Synthesis of 3-oxagranatane-type alkaloid analogs from carbohydrates

Article abstract of DOI:10.1016/S0040-4020(00)01004-8

3-Oxagranatane derivatives have been synthesized from dialdehydes obtained by the periodate oxidation of D-glucopyranosides. Reduction of the carbonyl group and removal of the substituents afforded bicyclic iminosugar analogs.

Full text of DOI:10.1016/S0040-4020(00)01004-8

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 235±239
Synthesis of 3-oxagranatane-type alkaloid analogs
from carbohydrates
a
Attila Agocs, Pal Herczegh, Szilvia Jager, Laszlo Kiss and Gyula Batta
a,
b
b
a
*
Â
Â
Â
Â
È
aResearch Group for Antibiotics of the Hungarian Academy of Sciences, University of Debrecen, P.O. Box 70, H-4010 Debrecen, Hungary
bDepartment of Biochemistry, University of Debrecen, P.O. Box 55, H-4010, Debrecen, Hungary
Received 17 July 2000; revised 2 October 2000; accepted 19 October 2000
AbstractÐ3-Oxagranatane derivatives have been synthesized from dialdehydes obtained by the periodate oxidation of d-glucopyranosides.
Reduction of the carbonyl group and removal of the substituents afforded bicyclic iminosugar analogs. q 2000 Elsevier Science Ltd. All
rights reserved.
Iminosugars (i.e. polyhydroxypyrrolidines and piperidines),
and structurally related saccharide-analog alkaloids carry-
ing piperidine building blocks, are potent inhibitors of
different glycosidase enzymes.1 This property is manifested
in various biological effects, such as inhibition of glyco-
protein processing, antiviral (anti-HIV), antitumor, insecti-
cide, and nematicide activities,1 and thus the synthesis of
these natural products and their structural analogs has
become an intensively studied subject. Calystegines, a
recently discovered family2 of the iminosugars, contain a
bridged tropane skeleton (Fig. 1). With this structure in
mind, we decided to investigate the glycosidase enzyme
inhibitory properties of certain carbohydrate analogs
carrying an oxagranatane skeletone, which are readily
available from simple saccharides in a few synthetic steps.
acetonedicarboxylic acid in aqueous medium (Scheme 1).
In a diastereoselective reaction a single ketone isomer (3)
with 3-oxagranatane skeleton was formed. Stereoselective
reduction of the oxo function in 3 with lithium aluminium
hydride furnished 4 carrying an axially-oriented hydroxyl
group. Removal of the N-benzyl function by catalytic
hydrogenation gave 5, whose acetal function was hydro-
lyzed in acidic medium to obtain the target compound 6.
In order to study the role of the con®guration of the
glycosidic center on the stereochemical outcome of the
È
Robinson±Schopf reaction, the transformations described
above were also performed with the b-anomer (7, methyl
b-d-glucopyranoside) of 1. In this case the ketone 8 and
(after reduction) the diol 9 were obtained, indicating that
the 4-OCH3 and the 2-CH2OH are present in an ener-
getically rather unfavorable cis±diaxial relationship at the
double-chair oxagranatane skeletone of 8 and 9. A similar,
diaxially-substituted product was also observed by
Masamune et al.4,5 The development of such a stereo-
chemistry can be explained by an attack of acetone-
dicarboxylic acid on the intermediary cyclic hemiaminal
The synthesis of a few compounds with a 3-oxagranatane
structure was reported by the groups of Guthrie3 and
Masamune.4,5 The former authors3 prepared the substituted
È
derivatives of 3-oxagranatane using the Robinson±Schopf
reaction6,7 of the dialdehydes derived from b-l-arabino-
pyranose or a-l-rhamnopyranose by means of periodate
oxidation. Masamune et al.4,5 employed a dioxo compound
as the starting material, which was obtained upon ozonoly-
sis of 2,5-dihydrofurane derivatives. At the same time,
neither of the two groups investigated the enzyme inhibitory
properties of the products prepared.
È
of the Robinson±Schopf reaction from the side opposite
to that on which the bulky hydroxyalkyl and methoxy
substituents are located, and thus compound 8 is formed
Our present methodology is based on the oxidation of
methyl a-d-glucopyranoside (1) with sodium metaperiodate
È
and subsequent Robinson±Schopf reaction of the resulting,
non-isolated chiral dialdehyde (2) with benzylamine and
Keywords: alkaloids; carbohydrate mimetics; aza compounds.
* Corresponding author. Tel.: 136-52-152-900/2463; fax: 136-52-512-
914; e-mail: herczeghp@tigris.klte.hu
Figure 1.
0040±4020/01/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01004-8

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A. Agocs et al. / Tetrahedron 57 (2001) 235±239
236
Scheme 1.
after decarboxylation (Scheme 2). The exclusive formation
of 4 can also be similarly explained by the decisive directing
effect of the bulky 2-CH2OH function.
supported the cis-diaxial relationship between the
2-CH2OH and the 4-OCH3 groups. It is interesting to note
that the chemical shift of the axial proton at the C-4 pseudo-
anomeric center in compounds 4 and 5 is higher with 0.3±
0.5 ppm than that of the respective, equatorially-oriented
proton of 8 and 9. This phenomenon is opposite to that
observed for hexospyranose derivatives.8 The con®guration
of the C-7 chiral center in 4 could be easily deduced from
the coupling constants shown in Fig. 2.
The structural properties of the 3-oxagranatane derivatives
were readily substantiated by the NMR spectra. The
structure of 3 was deduced from the results of 2D NOE
experiments (Fig. 2). The con®guration of the chiral centers
of 8 was established according to the NOE data shown in
Fig. 2, and all of these measurements unequivocally
As the acid hydrolysis of 5 was rather sluggish, the trans-
formations described above were also performed starting
with benzyl b-d-glucopyranoside (10) to result in the
N,O-dibenzyl derivative 11 (Scheme 3). The crude 11 was
subjected to catalytic hydrogenation, however, instead of
the expected product 5, only the piperidine derivative 12
could be isolated from the reaction mixture. The formation
of 12 can be explained if the hydrogenolysis of the O-benzyl
group is considerably faster than that of the N-benzyl func-
tion, and thus upon removal of this latter the hemiacetal-
structure suffers reduction as well.
Scheme 2.
Figure 2.

Â
A. Agocs et al. / Tetrahedron 57 (2001) 235±239
237
Scheme 3.
The enzyme inhibitory studies revealed that the iminosugar
analogs 5, 6, and 9 were not active towards eleven enzymes:
b-glucosidases (from almonds (Sigma), Aspergillus
carbonarius, A. niger, A. phoenicis), b-galactosidases
(from testicles of bull, A. carbonarius, A. niger, A. phoeni-
cis), a-glucosidase (from bakers yeast, Sigma), a-galacto-
sidase (green coffee beans, Sigma) and the a-mannosidase
(Jack beans, Sigma). At the same time, 12 was shown to
possess a medium inhibitory effect ꢀKi ˆ 5 £ 1024† on the
almond b-glucosidase enzyme (crude, lyophilized powder).
1.1. (1R,2R,4S,5S)-9-Aza-9-benzyl-2-hydroxymethyl-4-
methoxy-3-oxabicyclo[3.3.1]nonane-7-one (3)
Methyl a-d-glucopyranoside (3.88 g, 20 mmol) was
dissolved in water (100 mL) and sodium periodate (8.56 g,
40 mmol) was added in portions at 08C. The solution was
left in the dark for 3 h at room temperature after the pH was
adjusted to 5±6 with a 1 M NaHCO3 solution (18 mL). eth-
anol was (250 mL) added, the precipitate was ®ltered off
and the solution was evaporated. The syrupy dialdehyde
was directly subjected to further transformations. Sodium
acetate (8 g) and acetic acid (10 mL) were dissolved water
(50 mL), and then benzylamine (4.6 mL, 43 mmol) and
acetonedicaboxylic acid (6.1 g, 42 mmol) were added. To
the stirred solution the dialdehyde (in 30 mL water) was
poured. The solution was left stirred overnight and the
solution with some brown precipitate was neutralized with
the slow addition of potassium carbonate. The slurry was
washed with ethyl acetate (2£100 mL), and the organic
phase was dried and evaporated. Column chromatography
in hexane: acetoneˆ6:4 resulted in 1.35 g (24%) of a dark
brown syrup. MS 292 (M11, PSP), [a]2D3ˆ122.0 (c0.72,
CH2Cl2), nmax(KBr) 3444, 3028, 2932, 1738, 1422, 1214,
1. Experimental
The organic extracts were dried over magnesium sulfate.
and the solutions were concentrated at 35±408C (bath) at
ca. 17 mmHg. For TLC precoated aluminium-backed plates
(Silica gel 60 F254, Merck, layer thickness: 0.2 mm) were
used. Compounds were visualized by charring with 5%
sulfuric acid in ethanol or spraying with 7% ammonium
molibdate in 5% sulfuric acid and heating. Column chroma-
tography: Merck Silica gel 60 (0.062±0.200 mm). Speci®c
rotations were measured on a Perkin±Elmer 141 MC polari-
1046 cm21
.
1H NMR (500 MHz): dˆ2.34 (1H, dt,
1
meter. The H and 13C NMR spectra were recorded on
J8a,8eˆ15.7 Hz, J1,8eˆ1.6 Hz, J6e,8eˆ1.6 Hz, H8e), 2.44
(1H, dd, J6a,6eˆ15.8 Hz, J5,6aˆ5.9 Hz, H6a), 2.52 (1H, dt,
J5,6eˆ1.6 Hz, J6e,8eˆ1.6 Hz, J6a,6eˆ15.8 Hz, H6e), 2.8 (1H,
dd, J8a,8eˆ15.7 Hz, J1,8aˆ6.0 Hz, H8a), 3.14 (2H, m, H5 and
H1), 3.45 (3H, s, OMe), 3.8 (1H, t, J2,10aˆJ2,10bˆ5.8 Hz,
Bruker WP 200 SY and Bruker AM 500 instruments in
CDCl3 with TMS as the internal standard. Plasmaspray
(PSP) mass spectra were recorded on a VG TRIO-2
instrument connected with a Waters 501 HPLC pump in
an isocratic mode; samples were dissolved in a 0.1 M
ammonium acetate buffer/methanol mixture (1:1) and
injected into the same solvent system at a ¯ow rate of
1 mL/min; PSP tip interface temperature 2108C.
J1,2ˆ0 Hz, H2), 3.88 (1H, dd, J10a,10bˆ11.3 Hz, J2,10a
5.8 Hz, H10a), 3.92 (2H, s, N±CH2), 4.08 (1H, dd, J2,10b
ˆ
ˆ
5.8 Hz, J10a,10bˆ11.3 Hz, H10b), 4.9 (1H, d, J4,5ˆ2.4 Hz,
H4), 7.4 (5H, m, aromatic). 13C NMR: dˆ33.7; 40.2 (C6,
C8); 55.0 (C5); 56.2 (OMe); 56.4 (C1) 58.7 (N±CH2); 62.9
(C10); 78.4 (C2); 97.9 (C4); 127.8±128.6; 137.0 (6C,
aromatic); 206.5 (CvO). Anal. calcd for C16H21NO4: C
65.96%, H 7.27%, N 4.81%. Found: C 66.05%, H 7.20%,
N 4.93%.
Glycosidase activities were measured in 0.2 M citrate-
phophate buffer (pH 5.2) at 378. The total volume was
5 mL. The reaction was initiated by addition of the
substrate, and the hydrolysis was allowed to proceed
for 20 min and stopped by the addition of 1 mL of
the reaction mixture to 0.5 M borate buffer (2 mL, pH
10). The concentration of p-nitrophenolate ion was
measured spectrophotomertically at 400 nm. Substrate
1.2. (1R,2R,4S,5S,7R)-9-Aza-9-benzyl-7-hydroxy-2-
hydroxymethyl-4-methoxy-3-oxabicyclo[3.3.1] nonane
(4)
concentration
ranges
for
p-nitrophenyl
glyco-
pyranosides were 0.1±5 mM. Inhibition constants were
determined from Lineweaver±Burk and Dixon plots,
®tted by a least-squares treatment.
Compound 3 (1 g, 3.4 mM) was dissolved in abs. THF
(30 mL) and LiAlH4 (180 mg, 5.1 mM) was slowly added

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A. Agocs et al. / Tetrahedron 57 (2001) 235±239
238
to the stirred solution. One hour later the suspension was
diluted with ethyl acetate (100 mL) and sat. NaHCO3 solu-
tion was added. The organic phase was washed with sat.
NaHCO3 solution (100 mL), dried and evaporated. Chroma-
tography in hexane/acetoneˆ6:4 resulted in 820 mg (82%)
of a brown syrup. MS 294 (M11, PSP), [a]2D3ˆ116.3
(c0.96, CH2Cl2), nmax(KBr) 3390, 2930, 1650, 1494, 1190,
10 mmol) and applying the procedure described for 3
0.61 g (21%) of 8 was obtained. MS 292 (M11, PSP),
[a]2D3ˆ262.8 (c0.95, CH2Cl2), nmax(KBr) 3444, 3025,
1
2932, 1738, 1420, 1204, 1026 cm21. H NMR (500 MHz):
dˆ2.2 (1H, d, J6a,6eˆ 15.4 Hz, J5,6eˆ0 Hz, H6e), 2.26 (1H,
dd, J8a,8eˆ15.2 Hz, J1,8eˆ1.2 Hz, H8e), 2.74 (1H, dd,
6.3 Hz, H6a), 2.83 (1H, dd,
J6a,6eˆ15.4 Hz, J5.6a
ˆ
1040 cm21
.
1H NMR: dˆ1.55 (1H, dd, J6a,6eˆ15.6 Hz,
J1,8aˆ6.1 Hz, J8a,8eˆ15.2 Hz, H8a), 3.3 (1H, dd,
J1,2ˆ0 Hz, J1,8aˆ6.1 Hz, J1,8eˆ1.2 Hz, H1), 3.41 (1H, d,
J4,5ˆ0 Hz, J5.6aˆ6.3 Hz, H5), 3.45 (3H, s, OMe), 3.68
(1H, t, J2,10aˆJ2,10bˆ5.3 Hz, H2), 3.89 (1H, dd,
J10a,10bˆ11.4 Hz, J2,10aˆ5.3 Hz, H10a), 3.94 (2H, s,
N±CH2), 4.06 (1H, dd, J10a,10bˆ11.4 Hz, J2,10bˆ5.3 Hz,
H10b), 4.4 (1H, s, H4), 7.45 (5H, m, aromatic). 13C NMR:
dˆ38.6; 41.0 (C6, C8); 55.1 (C1); 55.8 (OMe); 56.6 (C5);
57.8 (N±CH2); 77.8 (C2); 100.6 (C4); 127.6±128.6; 137.2
(6C, aromatic); 206.7 (CvO). Anal. calcd for C16H21NO4: C
65.96%, H 7.27%, N 4.81%. Found: C 66.01%, H 7.30%, N
4.85%.
J5,6eˆ1.1 Hz, H6e), 1.85 (1H, dd, J8a,8eˆ15.7 Hz, J1,8e
ˆ
1.1 Hz, H8e), 2.0 (1H, dt, J7,6aˆ5.2 Hz, J5,6aˆ5.7 Hz,
J6a,6eˆ15.6 Hz, H6a), 2.3 (1H, dt, J7,8aˆ5.1 Hz,
J1,8aˆ5.5 Hz, J8a,8eˆ15.7 Hz, H8a), 2.8 (2H, m, H5 and
H1), 3.45 (3H, s, OMe), 3.73 (2H, s, N±CH2), 3.9 (4H, m,
H2, H7 and H10a,b), 5.0 (1H, d, J4,5ˆ2.6 Hz, H4), 7.35 (5H,
m, benzyl).13C NMR: dˆ22.5; 29.6 (C6,C8); 50.9 (C5);
52.5 (C1); 55.6 (N±CH2); 56.6 (OMe); 62.0 (C7); 65.7
(C10); 77.4 (C2); 99.2 (C4); 126.9±128.8; 137.2 (6C,
aromatic). Anal. calcd for C16H23NO4: C 65.51%, H
7.90%, N 4.77%. Found: C 65.62%, H 7.81%, N 4.86%.
1.3. (1R,2R,4S,5S,7R)-9-Aza-7-hydroxy-2-hydroxy-
methyl-4-methoxy-3-oxabicyclo[3.3.1]nonane (5)
1.6. (1R,2R,4R,5S,7R)-9-Aza-7-hydroxy-2-hydroxy-
methyl-4-methoxy-3-oxabicyclo[3.3.1]nonane (9)
Compound 4 (1.1 g) was dissolved in acetic acid (30 mL)
and hydrogenated overnight over Pd/C catalyst (200 mg).
After ®ltration and evaporation the syrup was dissolved in
water and stirred 10±20 min with some Serdolit Blue (OH2
form resin). Chromatography in dichloromethane/methanol
8:2 and freeze-drying resulted in 455 mg (58%) of a brown-
ish yellow syrup. MS 204 (M11, PSP), [a]2D3ˆ124.7 (c0.8,
methanol), nmax(KBr) 3442, 2930, 1620, 1450, 1098,
Starting from 8 (460 mg, 1.56 mmol) and using the proce-
dures described for 4 and 5, 133 mg (42%) of 9 was obtained
after freeze-drying. MS 204 (M11, PSP), [a]2D3ˆ246.2
(c1.1, methanol), nmax(KBr) 3412, 2930, 1444, 1104,
1
1030 cm21. H NMR (D2O): dˆ1.8 (2H, m, H6e, H8e)
2.2 (2H, m, H6a, H8a), 2.95 (2H, 2m, H5, H1), 3.5 (3H, s,
OMe), 3.9 (4H, m, H2, H7, H10a,b), 4.63 (1H, s, H4). 13C
NMR: dˆ33.9; 36.8 (C6, C8); 44.0 (C5); 48.3 (C1); 56.0
(OMe); 63.4 (C7); 65.6 (C10); 75.6 (C2); 99.4 (C4). Anal.
calcd for C9H17NO4: C 53.19%, H 8.43%, N 6.89%. Found:
C 53.05%, H 8.54%, N 6.92%.
1
1017 cm21. H NMR (D2O): dˆ1.83 and 2.03 (3H, 2m,
H6a,e, H8e) 2.21 (1H, dt, J7,8aˆ5.0 Hz, J1,8aˆ5.3 Hz,
J8a,8eˆ15.7 Hz, H8a), 3.24 (2H, m, H5, H1), 3.5 (3H, s,
OMe), 3.7 (1H, dd, J10a,10bˆ11.1 Hz, J2,10aˆ5.6 Hz, H10a),
4.05 (3H, m, H2, H7, H10b), 5.1 (1H, d, J4,5ˆ2.7 Hz, H4).
13C NMR: dˆ24.0; 29.2 (C6, C8); 45.0 (C5); 48.1 (C1);
57.4 (OMe); 62.0 (C7); 62.4 (C10); 77.8 (C2); 97.1 (C4).
Anal. calcd for C9H17NO4: C 53.19%, H 8.43%, N 6.89%.
Found: C 53.11%, H 8.49%, N 6.78%.
1.7. (1R,2R,4S,5S)-9-Aza-9-benzyl-2-hydroxymethyl-4-
benzyloxy-3-oxabicyclo[3.3.1]nonane-7-one (11)
Starting from benzyl b-d-glucopyranoside 10 (2 g,
7.5 mmol) and employing the procedure described for 3,
295 mg (13%) of a dark brown syrup was obtained. MS
368 (M11, PSP), [a]2D3ˆ254.4 (c0.5, CH2Cl2), nmax(KBr)
1.4. (1R,2R,4S,5S,7R)-9-Aza-4,7-dihydroxy-2-hydroxy-
methyl-3-oxabicyclo[3.3.1]nonane (6)
1
3370, 3110, 3030, 1698, 1454, 1246, 1102 cm21. H NMR
(aceton-d6): dˆ2.3 (2H, m, H6e and H8e), 2.7 (2H, m, H6a,
H8a), 3.2 and 3.4 (2H, 2m, H1 and H5), 3.75 (1H, dd,
J2,10aˆ5.4 Hz, J2,10bˆ5.0 Hz, H2), 3.6 (1H, dd,
J10a,10bˆ11.0 Hz, J2,10aˆ5.4 Hz, H10a), 3.9 (2H, d, O±CH2),
4.07 (1H, dd, J10a,10bˆ11.0 Hz, J2,10bˆ5.0 Hz, H10b), 4.7
(1H, d, J4,5ˆ0.5 Hz, H4) 7.45 (10H, m, aromatic). 13C
NMR: dˆ37.8; 40.5 (C6, C8); 54.3 (C1); 55.7 (OMe);
56.8 (C5); 62.3 (N±CH2); 68.8 (O±CH2); 78.2 (C2); 98.2
(C4); 126.5±127.8; 137.7 (12C, aromatic); 199.6 (CvO).
Anal. calcd for C22H25NO4: C 71.91%, H 6.86%, N 3.81%.
Found: C 71.82%, H 6.97%, N 3.85%.
Compound 5 (100 mg) was dissolved in a mixture of
tri¯uoracetic acid (5 mL) and water (0.5 mL) and left at
608C for 6 h. The solution was evaporated and puri®ed
with dichloromethane: methanolˆ 9:1 to give 81 mg
(87%) of a colorless oil. MS 190 (M11, PSP), 172
(M2H2O11), [a]2D3ˆ13.3 (c1.25, methanol), nmax(KBr)
3400, 2956, 1440, 1206, 1138, 1020 cm21 1H NMR
.
(D2O): dˆ1.80 (3H, 2m, H6a,e and H8e) 2.15 (1H, m,
H8a), 3.3 (2H, m, H5 and H1), 3.7 (3H, m, H2, H7,
H10a), 3.95 (1H, m, H10b), 5.55 (1H, d, J4,5ˆ4.0 Hz, H4).
13C NMR: dˆ38.4; 39.0 (C6, C8); 50.9 (C5); 56.3 (C1);
65.8 (C7); 77.0 (C10); 78.1 (C2); 101.9 (C4). Anal. calcd
for C8H15NO4: C 50.78%, H 7.99%, N 7.40%. Found: C
50.70%, H 8.11%, N 7.45%
1.8. (2R,4S,6S)-2-(1R)-1,2-Dihydroxyethyl-4-hydroxy-6-
hydroxymethylpiperidine (12)
Compound 11 (350 mg, 0.95 mmol) was reduced and
hydrogenated as described for 4 and 5. The polar product
was puri®ed in dichloromethane:methanolˆ3:7 and freeze-
dried to give 102 mg (56%) of a brownish yellow syrup. MS
192 (M11, PSP), [a]D23ˆ13.7 (c0.45, methanol), nmax(KBr)
1.5. (1R,2R,4R,5S)-9-Aza-9-benzyl-2-hydroxymethyl-4-
methoxy-3-oxabicyclo[3.3.1]nonane-7-one (8)
Starting from methyl b-d-glucopyranoside (1.95 g,

Â
A. Agocs et al. / Tetrahedron 57 (2001) 235±239
239
3430, 2920, 1422, 1122, 1068 cm21. 1H NMR (D2O) dˆ1.7
References
and 2.0 (4H, 2m, 4H, H3a,b, H5a,b), 3.4±4.2 (8H, 3m, other
protons). 13C NMR: dˆ25.5; 29.3 (C3, C5); 57.9 (C6); 58.4
(C2); 65.6 (CH2±OH); 67.8 (C20); 70.7 (C4); 77.0 (C10).
Anal. calcd for C8H17NO4: C 50.25%, H 8.96%, N 7.32%.
Found: C 50.21%, H 9.04%, N 7.44%.
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È
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The authors thank for the ®nancial supports received from
the Hungarian Scienti®c Research Fund (Grants No. T
019338, 029089, 30138 and 023592) and the Ministry of
Education for FKFP 500/1997 and 325/1997 support.
265.