[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in four steps from ((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)methan-1-ol following the procedures for Examples 5a, 5b, 5c, and 5d.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate was prepared from (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Sigma-Aldrich, 99% ee) by a known literature procedure (H. S. Kim, D. Barak, T. K. Harden, J. L. Boyer and K. A. Jacobson, J. Med. Chem., 2001, 44, 3092). The title compound was prepared in the same way as described by M. Lemaire, F. Posada, J.-G. Gourcy and G. Jeminet, Synlett, 1995, 627. A solution of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (3.9 g, 18.55 mmol) and benzylamine (8.10 ml, 74.2 mmol) was refluxed in CH3CN (50 ml) for 48 h. The solvent was evaporated and the residue dissolved in EtOAc and washed with aqueous sat. NaHCO3, dried and the solvent evaporated. The residue was chromatographed (EtOAc-hex, 6:4 then 8:2) to give (S)—N-benzyl-1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (3.1 g, 14.01 mmol, 76% yield) as a yellow oil. The title compound was prepared in the same way The solvent was evaporated the residue dissolved in EtOAc washed with aqueous sat. NaHCO3 dried the solvent evaporated The residue was chromatographed (EtOAc-hex, 6:4

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol (27 g, 0.2 mol), triphenylphosphine (53.5 g, 0.2 mol) and N-hydroxyphthalimide (33.3 g, 0.2 mol) in dry tetrahydrofuran (500 ml) cooled to 0° C. was added diethylazodicarboxylate (38.5 g, 0.22 mol). After stirring for 18 hours at 20° C. the originally dark red solution turned pale yellow and was then evaporated to dryness under reduced pressure. The residue was loaded onto a silica column in chloroform and eluted with hexane-acetone (3:1), yielding (R)-N-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)phthalimide as white plates (31.2 g, 55%), m.p. 100°-2° C. [α]D20 =+15.6° (C 0.98 in methanol); 1R: υmax (nujol) 1790, 1770, 1720, 1600 cm-1 ; 1H NMR: δH (CDCl3), 1.35 (3H, s, CH3), 1.41 (3H, s, CH3), 3.97 (1H, q, J=5.5, 8.8 Hz, CH2ON/CH2OC), 4.17 (2H, m, 1H of CH2ON+1H of CH2OC), 4.32 (1H, q, J=5.5, 10.0 Hz, CH2ON/CH2OC), 4.50 (1H, m, CH), 7.74-7.87 (4H, m, aromatic); m/z 262 (M+-CH3, 50%). was then evaporated to dryness under reduced pressure eluted with hexane-acetone (3:1)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol (27 g, 0.2 mol), triphenylphosphine (53.5 g, 0.2 mol) and N-hydroxyphthalimide (33.3 g, 0.2 mol) in dry tetrahydrofuran (500 ml) cooled to 0° C. was added diethylazodicarboxylate (38.5 g, 0.22 mol). After stirring for 18 hours at 20° C. the originally dark red solution turned pale yellow and was then evaporated to dryness under reduced pressure. The residue was loaded onto a silica column in chloroform and eluted with hexane-acetone (3:1), yielding (R)-N-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)phthalimide as white plates (31.2 g, 55%), m.p. 100°-2° C. [α]D20 =+15.6° (C 0.98 in methanol); 1R: υmax (nujol) 1790, 1770, 1720, 1600 cm-1 ; 1H NMR: δH (CDCl3), 1.35 (3H, s, CH3), 1.41 (3H, s, CH3), 3.97 (1H, q, J=5.5, 8.8 Hz, CH2ON/CH2OC), 4.17 (2H, m, 1H of CH2ON+1H of CH2OC), 4.32 (1H, q, J=5.5, 10.0 Hz, CH2ON/CH2OC), 4.50 (1H, m, CH), 7.74-7.87 (4H, m, aromatic); m/z 262 (M+-CH3, 50%). was then evaporated to dryness under reduced pressure eluted with hexane-acetone (3:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of (S)- or (R)-2-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione (74.9 g, 0.27 mol) in dichloromethane (480 mL) at 3-5° C. was added methylhydrazine (15.8 mL, 0.29 mole) dropwise. The color of the suspension turned from yellow to white. The cooling bath was removed and the mixture was stirred for 2 hrs at ambient temperature. The resulting suspension was concentrated on a rotary evaporator. To the white solid was added ether (0.5 L) and the resulting mixture was stirred for 1.5 h at ambient temperature. The white precipitate was filtered and washed with ether (0.2 L). The filtrate was concentrated on rotary evaporator to give (S)- or (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (39.0 g, 98.3%): 1H NMR (CDCl3): δ 1.35 (s, 3H), 1.42 (s, 3H), 3.73 (m, 3H), 4.05 (m, 1H), 4.33 (m, 1H), 5.39 (m, 2H); MS (APCI+)=148.1 (M++1) The cooling bath was removed The resulting suspension was concentrated on a rotary evaporator To the white solid was added ether (0.5 L) the resulting mixture was stirred for 1.5 h at ambient temperature The white precipitate was filtered washed with ether (0.2 L) The filtrate was concentrated on rotary evaporator

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel was charged with N-hydroxyphthalimide (68.0 g, 0.416 mol) and tetrahydrofuran (1.2 L) under nitrogen atmosphere. To this solution was added triphenylphosphine (109.2 g, 0.416 mol) and (R)- or (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (55.0 g, 0.416 mol). The mixture was cooled to 3-5° C. and diethyl azodicarboxylate (85.2 mL, 0.541 mol) was added dropwise, while keeping the inner temperature below 15° C. The reaction mixture was warmed to ambient temperature, and stirred for 18 hrs. The tetrahydrofuran was evaporated under reduced pressure. To the remaining orange solid was added dichloromethane (0.5 L) and the mixture was stirred for 1 h. The white solid (Ph3PO) was filtered and washed with dichloromethane (0.1 L). The solvent was removed and ethanol (0.5 L) was added to the resulting solid. The mixture was stirred for 2 h at 3-5° C. The white solid was filtered, washed with a small amount of cold EtOH and dried in vacuum oven at 40° C. to give (S)- or (R)-2-(2,2-Dimethyl-[1,3]dioxolan-4ylmethoxy)-isoindole-1,3-dione (112.5 g, 97%) as a white solid: 1H NMR (CDCl3): δ 1.33 (s, 3H), 1.99 (s, 3H), 3.96 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 4.48 (m, 1H), 7.59 (m, 2H), 7.84 (m, 2H); MS (APCI+)=278 (M++1). A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel the inner temperature below 15° C The reaction mixture was warmed to ambient temperature The tetrahydrofuran was evaporated under reduced pressure To the remaining orange solid was added dichloromethane (0.5 L) the mixture was stirred for 1 h The white solid (Ph3PO) was filtered washed with dichloromethane (0.1 L) The solvent was removed ethanol (0.5 L) was added to the resulting solid The mixture was stirred for 2 h at 3-5° C The white solid was filtered washed with a small amount of cold EtOH dried in vacuum oven at 40° C.

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel was charged with N-hydroxyphthalimide (68.0 g, 0.416 mol) and tetrahydrofuran (1.2 L) under nitrogen atmosphere. To this solution was added triphenylphosphine (109.2 g, 0.416 mol) and (R)- or (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (55.0 g, 0.416 mol). The mixture was cooled to 3-5° C. and diethyl azodicarboxylate (85.2 mL, 0.541 mol) was added dropwise, while keeping the inner temperature below 15° C. The reaction mixture was warmed to ambient temperature, and stirred for 18 hrs. The tetrahydrofuran was evaporated under reduced pressure. To the remaining orange solid was added dichloromethane (0.5 L) and the mixture was stirred for 1 h. The white solid (Ph3PO) was filtered and washed with dichloromethane (0.1 L). The solvent was removed and ethanol (0.5 L) was added to the resulting solid. The mixture was stirred for 2 h at 3-5° C. The white solid was filtered, washed with a small amount of cold EtOH and dried in vacuum oven at 40° C. to give (S)- or (R)-2-(2,2-Dimethyl-[1,3]dioxolan-4ylmethoxy)-isoindole-1,3-dione (112.5 g, 97%) as a white solid: 1H NMR (CDCl3): δ 1.33 (s, 3H), 1.99 (s, 3H), 3.96 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 4.48 (m, 1H), 7.59 (m, 2H), 7.84 (m, 2H); MS (APCI+)=278 (M++1). A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel the inner temperature below 15° C The reaction mixture was warmed to ambient temperature The tetrahydrofuran was evaporated under reduced pressure To the remaining orange solid was added dichloromethane (0.5 L) the mixture was stirred for 1 h The white solid (Ph3PO) was filtered washed with dichloromethane (0.1 L) The solvent was removed ethanol (0.5 L) was added to the resulting solid The mixture was stirred for 2 h at 3-5° C The white solid was filtered washed with a small amount of cold EtOH dried in vacuum oven at 40° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (4S)-2,2-Dimethyl-1,3-dioxolan-4-ylmethanol (362 mg, 2.74 mM) was dissolved in pyridine (9 ml), stirred at ambient temperature, and treated in portions with 4-nitrophenyl chloroformate (552 mg, 2.74 mM). After 6 hours, solvent was evaporated, the residue redissolved in ethyl acetate (15 ml), washed with water (15 ml), sodium bicarbonate solution (15 ml), brine (15 ml), and dried (magnesium sulfate). Removal of the solvent gave the product as an oil sufficiently pure for further use (858 mg). solvent was evaporated the residue redissolved in ethyl acetate (15 ml) washed with water (15 ml), sodium bicarbonate solution (15 ml), brine (15 ml) dried (magnesium sulfate) Removal of the solvent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the procedure for 1-(allyloxy)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using (S)-(+)-2,2,-dimethyl-1,3-dioxolane-4-methanol in place of allyl alcohol, the title compound was synthesized.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-(+)-2,2-Dimethyl-1,3-dioxolane-4-methanol (6, 1.17 g, 8.9 mmol) and 4-iodobenzylbromide (2.5 g, 8.4 mmol) were refluxed under Dean-Stark conditions in toluene (80 mL) in the presence of KOH (8.8 g, 154.0 mmol) for 12 h. The reaction mixture was allowed to cool down and H2O (30 mL) was added. After separation of the phases the water layer was washed with toluene (2×15 mL). Combined organic layers were washed with H2O (30 mL) and concentrated in vacuo. The residue was treated with 80% aq. AcOH (25 mL) for 48 h at rt. The solvent was removed in vacuo and the residue was co-evaporated twice with toluene/EtOH (30 mL, 5:1, v/v). The residue was dried under diminished pressure to afford (R)-3-(4-iodobenzyloxy)propane-1,2-diol (7, 100%, 2.3 g) as yellowish oil that was used in the next step without further purification. to cool down After separation of the phases the water layer was washed with toluene (2×15 mL) Combined organic layers were washed with H2O (30 mL) concentrated in vacuo The residue was treated with 80% aq. AcOH (25 mL) for 48 h at rt The solvent was removed in vacuo The residue was dried under diminished pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-(+)-2,2-Dimethyl-1,3-dioxolane-4-methanol (6, 1.17 g, 8.9 mmol) and 4-iodobenzylbromide (2.5 g, 8.4 mmol) were refluxed under Dean-Stark conditions in toluene (80 mL) in the presence of KOH (8.8 g, 154.0 mmol) for 12 h. The reaction mixture was allowed to cool down and H2O (30 mL) was added. After separation of the phases the water layer was washed with toluene (2×15 mL). Combined organic layers were washed with H2O (30 mL) and concentrated in vacuo. The residue was treated with 80% aq. AcOH (25 mL) for 48 h at rt. The solvent was removed in vacuo and the residue was co-evaporated twice with toluene/EtOH (30 mL, 5:1, v/v). The residue was dried under diminished pressure to afford (R)-3-(4-iodobenzyloxy)propane-1,2-diol (7, 100%, 2.3 g) as yellowish oil that was used in the next step without further purification. to cool down After separation of the phases the water layer was washed with toluene (2×15 mL) Combined organic layers were washed with H2O (30 mL) concentrated in vacuo The residue was treated with 80% aq. AcOH (25 mL) for 48 h at rt The solvent was removed in vacuo The residue was dried under diminished pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: According to the procedure of the reference [FEBS Letters, Vol. 116, 161 (1980)], D-mannitol was used as a starting material to give 25 g of the desired compound (needles) through 1,2-isopropylidene-sn-glycerol.