Glycosidase Inhibitors
3744±3747
57%). Rf 0.27 (pentane/ethyl acetate 5:1); [a]D
1168 (c 1.0 in
3-C, CH2Ph), 62.3 (5-C), 39.3 ((NH-CH2), 37.7 (4-C), 28.5 ((CH3)3C); ESI-
MeOH); UV: l 331 (2.89), 228 (4.19); 1H NMR (400 MHz, CDCl3):
d 7.35 ± 7.26 (m, 5H, Ph), 5.98 (dd, 1H, J 10.4, 1.6 Hz, 3-H), 5.19 (d, 1H,
J 15.0 Hz, 6-Hb), 5.06 (d, 1H, J 3.4 Hz, 1-H), 4.87 (dd, 1H, J 10.4,
3.4 Hz, 2-H), 4.53 (d, 1H, J 12.0 Hz, CH2Ph), 4.36 (d, 1H, J 15.0 Hz,
6-Ha), 2.08 (s, 3H, CH3CO), 1.97 (s, 3H, CH3CO); 13C NMR (CDCl3): d
170.1, 169.4 (2CH3CO), 143.7 (CH2NO2), 136.7 (C, Ph), 134.5 (4-C), 128.8,
128.5, 128.1 (5C, Ph), 95.0 (1-C), 78.9 (CH2NO2), 72.3, 70.3 (2-, 3-C), 67.5
(CH2Ph), 56.9 (5-C), 20.8, 20.7 (2 Â CH3CO); ESI-MS: calcd for
MS: calcd for C18H27NO6Na : 376.1736, found 376.1734. 11b: Rf 0.15
(toluene/ethyl acetate 1:1); 1H NMR (200 MHz, CDCl3): d 7.40 ± 7.20 (m,
5H, Ph), 4.92 (brd, 1H, OH), 4.88 (d, 1H, J 3.2 Hz, 1-H), 4.69 (d, 1H, J
11.8 Hz, CH2Ph), 4.42 (d, 1H, J 11.8 Hz, CH2Ph), 3.65 ± 3.25 (m, 6H), 2.98
(m, 1H), 2.32 (brd, 1H, J 7.8 Hz, NH), 1.78 (m, 1H, 4-H), 1.38 (s, 9H,
tBu); 13C NMR ([D6]acetone): d 157.0 (NH-COO), 137.3, 128.7, 128.1
(6C, Ph), 98.0 (1-C), 80.0 ((CH3)3C), 73.7, 71.4, 69.4 (2-, 3-C, CH2Ph), 61.4
(5-C), 43.6 (4-C), 39.2 (NH-CH2), 28.6 ((CH3)3C); ESI-MS: calcd for
C17H19NO8Na : 388.1008, found 388.1000.
C18H27NO6Na : 376.1736, found 376.1734.
Benzyl (4R,4S)-4-deoxy-4-C-nitromethylene-b-d-arabino-pyranoside (9):
NaBH4 (53 mg, 1.40 mmol) in EtOH (5 mL) was slowly added at 08C
within 15 min to a stirred solution of 8a and 8b (0.50 g, 1.17 mmol) in
EtOH (15 mL). The solution was then allowed to warm to room temper-
ature and stirred further for 40 min. Afterwards the solvent was evaporated
and the residue dissolved in dry methanol (15 mL). A freshly prepared
solution of NaOMe in MeOH (0.5 mL, 0.2n) was added. After completion
of the deprotection (according to tlc after 30 min), ion exchange resin
Noeuromycin (3): A solution of 11a (42 mg, 0.12 mmol) in dry EtOH
(100 mL) was hydrogenated over Pd/C (10%) under atmospheric pressure
at room temperature for about 16 h. Afterwards the catalyst was filtered
off, the solvent evaporated and HCl (1.5 mL, 0.2n) was added to the
residue. After heating to 408C for 5 min the solvent was evaporated to give
hydrochloride 3 as a pale yellow solid (23 mg, 98%), which has identical
analytical data reported in ref. [11].
5-epi-Noeuromycin (12): A solution of 11b (49 mg, 0.136 mmol) in EtOH
(100 mL) was hydrogenated over Pd/C (10%) under atmospheric pressure
at room temperature for about 16 h. Afterwards the catalyst was filtered off
and the solvent evaporated. HCl (1.5 mL, 0.2n) was added to the residue.
After heating the mixture to 408C for 5 min the solvent was evaporated to
give hydrochloride 12 as a pale yellow solid (27 mg, 98%). 1H NMR
(200 MHz, D2O): d 5.20 (d, J 3.6 Hz, b-pyranose), 4.98 (m, a-anomer),
4.50 (d, J 7.8 Hz, a-pyranose), 4.10 (m), 4.02 ± 3.90 (m), 3.80 ± 3.50 (m),
3.45 ± 3.09 (m), 3.08 (d, J 12.8 Hz), 3.00 ± 2.80 (m), 2.70 (m), 2.34 (m, main
isomer), 2.05 (m); 13C NMR (D2O): main isomer: d 77.2 (2-C), 68.6, 66.8
(3-, 4-C), 59.3 (6'-C), 39.8 (5-, 6-C), 39.4; minor isomers: d 96.2, 92.1, 91.3,
74.9, 73.7, 72.0, 70.2, 68.6, 68.2, 66.8, 59.7, 59.2, 46.1, 38.3, 37.4.
Amberlite IR 120 H (about 3 mL, carefully washed before with H2O then
with Et2O) was added. The mixture was stirred until pH ꢀ6 (about 30 min)
to remove cations. The resin was filtered off, and the filtrate evaporated to
give 9 (Rf 0.66, CHCl3/MeOH 8:1) as colorless syrup (0.32 g, 96%).
Column chromatography of the (4R,4S)-isomeric mixture with pentane/
ethyl acetate 1:1, provided a pure sample of (4R)-9 which structure was
assigned unequivocally by giving pure 10 after catalytic hydrogenation.
(4R)-9: Rf 0.43 (toluene/ethyl acetate 1:1); 1H NMR (400 MHz, [D6]ace-
tone): d 7.45 ± 7.23 (m, 5H, Ph), 4.93 (d, 1H, J 3.2 Hz, 1-H), 4.84 (dd,
1H, J 13.2, 4.9 Hz), 4.75 (d, 1H, J 12.4 Hz), 4.53 (m, 2H), 4.27 (d, 1H,
J 4.8 Hz), 3.80 ± 3.65 (m, 4H), 3.48 (m, 1H, 2-H), 2.45 (m, 1H, 4-H);
13C NMR ([D6]acetone): d 137.4, 127.5, 127.0, 126.7 (6C, Ph), 98.2 (1-C),
73.5, 73.2, 68.6, 68.3 (CH2Ph, 2-, 3-, 4-C, CH2NO2), 59.3 (5-C), 41.3 (4-C);
ESI-MS: calcd for C13H17NO6Na : 306.0953, found 306.0954.
Acknowledgements
Isofagomine (2) and 5-epi-isofagomine (10): A solution of 9 (354 mg,
1.25 mmol, (4R:4S) ꢀ4:3) derived from a mixture of 7a:7b (about 3:1) in
methanol (200 mL) was hydrogenated over Pd/C (10%) under normal
pressure at room temperature (about 16 h) until TLC indicated only two
spots of 2 (Rf 0.38, iPrOH/H2O/NH4OH 7:2:1) and 10 (Rf 0.26) and the
spot of benzyl (4R,4S)-4-C-aminomethylene-4-deoxy-b-d-arabino-pyrano-
side at Rf 0.55 completely disappeared (ninhydrin). The catalyst was
filtered off, the solvent evaporated and the residue chromatographed with
iPrOH/H2O/NH4OHC providing 2 (98 mg, 53%) and 10 (77 mg, 42%) as
colorless solids. Addition of HCl (2.0 mL, 0.2n) and subsequent evapo-
ration provided the corresponding hydrochlorids of 2 and 10, which had
identical analytical data to those reported in refs. [4], [5], and [16].
We thank the Danish National Research Councils for support through the
THOR program and for support from the Lundbeck Foundation. We also
thank the Deutsche Forschungsgmeinschaft for a scholarship (J.A.).
[1] S. Inoue, T. Tsuruka, T. Niida, J. Antibiot. 1966, 19, 288 ± 292.
[2] T. M. Jespersen, W. Dong, M. R. Sierks, T. Skrydstrup, I. Lundt, M.
Bols, Angew. Chem. 1994, 106, 1858 ± 1860; Angew. Chem. Int. Ed.
Engl. 1994, 33, 1778 ± 1779.
[3] A. Bülow, I. W. Plesner, M. Bols, J. Am. Chem. Soc. 2000, 122, 8567 ±
8568.
Benzyl 4-C-tert-butyloxycarbonylaminomethylene-4-deoxy-b-d-arabino-
pyranoside (11a) and benzyl 4-C-tert-butyloxycarbonylaminomethylene-
4-deoxy-b-d-xylo-pyranoside (11b): A solution of 9 (140 mg, 0.49 mmol) in
dry MeOH (10 mL) and NEt3 (0.01 mL) was hydrogenated over Pd/C
(10%, 30 mg) at atmospheric pressure and room temperature for about 2 h.
The catalyst was filtered off, the filtrate evaporated and the residue
dissolved in a mixture of CHCl3 (20 mL) and NEt3 (1.0 mL). To the solution
Boc2O (248 mg, 0.59 mmol) was added, and the solution stirred for 2 h at
room temperature. Afterwards the solvent was evaporated and the residue
was purified by chromatography (pentane/ethyl acetate 1:1) providing 11a
(76 mg, 44%) and 11b (71 mg, 41%) as white solids. 11a: Rf 0.23
(toluene/ethyl acetate 1:1); 1H NMR (200 MHz, CDCl3): d 7.40 ± 7.20 (m,
5H, Ph), 4.81 (m, 3H, 1-H, CH2Ph, OH), 4.48 (d, 1H, J 11.4 Hz, CH2Ph),
3.89 (m, 1H, 2-H), 3.65 (m, 3H), 3.52 (dd, 1H, J 11.4, 8.0 Hz), 3.30 (m,
1H), 3.00 (m, 1H), 2.21 (brd, 1H, J 5.2 Hz, NH), 2.15 (m, 1H, 4-H), 1.37
(s, 9H, tBu); 1H NMR (400 MHz, [D6]acetone/D2O 1:1): d 7.40 ± 7.20 (m,
5H, Ph), 5.18 (d, 1H, J 11.7 Hz, 1-H), 5.02 (d, 1H, J 11.7 Hz, CH2Ph),
4.86 (d, 1H, J 11.7 Hz, CH2Ph), 4.31 (dd, 1H, J 8.0, 4.8 Hz), 3.99 (dd,
1H, J 11.8, 3.2 Hz, 2-H), 3.92 (m, 1H), 3.84 (dd, 1H, J 11.6, 5.2 Hz), 3.57
(dd, 1H, J 14.0, 4.8 Hz), 3.54 (dd, 1H, J 14.0, 9.6 Hz), 2.47 (m, 1H, 4-H),
1.42 (s, 9H, tBu); 13C NMR ([D6]acetone): d 157.4 (NH-COO), 137.3,
128.7, 128.3, 128.2 (6C, Ph), 97.8 (1-C), 80.2 ((CH3)3C), 70.4, 70.1, 68.7 (2-,
[4] T. M. Jespersen, M. Bols, M. R. Sierks, T. Skrydstrup, Tetrahedron
1994, 50, 13449 ± 13460.
[5] Y. Ichikawa, Y. Igarashi, M. Ichikawa, Y. Suhara, J. Am. Chem. Soc.
1998, 120, 3007 ± 3018.
[6] G. Pandey, M. Kapur, Tetrahedron Lett. 2000, 41, 8821 ± 8824.
[7] S. U. Hansen, M. Bols, J. Chem. Soc. Perkin Trans. 1 2000, 911 ± 916.
[8] Y. J. Kim, M. Ichikawa, Y. Ichikawa, J. Org. Chem. 2000, 65, 2599 ±
2602.
[9] G. Zhao, U. C. Deo, B. Ganem, Org. Lett. 2001, 3, 201 ± 203.
[10] M. Bols, Carbohydrate Building Blocks, Wiley, New York, 1996.
[11] L. Huizhen, X. Liang, H. Sùhoel, A. Bülow, M. Bols, J. Am. Chem.
Soc. 2001, 123, 5116 ± 5117.
[12] A. Hansen, T. M. Tagmose, M. Bols, Tetrahedron 1997, 53, 697 ± 706.
[13] K. Heyns, J. Lenz, H. Paulsen, Chem. Ber. 1962, 95, 2964 ± 75.
[14] Y. Tsuda, N. Matsuhira, K. Kanemitsu, Chem. Pharm. Bull. 1985, 33,
4095 ± 4097. See also: Y. Tsuda, N. M. Hanajima, K. Yoshimoto, Chem.
Pharm. Bull. 1983, 31, 3778 ± 3780.
[15] M. Bols, R. Hazell, I. Thomsen, Chem. Eur. J. 1997, 3, 940 ± 7.
[16] C. Schneider, U. Kazmaier, Eur. J. Org. Chem. 1998, 1155 ± 1159.
Received: March 8, 2001 [F3117]
Chem. Eur. J. 2001, 7, No. 17
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