Practical Synthesis of the Fluorogenic Enzyme Substrate 4-Methylumbelliferyl α-l-Idopyranosiduronic Acid

Abstract

A practical and concise synthesis of 4-methylumbelliferyl α-l-idopyranosiduronic acid, a fluorogenic enzyme substrate diagnostic for α-l-iduronidase, was accomplished. It features successive radical bromination and radical reduction of easily accessible methyl 4-methyl­umbelliferyl-2,3,4-tri-O-acetyl-β-d-glucouronate in four steps with 28% overall yield.

Key words

α-l-Iduronidase - 4-methylumbelliferyl α-l-idopyranosiduronic acid - radical reduction - radical bromination - fluorogenic enzyme substrate - synthesis

• References and Notes

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• 17 Characterization Data of Compound 13 Mp 89–91 °C; [α]_D ²⁵ –08.1 (c 0.068, CH₂Cl₂). ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.75 (d, J = 8.8 Hz, 1 H, H-5), 7.16 (s, 1 H, H-8), 7.11 (d, J = 8.9 Hz, 1 H, H-6), 6.28 (s, 1 H, H-3), 6.02 (s, 1 H, H-1′), 5.16 (s, 1 H, H-3′), 5.04 (s, 2 H, H-2′, H-4′), 4.99 (s, 1 H, H-5′), 3.66 (s, 3 H, OCH₃), 2.41 (s, 3 H, 4-CH₃), 2.16 (s, 3 H, OAc), 2.10 (s, 3 H, OAc), 2.05 (s, 3 H, OAc). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 169.1 (OAc), 169.0 (C × 2, OAc), 167.3 (COOMe), 159.8 (C-2), 158.1 (C-7), 154.2 (C-9), 153.1 (C-4), 126.7 (C-5), 114.8 (C-10), 113.4 (C-6), 112.2 (C-3), 103.8 (C-8), 95.2 (C-1′), 67.5 (C-5′), 66.8 (C-3′), 66.4(C-4′), 66.0 (C-2′), 52.3 (OCH₃), 20.5 (C × 2, OAc), 20.3 (OAc), 18.0 (4-CH₃). HRMS (ESI⁺): m/z calcd for C₂₃H₂₅O₁₂ [M + H]⁺: 493.1341; found: 493.1346.
• 18 Characterization Data of Compound 14 Mp 119–121 °C; [α]_D ²⁵ –111.7 (c 0.081, CH₃OH). ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.73 (d, J = 8.5 Hz, 1 H, H-5), 7.07–7.04 (m, 2 H, H-8, H-6), 6.26 (s, 1 H, H-3), 5.70 (d, J = 4.9 Hz, 1 H, H-1′), 5.57 (d, J = 5.8 Hz, 1 H, 2′-OH), 5.38–5.36 (m, 2 H, 3′-OH, 4′-OH), 4.65 (d, J = 4.3 Hz, 1 H, H-5′), 3.82–3.78 (m, 1 H, H-4′), 3.67–3.63 (m, 4 H, H-3′, COOMe), 3.58–3.53 (m, 1 H, H-2′), 2.40 (s, 3 H, 4-CH₃). ¹³C NMR (101 MHz, DMSO-d₆ ): δ = 170.0 (COOMe), 160.0 (C-2), 159.6 (C-7), 154.3 (C-9), 153.2 (C-4), 126.6 (C-5), 114.2 (C-10), 113.3 (C-6), 111.8 (C-3), 103.3 (C-8), 99.0 (C-1′), 71.8 (C-5′), 71.4 (C-3′), 70.7 (C-2′), 70.0 (C-4′), 51.7 (OCH₃), 18.1 (4-CH₃). HRMS (ESI⁺): m/z calcd for C₁₇H₁₉O₉ [M + H]⁺: 367.1024; found: 367.1029.
• 19 Characterization Data of 4-Methylumbelliferyl α-l-Idopyranosiduronic Acid (1) Mp 205–207 °C; [α]_D ²⁵ –38.3 (c 0.021, CH₃OH). ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.87(s, 1 H, H-8), 7.65 (d, J = 8.8 Hz, 1 H, H-5), 7.34 (dd, J = 8.8, 2.4 Hz, 1 H, H-6), 6.21 (s, 1 H, H-3), 5.51 (d, J = 7.0 Hz, 1 H, 2′-OH), 5.19 (d, J = 4.9 Hz, 1 H, H-1′), 4.96 (d, J = 3.8 Hz, 1 H, 3′-OH), 3.99 (d, J = 6.2 Hz, 1 H, H-3′), 3.25–3.17 (m, 3 H, H-2′, H-4′, H-5′), 2.40 (s, 3 H, 4-CH₃). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 172.1 (COOH), 160.8 (C-2), 160.4 (C-7), 154.6 (C-9), 153.4 (C-4), 126.0 (C-5), 113.6 (C × 2, C-10, C-6), 111.3 (C-3), 103.6 (C-8), 97.3 (C-1′), 74.4 (C-5′), 73.1 (C-3′), 72.5 (C-4′), 71.1 (C-2′), 18.1 (4-CH₃). HRMS (ESI⁺): m/z calcd for C₁₆H₁₇O₉ [M + H]⁺: 353.0867; found: 353.0868.