Phenyl 2-Deoxy-2-iodo-1-thio-glycosides: New Glycosyl Donors for the Stereoselective Synthesis of 2-Deoxy-oligosaccharides

Abstract

Phenyl 2-deoxy-2-iodo-1-thioglycosides, prepared from simple pentoses by olefination and iodine-induced cyclization, have proved to be efficient glycosyl donors for the stereoselective synthesis of 2-deoxy-2-iodo-oligosaccharides, which are precursors of 2-deoxy-oligosaccharides.

2-deoxy-oligosaccharides - glycosylation - stereoselectivity - cyclizations - iodine

References

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12

Compound 2: To a solution of 4 mmol of the phosphine oxide in 26 mL of THF at -78 ºC, 4.2 mmol of BuLi were added. The mixture was left to stir at low temperature for 30 min. A solution of 1 mmol of 1 in 2 mL of THF was then added dropwise. The mixture was allowed to warm to r.t. overnight. A sat. solution of NH₄Cl was then added and the olefination product extrated with Et₂O. The combination of ethereal layers was dried with MgSO₄ and concentrated. The reaction crude was purified by MPLC (hexane to EtOAc/hexane = 1:3) to render 2 (80% yield) as a mixture of diastereoisomers (E/Z-ratio = 87:13) as a syrup. Compound 2 E: ¹H NMR (400 MHz, CDCl₃): δ = 7.40-7.15 (m, 20 H, aromatics), 6.46 (d, 1 H, J _2,1 = 15.2 Hz, H-1), 5.87 (dd, 1 H, J _1,2 = 15.2 Hz, J _3,2 = 7.6 Hz, H-2), 4.65 (d, 1 H, J = 12.0 Hz, CH₂Ph), 4.57 (d, 1 H, J = 11.4 Hz, CH₂Ph), 4.52 (d, 1 H, J = 11.4 Hz, CH₂Ph), 4.49 (s, 2 H, CH₂Ph), 4.38 (d, 1 H, J = 12.0 Hz, CH₂Ph), 4.16 (dd, 1 H, J _5,4 = 8.0 Hz, J _3,4 = 3.6 Hz, H-4), 4.00 (m, 1 H, H-5), 3.58 (m, 3 H, H-3, H-6), 2.76 (d, 1 H, J = 5.2 Hz, OH). ¹³C NMR (100.6 MHz, CDCl₃):
δ = 140.8, 137.7, 137.5, 134.0 (C, aromatics), 130.2-126.0 (CH aromatics, C-1, C-2), 80.4 (C-3), 79.1 (C-4), 74.1, 73.2, 70.7 (CH₂Ph), 70.1 (C-6), 69.9 (C-5). Compound 2 Z:
¹H NMR (400 MHz, CDCl₃): δ = 7.50-7.15 (m, 20 H, aromatics), 6.67 (d, 1 H, J _2,1 = 9.9 Hz, H-1), 6.12 (dd, 1 H, J _1,2 = 9.9 Hz, J _3,2 = 9.3 Hz, H-2), 4.88 (d, 1 H, J = 11.0 Hz, CH₂Ph), 4.84 (d, 1 H, J = 11.5 Hz, CH₂Ph), 4.73 (d, 1 H, J = 11.0 Hz, CH₂Ph), 4.68 (d, 1 H, J = 12.0 Hz, CH₂Ph), 4.63 (d, 1 H, J = 11.5 Hz, CH₂Ph), 4.58 (d, 1 H, J = 12.0 Hz, CH₂Ph), 4.21 (m, 1 H, H-5), 3.85 (dd, 1 H, J _5,4 = 6.9 Hz, J _3,4 = 3.9 Hz, H-4), 3.77 (m, 3 H, H-3, H-6), 3.12 (d, 1 H, J = 5.1 Hz, OH). ¹³C NMR (100.6 MHz, CDCl₃): δ = 140.8, 137.7, 137.5, 134.0 (C, aromatics), 130.2-126.0 (CH aromatics, C-1, C-2), 80.4 (C-3), 79.1 (C-4), 74.1, 73.2, 70.7 (CH₂Ph), 70.1 (C-5), 64.9 (C-6).

13

Compound 3: A 0.175 M suspension of 1.3 mol of KH 30% in dry Et₂O was added dropwise to a 0.085 M solution of 2 (1 mol) in dry Et₂O at 0 ºC, and the resulting mixture was allowed to stir for 30 min until complete formation of the alcoholate. The mixture was cooled to -78 ºC and a 0.43 M solution of iodine (3 mol) in Et₂O was then added. The reaction was allowed to stir at low temperature for 1 h. A solution of Na₂S₃O₃ was then added and the reaction product extracted with Et₂O. The combination of the etheral layers was concentrated and the residue purified by radial chromatography to afford 3 (61%) as a yellowish syrup. Compound 3: [α]_D ²⁵ +67.8 (c 0.0217, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.70-7.10 (m, 20 H, aromatics), 5.68 (s, 1 H, H-1), 4.88 (d, 1 H, J = 10.4 Hz, CH₂Ph), 4.87 (d, 1 H, J _3,2 = 3.6 Hz, H-2), 4.72 (d, 1 H, J = 11.2 Hz, CH₂Ph), 4.70 (d, 1 H, J = 11.6 Hz, CH₂Ph), 4.54 (d, 1 H, J = 11.2 Hz, CH₂Ph), 4.52 (d, 1 H, J = 10.4 Hz, CH₂Ph), 4.48 (d, 1 H, J = 11.6 Hz, CH₂Ph), 4.41 (ddd, 1 H, J _4,5 = 8.8 Hz, J _6a,5 = 4.4 Hz, J _6b,5 = 1.6 Hz, H-5), 3.99 (dd, 1 H, J _5,4 = 8.8 Hz, J _3,4 = 8.4 Hz, H-4), 3.85 (dd, 1 H, J _6b,6a = 10.8 Hz, J _5,6a = 4.4 Hz, H-6a), 3.73 (dd, 1 H, J _6a,6b = 10.8 Hz, J _5,6b = 1.6 Hz, H-6b), 3.10 (dd, 1 H, J _4,3 = 8.4 Hz, J _2,3 = 3.6 Hz, H-3). ¹³C NMR (100.6 MHz, CDCl₃): δ = 138.0, 137.2, 133.9 (C, aromatics), 132.0-127.4 (CH, aromatics), 89.6 (C-1), 77.5 (C-3), 76.2 (C-4), 75.3 (CH₂Ph), 73.3 (CH₂Ph, C-5), 71.0 (CH₂Ph), 68.7 (C-6), 34.8 (C-2).

14a Landais Y. Panchenault D. Synlett  1995,  1191 

14b Bravo F. Castillón S. Eur. J. Org. Chem.  2001,  507 

15 Suzuki K. Mukaiyama T. Chem. Lett.  1982,  1525 

16

Compound 5: To a solution of 4 mmol of the phosphine oxide in 26 mL of THF at -78 ºC, 4.2 mmol of BuLi were added. The mixture was left to stir at low temperature for 30 min. A solution of 1 mmol of the 4 in 2 mL of THF was then added dropwise. The mixture was allowed to warm to r.t. first and then heated to reflux. A sat. solution of NH₄Cl was then added and the olefination product extrated with Et₂O. The combination of ethereal layers was dried with MgSO₄ and concentrated. The reaction crude was purified by MPLC (hexane to EtOAc/hexane = 1:3) to render 5 (72% yield) as a mixture of diastereoisomers (E/Z-ratio = 80:20) as a syrup. Compound 5 E: ¹H NMR (400 MHz, CDCl₃): δ = 7.39-7.25 (m, 20 H, aromatics), 6.54 (d, 1 H, J _2,1 = 15.1 Hz, H-1), 5.94 (dd, 1 H, J _1,2 = 15.1 Hz, J _3,2 = 8.4 Hz, H-2), 4.75 (d, 1 H, J = 10.8 Hz, CH₂Ph), 4.67 (d, 1 H, J = 12.0 Hz, CH₂Ph), 4.56 (d, 1 H, J = 10.8 Hz, CH₂Ph), 4.51 (d, 1 H, J = 12.0 Hz, CH₂Ph), 4.48 (d, 1 H, J = 12.0 Hz, CH₂Ph), 4.40 (d, 1 H, J = 12.0 Hz, CH₂Ph), 4.22 (dd, 1 H, J _2,3 = 8.4 Hz, J _4,3 = 4.4 Hz, H-3), 3.82 (m, 1 H, H-5), 3.69 (dd, 1 H, J _5,4 = 7.6 Hz, J _3,4 = 4.4 Hz, H-4), 3.61 (m, 2 H, H-6), 2.78 (bs, 1 H, OH). ¹³C NMR (100.6 MHz, CDCl₃): δ = 138.2, 138.1, 137.8, 134.6 (C, aromatics), 129.1-126.9 (CH, aromatics), 128.8 (C-1), 128.4 (C-2), 81.3 (C-3), 80.8 (C-4), 74.2, 73.4 (CH₂Ph), 70.9 (C-6), 70.8 (C-5), 70.5 (CH₂Ph). Compound 5 Z: ¹H NMR (400 MHz, CDCl₃): δ = 7.39-7.25 (m, 20 H, aromatics), 6.62 (d, 1 H, J ₂₁ = 9.6 Hz, H-1), 6.00 (pseudo t, 1 H, J ₁₂ = J ₃₂ = 9.6 Hz, H-2), 4.89-4.35 (m, 6 H, CH₂Ph), 3.91 (m, 1 H, H-5), 3.83 (dd, 1 H, J ₅₄ = 7.6 Hz, J ₃₄ = 3.4 Hz, H-4), 3.71 (dd, 1 H, J ₂₃ = 9.6 Hz, J ₄₃ = 3.4 Hz, H-3), 3.67 (m, 2 H, H-6), 2.85 (bs, 1 H, OH). ¹³C NMR (100.6 MHz, CDCl₃): δ = 138.1, 137.8, 135.5, 134.4 (C, aromatics), 129.8-126.5 (CH, aromatics, C-1, C-2), 80.9 (C-3), 77.1 (C-4), 74.1, 73.3 (CH₂Ph), 71.0, 70.8, 70.5 (C-5, C-6, CH₂Ph).

17 Freeman F. Robarge KD. Carbohydr. Res.  1986,  154:  270 

18

Compound 6: To a 0.5 M solution of 5 (0.084 g, 0.16 mmol) (E/Z = 2:3) in CH₃CN, NaHCO₃ (0.48 mmol) was added. The mixture was cooled to 0 ºC and left to stir at this temperature for 5 min. NIS (0.48 mol) was then added and the reaction mixture was allowed to warm to r.t. and stirred for 8 h. The mixture was diluted with Et₂O and washed with a sat. solution of Na₂S₃O₃. The combined aqueous layer was extracted with Et₂O. The combination of ethereal layers was dried with MgSO₄ and concentrated. The residue was purified by radial chromatography to afford 0.060 g (58% yield) as a β/α mixture = 2:3. Compound 6β: [α]_D ²⁵ +16.0 (c 0.7708, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.70-7.20 (m, 20 H, aromatics), 5.11 (d, 1 H, J _2,1 = 10.6 Hz, H-1), 4.92 (d, 1 H, J = 10.4 Hz, CH₂Ph), 4.75 (d, 1 H, J = 10.4 Hz, CH₂Ph), 4.62 (d, 1 H, J = 11.4 Hz, CH₂Ph), 4.60 (d, 1 H, J = 12.4 Hz, CH₂Ph), 4.52 (d, 1 H, J = 11.4 Hz, CH₂Ph), 4.51 (d, 1 H, J = 12.4 Hz, CH₂Ph), 4.18 (m, 1 H, H-3, H-5), 4.02 (dd, 1 H, J _1,2 = 10.4 Hz, J _3,2 = 2.4 Hz, H-2), 3.72 (m, 1 H, H-4, H-6a, H-6b). ¹³C NMR (100.6 MHz, CDCl₃): δ = 138.4, 138.1, 137.6 (C, aromatics), 133.2 (CH, aromatic), 131.7 (C, aromatic), 128.7-127.4 (CH, aromatics), 84.3
(C-1), 78.7 (C-3), 76.1 (C-4), 75.9 (C-5), 75.7, 73.3, 72.2 (CH₂Ph), 69.3 (C-6), 31.8 (C-2). Compound 6α (spectroscopical data extracted from the α/β-mixture spectrum): ¹H NMR (400 MHz, CDCl₃): δ = 7.70-7.20 (m, 20 H, aromatics), 5.32 (d, 1 H, J _2,1 = 5.4 Hz, H-1), 4.91 (d, 1 H, J = 11.6 Hz, CH₂Ph), 4.79 (d, 1 H, J = 10.8 Hz, CH₂Ph), 4.68 (ddd, 1 H, J _4,5 = 10.0 Hz, J _6a,5 = 2.8 Hz, J _6b,5 = 2.4 Hz, H-5), 4.57 (dd, J _1,2 = 5.6 Hz, J _3,2 = 2.4 Hz, H-2), 4.52 (d, 2 H, J = 10.4 Hz, CH₂Ph), 4.42 (d, 1 H, J = 11.2 Hz, CH₂Ph), 4.40 (d, 1 H, J = 12.4 Hz, CH₂Ph), 4.09 (dd, 1 H, J _2,3 = 2.4 Hz, J _4,3 = 2.4 Hz, H-3), 3.77 (m, 2 H, H-4, H-6a), 3.62 (dd, 1 H, J _6a,6b = 10.8 Hz, J _5,6b = 2.4 Hz, H-6b). ¹³C NMR (100.6 MHz, CDCl₃): δ = 131.4-126.8 (C, CH, aromatics), 90.0 (C-1), 78.1, 76.3, 75.6, 73.5, 72.0, 68.8, 67.7 (C-3, C-4, C-5, C-6, 3 × CH₂Ph), 27.0 (C-2).

19

General Procedure of Glycosylation: A solution of the glycosyl donor (1 mmol) and the glycosyl acceptor (2 mmol) in CH₂Cl₂ (4 mL) were allowed to stir with 4 Å molecular sieves for 2 h. The mixture was then cooled to -78 ºC, and NIS (3 mmol) and TfOH (0.2 mmol) were added. The mixture was allowed to warm to -40 ºC and stirred for 2-4 h. The reaction mixture was then diluted with CH₂Cl₂ and washed with a solution of Na₂S₃O₃. The ethereal layer was dried with Na₂SO₄ and concentrated. The residue was then purified by radial chromatography.

20 Veeneman GH. van Leeuwen SH. van Boom JH. Tetrahedron Lett.  1990,  31:  1331