- Sequential chlorination–glycosylation - 1.利用鈀金屬催化反應製備唾液酸衍生物 2.利用(TCT/DMF)試劑製備氯醣供體 3.二甲基甲醯胺促進(

3. Conclusion

In summary, we developed a mild and efficient TCT-DMF chlorination method for different carbohydrate substrates including glycosyl hemiacetals and glycosyl orthoesters. A new protocol in utilization of stoichimetric TCT/DMF for preparation of an array of α-glycosyl chlorides and N-acetyl neuraminic acid glycal with ease of manipulation was also

described accordingly. Readily-accessible glycosyl chlorides allow a new entry to explore its practical use in synthetic carbohydrate chemistry. Furthermore, based on this new chlorination method, a simple sequential chlorination-glycosylation strategy is developed, which should find useful for oligosaccharide synthesis.

4. Experimental

General: Chemicals used in this study were purchased as reagent grade from commercial venders and used without purification. All solvents used in the experiments were dried and distilled by standard techniques including: (1) distillation over CaH2 for CH2Cl2, DMF, toluene, MeOH and (2) drying over molecular sieve for C2H4Cl2. Optical rotations were measured with a JASCO DIP-1000 polarimeter at 27 ˚C. Flash column chromatography was performed on silica gel 60 (70−230 mesh, E. Merck). ¹H and ¹³C NMR spectra were recorded with 300 MHz and 75 MHz spectrometers by either the Brüker console or Varian Unity-300. Chemical shift (δ ppm) was calibrated against the residual proton and ¹³C signal of deuterated chloroform (CDCl3). Coupling constant(s) in hertz (Hz) were measured from 1H NMR spectra. Molecular weights of disaccharides [M + Na]⁺were determined by BioTOF Ultraflex II (Bruker Daltonics, Billeriaca, MA 01821, USA).

General procedure for preparation of glycosyl hemiacetals: 56, 61a−68a

RO2 O₂R

RO₂ OH

s56, s61-s68 56, 61a-68a

N2H4.AcOH, DMF

Per-O-acyl hexopyranosyl substrate (1 equiv of s56, s61-s68) in DMF solution (4 mL DMF per 1 mmol of sugar substrate) was stirred with hydrazine acetate (1.5 equiv) at rt.⁴⁴ Upon completion of the anomeric deacetylation (ca. 1−3 h), 1 mL of water was added and DMF was removed under reduced pressure. The residue is dissolved in EtOAc followed by washing with 1% HCl, saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated to give the

crude glycosyl hemiacetal (56, 61a-68a) for TCT/DMF chlorination. For per-O-benzoyl galactopyranosyl benzoate s68, the procedure is the same as above, but a higher temperature (45 °C) was required and the complete removal of anomeric benzoate needed 15 h.

General procedure for preparation of glycosyl hemiacetals: 11a−14a:

RO STol

RO OH

s69−s72 69a−72a

NBS, acetone

To a 9:1 acetone/H2O solution of thioglycoside (1.3 mmol of s69-s72) (30 mL) was added NBS (0.79 g, 4.4 mmol) and the mixture was stirred at 0 °C for 30 min.⁴⁵ After then saturated NaHCO3 (40 mL) was added to quench the reaction, followed by the removal of acetone under reduced pressure. The resulting residue was diluted with CH2Cl2, and washed with saturated Na2S2O3 , brine , dried over MgSO4 and concentrated for standard column chromatography to furnish the desired glycosyl hemiacetal (69a-72a).

Preparation of D-mannofuranosyl hemiacetal 73a,³² glycosyl orthoesters 74a,⁴⁶ 76a⁴⁷ and hexopyranosyl diols 77a,⁴⁶ 78a⁴⁸ were based on literature procedures.

TCT-DMF chlorination protocol A: DMF (1.55 mL, 20.0 mmol) was added to 2,4,6-trichloro-[1,3,5]-triazine (TCT) (1.0 g, 5.5 mmol) and the resulting suspension was stirred at rt for 15 min under N2. Glycosyl hemiacetal (5.0 mmol) (56, 61a-68a or 72a) in dichloroethane solution (DCE) was added to the TCT-DMF suspension, and followed by addition of DBU (0.8 mL, 5.5 mmol). The reaction mixture was stirred at 60˚C and progress of

reaction was monitored by TLC (ca. 1–4 h). Upon completion of chlorination, the temperature was brought to rt and Et2O was added to the mixture for the precipitation of cyanuric salt. After removal of cyanuric salt by filtration, the combined filtrate was concentrated to yield the crude glycosyl chloride. Further purification was performed by fast chromatography elution over a short pad of silica gel to furnish the respective α-glycosyl chloride 57, 61b-68b or 72b TCT-DMF chlorination protocol B for substrates 69a, 70a, 71a, 73a, 74a, 76a, 77a, 78a:

Similar to protocol A except that CH2Cl2 and excess K2CO3 (5 mol equiv) were used as solvent and proton scavenger respectively to replace DCE and DBU in protocol A. The reaction was stirred at 45 ˚C and reaction was monitored by TLC examination. For glycosyl orthoesters 74a and 76a, K2CO3 was omitted to achieve cleavage of orthoester function. Subsequent workup followed the same procedure as described above (protocol A) to obtain the respective α-glycosyl chloride 69b, 70b, 71b, 73b, 74b, 76b, 77b, 78b..

2,3,6-Tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-α-D-glucopyranosyl chloride (57). Protocol A; eluent for column chromatographic purification, EtOAc/Hexane = 1/1, white solid (87% yield); Rf = 0.45 (TLC developing solution: EtOAc/Hexane = 1/1); ¹H NMR (300 MHz, CDCl3) : δ 6.14 (d, J = 3.0 Hz, 1H, H-1’), 5.49 (t, J = 9.0 Hz, 1H), 5.29 (dd, J

= 3.3, 1.0 Hz, 1H), 5.07 (dd, J = 10.7, 7.8 Hz, 1H), 4.95 (dd, J = 10.5, 3.4 Hz, 1H), 4.92 (dd, J = 10.0, 3.9 Hz, 1H), 4.46 (d, J = 7.8 Hz, 1H), 4.01−4.23 (m, 5H), 3.75−3.89 (m, 2H), 2.10 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.90 (s, 3H); ¹³C NMR (75 MHz, CDCl3): δ 170.2, 170.1, 170.0, 169.9, 169.2, 168.8, 100.7 (C-1’), 89.9 (C-1), 75.0, 71.2, 70.8, 70.9, 70.7, 68.9, 68.8, 66.5, 61.1, 60.8, 60.3, 20.6, 20.5, 20.3. The spectroscopic data agrees with the literature values.⁴⁹

2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl chloride (61b): Protocol A; eluent for column chromatographic purification, EtOAc/Hexane = 1/2, white solid (89% yield); Rf = 0.42 (TLC developing solution: EtOAc/Hexane = 1/2); ¹H NMR (300 MHz, CDCl3) : δ 6.24 (d, J = 4.0 Hz, 1H, H-1), 5.50 (t, J = 9.8 Hz, 1H), 5.08 (t, J = 9.8 Hz, 1H), 4.96 (dd, J = 9.8, 4.0 Hz, 1H), 4.34–4.19 (m, 2H), 4.07 (dd, J = 14.1, 3.7 Hz, 1H), 2.04 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H), 1.98 (s, 3H); ¹³C NMR (75 MHz, CDCl3) : δ 170.4, 169.78, 169.7, 169.3, 90.0 (C-1), 70.6, 70.3, 69.3, 67.3, 61.0, 20.6, 20.5, 20.5, 20.4. The spectroscopic data agrees with the literature values.⁴⁹

2,3,4,6-Tetra-O-acetyl-α-D-galactopyranosyl chloride (62b): Protocol A; eluent for column chromatographic purification, EtOAc/Hexane = 1/2, white solid (90 % yield); Rf = 0.42 (TLC developing solution: EtOAc/Hexane = 1/2); ¹H NMR (300 MHz, CDCl3) : δ 6.34 (d, J = 3.9 Hz, 1H, H-1), 5.49 (dd, J = 3.2, 1.2 Hz, 1H), 5.39 (dd, J = 10.7, 3.3 Hz, 1H), 5.22 (dd, J = 10.7, 3.9 Hz, 1H), 4.49 (t, J = 6.3 Hz, 1H), 4.28–3.95 (m, 2H), 2.12 (s, 3H), 2.08 (s, 3H), 2.03 (s, 3H), 1.98 (s, 3H); ¹³C NMR (75 MHz, CDCl3) : δ 170.3, 170.1, 169.9, 169.7, 91.1 (C-1), 69.3, 67.8, 67.2, 67.1, 61.0, 20.7, 20.6, 20.6, 20.5. The spectroscopic data agrees with the literature values.⁵

2,3,4,6-Tetra-O-acetyl-α-D-mannopyranosyl chloride (63b): Protocol A; eluent for column chromatographic purification, EtOAc/Hexane = 1/2, white solid (92 % yield); Rf = 0.40 (TLC developing solution: EtOAc/Hexane = 1/2); ¹H NMR (300 MHz, CDCl3) : δ 5.96 (d, J = 0.9 Hz, 1H, H-1), 5.59 (dd, J = 10.1, 3.3 Hz, 1H), 5.42–5.25 (m, 2H), 4.37–4.04 (m, 3H), 2.16 (s, 3H), 2.09 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H); ¹³C NMR (75 MHz, CDCl3) : δ 170.8, 170.0, 169.9, 169.8, 89.0 (C-1), 71.8, 71.5, 68.0, 65.5, 61.9, 21.0, 21.0, 20.9, 20.8. The spectroscopic data agrees with the literature values.⁵

3,4,6-Tri-O-acetyl-2-azido-2-deoxy-α-D-glucopyranosyl chloride (64b): Protocol A; eluent for column chromatographic purification, EtOAc/Hexane = 1/2, white solid (76% yield); Rf = 0.40 (TLC developing solution: EtOAc/Hexane = 1/2); ¹H NMR (300 MHz, CDCl3) : δ 6.09 (d, J = 3.8 Hz, 1H, H-1), 5.52 (t, J = 9.0 Hz, 1H), 5.08 (t, J = 9.6 Hz, 1H), 4.35–4.26 (m, 2H), 4.10 (d, J = 4.0 Hz, 1H), 3.84 (dd, J = 10.3, 3.8 Hz, 1H), 2.07 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H); ¹³C NMR (75 MHz, CDCl3) : δ 170.8, 170.1, 170.0, 92.0 (C-1), 71.0, 67.9, 62.5, 61.4, 21.0, 20.9, 20.8. The spectroscopic data agrees with the literature values.⁵⁴

3,4,6-Tri-O-acetyl-2-azido-2-deoxy-α-D-galactopyranosyl chloride (65b): Protocol A;

eluent for column chromatographic purification, EtOAc/Hexane = 1/2, white solid (88% yield);

Rf = 0.40 (TLC developing solution: EtOAc/Hexane = 1/2); ¹H NMR (300 MHz, CDCl3) : δ 6.13 (d, J = 3.8 Hz, 1H, H-1), 5.45 (dd, J = 3.1, 1.1 Hz, 1H), 5.31 (dd, J = 10.9, 3.2 Hz, 1H), 4.45 (t, J = 6.5 Hz, 1H), 4.11–4.02 (m, 3H), 2.10 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H); ¹³C NMR (75 MHz, CDCl3) : δ 170.2, 169.7, 169.4, 92.5 (C-1), 69.6, 68.6, 66.6, 60.8, 58.4, 20.5, 20.4, 20.3. The spectroscopic data agrees with the literature values.²⁹

3,4,6-Tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbamyl)-α-D-glucopyranosyl

chloride (66b): Protocol A; eluent for column chromatographic purification, EtOAc/Hexane = 1/2, white solid (75% yield); Rf = 0.40 (TLC developing solution: EtOAc/Hexane = 1/2); ¹H NMR (300 MHz, CDCl3) : δ 6.17 (d, J = 3.6 Hz, 1H), 5.44 (d, J = 9.2 Hz, 1H), 5.33 (t, J = 10.0 Hz, 1H), 5.17 (t, J = 9.8 Hz, 1H), 4.78 (d, J = 12.0 Hz, 1H), 4.62 (d, J = 12.0 Hz, 1H), 4.36–4.17 (m, 3H), 4.10 (d, J = 11.2 Hz, 1H), 2.07 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H); ¹³C NMR (75 MHz, CDCl3) : δ 170.9, 170.5, 169.2, 154.0, 95.1, 93.3, 74.7, 70.9, 69.8, 67.0, 61.1, 55.4, 20.6, 20.6, 20.5. The spectroscopic data agrees with the literature values.⁴⁹

2,3,4-Tri-O-acetyl-α-L-rhamnopyranosyl chloride (67b): Protocol A; eluent for column chromatographic purification, EtOAc/Hexane = 1/5, a colorless syrup (79% yield); Rf = 0.45 (TLC developing solution: EtOAc/Hexane = 1/4); ¹H NMR (300 MHz, CDCl3) : δ 5.89 (d, J

=1.8 Hz, 1H, H-1), 5.52 (dd, J = 10.0, 3.4 Hz, 1H), 5.33 (dd, J = 3.3, 1.6 Hz, 1H), 5.09 (t, J = 10.1 Hz, 1H), 4.14-4.10 (m, 1H), 2.13 (s, 3H), 2.03 (s, 3H), 1.96 (s, 3H), 1.23 (d, J = 6.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl3) : δ 169.8, 169.7, 169.6, 89.0 (C-1), 71.8, 70.3, 69.4, 67.7, 20.8, 20.7, 20.6, 17.1. The spectroscopic data agrees with the literature values.⁵⁰

2,3,4,6-Tetra-O-benzoyl-α-D-galactopyranosyl chloride (68b): Protocol A; eluent for column chromatographic purification, EtOAc/Hexane = 1/4, white solid (80% yield); Rf = 0.48 (TLC developing solution: EtOAc/Hexane = 1/3); [α]²⁷D = +58.5 (c = 1.21, CHCl3); ¹H NMR (300 MHz, CDCl3) : δ 8.14–7.93 (m, 6H), 7.87–7.77 (m, 2H), 7.59–7.48 (m, 10H), 7.24 (dd, J = 8.2, 7.2 Hz, 3H), 6.66 (d, J = 3.9 Hz, 1H, H-1), 6.17–6.00 (m, 2H), 5.85 (dd, J = 10.4, 3.9 Hz, 1H), 4.94 (t, J = 6.4 Hz, 1H), 4.63 (dd, J = 11.5, 6.7 Hz, 1H), 4.44 (dd, J = 11.5, 6.1 Hz, 1H); ¹³C NMR (75 MHz, CDCl3) : δ 165.9, 165.6, 165.4, 165.3, 133.7, 133.3, 133.3, 129.9, 129.9, 129.8, 129.7, 129.2, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 91.5 (C-1), 70.0, 68.7, 68.3, 67.9, 61.7.

2,3,4,6-Tetra-O-benzyl-α-D-galactopyranosyl chloride (69b): Protocol B; eluent for column chromatographic purification, EtOAc/Hexane = 1/9, a colorless syrup (85% yield); Rf = 0.35 (TLC developing solution: EtOAc/Hexane = 1/9); ¹H NMR (300 MHz, CDCl3) : δ 7.48–7.25 (m, 20H), 6.17 (d, J = 3.8 Hz, 1H, H-1), 4.97 (d, J = 11.3 Hz, 1H), 4.88 (d, J = 11.7 Hz, 1H), 4.81–4.70 (m, 3H), 4.58 (d, J = 11.3 Hz, 1H), 4.50 (d, J = 11.8 Hz, 1H), 4.50 (d, J = 11.8 Hz, 1H), 4.27–4.20 (m, 2H), , 4.04– 3.96 (m, 2H), 3.56 (d, J = 6.7 Hz, 2H); ¹³C NMR (75 MHz, CDCl3) : δ 138.4, 138.2, 137.8, 137.6, 128.4, 128.3, 128.2, 127.9, 127.8, 127.8, 127.7, 127.6,

127.5, 94.9 (C-1), 78.3, 76.2, 75.0, 74.3, 73.4, 73.3, 73.0, 72.3, 67.9. The spectroscopic data agrees with the literature values.¹³

2,3-Di-O-benzyl-4,6-O-benzylidene-α-D-galactopyranosyl chloride (70b): Protocol B;

eluent for column chromatographic purification, EtOAc/Hexane/CH2Cl2 = 1/4/1, a colorless syrup (85% yield); Rf = 0.32 (TLC developing solution: EtOAc/Hexane = 1/4); [α]²⁷D = +88.1 (c = 0.81, CHCl3); ¹H NMR (300 MHz, CDCl3) : δ 7.53–7.24 (m, 15H), 6.23 (d, J = 3.6 Hz, 1H, H-1), 5.51 (s, 1H), 4.92–4.70 (m, 4H), 4.29–4.11 (m, 3H), 4.09–4.01 (m, 2H), 3.93 (bs, 1H);

13C NMR (75 MHz, CDCl3) : δ 138.3, 137.7, 137.4, 128.9, 128.3, 128.2, 128.1, 127.8, 127.6, 127.6, 126.1, 100.8, 95.2 (C-1), 75.3, 75.1, 73.9, 73.2, 72.3, 68.7, 65.5. The spectroscopic data agrees with the literature values.¹³

2,3-Di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranosyl chloride (71b): Protocol B; eluent for column chromatographic purification, EtOAc/Hexane/CH2Cl2 = 1/4/1, a colorless syrup (82% yield); Rf = 0.30 (TLC developing solution: EtOAc/Hexane = 1/4); [α]²⁷D = +26.1 (c = 1.16, CHCl3); ¹H NMR (300 MHz, CDCl3) : δ 7.65–7.23 (m, 15H), 6.04 (d, J = 4.0 Hz, 1H, H-1), 5.59 (s, 1H), 4.91–4.74 (m, 4H), 4.34 (dd, J = 10.1, 4.9 Hz, 1H), 4.33–4.10 (m, 2H), 3.85–3.60 (m, 3H); ¹³C NMR (75 MHz, CDCl3) : δ 138.3, 137.3, 136.9, 129.0, 128.5, 128.3, 128.3, 128.2, 128.1, 128.0, 127.9, 127.6, 126.0, 101.3, 93.3 (C-1), 80.9, 79.1, 77.7, 75.3, 73.2, 68.2, 65.2.

2,3-Di-O-benzoyl-3-O-benzyl-6-O-t-butyldimethylsilyl-α-D-glucopyranosyl chloride (72b):

72b was obtained as a colorless syrup (70% yield) upon column chromatography purification over silica gel with 1/9 EtOAc/Hexane elution. For 72b, Rf = 0.35 (TLC developing solution:

EtOAc/Hexane = 1/9); [α]²⁷D = +108.8 (c = 0.45, CHCl3); ¹H NMR (300 MHz, CDCl3) : δ 8.06-8.03 (m, 4H), 7.61 (t, J = 7.4 Hz, 2H), 7.47 (dd, J = 10.5, 4.7 Hz, 4H), 7.24 (s, 5H), 6.55 (d, J = 3.9 Hz, 1H), 6.18 (t, J = 9.7 Hz, 1H), 5.35 (dd, J = 10.1, 4.0 Hz, 1H), 4.74 (q, J = 10.9 Hz, 2H), 4.33– 4.09 (m, 4H), 4.02 (dd, J = 12.0, 1.5 Hz, 1H), 1.06 (s, 9H), 0.24 (s, 3H), 0.22 (s, 3H);

13C NMR (75 MHz, CDCl3) : δ 165.6, 165.5, 137.3, 133.6, 133.2, 130.0, 129.7, 129.4, 128.6, 128.5, 128.3, 128.3, 128.0, 127.8, 91.3, 75.0, 74.6, 74.6, 72.0, 71.8, 61.1, 25.9, 18.4.

2,3:5,6-Di-O-isopropylidene-α-D-mannofuranosyl chloride (73b): 73b was obtained as a colorless syrup (89% yield) upon column chromatography purification over silica gel with 1/5 EtOAc/Hexane elution. For 73b, Rf = 0.30 (TLC developing solution: EtOAc/Hexane = 1/9);

1H NMR (300 MHz, CDCl3) : δ 6.02 (s, 1H, H-1), 4.91 (d, J = 5.8, 1H), 4.84 (dd, J = 5.8, 3.6 Hz, 1H), 4.40−4.38 (m, 1H), 4.16 (dd, J = 11.0, 3.6 Hz, 1H), 4.05 (dd, J = 8.9 Hz, 6.1 Hz, 1H), 3.97 (dd, J = 8.8, 4.4 Hz, 1H), 1.42 (s, 6H), 1.33 (s, 3H), 1.28 (s, 3H); ¹³C NMR (75 MHz, CDCl3) : δ 113.2, 109.4, 97.5, 89.1, 82.3, 78.4, 72.2, 66.6, 26.8, 25.7, 25.0, 24.5. The spectroscopic data agrees with the literature values.³²

2-O-Acetyl-3,4,6-tri-O-benzyl-α-D-galactopyranosyl chloride (74b): Galactopyranosyl hemiacetal 74a was prepared according to the reported procedure.⁸ Preparation of 74b from 74a employed protocol A as described in the general procedure. Chromatography purification of 74b was achieved by 1/4 EtOAc/Hexane elution and 74b was obtained a colorless syrup (85% yield). For 74b, Rf = 0.48 (TLC developing solution: EtOAc/Hexane = 1/4); ¹H NMR (300 MHz, CDCl3) : δ 7.51–7.24 (m, 15H), 6.46 (d, J = 3.9 Hz, 1H, H-1), 5.48 (dd, J = 9.9, 3.9 Hz, 1H), 4.99 (d, J = 11.3 Hz, 1H), 4.75 (s, 2H), 4.63 (d, J = 11.3 Hz, 1H), 4.52 (d, J = 11.0 Hz, 1H), 4.48 (d, J = 11.0 Hz, 1H), 4.30 (t, J = 6.5 Hz, 1H), 4.14–4.01 (m, 2H), 3.76–3.54 (m, 2H),

2.12 (s, 3H); ¹³C NMR (75 MHz, CDCl3) : δ 170.0, 138.0, 137.8, 137.5, 128.7, 128.3, 128.29, 128.1, 128.1, 128.0, 127.8, 127.7, 127.6, 127.5, 127.3, 127.0, 93.0 (C-1), 76.1, 74.9, 73.8, 73.3, 72.8, 72.3, 70.8, 67.7, 20.7. The spectroscopic data agrees with the literature values.³⁶

2-O-Acetyl-3,4,6-tri-O-benzyl-α-D-mannopyranosyl chloride (76b): Mannopyranosyl hemiacetal 76a was prepared according to the reported procedure.¹²Preparation of 76b from 76a employed protocol A as described in the general procedure. Chromatography purification of 76b was achieved by 1/5 EtOAc/Hexane elution and 76b was obtained a colorless syrup (92% yield). For 76b, Rf = 0.45 (TLC developing solution: EtOAc/Hexane = 1/5); ¹H NMR (300 MHz, CDCl3) : δ 7.42– 7.12 (m, 15H), 6.07 (d, J = 1.6 Hz, 1H, H-1), 5.47 (dd, J = 3.3, 1.8 Hz, 1H), 4.87, 4.52 (2d, J = 10.7 Hz, 2H), 4.70, 4.56 (2d, J = 11.7 Hz, 2H), 4.63, 4.46 (2d, J = 13.0 Hz, 2H), 4.26 (dd, J = 9.1, 3.3 Hz, 1H), 4.05−4.00 (m, 1H), 3.96 (t, J = 9.6 Hz, 1H), 3.84 (dd, J = 11.1, 3.7 Hz, 1H), 3.69 (dd, J = 11.1, 1.8 Hz, 1H), 2.16 (s, 3H); ¹³C NMR (75 MHz, CDCl3) : δ 170.0, 138.0, 137.8, 137.4, 128.4, 128.3, 128.1, 127.9, 127.8, 127.8, 127.7, 127.7, 90.3 (C-1), 76.6, 75.3, 74.2, 73.5, 73.4, 72.1, 70.9, 67.9, 21.0. The spectroscopic data agrees with the literature values.⁵¹

3,4,6-Tri-O-benzyl-2-O-formyl-α-D-galactopyranosyl chloride (77b): Galactopyrano- syl hemiacetal 77a was prepared according to the reported procedure.¹⁴Preparation of 77b from 77a employed protocol A as described in the general procedure. Chromatography purification of 77b was achieved by 1/5 EtOAc/Hexane elution and 77b was obtained as a colorless syrup (70% yield). For 77b, Rf = 0.42 (EtOAc/Hexane = 1/5); [α]²⁷D = +50.6 (c = 0.91, CHCl3); ¹H NMR (300 MHz, CDCl3) : δ 8.10 (d, J = 0.9 Hz, 1H), 7.42–7.20 (m, 15H), 6.37 (d, J = 3.7 Hz, 1H, H-1), 5.58–5.47 (m, 1H), 4.93 (d, J = 11.3 Hz, 1H), 4.70 (s, 2H), 4.55 (d, J = 11.3 Hz, 1H),

4.49 (d, J = 11.8 Hz, 1H), 4.42 (d, J = 11.8, 1H), 4.27–4.23 (m, 1H), 4.08–3.99 (m, 2H), 3.66–3.51 (m, 2H); ¹³C NMR (75 MHz, CDCl3) : δ 160.2, 138.2, 138.0, 137.8, 128.8, 128.7, 128.6, 128.4, 128.2, 128.1, 128.0, 127.7, 92.7 (C-1), 76.3, 75.3, 74.1, 73.8, 73.2, 72.7, 70.8, 68.0.

3,4,6-Tri-O-benzyl-2-O-formyl-α-D-mannopyranosyl chloride (78b): Hemiacetal 78a was prepared according to the reported procedure.⁵⁰ Preparation of 78b from 78a employed the protocol A as described in the general procedure. Column chromatography purification of 78b was achieved by 1/5 EtOAc/Hexane elution and 78b was obtained as a colorless syrup (94%

yield). For 78b, Rf = 0.41 (TLC developing solution: EtOAc/Hexane = 1/5); [α]²⁷D = +48.5 (c = 1.56, CHCl3); ¹H NMR (300 MHz, CDCl3) : δ 8.17 (s, 1H), 7.44–7.08 (m, 15H), 6.10 (d, J = 1.4 Hz, 1H, H-1), 5.59 (d, J = 1.3 Hz, 1H), 4.87 (d, J = 10.7 Hz, 1H), 4.75–4.60 (m, 3H), 4.56–4.46 (m, 2H), 4.30 (dd, J = 8.6, 3.0 Hz, 1H), 4.10–3.96 (m, 2H), 3.84 (dd, J = 11.0, 3.2 Hz, 1H), 3.69 (dd, J = 11.0, 1.5 Hz, 1H); ¹³C NMR (75 MHz, CDCl3) : δ 159.6, 137.8, 137.7, 137.1, 128.5, 128.3, 128.2, 128.0, 127.9, 127.9, 127.8, 127.7, 127.7, 89.8 (C-1), 76.4, 75.3, 74.2, 73.4, 73.2, 72.3, 70.4, 67.6.

N-acetyl neuraminic acid -HCl a

c -MeOH

72% over 4 steps from N-acetyl neuraminic acid

Preparation of methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2,6-anhydro-

D-glycero-D-galacto-non-2-enonate, Neu5Ac glycal (81):

Conditions and reagents: (a) (b) One-pot Fischer glycosidation acetylation, 6−7 h;³⁹ (c) TCT (1.1 equiv), DMF (4 equiv), DBU (1.1 equiv) in DCE at 65˚C, 3 h. (72% over 4 steps)

To a suspension of N-acetyl neuraminic acid (0.62 g, 2.0 mmol) in dry MeOH (20 mL) was added pre-dried p-toluenesulfonic acid monohydrate (37 mg, 0.2 mmol), and the suspension was stirred at rt for 2 h. The turbid mixture gradually became clear and upon complete acetylation, the mixture was concentrated to give crude NANA methyl ester. To NANA ester was added acetic anhydride (1.5 mL, 16 mmol) and CH3CN (1.5 mL) and the resulting suspension was stirred at rt for 3 h until becoming a clear solution. After then, saturated NaHCO3 solution was added to quench the reaction, followed by addition with CH2Cl2. The resulting CH2Cl2 was washed by saturated NaHCO3 (× 3), brine, dried over MgSO4, filtered and concentrated to furnish the crude product 79 directly used for the next step.

To the mixture of TCT (0.43 g, 2.4 mmol) and DMF (0.61 mL, 8 mmol) was added a solution of

70b (1.5 equiv) (72% over 2 steps) O O

79 in DCE (10 mL) followed by addition of DBU (0.60 mL, 4 mmol). The reaction mixture was then stirred at 65 ˚C for 3 h. After cooling to rt, the resulting mixture was diluted with CH2Cl2

(30 mL), which was then washed with 1% HCl, saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated for column chromatography purification over silica gel (elution by CH2Cl2/MeOH mixture gradient from 1/0 to 49/1) to give peracetyl Neu5Ac glycal 81 as a white glassy solid (0.66 g, 72% over 4 steps). For Methyl 5-acetamido-4,7,8,9-tetra-O- acetyl-2,6-anhydro-3,5-dideoxy-D-glycero-D-galacto-non-2-enonate (81). ¹H NMR (300 MHz, CDCl3): δ 6.08 (d, J = 8.9 Hz, 1H), 5.92 (d, J = 3.1 Hz, 1H), 5.48−5.45 (m, 2H), 5.30−5.24 (m, 1H), 4.59 (dd, J = 12.3, 3.1 Hz, 1H), 4.34−4.25 (m, 1H), 4.13 (dd, J = 12.3, 7.3 Hz, 1H), 3.74 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.86 (s, 3H); ¹³C NMR (75 MHz, CDCl3): δ 170.7, 170.5, 170.1, 170.1, 170.1, 161.5, 145.0, 107.9, 76.6, 70.8, 68.0, 67.6, 61.9, 52.5, 46.3, 23.0, 20.7, 20.6. The spectroscopic data agrees with the literature values.⁵²

Sequential tandem chlorination−glycosylation

A mixture of commercially available glycosyl acceptor 82 (0.26 g, 1.0 mmol) and AW300 MS (1.0 g) in 4/1 CH2Cl2/toluene (5 mL) was stirred at rt under N2 for 30 min. The mixture was then cooled at −25 ˚C cooling bath followed by addition of AgCO3 (1.1 g, 4.0 mmol) and

O (76% over 2 steps)

AgOTf (0.13 g, 0.5 mmol). Freshly prepared 70b (0.67 g, 1.5 mmol of 70a) in CH2Cl2 (5 mL) was gradually delivered to the reaction mixture over 1 h by the syringe pump. The resulting mixture was subsequently stirred from −25 ˚C to rt. Upon the complete consumption of 82 as shown by TLC, the resulting mixture was filtered through Celite to remove the silver salts. The filtrate was concentrated for column chromatography purification over silica gel (EtOAc/Hexane elution: gradient from 0/1 to 3/7) to give the disaccharide 83 as a 5:1 α/β-anomeric mixture. (2,3-Di-O-benzyl-4,6-O-benzylidene-α-D-galactopyranosyl)-(1→6)- 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose (83α): white solid, mp = 108 ˚C; Rf = 0.55 (TLC developing solution: EtOAc/Hexane = 2/3); [α]²⁷D = +29.1 (c = 1.20, CHCl3); ¹H NMR anomeric CH), 75.9, 75.5, 74.7, 73.2, 72.0, 71.0, 70.6, 70.5, 69.4, 67.0, 66.6, 62.5, 26.1, 26.0, 24.9, 24.5; HRMS (Bio-ToFII): calcd for C39H46O11Na requires 713.2938; found: m/z = 713.2932 [M + Na]⁺.

Sequential tandem chlorination−orthogonal glycosylation

A mixture of thioglycosyl acceptor 84(0.56 g, 1.0 mmol) and AW300 MS (1.0 g) in 4/1 CH2Cl2/toluene (5 mL) was stirred at rt under N2 for 30 min. The mixture was then cooled at

−25 ˚C cooling bath followed by addition of AgCO3 (1.1 g, 4.0 mmol) and AgOTf (0.13 g, 0.5 mmol). Freshly prepared 70b (0.90 g, 2.0 mmol of 70a) in CH2Cl2 (5 mL) was gradually delivered to the reaction mixture over 4 h. The mixture was subsequently stirred at −25 ˚C until the complete consumption of 84 as shown by TLC, the resulting mixture was filtered through Celite to remove the silver salts. The filtrate was concentrated for column chromatography purification over silica gel (EtOAc/Hexane/CH2Cl2 elution: gradient from 0/8/2 to 2/6/2) to give the disaccharide 85 as the single α anomer (0.75 g, 76%). The stereochemistry of α anomer was determined via the method described above.⁵³ For Tolyl 4-O-(2,3-Di-O-benzyl- 4,6-O-benzylidene-α-D-galactopyranosy-l)-(1→4)-O-2,3,6-tri-benzyl–thio-β-D-galactopyr anoside (85): white solid (recrystallized from Et2O and hexane), melting point can not be measured due to decomposition over 180 ˚C; Rf = 0.46 (TLC developing solution:

EtOAc/Hexane = 2/3); [α]²⁷D = +50.7 (c = 1.32, CHCl3); ¹H NMR (300 MHz, CDCl3) : δ 7.68 (d, J = 8.1 Hz, 2H), 7.59–7.31 (m, 30H), 7.12 (d, J = 8.1 Hz, 2H), 5.40 (s, 1H), 5.25 (d, J = 3.3 Hz, 1H, H-1’), 5.12 (d, J = 11.7 Hz, 1H), 4.87–4.75 (m, 6H), 4.68–4.59 (m, 2H), 4.44–4.01 (m, 9H), 3.87 (t, J = 9.4 Hz, 1H), 3.75–3.54 (m, 3H), 3.46 (d, J = 12.5 Hz, 1H), 2.22 (s, 3H); ¹³C NMR (75 MHz, CDCl3) : δ 138.8, 138.7, 138.1, 138.0, 137.9, 137.7, 136.8, 131.9, 129.92, 129.5, 128.7, 128.3, 128.2, 128.2, 128.0, 127.8, 127.8, 127.7, 127.5, 127.4, 127.3, 127.24, 126.8, 126.2, 100.6, 99.9 (JC-H = 169 Hz, anomeric CH), 86.9, 82.7, 77.1, 76.5, 75.8, 75.5, 75.1, 74.3, 73.9, 73.1, 72.7, 71.9, 70.7, 69.2, 67.0, 62.4, 20.9. HRMS (Bio-ToFII): calcd for C61H62O10SNa requires 1009.3961; found: m/z = 1009.3956 [M + Na]⁺.

5. References

(1) Toshima, K. Glycosyl Halides. In Glycoscience; Fraser-Reid, B., Tatsuta, K. Thiem, J., Eds,; Springer: Berlin, Heidelberg 2008, pp 429-449.

(2) Demchenko, A. V. Handbook of Chemical Glycosylation; Wiley-VCH; 2008, pp 29-85.

(3) Brito-Arias, M. Synthesis and Characterization of Glycosides; Springer; 2006, pp 151-161.

(4) Köenigs, W.; Knorr, E. Chem. Ber. 1901, 34, 957.

(5) Montero, J.-L.; Winum, J.-Y., et al. Carbohydr. Res. 1997, 297, 175-180.

(6) Chosh, R.; Chakraborty, A.; Maiti, S. Tetrahedron 2001, 57, 9631-9634.

(7) Wang, Q.-B.; Fu, J.; Zhang, J.-B. Cabohydr. Res. 2008, 343, 2989-2991.

(8) Cicchillo, R. M.; Norris, P. Cabohydr. Res. 2000, 328, 431-434.

(9) Pozsgay, V.; Dubois, E. P.; Pannell, L. J. Org. Chem. 1997, 62, 2832-2846.

(10) Khan, S. H.; O'Neill, R. A. Modern Methods in Carbohydrate Synthesis; Kováč, P.; CRC Press, 1996, pp 55-80.

(11) Edgar, K. J.; J. E. K. J. Org. Chem. 1992, 57, 2455-2467.

(12) Kartha, K. P. R.; Cura, P.; Aloui, M.; Readman, S. K.; Rutherford, T. J.; Field, R. A.

Tetrahedron:Asymmetry 2000, 11, 581-593.

(13) Sugiyama, S.; Diakur, J. M. Org. Lett. 2000, 2, 2713-2715.

(14) Chretien, F.; Chapleur, Y.; Castro, B.; Gross, B. J. Chem. Soc. Perkin Trans. 1 1980, 381-284.

(15) Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996, 37, 4903-4906.

(16) Copeland, C.; McAdam, D. P.; Stick, R. V. Aust. J. Chem. 1983, 36, 1239-1247.

(17) Hwang, C.-K.; Li, W.-S.; Nicolaou, K. C. Tetrahedron Lett. 1984, 25, 2295-2296.

(18) Maetz, P.; Rodriguez, M. Tetrahedron Lett. 1997, 38, 4221-4222.

(19) Blotny, G. Tetrahedron 2006, 62, 9507-9522.

(20) Giacomelli, G.; Porcheddu, A.; De Luca, L. Curr. Org.Chem. 2004, 8, 1497-1519.

(21) Bandgar, B. P.; Joshi, N. S.; Kamble, V. T.; Sawant, S. S. Aust. J. Chem. 2008, 61, 231-234.

(22) De Luca, L.; Giacomelli, G.; Nieddu, G. J. Org. Chem. 2007, 72, 3955-3957.

(23) Kolmakov, K. A. Can. J. Chem. 2007, 85, 1070-1074.

(24) Sun, L.; Guo, Y.; Peng, G.-S.; Li, C.-B. Synthesis-Stuttgart 2008, 21, 3487-3491.

(25) Zhang, Z.-H.; Tao, X. Y. Aust. J. Chem. 2008, 61, 77-79.

(26) De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67, 5152-5155.

(27) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2002, 4, 553-555.

(28) Huchel, U.; Schimdt, C.; Schimdt, R. R. Eur. J. Org. Chem. 1998, 1353-1360.

(29) Lemieux, R. U.; Ractliffe, R. M. Can. J. Chem. 1979, 57, 1244-1251.

(30) Pavliak, V.; Kováĉ, P.; Glaudeman, C. P. J. Carbohydr. Res. 1992, 229, 103-116.

(31) Lellouche, J. P.; Kotlyar, V. Synlett 2004, 564-571.

(32) Kim, C.; Hoang, R.; Theodorakis, E. A. Org. Lett. 1999, 1, 1295-1297.

(33) Oishi, T.; Inomiya, K.; Sato, H.; Lida, M.; Chida, N. Bull. Chem. Soc. Jpn. 2002, 75, 1927-1948.

(34) Brady, T. P.; Kim, S.-H.; Wen, K.; Kim, C.; Theodorakis, E. A. Chem. Eur. J. 2005, 11, 7175-7190.

(35) Newman, M. S.; Olson, D. R. J. Org. Chem. 1973, 38, 4203-4204.

(36) Wotovic, A.; Jacquinet, J. C. Carbohydr. Res. 1990, 205, 235-245.

(37) Boons, G. J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.

(38) Burkart, M. D.; Vincent, S. P.; Wong, C.-H. J. Chem. Soc. Chem. Commun. 1999,

1525-1526.

(39) Chao, C.-S.; Chen, C.-C.; Lin, S.-C.; Mong, K.-K. T. Cabohydr. Res. 2008, 343, 957-964.

(40) Kulikova, N. Y.; Shpirt, A. M.; Kononov, L. O. Synthesis 2006, 24, 4113-4114.

(41) Okamoto, K.; Kondo, T. ; Goto, T. Bull. Chem. Soc. Jpn. 1987, 60, 631-636.

(42) Demchenko, A. V. Curr. Org. Chem. 2003, 7, 35-79.

(43) Ekelf, K.; Oscarson, S. J. Org. Chem. 1996, 61, 7711-7718.

(44) Mori, M.; Ito, Y.; Ogawa, T. Carbohydr. Res. 1990, 195, 199-224.

(45) Oshitar, T.; Shibasaki, M.; Yoshizawa, T.; Tomita, M.; Takao, K.-I.; Kobayashi, S.

Tetrahedron 1997, 53, 10993-11006.

(46) Asai, N.; Fusetani, N.; Matsunaga, S. J. Nat. Prod. 2001, 64, 1210-1215.

(47) Garegg, P. J.; Maron, L. Acta Chem. Scand., Ser. B. 1979, B33, 39-41.

(48) Jonke, S.; Liu, K.-G.; Schimdt, R. R. Chem. Eur. J. 2006, 12, 1274-1290.

(49) Zhang, Z. Y.; Magnusson, G. Carbohydr. Res. 1996, 295, 41-55.

(50) Donahur, M. G.; Johnston, J. N. Bioorg. Med. Chem. Lett. 2006, 16, 5602-5604.

(51) Du, Y.; Kong, F. Z. J. Carbohydr. Chem. 1995, 14, 341-352.

(52) Bhaskar, K. V.; Duggan, P. J.; et al. J. Chem. Soc. Perkin Trans. 1 2001, 1098-1102.

(53) Bock, K.; Pedersen, C. J. Chem. Soc. Perkin Trans. 2 1974, 293-297.

(54) Paulsen, H.; Richter, A.; Sinnwell, V.; Stenzel, W. Carbohydr. Res. 1978, 64, 339-364.

Chapter 3 DMF functions as a “brake” molecule in highly α-stereoselective glycosylation

1. Introduction of α-stereoselective O-glycosylation

In recent decades, the biological functions of the natural oligosaccharides have been intensively explored. They are found to play important roles in cellular trafficking, viral infections, cell proliferation, differentiation, apoptosis, immune response, even enzyme folding etc. Most of these activities are mediated through the carbohydrate-protein recognitions (Figure 1).^1-4

Figure 1 - Biological functions of glycoconjugates

Extraction of pure glycans from nature is inefficient and tedious. Synthesis of oligosaccharide usually relied on chemical methods. Even though significant progresses on

stereoselective glycosylations have been achieved, none of these methods can work perfectly as an enzyme, which implies that the mixed isomers are always obtained. However, the higher homogeneity of synthetic oligosaccharides could be employed as a target for the biological evaluation, which may give us the more credible results. For this purpose, the new method for the development in highly sereoselective glycosylation still draws a great attention for the synthetic chemists.

1,2-cis-glycosidic linkages are widely occurred in various natural glycoconjugates. For example, α-D-gluco-, α-L-fuco-, α-D-galacto-, β-D-mannopyranosides are the common blocks of numerous glycans, such as polysulfated glycosaminoglycans, α-Gal Ceramide (KRN7000),⁵ globotriaosylceramide (Gb3),⁶ Lewis (Le) antigens,⁷ O-linked glycolproteins, N-linked glycans (Figure 2).

Figure 2 - Examples of bioactive α-glycosides

The construction of 1,2-cis-O-linkage in mannosides is a particular topic in which the different strategies were usually adopted, therefore the details regarding to the recent advances for β-mannosylation will be excluded in this context. In addition, 1,2-cis-gluco- and galactopyranosides are defined as α-anomers, which represent axially O-linked saccharides.

In this chapter, the reported approaches and our findings for α-selereoselective glycosylations in a series of gluco- and galactosides will be described in the later section. Generally, the

formation of α-anomers is favorable due to the stronger anomeric effect. In reality, many factors still render the stereochemistry outcomes fluctuate, which prompts the synthetic chemist to work out this challenge.

1.1. Earlier strategies for α-selective O-glycosylation

1.1.1. Lemieux’s in situ anomerization strategy

In 1968, Lemieux first announced in situ anomerization α-glycosylation.⁸ This elegant work is so called “halide-catalyzed glycosylation” for preparation of α-glycosides.⁹ It triggers a series of elaborative studies in relation to mechanisms and applications to oligosaccharide syntheses. Subsequent developments of α−glycosylation methods are largely based on this in situ anomerization concept. A brief mechanistic elaboration is given as follows (Scheme 1).

The other approaches to assemble α-linkages are overwhelmed by in situ anomerization strategy for several decades until some new methods were described very recently.

O BnO

X X = I or Br

BnO X

TBAI

TBAI = tetrabutylammoniun iodide

BnO BnO

O BnO

BnO

BnO O

OBn X

4C₁ B_2,5 ¹C₄

HOR

O BnO

BnOOR

α-anomer hali de exchange v ia in situ anomeri zation

Scheme 1 - α-selective glycosylation via in situ anomerization

Upon activation by free halides, they observed that the tetra-O-benzyl-α-D-glycopyrano- syl halides undergoes in situ anomerization to form β-glycosyl halide via the simple SN2-like

substitution by iodide nucleophile from tetrabutylammoniun iodide (TBAI). Such a β-glycosyl halide is highly reactive species, which is attacked by nucleophlic acceptors from α-face to provide α-glycosides exclusively. The conformational change of the oxocarbenium associated with the solvents or free halides may temporarily form contact-ion pair in order to facilitate the glycosylation in a favorable energy state.⁹ Although good α-selectivity can be obtained in some cases, the prolonged reaction time and the restricted application to armed per-O-benzylated glycosyl donor severely limits the synthetic utility of this strategy.

Recently, Gervay et al. reported a glycosylation protocol using trimethylsilyl iodide (TMSI) as reagent for in situ preparation of glycosyl iodide, which was used as a glycosyl donor for α−glycosylation.¹⁰ The application of this method was demonstrated in synthesis of carbohydrate antigen KRN7000 as killer T-cell activators (Scheme 2).¹¹ It shoud be noted that this approach is still a modification of in situ anomerization concept initiated by Lemieux.

O Scheme 2 - Gervay's synthesis of KRN7000

1.1.2. Solvent influence in α-selective glycosylations

In 1974, Schuerch et al. for the first time reported the use of l-O-tosyl-D-glucopyranose derivative with nonparticipating group at C-2 position to react with alcohol acceptor furnishing α−glycosylation product in ether solvent.^12,13 It was later reasoned that ether-type

solvents can solvate oxocarbenium ion (Figure 3). The dipole-dipole moment changes direction opposite to the dipole induced by oxygen atom in pyranose ring. This resulting force is named as “reverse anomeric effect”,¹⁴ which directs α-species to β-solvated intermediate.

Therefore, the acceptor attacks from α-face favorably to form α-glycosylated product. In addition, cyclopentyl methyl ether (CPME), 1,4-dioxane, and 1,2-dimethoxyethane (DME) have been also explored as solvents to enhance selectivity in α-glycosylations. Further investigation of mixed solvent systems (combined use with the halogenated solvent, such as CHCl3, DCE) indicated that α-selectivity is affected by solvents.¹⁵ However, the solvent participation in α-selectivity has never been a single force. Other experimental factors, such as promoter system, leaving group or substrate structures are believed to exert a synergistic effect in glycosylation processes.

O⁺ O

Et₂O

O⁺

O HO

O O

R Reverse anomeric eff ect

α-glycosides

Figure 3 - Ethereal solvents induce α-selective glycosylation

1.1.3. α-Selectivitive glycosylations enhanced by promoters

Regarding the effect of promoters in α-selective glycosylation, Boons et al. have reported a systematic investigation.¹⁶ The use of iodonium di-collidine perchlorate (IDCP) as a promoter for activation of thioglycoside in the dioxane-mixed cosolvent resulted in an improvement of α-selectivity. The study indicated that counter ions of Lewis acid promoter affect the stereoselectivity (Table 1). However, IDCP is not commercially available; its use requires additional preparations. In some cases, glycosylations promoted by IDCP do not complete regardless of the amount of promoter added. Taking these together limits its wide applications.

Table 1 - The effect of promoter for activation of thioglycosides

*All reactions were performed in the presence of MS 4A in toluene-dioxane (1:3 v/v) at RT

Besides IDCP, the ClO4^-counter ion has been shown to contribute to α−selectivity.¹⁷ It is proposed that activation of glycosyl diphenyl phosphate produces an equilibrated oxocarbenium-perchlorate contact ion-pair (CIP) and α−/β− glycosyl perchlorates (Figure 4).

The counter ion may occupy either β- or α-face of the oxocarbenium ion. Furthermore, ethereal solvent can solvate CIP to give the solvent-separated ion pair (SSIP). The catalytic

Entry Promoter system α/β ratio^*

1 IDCP 18.0:1

Iodonium di-collidine perchlorate (IDCP) N

2 I⁺ClO4

-7 NIS/TBDMSOTf 4.3:1

amount of ClO4^- counter ion plays a key role to enhance α-selectivity. However, the mechanistic study for this above reaction has not been elucidated.

ClO₄ -O⁺

R O

OP(OPh)₂ R

OClO₃ R

OClO3

ClO4 -O⁺

Solvent

α-glycosides HClO₄

β-glycosides

ClO₄

-ROH ROH

CIP

SSIP

HClO₄ R = OBn or N3

Figure 4 - Proposed mechanism of ClO4^- playing a role in α-selective glycosylation

1.1.4. α-Selective glycosylation with special anomeric leaving groups

In the current glycosylation methods, the anomeric leaving groups have been explored in α−selective glycosylations. The stereochemical preference of using the different leaving groups is less consistent. For example, glycosyl phosphate has been examined as a glycosyl donor to impart α−glycosylaton. The experimental conditions invoke the use of ethereal

在文檔中 1.利用鈀金屬催化反應製備唾液酸衍生物 2.利用(TCT/DMF)試劑製備氯醣供體 3.二甲基甲醯胺促進(alpha)選擇性醣質化反應 (頁 122-0)