A Concise Synthesis of N-Trichloroethoxycarbonyl Lactosamine Trichloroacetimidate Donor and its Application in the Synthesis of Gal(β1-4)GlcNAc(β1-3)L-Fuc(α-OAll)

Jun Xue; Sirajud D. Khaja; Robert D. Locke; Khushi L. Matta

doi:10.1055/s-2004-820032

LETTER

A Concise Synthesis of N-Trichloroethoxycarbonyl Lactosamine Trichloroacetimidate Donor and its Application in the Synthesis of Gal(β1-4)GlcNAc(β1-3)L-Fuc(α-OAll)

Jun Xue, Sirajud. D. Khaja, Robert D. Locke, Khushi L. Matta*
Molecular and Cellular Biophysics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
Fax: +1(716)8453458; e-Mail: khushi.matta@roswellpark.org;

Abstract

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Abstract

A large-scale practical approach is described for converting d-glucosamine into lactosamine donor. 2-Naphthylmethyl (NAP) functionality is utilized as anomeric protecting group of N-trichloroethoxycarboonyl (N-Troc) glucosamine, which can avoid an unexpected intermolecular aglycon transfer observed in TMSOTf-mediated glycosylation when using corresponding thioglycoside as glycosyl acceptor. N-Troc protected glucosamine 9 shows enhanced reactivity as glycosyl acceptor, which was confirmed by systemic comparison with various N-protected glucosamine derivatives in TMSOTf-mediated glycosylation. The lactosamine imidate 14 exhibits valuable glycosyl donor property for b-selective glycosylation which furnished the desired trisaccharide Gal(β1-4)GlcNAc(β1-3)L-Fuc(α-OAll) in high yield. This sequence is part of O-linked chains of human clotting factor IX and mammalian Notch 1, and it was also found to be required for fringe to inhibit Jagged1-dependent Notch activation.

Key words

glucosamine acceptor - lactosamine donor - N-trichloroethoxy carbonyl (N-Troc) - 2-naphthylmethyl (NAP) - intermolecular aglycon transfer

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References

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Glycosylation, General Procedure: A solution of acceptor (1.5 mmol, 1 equiv) and imidate donor (1.7 mmol, 1.1 equiv) in anhyd CH₂Cl₂ (10 mL) containing 4 Å MS (2 g) was stirred at -45 °C for 1 h under a N₂ atmosphere. TMSOTf (40 mL, 0.2 equiv) in CH₂Cl₂ (1 mL) was added dropwise, and the reaction was stirred at -45 °C for 1 h. After the reaction was completed, the solids were filtered off and the filtrate washed with sat. NaHCO₃, dried over Na₂SO₄, and concentrated to a crude residue that was applied to a silica gel column eluted with hexanes-EtOAc (2:1-1:1) to give a pure product.

Removal of 2-Naphthylmethyl (NAP) using DDQ: A solution of compound 12 (600 mg, 0.64 mmol) in a mixture of CH₂Cl₂-MeOH (10 mL, 4:1) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (871 mg, 3.84 mmol), and stirred at r.t. for 10 h. After the reaction was completed, the reaction mixture was concentrated and taken up in CH₂Cl₂ (50 mL), which was washed with sat. NaHCO₃ (2 × 50 mL), dried (Na₂SO₄), and concentrated. The crude reside was applied to a column of silica gel eluted with hexanes-EtOAc (2:1) to give a pure compound 13 as a syrup (432 mg, 85%).

Conversion of the Troc Carbamate into Acetamido: Cadmium dust (756 mg, 6.73 mmol) was added to a solution of 16 (400 mg, 0.34 mmol) in DMF-HOAc (1:1) and the reaction was stirred at r.t. under N₂. After 12 h the reaction mixture was filtered through Celite^®, rinsed with DMF (5 mL) then azeotroped with toluene (5 × 20 mL). The residue was treated with Ac₂O in pyridine-CH₂Cl₂ (1:1) for 4 h at r.t., then quenched with MeOH (1 mL). The reaction mixture was concentrated in vacuum and the residue was redissolved in CH₂Cl₂ (50 mL) and washed with brine (1 × 60 mL) then dried (Na₂SO₄). The organic extract was filtered, concentrated in vacuum and purified by flash chromatography (1:1, hexanes-EtOAc) to afford 17 (333.6 mg, 93%).

Physical data: Compound 11: ¹H NMR (400 MHz, CDCl₃) δ = 7.81-7.73 (m, 4 H, ArH), 7.50-7.40 (m, 3 H, ArH), 5.37-5.36 (d, J = 3.74 Hz, 1 H, H1_Gal), 5.24-5.20 (m, 2 H), 5.02-4.96 (m, 2 H), 4.75-4.71 (d, J = 13.18 Hz, 1 H), 4.68-4.60 (m, 2 H, OCH₂CCl₃), 4.54-4.52 (d, J = 7.70 Hz, 1 H), 4.38-4.23 (d, J = 10.8 Hz, 1 H), 4.23 (s, 1 H), 4.12-4.10 (m, 4 H), 3.85-3.75 (t, J = 9.8 Hz, J = 7.70 Hz, 1 H), 3.60-3.55 (m, 1 H), 3.49-3.47 (m, 2 H), 2.13 (s, 3 H, Ac), 2.07 (s, 3 H, Ac), 2.04 (s, 3 H, Ac), 1.97 (s, 3 H, Ac), 1.25 (s, 9 H, t-Bu). HRMS (FAB): m/z [M + H]⁺ calcd for C₃₉H₄₈O₁₇NCl₃: 908.2065; found: 908.2070. Compound 14: ¹H NMR (400 MHz, CDCl₃): δ = 8.78 (s, 1 H, OCNHCCl₃), 6.37-6.36 (d, J = 3.63 Hz, 1 H), 5.37-5.36 (d, J = 2.61 Hz, 1 H), 5.34-5.27 (m, 2 H), 5.14-5.10 (dd, J = 2.45 Hz, J = 7.99 Hz), 4.97-4.93 (dd, J = 4.11 Hz, J = 6.19 Hz), 4.71 (s, 2 H, OCH₂CCl₃), 4.55-4.53 (d, J = 7.84 Hz, 1 H), 4.44-4.42 (d, J = 10.32 Hz, 1 H), 4.18-4.03 (m, 7 H), 3.91-3.86 (m, 2 H), 2.15 (s, 3 H, Ac), 2.10 (s, 3 H, Ac), 2.06 (s, 3 H, Ac), 2.03 (s, 3 H, Ac), 1.97 (s, 3 H, Ac), 1.25 (s, 9 H, t-Bu). HRMS (FAB): calcd for [M - H]^- C₃₂H₄₂O₁₈N₂Cl₆: 951.0485; found: 951.0490. Compound 16: ¹H NMR (400 MHz, CDCl₃): δ = 8.16-8.15 (d, 2 H, ArH), 8.06-8.04 (d, 2 H, ArH), 7.60-7.41 (m, 6 H, ArH), 5.82-5.75 (m, 1 H, OCH₂CHCH₂), 5.57-5.56 (d, J = 6.34 Hz, 1 H), 5.32-5.30 (m, 3 H), 5.24-5.08 (m, 5 H), 4.95-4.92 (dd, J = 2.97 Hz, J = 10.34 Hz, 1 H), 4.79-4.77 (m, 2 H), 4.63-4.60 (dd, J = 3.40 Hz, J = 6.53 Hz, 1 H), 4.44-4.42 (d, J = 7.83 Hz, 1 H), 4.38-4.35 (d, J = 10.91 Hz, 1 H), 4.22-4.20 (dd, J = 6.88 Hz, 1 H), 4.14-4.02 (m, 6 H), 3.83-3.80 (t, J = 6.07 Hz, 1 H), 3.74 (t, 1 H), 3.60-3.45 (m, 2 H), 2.13 (s, 3 H, Ac), 2.05 (s, 3 H, Ac), 2.02 (s, 3 H, Ac), 1.96 (s, 3 H, Ac), 1.92 (s, 3 H, Ac), 1.22 (s, 9 H, t-Bu), 1.20 (d, 3 H, CH_3,fuc).¹³C NMR (100.6 MHz, CDCl₃): δ = 170.24, 170.09, 169.96, 169.74, 169.00, 167.17, 165.83, 154.01, 133.67, 133.44, 133.08, 130.35, 129.85, 129.82, 128.52, 128.29, 117.84, 101.16, 97.07, 95.55, 77.32, 77.23, 77.00, 76.67, 73.11, 72.83, 71.19, 70.93, 70.76, 70.50, 69.19, 69.17, 68.84, 66.66, 66.59, 64.72, 63.15, 60.90, 55.87, 27.25, 27.26, 20.68, 20.57, 20.49, 20.46, 16.20, 16.15. HRMS (FAB): calcd for [M + H]⁺ C₅₃H₆₄O₂₃NCl₃: 1204.2961; found 1204.2960. Compound 18: ¹H NMR (400 MHz, CDOD₃): δ = 6.01-5.90 (m, 1 H, OCH₂CHCH₂), 5.35-5.30 (d, 1 H, OCH₂CHCH ₂), 5.18-5.15 (d, 1 H, OCH₂CHCH ₂), 4.84-4.83 (d, J = 3.69 Hz, 1 H, H-1_fuc), 4.61-4.59 (d, J = 7.35 Hz, 1 H, H-1_Gal), 4.36-4.34 (d, J = 7.31, 1 H, H-1_GlcNAc), 4.15-4.13 (dd, 1 H, OCH ₂CHCH₂), 4.05-4.03 (dd, 1 H, OCH ₂CHCH₂), 3.97-3.92 (m, 2 H), 3.91-3.89 (d, J = 3.2 Hz, 1 H), 3.87-3.86 (d, J = 3.66 Hz, 1 H), 3.85-3.82 (dd, 1 H), 3.81-3.79 (m, 2 H), 3.76-3.65 (m, 5 H), 3.60-3.46 (m, 6 H), 1.99 (s, 3 H, NHAc), 1.22-1.21 (d, J = 6.51 Hz, 3 H, CH_3,fuc). ¹³C NMR (100.6 MHz, CDOD₃): δ = 174.39, 135.68 (OCH₂ CHCH₂), 117.58 (OCH₂CHCH₂), 105.18 (C1_Gal), 101.09 (C1_GlcNAc), 99.35 (C1_fuc), 80.97, 80.00, 77.18, 76.73, 74.87, 72.61, 71.08, 70.35, 69.57, 68.13, 67.34, 62.56, 61.96, 57.29, 23.17, 16.53. HRMS (FAB): [M + H]⁺ calcd for C₂₈H₃₉O₁₅N: 570.2398; found: 570.2396.