Introduction of 4-Chlorophenyl: A Protecting Group for the Hydroxy Function

Abstract

4-Chlorophenyl ether was utilized as a new protecting group for the hydroxy function. This group was readily introduced to a sugar hydroxy group by using diaryliodonium triflate. Regioselective introduction of this protecting group at the vicinal cis-diol was achieved by using a copper catalyst and diaryliodonium triflate. This protecting group is stable under the Lewis acidic conditions of glycosylation, but it can be readily removed by the initial conversion into the corresponding 4-methoxyphenyl ether with use of a Pd catalyst, followed by oxidation with ammonium cerium (IV) nitrate [(NH₄)₂Ce(NO₃)₆] (CAN).

Key words

4-chlorophenyl ether - 4-methoxyphenyl ether - carbo­hydrate - protecting group - hydroxy function - regioselective arylation

• References and Notes

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• 13 General Procedure for 4-Chlorophenylation of Mono-ols Sugar mono-ol (100 mg, 0.384 mmol, 1.0 equiv) was stirred in toluene (3.8 mL, 0.1 M). To the solution were added 4-chlorophenyl(4-methoxyphenyl)iodonium trifluoromethanesulfonate (7, 760 mg, 1.54 mmol, 4.0 equiv) and tBuOK (172 mg, 1.54 mmol, 4.0 equiv), and the mixture was stirred for overnight at rt. Upon completion, the mixture was concentrated in vacuo. The resulting crude product was purified by flash column chromatography on silica gel (Toluene/AcOEt = 5/1) to afford the corresponding 4-ChPhe protected sugar.
• 14 1,2:3,4-Di-O-isopropylidene-6-O-(4-chlorophenyl)-α-D-galactopyranose (4) ^{117.5 mg (83%), as a colorless oil.1}H NMR (CDCl₃, 400 MHz): δ = 7.22–7.20 (m, 2 H, Cl-Ph-OR-2H, Cl-Ph-OR-6H), 6.88–6.86 (m, 2 H, Cl-Ph-OR-3H, Cl-Ph-OR-5H), 5.56 (d, J = 5.03 Hz, 1 H, H-1), 4.65 (dd, J = 8.01, 2.52 Hz, 1 H, H-3), 4.35–4.33 (m, 2 H, H-2, H-4), 4.16–4.08 (m, 3 H, H-5, H-6, H-6'), 1.52 (s, 3 H, isopropyl), 1.47 (s, 3 H, isopropyl), 1.36 (s, 3 H, isopropyl), 1.34 (s, 3 H, isopropyl); ¹³C NMR (CDCl₃, 100 MHz): δ = 157.2, 129.2, 125.8, 116.1, 109.5, 108.7, 96.3, 70.9, 70.6, 70.5, 67.0, 66.2, 26.0, 26.0, 24.9, 24.4; HRMS: m/z calcd for C₁₈H₂₃ClNaO₆ [M + Na]⁺: 393.1075; found : 393.1061.
• 15 General Procedure for Methoxylation of 4-Chlorophenyl Protecting Groups A mixture of 4-ChPhe-protected sugar (12 mg, 0.0324 mmol, 1.0 equiv), tBuBrettPhos Pd G3 (2.8 mg, 0.00324 mmol, 0.1 equiv), tBuBrettPhos (1.6 mg, 0.00324 mmol, 0.1 equiv), tBuONa (12.5 mg, 0.139 mmol, 4.0 equiv) and MeOH (0.066 mL, 50 equiv) was stirred in dioxane (0.324 mL, 0.1 M) under Ar and heated to reflux for 0.5 h. After diluting with AcOEt, the organic phase was washed with H₂O and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The resulting crude product was purified by flash column chromatography on silica gel (n-Hexane/AcOEt = 1/1) to afford the corresponding MP-protected sugar.1,2:3,4-di-O-isopropylidene-6-O-(4-methoxyphenyl)-α-D-galactopyranose (3)10.0 mg (84%), as a colorless oil. ¹H NMR (CDCl₃, 400 MHz): δ = 6.90–6.86 (m, 2 H, MeO-Ph-OR-2H, MeO-Ph-OR-6H), 6.83–6.79 (m, 2 H, MeO-Ph-OR-3H, MeO-Ph-OR-5H), 5.57 (d, J = 5.03 Hz, 1 H, H-1), 4.64 (dd, J = 7.78, 2.29 Hz, H-3), 4.36–4.33 (m, 2 H, H-2, H-4), 4.16–4.07 (m, 3 H, H-5, H-6), 3.76 (s, 3 H, MeO), 1.51 (s, 3 H, isopropyl), 1.47 (s, 3 H, isopropyl), 1.36 (s, 3 H, isopropyl), 1.34 (s, 3 H, isopropyl); ¹³C NMR (CDCl₃, 100 MHz): δ = 153.9, 152.7, 115.9, 114.5, 109.4, 108.7, 96.3, 71.0, 70.6, 67.3, 66.1, 55.7, 26.0, 26.0, 24.9, 24.4; HRMS: m/z calcd for C₁₉H₂₆NaO₇ [M + Na]⁺: 389.1571; found: 389.1565.
• 16 General Procedure for Regioselective 4-Chlorophenylation of cis-Diols Under Ar, a test tube was charged with CuBr₂ (3.7 mg, 0.0167 mmol, 0.3 equiv) and Na₃PO₄ (37 mg, 0.223 mmol, 4.0 equiv), and then toluene (0.1 M) was added. The mixture was stirred for 10 min at rt. Sugar cis-diol (20.0 mg, 0.0558 mmol, 1.0 equiv) and bis(4-chlorophenyl)iodonium trifluoromethanesulfonate (41.8 mg, 0.0837 mmol, 1.5 equiv) were added and the reaction mixture was heated to reflux for 1 h. Then bis(4-chlorophenyl)iodonium trifluoromethanesulfonate (16.3 mg, 0.0227 mmol, 0.5 equiv) was added and the reaction mixture was heated to reflux for 2 h. The mixture was cooled to rt and water and sat. aqueous NH₄Cl were added. After diluting with AcOEt, the organic phase was washed with H₂O and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The resulting crude product was purified by flash column chromatography on silica gel (Toluene/AcOEt = 10/1) to afford the corresponding 4-ChPhe protected sugar. Benzyl 4,6-O-benzylidene-3-O-(4-chlorophenyl)-α-D-mannopyranoside (27b) 27a, 27b (75%), as a colorless oil. ¹H NMR (CDCl₃, 400 MHz): δ = 7.39–7.29 (m, 10 H, Ph), 7.23–7.19 (m, 2 H, ClPh), 7.03–6.99 (m, 2 H, Cl-Ph), 5.60 (s, 1 H, PhCH), 5.01 (d, J = 1.37 Hz, H-1), 4.74 (d, J = 11.9 Hz, 1 H, PhCH ₂), 4.64 (dd, J = 9.61, 3.66 Hz, 1 H, H-3), 4.54 (dd, J = 11.9 Hz, 1 H, PhCH ₂), 4.30 (dd, J = 10.1, 4.58 Hz, 1 H, H-6), 4.25 (dd, J = 9.61, 9.61 Hz, 1 H, H-4), 4.23–4.21 (m, 1 H, H-2), 3.99 (ddd, J = 10.1, 9.61, 4.58 Hz, 1 H, H-5), 3.90 (dd, J = 10.1, 10.1 Hz, 1 H, H-6'), 2.60 (d, J = 2.29 Hz, 0.9 H, OH); ¹³C NMR (CDCl₃, 100 MHz): δ = 156.6, 137.1, 136.6, 129.3, 128.9, 128.6, 128.2, 128.2, 127.2, 125.9, 118.6, 101.6, 99.2, 77.7, 76.6, 70.0, 69.6, 68.8, 63.9; HRMS: m/z calcd for C₂₆H₂₅NaClO₆ [M + Na]⁺: 491.1232; found: 491.1216.