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DOI: 10.1055/s-0029-1219906
Synthesis of Novel 3-Amino(Hydroxy)methyl-l-fuco-Azafagomines as Leads for Selective Inhibitors of α-l-Fucosidases
Publication History
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
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References and Notes
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.
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.
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.
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.