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

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.

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

References and Notes

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<A NAME="RD03910ST-12">12</A> Jiang S. Rycroft AD. Singh G. Wang X.-Z. Wu Y.-L. Tetrahedron Lett.  1998,  39:  3809 ; compound 5 was reported but not characterized Characterization Data for 5 [α]_D ^²² -34.9 (c 0.74, CH₂Cl₂). ^¹H NMR (300 MHz, CDCl₃): δ = 7.71-7.65 (m, 4 H, H_arom), 7.47-7.37 (m, 6 H, H_arom), 4.82-4.78 (m, 2 H, H-2, H-3), 4.58 (td, 1 H, J _4,5a = J _4,5b = 6.4 Hz, J _4,3 = 2.6 Hz, H-4), 4.08-3.93 (m, 2 H, H-5a, H-5b), 1.36 [s, 6 H, C(CH₃)₂], 1.07 [s, 9 H, C(CH₃)₃] ppm. ^¹³C NMR (75.4 MHz, CDCl₃): δ = 173.9 (C=O), 135.8, 133.2, 133.0, 130.0, 128.0, 127.9 (C arom.), 114.2 [C(CH₃)₂], 79.5 (C-4), 76.2, 75.9 (C-2, C-3), 61.7 (C-5), 26.9 [C(CH₃)₃], 26.1 [C(CH₃)₂], 19.4 [C(CH₃)₃] ppm. MS (CI): m/z (%) = 427 (5) [M + H]⁺. HRMS (CI): m/z calcd for C₂₄H₃₁O₅Si [M + H]⁺: 427.1941; found 427.1927

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<A NAME="RD03910ST-14">14</A>

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, H_arom), 7.48-7.38 (m, 6 H, H_arom), 7.28-7.26 (m, 5 H, H_arom), 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 (C_arom), 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, H_arom), 7.49-7.30 (m, 11 H, H_arom), 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 (C_arom), 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.

<A NAME="RD03910ST-15">15</A>

Crystal Data for 10
C₂₄H₃₀N₂O₇S, M_r = 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) Å^³, 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: [phone]; or e-mail: [e-mail].

<A NAME="RD03910ST-16">16</A>

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, H_arom), 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 (C_arom), 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.

<A NAME="RD03910ST-17">17</A> This process of oxidation-isomerization has been previously studied for hydrazines and some examples are reported, see: Stone KJ. Greenberg MM. Blackstock SC. Berson JA. J. Am. Chem. Soc.  1989,  111:  3659 ; see also ref. 11a

<A NAME="RD03910ST-18">18</A>

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.

For the conditions used in the biological tests, see:

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