HiRaC: High Rank Cryptosystem

Synthesis of hexa-O-acetyl-D-lactal (25)7_{: To a suspension of D-lactose (1.00 g) in acetic}

anhydride (2.7 g, 9.0 mol equiv) was added 1.0 g of 31% HBr acetic acid at room temperature (the temperature was kept at room temperature while cooled by a water bath). Although the mixture was stirred at room temperature for 4 h, the solid lactose did not completely dissolve. Additional 31 % HBr/acetic acid (4.0 g, thus making an overall total of 6.7 mol equiv of HBr) was added and the resulting mixture was stirred overnight at room temperature, at which point all of the solid lactose went into solution. The reaction mixture was poured onto a suspension of pulverized CuSO4.5H2O (0.18 g) and zinc (7.3 g) in a solution of water (10 mL)

and acetic acid (15 mL) containing sodium acetate (5.5 g). The resultant reaction mixture was stirred vigorously at room temperature for 1.5 h in a bath of running tap water. The mixture was then filtered and the solid collected was washed with ethyl acetate (100 mL) and then with water (100 mL). The organic layer of the filtrate was washed successively with saturated aqueous NaHCO3 (100 mL) and brine (100 mL), and then dried (Na2SO4). The solvent was

removed under reduced pressure to provide a crude solid which was purified by silica gel flash column chromatography using 50% ethyl acetate in hexanes as the eluent to afford hexa-O- acetyl- D-lactal (25) (1.2 g, 86%) as a colourless solid:

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Synthesis of 1-O-acetyl-3,6-di-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-gulcopyranosyl)-2- deoxy-2-iodo-α-D-mannopyranose (26)8_{: In a 200 mL acetic acid solution, glycal 25 (10.0 g,}

17.8 mmol), Cu(OAc)2 (3.6 g, 19.6 mmol), and I2 (5.4 g, 21.4 mmol) were added in respective

order. The resulting mixture was stirred at 80 ◦_{C overnight under argon atmosphere. Then the}

reaction was evaporated to dryness under reduced pressure and the obtained residue was diluted with DCM (500 mL). The organic layer was washed with aq. NaHCO3 (150 mL), aq.

Na2S2O3 (150 mL) and brine (150 mL) and dried over Na2SO4, and concentrated. The crude

residue was purified by silica gel column chromatography (n-hexane : ethyl acetate = 2/1) to yield the compound X as white solid ( 9.3 g, 70%). Spectroscopic data were in agreement with those reported in the literature.8

Synthesis of 3,6-di-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-gulcopyranosyl)-2-deoxy-2- iodo-α-D-mannopyranosyl azide (27)8_{: To the solution of iodoacetate 26 (9.0 g, 12.0 mmol)}

and TMSN3 (1.9 mL, 14.5 mmol) in dry DCM (100 mL), TMSOTf (435 µL, 2.4 mmol) was added

at 0 o_{C under argon atmosphere. The reaction mixture was gradually warmed to room}

temperature and then stirred overnight. The resulting mixture was then diluted with DCM (400 mL) and the organic phase was washed with aq. NaHCO3 (150 mL) dried over Na2SO4.

The organic layer was concentrated on rotary evaporator and the resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 1:1) to afford compound X as a white solid (7.0 g, 80%) as white solid. Spectroscopic data were in agreement with those reported in the literature.8

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Synthesis of ethyl [3,6-di-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-2- aminotriphenylphosphonium-2-deoxy-1-thio-β-D-glucopyranoside] iodide (28)8_{: In 100 mL}

of dry DCM, compound 27 (7.0 g, 9.6 mmol) and ethanethiol (831 μL, 11.5 mmol) and 4 Å MS were added under argon. The reaction mixture was then cooled down to 0 o_{C and stirred for}

30 min. Then a solution of PPh3 (2.6 g 10.1 mmol) in DCM (5 mL) was added dropwise. The

reaction mixture was allowed to warm gradually to room temperature and further stirred for additional 12 h. The molecular sieves was filtered off through a pad of Celite and the filtrate was concentrated under reduced pressure. The resulting crude residue was purified by silica gel column chromatography using ethyl acetate: ethanol (10/1) as eluent to yield the compound 28 (9.4 g, 95%) as yellow foam. The resulting Lanfont intermediate was stored and next steps were carried out in batches when required. Spectroscopic data were in agreement with those reported in the literature.8

Synthesis of Ethyl 3,6-O-di-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-2- deoxy-2-ohydroxylbenzylideneamino-1-thio-β-D-glucopyranoside (29)8_{: To a mixture of}

compound 28 (1.0 g, 1.0 mmol) and salicylaldehyde (1 mL in 2 mL of chlorobenzene in a Microwave tube, Et3N (2 mL) was added. Then the reaction was irradiated with 150 W of

microwave energy at 140 ◦_{C for 30 min. The resulting reaction mixture was then transferred}

into a round bottom flask and concentrated in vacuo. Purification by silica gel column chromatography (n-hexane/ethyl acetate = 1:1) afforded compound 11 (0.6 g, 80 %) as foam.

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The scale of the reaction was reduced due to the size limitation of microwave set-up. Spectroscopic data were in agreement with those reported in the literature.8

Synthesis of ethyl 3,6-O-di-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-2- deoxy-2-amino-1-thio-β-D-glucopyranoside hydrochloride (30)8_{: To a solution of compound}

29 (3.0 g, 4.0 mmol) in a mixture of acetone/DCM (8:1, 10 mL), aq. 3 M HCl solution (1.4 mL, 4.1 mmol) was added. The reaction mixture was then stirred for 1 h at room temperature and the progress of the reaction was monitored using TLC. On complete conversion of the starting material, the solution was diluted with toluene (6 mL) and the solvent was removed under vacuo. The residue was purified by silica gel column chromatography using ethyl acetate/ethanol (20:1) to yield compound 12 (1.9 g, 72%) as foam. Spectroscopic data were in agreement with those reported in the literature.8

Synthesis of ethyl 3,6-O-di-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-2- deoxy-2-N-Troc-1- thio-β-D-glucopyranoside (31)8_{: To a solution of 30 (0.5 g, 0.8 mmol) and}

Et3N (511 μL, 3.7 mmol) in DCM/H2O (1:1, 30 mL), TrocCl (1 mL, 7.9 mmol) was added. The

reaction was stirred then overnight at room temperature. The resulting solution was diluted with DCM (150 mL) and washed with aq. NaHCO3 (100 mL) and brine (100 mL). The organic

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purified by silica gel column chromatography using hexane/ethyl acetate (1/1) to afford compound 14 (0.5 g, 77%) as foam. Spectroscopic data were in agreement with those reported in the literature.8

Synthesis of ethyl-3,6-O-di-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-2- deoxy-2-N phthalimido-1-thio-β-D-glucopyranoside (32)8_{: To a solution of 30 (0.95 g, 1.4}

mmol) in pyridine (30mL), Et3N (247 μL, 1.8 mmol) was added. The reaction mixture was

stirred for 30 minutes followed by the addition of phthalic anhydride (0.2 g, 1.6 mmol). The resulting solution was stirred for 2 hours and then a second portion of phthalic anhydride (0.2 g, 1.6 mmol) and Et3N (247 μL, 1.8 mmol) were added. Then the resulting reaction mixture

was stirred for additional 2 hours and then the reaction was quickly moved to an preheated oil bath at 90 o_{C followed by the addition of Ac}

2O (10 mL). The mixture was then stirred for

another 30 min at 90 o_{C and after 30 minutes, the solution was concentrated in vacuo. The}

resulting residue was dissolved in DCM (100 mL) and the organic layer was washed with aq. 1 N HCl (70×3), water (60 mL), aq. NaHCO3 (50 mL), and brine (50 mL). The organic phase was

dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was

purified by silica gel column chromatography using hexane/ethyl acetate (1:1) to yield compound 13 (0.96 g, 20%) as white solid. Spectroscopic data were in agreement with those reported in the literature.8

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