Azidation of Partially Protected Carbohydrate Derivatives: Efficient Suppression of Acyl Migration

Abstract

Although azidation by nucleophilic substitution is widely used in organic chemistry, it has a limitation for partially protected carbohydrate derivatives under typical reaction conditions used for azidation (heating with NaN₃, phase-transfer catalyst (optional), DMF or DMSO) as it can cause substantial migration (70%) of O-acyl protective groups. Several approaches, including the use of a temporary protective group for the unprotected hydroxyl group, to avoid acyl migration have been compared. Addition of excess of ethyl trifluroacetate effectively suppressed benzoyl migration but inhibited substitution of the chlorine atom with the azido group. The most robust procedure involved addition of excess n-butyl formate to the reaction mixture. When this protocol was followed, migration of benzoyl groups in lactose derivatives with free hydroxy group at C-3′ or C-4′ was reduced to 4%, with the yield of the target, partially protected derivatives with an azido group in the aglycone approaching 92%.

Key words

azide - carbohydrate - protecting group - regioselectivity

• References and Notes

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• 16 Typical Procedure of Azidation of Chlorides in the Presence of TFAOEt or HCO₂Bu Suppressing Acyl Migration To the solution of CPP glycoside 1, 8, or 9 in DMF (2 mL per 0.1 g of substrate), NaN₃ (3 equiv) and 18-crown-6 (0.5 equiv) were added followed by addition of TFAOEt or HCO₂Bu (see Table 2 for the amounts). The flask was sealed, and the mixture was stirred at 70 °C for 18 h. DMF was evaporated in vacuo, toluene was added (4 × 5 mL) and then concentrated in vacuo. The residue was dissolved in EtOAc (30 mL), washed with water (2 × 30 mL), and the aqueous layer was back extracted with EtOAc (2 × 30 mL). The combined organic extract was dried over Na₂SO₄, filtered, concentrated under reduced pressure, and dried in vacuo. The residue was purified by silica gel column chromatography (PhMe → PhMe/EtOAc, 1:1) to give pure APP glycosides 2, 3, or 10, respectively (see Supporting Information for more details). 4-(3-Azidopropoxy)phenyl 2,3,6-tri-O-benzoyl-4-O-(2,3,6-tri-O-benzoyl-β-d-galactopyranosyl)-β-d-glucopyranoside (2) APP glycoside 2 was prepared from CPP glycoside 1 (150 mg, 0.13 mmol) using the standard procedure (Table 2, entry 6). The final product was crystallized from CH₂Cl₂–light petroleum to give the title compound as colorless crystals (135 mg, 89%). R_f  = 0.57 (PhMe/EtOAc, 4:1); mp 201–202 °C; [α]_D ²⁴ +31.2 (c 0.97, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.99 (tt (app p), J = 6.3 Hz, 2 H, CH₂CH₂N₃), 2.66 (d, J = 6.5 Hz, 1 H, 4-OH Gal), 3.47 (t, J = 6.6 Hz, 2 H, CH₂N₃), 3.69 (dd, J ₅,_6a = 6.6 Hz, J _6a,_6b = 10.9 Hz, 1 H, H-6a Gal), 3.77 (dd (app t), J = 6.2 Hz, 1 H, H-5 Gal), 3.91 (t, J = 6.0 Hz, 2 H, OCH₂), 4.02 (ddd, J ₅,_6b = 2.0 Hz, J ₅,_6a = 5.7 Hz, J ₄,₅ = 9.8 Hz, 1 H, H-5 Glc), 4.16 (dd, J ₅,_6b = 5.9 Hz, J _6a,_6b = 10.9 Hz, 1 H, H-6b Gal), 4.20 (dd, J ₃,₄ = 3.3 Hz, J ₄,_OH = 6.5 Hz, 1 H, H-4 Gal), 4.27 (dd, J ₃,₄ = 8.9 Hz, J ₄,₅ = 9.8 Hz, 1 H, H-4 Glc), 4.52 (dd, J ₅,_6a = 5.7 Hz, J _6a,_6b = 11.9 Hz, 1 H, H-6a Glc), 4.64 (dd, J ₅,_6b = 2.0 Hz, J _6a,_6b = 11.9 Hz, 1 H, H-6b Glc), 4.84 (d, J ₁,₂ = 7.9 Hz, 1 H, H-1 Gal), 5.16 (d, J ₁,₂ = 7.7 Hz, 1 H, H-1 Glc), 5.20 (dd, J ₃,₄ = 3.3 Hz, J ₂,₃ = 10.4 Hz, 1 H, H-3 Gal), 5.68 (dd, J ₁,₂ = 7.7 Hz, J ₂,₃ = 9.6 Hz, 1 H, H-2 Glc), 5.78 (dd, J ₁,₂ = 7.9 Hz, J ₂,₃ = 10.4 Hz, 1 H, H-2 Gal), 5.85 (dd, J ₃,₄ = 8.9 Hz, J ₂,₃ = 9.6 Hz, 1 H, H-3 Glc), 6.59–6.70 (m, 2 H, OC₆H₄O), 6.83–6.93 (m, 2 H, OC₆H₄O), 7.18–7.66 (m, 18 H, Ph), 7.89–8.08 (m, 12 H, H-2(6) Ph). ¹³C NMR (75 MHz, CDCl₃): δ = 28.7 (CH₂CH₂N₃), 48.2 (CH₂N₃), 61.9 (C-6 Gal), 62.6 (C-6 Glc), 64.9 (OCH₂), 66.8 (C-4 Gal), 69.7 (C-2 Gal), 71.7 (C-2 Glc), 72.7 (C-5 Gal), 73.0 (C-3 Glc), 73.1 (C-5 Glc), 74.1 (C-3 Gal), 76.4 (C-4 Glc), 100.4 (C-1 Glc), 101.2 (C-1 Gal), 115.1, 118.8 (OC₆H₄O), 128.34, 128.38, 128.40, 128.41, 128.6, 128.8, 128.9, 129.2, 129.49, 129.54, 129.59, 129.61, 129.67, 129.69, 129.78, 129.84, 133.18, 133.22, 133.24, 133.4 (Ph), 151.1 (C-1 OC₆H₄O), 154.7 (C-4 OC₆H₄O), 165.0, 165.2, 165.6, 165.72, 165.74, 166.0 (CO). HRMS (ESI): m/z calcd for C₆₃H₅₅N₃O₁₈Na⁺ [M + Na]⁺: 1164.3373; found: 1164.3357. 4-(3-Azidopropoxy)phenyl 2,3,6-tri-O-benzoyl-4-O-(2,4,6-tri-O-benzoyl-β-d-galactopyranosyl)-β-d-glucopyranoside (3) APP glycoside 3 was prepared from CPP glycoside 8 (1.500 g, 1.32 mmol) using the standard procedure (Table 2, entry 9). The final product was lyophilized from benzene to give a white foam (1.392 mg, 92%). R_f = 0.43 (PhMe/EtOAc, 4:1); [α]_D ²⁴ +10.9 (c 1.00, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 2.00 (tt (app p), J = 6.3 Hz, 2H, CH₂CH₂N₃), 2.74 (d, J = 6.3 Hz, 1 H, 3-OH Gal), 3.48 (t, J = 6.6 Hz, 2 H, CH₂N₃), 3.54 (dd, J ₅,_6a = 9.5 Hz, J _6a,_6b = 13.4 Hz, 1 H, H-6a Gal), 3.75–3.86 (m, 2 H, H-5 Gal, H-6b Gal), 3.93 (t, J = 5.9 Hz, 1 H, OCH₂), 3.96–4.06 (m, 2 H, H-3 Gal, H-5 Glc), 4.26 (dd, J ₃,₄ = 8.9 Hz, J ₄,₅ = 9.9 Hz, 1 H, H-4 Glc), 4.59 (dd, J ₅,_6a = 5.7 Hz, J _6a,_6b = 12.0 Hz, 1 H, H-6a Glc), 4.71 (dd, J ₅,_6b = 1.4 Hz, J _6a,_6b = 12.0 Hz, 1 H, H-6b Glc), 4.79 (d, J ₁,₂ = 7.8 Hz, 1 H, H-1 Gal), 5.15 (d, J ₁,₂ = 7.7 Hz, 1 H, H-1 Glc), 5.35 (dd, J ₁,₂ = 7.9 Hz, J ₂,₃ = 9.8 Hz, 1 H, H-2 Gal), 5.54 (d, J ₃,₄ = 3.3 Hz, 1 H, H-4 Gal), 5.71 (dd, J ₁,₂ = 7.7 Hz, J ₂,₃ = 9.8 Hz, 1 H, H-2Glc), 5.82 (dd, J ₃,₄ = 8.9 Hz, J ₂,₃ = 9.8 Hz, 1 H, H-3 Glc), 6.58–6.75 (m, 2 H, OC₆H₄O), 6.83–7.00 (m, 2 H, OC₆H₄O), 7.07 (dd (app t), J = 7.7 Hz, 2 H, Ph), 7.27–7.73 (m, 16 H, Ph), 7.88–8.13 (m, 12 H, Ph). ¹³C NMR (75 MHz, CDCl₃): δ = 28.8 (CH₂CH₂N₃), 48.2 (CH₂N₃), 61.5 (C-6 Gal), 62.8 (C-6 Glc), 64.9 (OCH₂), 70.0 (C-4 Gal), 71.6 (C-5 Gal), 71.6 (C-2 Glc), 71.9 (C-3 Glc), 72.8, 73.3 (C-3 Gal or C-5 Glc), 73.7 (C-2 Gal), 76.1 (C-4 Glc), 100.6 (C-1 Gal), 100.7 (C-1 Glc), 115.1 (OC₆H₄O), 118.9 (OC₆H₄O), 128.1, 128.4, 128.5, 128.6, 128.6, 128.9, 129.2, 129.5, 129.6, 129.6, 129.7, 129.8, 129.8, 130.1, 133.1, 133.2, 133.3, 133.4, 133.5, 133.5 (Ph), 151.2 (OC₆H₄O), 154.7 (OC₆H₄O), 165.2, 165.4, 165.7, 165.8, 165.9, 166.4 (CO). HRMS (ESI): m/z calcd for C₆₃H₅₅N₃O₁₈Na⁺ [M + Na]⁺: 1164.3373; found: 1164.3360.
• 17 Basic impurities that allegedly cause acyl migration might also be trapped by addition of acids. However, we strongly discourage adding any acids to the azidation reaction mixture due to the high probability of formation hydrazoic acid, which is a poisonous and highly explosive compound.
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• 20 Caution! The formation of EtN₃ is expected in this reaction (as follows from Scheme 3). This compound has a boiling point of 50 °C and is heat and impact sensitive. However, no detonation was detected during reactions even at 1.5 g scale.
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