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Synlett 2004(5): 0861-0865  
DOI: 10.1055/s-2004-820032
LETTER
© Georg Thieme Verlag Stuttgart · New York

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;
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Publication History

Received 12 December 2003
Publication Date:
10 March 2004 (online)

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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

    References

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16

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.

17

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%).

18

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%).

19

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, H1Gal), 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, CH3,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-1fuc), 4.61-4.59 (d, J = 7.35 Hz, 1 H, H-1Gal), 4.36-4.34 (d, J = 7.31, 1 H, H-1GlcNAc), 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, CH3,fuc). 13C NMR (100.6 MHz, CDOD3): δ = 174.39, 135.68 (OCH2 CHCH2), 117.58 (OCH2CHCH2), 105.18 (C1Gal), 101.09 (C1GlcNAc), 99.35 (C1fuc), 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.