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Synlett 2010(9): 1367-1370  
DOI: 10.1055/s-0029-1219906
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Novel 3-Amino(Hydroxy)methyl-l-fuco-Azafagomines as Leads for Selective Inhibitors of α-l-Fucosidases

Elena Moreno-Clavijoa, Ana T. Carmona*a, Antonio J. Moreno-Vargasa, Eleuterio Álvarezb, Inmaculada Robina*a
a Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Prof. García González 1, 41012 Seville, Spain
Fax: +34(954)624960; e-Mail: robina@us.es; e-Mail: anatere@us.es;
b Instituto de Investigaciones Químicas ‘Isla de la Cartuja’, CSIC-USE, Américo Vespucio 49, 41092 Sevilla, Spain
Further Information

Publication History

Received 8 February 2010
Publication Date:
10 May 2010 (online)

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Abstract

The synthesis of 3-substituted l-fuco-azafagomines from d-lyxose is reported. They represent the first example of aza-C-glycosides having a biimino (-NH-NH-) moiety. The key step of the synthesis is the introduction of the hydrazine moiety by reductive hydrazination of a 1-deoxy-ketohexose with tert-butyl carbazate. Their glycosidase inhibitory properties are also reported.

Key words

azasugars - glycosidases - fucosidase inhibitors - aza-fagomines - C-glycosides

    References and Notes

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14

Analytical Data for 8
[α]D ²5 -18.2 (c 1.19, CH2Cl2). ¹H NMR (500 MHz, DMSO-d 6): δ = 7.61-7.58 (m, 4 H, Harom), 7.48-7.38 (m, 6 H, Harom), 7.28-7.26 (m, 5 H, Harom), 5.18 (br d, 1 H, J NH,3 = 3.2 Hz, NH), 5.05 (d, 1 H, ² J H,H = 12.7 Hz, CH2 of Cbz), 5.02 (d, 1 H, CH2 of Cbz), 4.08 (dd, 1 H, J 5,4 = 5.5 Hz, J 5,6 = 4.8 Hz,
H-5), 3.97 (qd, 1 H, J 6,Me-6 = 7.2 Hz, H-6), 3.96 (t, 1 H, J 4,3 = 5.5 Hz, H-4), 3.65 (d, 2 H, J 1 ′ ,3 = 6.7 Hz, H-1′), 3.05 (m, 1 H, H-3), 1.34 (d, 3 H, Me-6), 1.33, 1.24 [2 s, 3 H each, C(CH3)2], 0.99 [s, 9 H, C(CH3)3] ppm. ¹³C NMR (125.7 MHz, DMSO-d 6): δ = 156.0 (C=O of Cbz), 136.7, 135.0, 132.7, 129.9, 128.2, 127.9, 127.8, 127.6, 127.3 (Carom), 108.0 [C(CH3)2], 72.6 (C-5), 70.8 (C-4), 66.2 (CH2 of Cbz), 63.7 (C-1′), 58.7 (C-3), 50.9 (C-6), 26.8, 25.7 [C(CH3)2], 26.5 [C(CH3)3], 18.7 [C(CH3)3], 15.9 (Me-6) ppm. MS-FAB: m/z (%) = 597 (40) [M + Na]+, 575 (8) [M + H]+. HRMS-FAB: m/z calcd for C33H42N2O5NaSi [M + Na]+: 597.2761; found: 597.2780.
Analytical Data for 9
[α]D ²6 -64.5 (c 0.82, CH2Cl2). ¹H NMR (500 MHz, DMSO-d 6): δ = 7.63-7.61 (m, 4 H, Harom), 7.49-7.30 (m, 11 H, Harom), 5.18 (br s, 2 H, CH2 of Cbz), 5.09 (br s, 1 H, NH), 4.56 (q, 1 H, J 6,Me-6 = 7.2 Hz, H-6), 3.99 (d, 1 H, J 5,4 = 5.0 Hz, H-5), 3.80 (dd, 1 H, J 4,3 = 9.4 Hz, H-4), 3.77 (dd, 1 H, ² J 1 ′ a,1 ′ b = 10.7 Hz, J 1 ′ a,3 = 3.0 Hz, H-1′a), 3.59 (dd, 1 H, J 1 ′ b,3 = 9.0 Hz, H-1′b), 2.89 (m, 1 H, H-3), 1.28 (d, 3 H,
Me-6), 1.20 [s, 6 H, C(CH3)2], 0.98 [s, 9 H, C(CH3)3] ppm. ¹³C NMR (125.7 MHz, DMSO-d 6): δ = 155.2 (C=O of Cbz), 136.9, 135.0, 132.6, 129.9, 128.2, 127.9, 127.8, 127.7, 127.1 (Carom), 108.0 [C(CH3)2], 75.0 (C-5), 70.0 (C-4), 66.3 (CH2 of Cbz), 63.3 (C-1′), 59.9 (C-3), 49.1 (C-6), 27.8, 26.3 [C(CH3)2], 26.5 [C(CH3)3], 18.7 [C(CH3)3], 16.1 (Me-6) ppm. MS-FAB: m/z (%) = 597 (50) [M + Na]+, 575 (10)
[M + H]+. HRMS-FAB: m/z calcd for C33H42N2O5NaSi [M + Na]+: 597.2761; found: 597.2802.

15

Crystal Data for 10
C24H30N2O7S, Mr = 490.56, orthorhombic, space group P2 1 2 1 2 1 (no. 19), a = 5.9856 (3) Å, b = 16.5688 (8) Å, c = 24.4976 (11) Å, V = 2429.5 (2) ų, Z = 4, ρ calcd  = 1.341 g cm-³, λ (Mo Kα1) = 0.71073 Å, F(000) = 1040, µ = 0.180 mm-¹, T = 173 (2) K, 34818 reflections measured, 4999 unique (R int = 0. 0847) which were used in all calculations. The final R1 = 0.0430 [I > 2σ(I)], wR2 = 0.1047 (all data). Flack parameter = -0.02 (8). Full crystallographic data for this structure have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC 764937. These data can obtained free of charge on application to CCDC, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033; or e-mail: deposit@ccdc.cam.ac.uk.

16

Analytical Data for 10
Mp 130-132 ˚C (EtOAc-PE). [α]D ²³ -6.4 (c 0.45, CH2Cl2). ¹H NMR (500 MHz, DMSO-d 6): δ = 7.76 (d, 2 H, ³ J H,H = 8.0 Hz, H-Ts), 7.46 (d, 2 H, H-Ts), 7.37-7.30 (m, 5 H, Harom), 5.17 (br s, 1 H, NH), 5.04 (d, 1 H, ² J H,H = 12.7 Hz, CH2 of Cbz), 5.01 (d, 1 H, CH2 of Cbz), 4.16 (t, 1 H, J 5,4 = J 5,6 = 5.5 Hz, H-5), 4.04-3.97 (m, 3 H, H-6, H-1′a, H-1′b), 3.83 (dd, 1 H, J 4,3 = 4.5 Hz, H-4), 3.10 (m, 1 H, H-3), 2.41 (s, 3 H, CH3 of Ts), 1.28 (d, 3 H, J 6,Me-6 = 7.0 Hz, Me-6), 1.31, 1.23 [2 s, 3 H each, C(CH 3 )2] ppm. ¹³C NMR (125.7 MHz, DMSO-d 6, 353 K): δ = 156.1 (C=O of Cbz), 145.1, 136.7, 132.0, 130.2, 128.3, 127.8, 127.6, 127.5 (Carom), 108.1 [C(CH3)2], 72.2 (C-5), 70.0, 69.9 (C-4, C-1′), 66.3 (CH2 of Cbz), 56.1 (C-3), 50.1 (C-6), 26.6, 25.6 [C(CH3)2], 21.1 (Me of Ts), 15.7 (Me-6) ppm. MS-FAB: m/z (%) = 513 (100) [M + Na]+, 491 (10) [M + H]+. HRMS-FAB: m/z calcd for C24H30N2O7SNa [M + Na]+: 513.1671; found: 513.1678. Anal. Calcd for C24H30N2O7S: C, 58.76; H, 6.16; N, 5.71; S, 6.54. Found: C, 58.75; H, 6.11; N, 5.82; S, 6.50.

18

Analytical Data for 3a
[α]D ²² -44.6 (c 0.6, MeOH). ¹H NMR (500 MHz, CD3OD): δ = 3.85-3.82 (m, 2 H, H-5, H-1′a), 3.74 (dd, 1 H, ² J 1 ′ b,1 ′ a = 11.6 Hz, J 1 ′ b,3 = 5.5 Hz, H-1′b), 3.63 (dd, 1 H, J 4,3 = 10.3 Hz, J 4,5 = 2.8 Hz, H-4), 3.35 (qd, 1 H, J 6,Me-6 = 6.8 Hz, J 6,5 = 1.2 Hz, H-6), 3.24 (ddd, 1 H, J 3,1 ′ a = 2.9 Hz, H-3), 1.28 (d, 3 H, Me-6) ppm. ¹³C NMR (125.7 MHz, CD3OD):
δ = 69.6 (C-5), 68.1 (C-4), 60.1 (C-1′), 58.0 (C-6), 57.5 (C-3), 14.0 (Me-6) ppm. MS (CI): m/z (%) = 163 (40) [M + H]+. HRMS (CI): m/z calcd for C6H15N2O3 [M + H]+: 163.1083; found: 163.1083.
Analytical Data for 15
[α]D ²² -12.3 (c 0.85, MeOH). ¹H NMR (500 MHz, CD3OD): δ = 3.85 (dd, 1 H, ² J 1 ′ a,1 ′ b = 11.5 Hz, J 1 ′ a,3 = 3.7 Hz, H-1′a), 3.81 (dd, 1 H, J 4,3 = 7.4 Hz, J 4,5 = 2.9 Hz, H-4), 3.77 (dd, 1 H, J 1 ′ b,3 = 6.9 Hz, H-1′b), 3.71 (m, 1 H, H-5), 3.51 (qd, 1 H, J 6,Me-6 = 6.9 Hz, J 6,5 = 5.4 Hz, H-6), 3.36 (td, 1 H, H-3), 1.34 (d, 3 H, Me-6) ppm. ¹³C NMR (125.7 MHz, CD3OD): δ = 70.1 (C-5), 65.4 (C-4), 60.5 (C-3), 60.2 (C-1′), 56.6 (C-6), 13.2 (Me-6) ppm. MS (CI): m/z (%) = 163 (65) [M + H]+. HRMS (CI): m/z calcd for C6H15N2O3 [M + H]+: 163.1083; found: 163.1087.