
methyl a-
of the enediyne antibiotic kedarcidin.9 In this work our
goal was to synthesize new NꢀO-interglycosidic disac-
L-kedarosaminide, a carbohydrate component
/
(3) under Mitsunobu conditions were dephthaloylated
with hydrazine hydrate, and the resulting crude O-(a-
charides similar to those present in the molecules of
antibiotics 1 and 2.
There are two practical methods for the synthesis of
and b-
were used in the next step (Scheme 1). Methyl 4,6-O-
-erythro-hexopyranosid-3-
D-glucopyranosyl)hydroxylamines (5a and 5b)
the NꢀO-interglycosidic bond in disaccharides: (i) the
/
benzylidene-2-deoxy-a-
D
ulose12 (6) was selected as the other building block of
our target disaccharides. The freshly prepared 5a and 5b
were allowed to react with a 1.5 molar excess of the
* Corresponding author. Fax: ꢁ36-52-512914.
/
E-mail address: antibiotics@tigris.klte.hu (F. Sztaricskai).
0008-6215/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0008-6215(03)00270-2

1788
M. Hornya´k et al. / Carbohydrate Research 338 (2003) 1787ꢀ1792
/
Fig. 1. Structures of calicheamycin gI1 (1) and esperamycin A1 (2).
Fig. 2. Reduction of an Ã
/
O-NÄ
/
interglycosidic linkage.

M. Hornya´k et al. / Carbohydrate Research 338 (2003) 1787ꢀ
/1792
1789
Scheme 1. Synthesis of the target N-O-glycosidic disaccharide 9a.
˚
glyculoside 6 in the presence of 4 A molecular sieves and
in the case of 5b the yield was only 40% because the
product partly decomposed upon column-chromato-
graphic purification.
In the H NMR spectra of 7a and 7b no duplicate
signals appear, implying that one of the possible
stereoisomers was formed exclusively in both cases. In
pyridine p-toluenesulfonate (PPTS) in dry benzene to
afford methyl 4,6-O-benzylidene-2,3-dideoxy-3-(2,3,4,6-
1
tetra-O-benzyl-a- and b-
-erythro-hexopyranoside (7a and 7b). Although the
condensation of 5a with 6 proceeded almost completely,
D-glucopyranosyloxy)imino-a-
D

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M. Hornya´k et al. / Carbohydrate Research 338 (2003) 1787ꢀ1792
/
the 13C NMR spectrum of 7a the chemical shift for C-3
(149.4 ppm) indicates the presence of the CÄN double
bond. The J1?,2? value of 4.0 Hz implies the a anomeric
configuration of the -glucopyranosyl unit of the
disaccharide. The J1?,2? value of 8.3 Hz observed in
the spectrum of 7b supports that the glucopyranosyl
Silica gel 60 F254 sheets (Merck). Evaporation of the
solutions were carried out under diminished pressure
(bath temperature max 40 8C).
/
3
D
3
1.2. Methyl 4,6-O-benzylidene-2,3-dideoxy-3-(2,3,4,6-
tetra-O-benzyl-a-D-glucopyranosyloxy)imino-a-D-
erythro-hexopyranoside (7a)
moiety carries an axial (b anomeric) proton, and the 13
C
NMR shift for C-3 (149.6 ppm) indicates a CÄ
bond.
Reduction of 7a and 7b with sodium cyanoborohy-
dride in methanol (pH Â5) resulted in the stereoselec-
tive formation of the target disaccharides 8a and 8b with
the planned NꢀO-interglycosidic bond with good yields.
/
N double
To a stirred solution of 4a10 (0.15 g, 0.22 mmol) in
MeOH (6 mL) hydrazine hydrate (0.017 mL, 0.35 mmol)
was added. After the disappearance of the starting
material, the mixture was filtered through a pad of
/
/
Celite, which was then washed with 2ꢂ15 mL of Et2O.
/
3
The J1,2ax value 3.9 Hz for 8a confirms the a anomeric
configuration at C-1, and the change in the 13C NMR
shift to 56.18 ppm indicates a successful reduction of the
The solvent was removed in vacuo, and the residue was
redissolved in Et2O (15 mL) and filtered again through a
Celite pad. To the crude, syrupy 5a the C-3 keto sugar 6
3
double bond. The J1?,2? coupling constant (3.9 Hz)
implies that the a anomeric configuration of the non-
reducing unit remained unchanged. In the disaccharide
(0.081 g, 0.32 mmol) was added, and 3ꢂ10 mL of dry
/
C6H6 was distilled off from the mixture. The syrupy
residue obtained was dissolved in dry C6H6 (10 mL),
and the solution stirred in the presence of several
3
8b the J1?,2? value 8.3 Hz denotes the axial orientation
˚
crystals of PPTS and 4 A molecular sieves for 48 h.
After evaporation, the residue was purified by column
(and the b anomeric configuration) of H-1? whereas the
3J1,2ax value 4.3 Hz indicates the a-glycosidic structure
of the 2,3-dideoxy sugar unit. The structures of 7a and
7b, as well as 8a and 8b were convincingly proved by
means of electron-spray (ES) mass spectral investiga-
tion.
chromatography (20:1 hexaneꢀ
/
Et2O) to afford 0.170 g
114 8C; [a]2D5
(approx. 100%) of pure 7a: mp 112ꢀ
/
ꢁ
/
1108
1
(c 2.0, CHCl3); H NMR (CDCl3): d 2.37 (dd, 1 H,
J2a,2e 14.9 Hz, H-2a), 3.33 (s, 3 H, OCH3), 3.64 (d, 1 H,
H-2e), 3.78 (dd, 1 H, J6?e,6?a 11 Hz, J6?e,5? 2 Hz, H-6?e),
Finally, removal of the protecting groups of 8a by
catalytic hydrogenation (Pd/C; MeOH) furnished meth-
3.80 (dd, 1 H, J2?,3? 9.5 Hz, H-2?), 3.81 (t, 1 H, J3?,4?ꢃ
4?,5?ꢃ9.5 Hz, H-4?); 3.87 (dd, 1 H, J6?a,5? 3.1 Hz, H-6?a),
3.89 (t, 1 H, J6a,6e J5,6a 10.4 Hz, H-6a), 4.00 (ddd, 1
/
yl
2,3-dideoxy-3-(a-
D
-glucopyranosyloxy)amino-a-
D
-
J
/
ribo-hexopyranoside (9a), which was purified with
column chromatography. Unfortunately, under com-
parable conditions 8b was unstable and decomposed.
ꢃ
/
ꢃ
/
H, H-5?), 4.02 (t, 1 H, H-3?), 4.11 (m, 1 H, J5,6e 4.8 Hz,
H-5), 4.32 (d, 1 H, J4,5 9.8 Hz, H-4), 4.35 (1 H, H-6e),
3
3
The small J1,2ax and J1?,2? values (3.9 Hz) observed in
1
the H NMR spectrum of the disaccharide 9a prove the
4.56ꢀ
4.3 Hz, H-1), 5.63 (s, 1 H, C6H5CH), 5.87 (d, 1 H, J1?,2? 4
Hz, H-1?), 7.2ꢀ
7.6 (m, 25 H, C6H5); 13C NMR (CDCl3):
/
5.06 (8ꢂ
/
d, 8 H, 4ꢂ
/
C6H5CH2), 4.91 (d, 1 H, J1,2a
a anomeric configuration of both sugar units. In
addition, the 13C NMR shift for C-1? (102.78 ppm)
indicates an a anomeric carbon, while the lower value
observed for C-3 (59.05 ppm) is attributable to the
vicinity of the nitrogen atom.
/
d 32.76 (C-2), 55.10 (OCH3), 65.64 (C-5), 68.81 (C-6?),
69.98 (C-6), 71.32 (C-5?), 73.42, 73.83, 75.71
(OCH2C6H5), 78.3 (C-4?), 78.92 (C-4), 79.71 (C-2?),
82.87 (C-3?), 98.96 (C-1), 99.36 (C-1?), 102.99
(C6H5CH), 126.6, 128.2, 129.1, 137.2, 137.7 (C6H5),
149.4 (C-3); MSelectrospray Mꢁ
/
Hꢁ 802.9, Mꢁ
/
Naꢁ
1. Experimental
824.9, Mꢁ
/
Kꢁ 841. Anal. Calcd for C48H51NO10: C,
71.89; H, 6.41; N, 1.75. Found: C, 71.79; H, 6.56; N,
1.70.
1.1. General methods
Melting points were determined with a Kofler hot-stage
apparatus, and the data are uncorrected. The specific
1.3. Methyl 4,6-O-benzylidene-2,3-dideoxy-3-(2,3,4,6-
tetra-O-benzyl-b-D-glucopyranosyloxy)imino-a-D-
erythro-hexopyranoside (7b)
optical rotation values were measured on a Perkinꢀ
/
Elmer 241 automatic polarimeter at room temperature.
The 1H and 13C NMR spectra were recorded with
Bruker 200, 360 and 500 MHz spectrometers with Me4Si
as the internal standard. The mass spectra were obtained
with a VG Micromass 7035 spectrometer. Column
chromatography was performed on Silicagel 60 (Merck,
To a stirred solution of 4b10 (0.685 g, 1.0 mmol) in
MeOH (6 mL) hydrazine hydrate (0.072 mL, 1.5 mmol)
was added. The reaction and purification were per-
formed as described for 7a, and 0.317 g (40%) of 7b was
1
isolated: mp 170ꢀ
/
173 8C; [a]2D5
NMR (CDCl3): d 2.35 (dd, 1 H, J2a,2e 15.1 Hz, H-2a),
3.23 (s, 3 H, OCH3), 3.61 (d, 1 H, H-2e), 3.54 (ddd, 1 H,
ꢁ
/
628 (c 5.0, CHCl3); H
size 0.063ꢀ
/
0.1 mm), and the thin-layer chromatographic
(TLC) examinations were carried out on precoated

M. Hornya´k et al. / Carbohydrate Research 338 (2003) 1787ꢀ
/1792
1791
H-5?), 3.60 (t, 1 H, J1?,2?ꢃ
1 H, H-2e), 3.71 (t, 1 H, H-3?), 3.73 (t, 1 H, J3?,4?ꢃ
4?,5?ꢃ8.56 Hz, H-4?), 3.76 (d, 2 H, J6?a,6?e 11 Hz, H-6?
/
J
2?3?ꢃ
/
8.49 Hz, H-2?), 3.61 (d,
1.5. Methyl 4,6-O-benzylidene-2,3-dideoxy-3-(2,3,4,6-
tetra-O-benzyl-b- -glucopyranosyloxy)amino-a- -ribo-
hexopyranoside (8b)
/
D
D
J
/
and H-6?e), 3.87 (t, 1 H, J6a,6e 10.3 Hz, H-6a), 4.09 (ddd,
1 H, J5,6e 4.64 Hz, H-5), 4.30 (d, 1 H, J4,5 9.4 Hz, H-4),
To a stirred solution of 7b (0.1 g, 0.12 mmol) in the
mixture of dry CH2Cl2 (2 mL) and dry MeOH (5 mL)
sodium cyanoborohydride (0.032 g, 0.48 mmol) was
added in small quantities. The reaction and purification
4.35 (1 H, ddd, H-6e), 4.48ꢀ
C6H5CH2), 4.91 (d, 1 H, J1,2a 4.2 Hz, H-1), 5.29 (d, 1
7.6
/
4.99 (8ꢂ
/
d, 8 H, 4ꢂ
/
H, J1?,2? 8.29 Hz, H-1?), 5.67 (s, 1 H, C6H5CH), 7.2ꢀ
/
(m, 25 H, C6H5); 13C NMR (CDCl3): d 31.7 (C-2), 55.0
(OCH3), 65.36 (C-5), 68.84 (C-6?), 70.0 (C-6), 75.0 (C-
5?), 73.91, 73.73, 75.75 (OCH2C6H5), 77.83 (C-4?), 78.65
(C-4), 81.44 (C-2?), 85.22 (C-3?), 98.9 (C-1), 102.8
(C6H5CH), 105.9 (C-1?), 126.6, 128.2, 129.1, 137.2,
was performed as described bove for 8a, to afford 70 mg
1
(70%) of pure, syrupy 8b: [a]D25
ꢁ
/
458 (c 2.0, CHCl3); H
NMR (CDCl3): d 1.80 (ddd, 1 H, J2a,2e 14.9, J2a,3 4.1
Hz, H-2a), 2.50 (d, 1 H, H-2e), 3.35 (s, 3 H, OCH3), 3.45
(t, 1 H, H-2), 3.51 (dd, 1 H, H-5?), 3.68 (dd, 1 H, J6e,6a
10.4, J5,6e 3.9 Hz, H-6e), 3.70 (t, 1 H, H-3?), 3.72 (m, 2
H, H-3 and H-4?), 3.79 (dd, 1 H, J4,5 10.2, J3,4 3.9 Hz, H-
4), 4.23 (m, 1 H, H-5), 4.27 (dd, 1 H, J5,6a 5.1 Hz, H-6),
137.7 (C6H5), 149.6 (C-3); MSelectrospray Mꢁ
/
Hꢁ 802.9,
Mꢁ
/
Naꢁ 824.9, MꢁKꢁ 841. Anal. Calcd for
/
C48H51NO10: C, 71.89; H, 6.41; N, 1.75. Found: C,
71.91; H, 6.52; N, 1.55.
4.50ꢀ
4.3 Hz, H-1), 4.93 (d, 1 H, J1?,2? 8.3 Hz, H-1?), 6.10 (s, 1
H, C6H5CH), 7.1ꢀ
7.5 (m, 25 H, C6H5); 13C NMR
/
5.0 (4ꢂ
/
d, 8 H, 4ꢂ
/
C6H5CH2), 4.67 (d, 1 H, J1,2a
/
(CDCl3): d 30.0 (C-2), 55.2 (C-3), 55.8 (OCH3), 58.9 (C-
5), 68.8 (C-6?), 70.0 (C-6), 75.0 (C-5?), 73.8, 74.9, 75.7
(OCH2C6H5), 78.2 (C-4?), 78.8 (C-4), 81.7 (C-2?), 85.4
(C-3?), 98.7 (C-1), 102.5 (C6H5CH), 106.4 (C-1?), 126.6,
1.4. Methyl 4,6-O-benzylidene-2,3-dideoxy-3-(2,3,4,6-
tetra-O-benzyl-a-D-glucopyranosyloxy)-amino-a-D-ribo-
hexopyranoside (8a)
128.2, 129.1, 137.2, 137.7 (C6H5); MSelectrospray Mꢁ
/
Hꢁ
To a solution of 7a (0.1 g, 0.12 mmol) in a mixture of
dry CH2Cl2 (2 mL) and dry MeOH (5 mL) sodium
cyanoborohydride (0.032 g, 0.48 mmol) was added in
small quantities. After adding each portion of the
reducing agent the pH of the solution was adjusted to
5.5 with HCl in MeOH. After 3 h the solvent was
evaporated, and the residue was dissolved in CH2Cl2 (15
mL). The organic solution was washed with satd
NaHCO3 solution (15 mL) and water (5 mL), and
then dried over MgSO4, filtered, and concentrated. The
resulting syrup was purified by column chromatography
804.96, Mꢁ
/
Naꢁ 826.95, MꢁKꢁ 843.0. Anal. Calcd
/
for C48H53NO10: C, 71.71; H, 6.64; N, 1.74. Found: C,
71.62; H, 6.53; N, 1.76.
1.6. Methyl 2,3-dideoxy-3-(a-
glucopyranosyloxy)amino-a-D-ribo-hexopyranoside (9a)
D-
A solution of 8a (0.1 g, 0.12 mmol) in dry MeOH (10
mL) was hydrogenated in the presence of Pd/C catalyst
(0.1 g) at atmospheric pressure. After 12 h, the catalyst
(50:1 tolueneꢀ
/
Et2O) to yield 0.082 g (82%) of pure
syrupy 8a: [a]D25 75.258 (c 5.0, CHCl3); 1H NMR
(CDCl3): d 1.87 (ddd, 1 H, J2a,2e 15, J2a,3 4.2 Hz, H-2a),
ꢁ
/
was filtered off and washed with MeOH (3ꢂ5 mL). The
/
combined methanolic solution was evaporated to dry-
ness, and the residual syrup was purified by means of
2.36 (d, 1 H, H-2e), 3.31 (s, 3 H, OCH3), 3.56 (dd, 1 H,
J
column chromatography (9:1:0.1 CH2Cl2ꢀ
/
MeOHꢀ
/
2?3? 9.9 Hz, H-2?), 3.62 (t, 1 H, J3?,4? 9.55 Hz, H-4?), 3.70
concd NH4OH) to afford 0.037 g (84%) of syrupy 9a:
1
(dd, 1 H, J6e,6a 10.4, J5,6e 3.9 Hz, H-6e), 3.74 (dd, 1 H,
J4,5 10.6, J3,4 3.9 Hz, H-4), 3.80 (t, 1 H, H-3), 3.87 (t, 1
H, H-3?), 4.02 (dd, 1 H, H-5?), 4.09 (m, 1 H, H-5), 4.29
[a]2D5
ꢁ97.28 (c 2.0, CHCl3); H NMR (D2O): d 1.89
/
(ddd, 1 H, J2a,2e 14.9, J2a,3 4.1 Hz, H-2a), 2.46 (d, 1 H,
H-2e), 3.43 (s, 3 H, OCH3), 3.47 (dd, 1 H, H-5?), 3.56
(dd, 1 H, J2?,3? 9.9 Hz, H-2?), 3.26 (t, 1 H, J3?,4? 9.65 Hz,
H-4?), 3.59 (t, 1 H, H-3), 3.62 (t, 1 H, H-3?), 3.89 (dd, 1
H, J6e,6a 10.4, J5,6e 3.9 Hz, H-6e), 3.71 (dd, 1 H, J4,5 10.6,
J3,4 3.9 Hz, H-4), 3.92 (dd, 1 H, J5,6a 5.1 Hz, H-6a), 3.98
(m, 1 H, H-5), 4.82 (d, 1 H, J1,2a 3.9 Hz, H-1), 5.35 (d, 1
H, J1?,2? 3.9 Hz, H-1?); 13C NMR (D2O): d 33.25 (C-2),
55.9 (OCH3), 59.05 (C-3), 62.31 (C-6?), 62.65 (C-6),
68.65 (C-4), 69.32 (C-5), 71.31 (C-4?), 73.06 (C-5?), 73.15
(C-2?), 74.8 (C-3?), 100.8 (C-1), 102.78 (C-1?). Anal.
Calcd for C13H25NO10: C, 43.94; H, 7.09; N, 3.94.
Found: C, 44.11; H, 7.14; N, 4.01.
(dd, 1 H, J5,6a 5.1 Hz, H-6a), 4.50ꢀ
C6H5CH2), 4.70 (d, 1 H, J1,2a 3.9 Hz, H-1), 5.35 (d, 1 H,
7.6 (m,
/
4.93 (8ꢂ
/
d, 8 H, 4ꢂ
/
J1?,2? 3.9 Hz, H-1?), 5.59 (s, 1 H, C6H5CH), 7.2ꢀ
/
25 H, C6H5); 13C NMR (CDCl3): 33.15 (C-2), 55.55
(OCH3), 56.18 (C-3), 59.22 (C-5), 69.12 (C-6?), 70.05 (C-
6), 70.99 (C-5?), 73.02, 73.85, 75.95 (OCH2C6H5), 78.26
(C-4?), 79.15 (C-4), 80.05 (C-2?), 82.41 (C-3?), 98.8 (C-1),
100.7 (C-1?), 102.8 (C6H5CH), 126.6, 128.2, 129.1,
137.2, 137.7 (C6H5); MSelectrospray Mꢁ
/
Hꢁ 804.96,
Mꢁ
/
Naꢁ 826.95, MꢁKꢁ 843.0. Anal. Calcd for
/
C48H53NO10: C, 71.71; H, 6.64; N, 1.74. Found: C:
69.82; H, 6.82; N, 1.63.

1792
M. Hornya´k et al. / Carbohydrate Research 338 (2003) 1787ꢀ1792
/
4. Zein, N.; Sinha, A. M.; McGahren, W. J.; Elestad, G. A.
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Acknowledgements
/
This work was financially supported by the Hungarian
Academy of Sciences, and by the National Scientific
Research Found (Budapest, Hungary) with the Grants
OTKA T 029075, T 029027 and T 042567. The authors
thank Dr Zolta´n Dinya for the mass spectral measure-
ments. A part of this work is included in the Ph.D.
Theses of M.H.
Solomon, W.; Doyle, T. W.; Casazza, A. M. Proc. Natl.
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