[(2S)-2-(bromomethyl)-3-methylbutoxy]methylbenzene

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine (15.4 g, 0.084 mol) in anhydrous THF (250 mL) at −78° C. was added dropwise 2.5 M n-BuLi in hexanes (34 mL, 0.085 mol) over 45 min. After stirring for 30 min at −78° C., a solution of (S)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene (15.6 g, 0.056 mol) in THF (100 L) was added dropwise over 30 min. The mixture was stirred for 2 h at −78° C. and then at −20° C. for 18 h. After evaporation, the residue was partitioned between H2O (200 mL) and EtOAc (3×200 mL). The combined organic layers were washed with brine (0.5 L), dried over MgSO4, evaporated, and purified by flash chromatography on silica gel eluting with 1:25 EtOAc/hexane to give (2S,5R)-2-((S)-2-(benzyloxymethyl)-3-methylbutyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine (18.5 g, 80%). 1H NMR (400 MHz, CDCl3): δ8.00 (s, 1H), 7.34-7.24 (m, 5H), 4.50 (s, 2H), 4.03 (m, 1H), 3.93 (m, 1H), 3.72 (s, 3H), 3.62 (s, 3H), 3.54-3.42 (m, 2H), 2.27 (m, 1H), 1.94-1.88 (m, 1H), 1.80-1.61 (m, 1H), 1.47-1.42 (m, 1H), 1.05 (d, J=6.4 Hz, 3H), 0.88 (d, J=6.4 Hz, 3H), 0.80 (d, J=6.4 Hz, 3H), 0.68 (d, J=6.4 Hz, 3H); MS: 403 (M++1). The mixture was stirred for 2 h at −78° C. at −20° C. for 18 h After evaporation the residue was partitioned between H2O (200 mL) and EtOAc (3×200 mL) The combined organic layers were washed with brine (0.5 L) dried over MgSO4 evaporated purified by flash chromatography on silica gel eluting with 1:25 EtOAc/hexane

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

Procedure: To a solution of (R)-2-(benzyloxymethyl)-3-methylbutan-1-ol (54 g, 0.26 mol) in dry CH2Cl2 (2 L) at 0° C., Ph3P (88 g, 0.31 mol) and NBS (55.5 g, 0.31 mol) were added in portions. After stirring for 18 h at rt, the mixture was evaporated and the residue was purified by flash chromatography on silica gel to give (S)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene (43 g, 61%). 1H NMR (400 MHz, CDCl3): 0.94 (m, 6H), 1.71 (m, 1H), 1.85 (m, 1H), 3.48 (m, 1H), 3.57 (m, 1H), 3.62 (m, 1H), 3.68 (m, 1H), 4.52 (s, 2H), 7.31 (m, 5H) the mixture was evaporated the residue was purified by flash chromatography on silica gel

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

Procedure: To a solution of (R)-2-(benzyloxymethyl)-3-methylbutan-1-ol (54 g, 0.26 mol) in dry CH2Cl2 (2 L) at 0° C., Ph3P (88 g, 0.31 mol) and NBS (55.5 g, 0.31 mol) were added in portions. After stirring for 18 h at rt, the mixture was evaporated and the residue was purified by flash chromatography on silica gel to give (S)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene (43 g, 61%). 1H NMR (400 MHz, CDCl3): 0.94 (m, 6H), 1.71 (m, 1H), 1.85 (m, 1H), 3.48 (m, 1H), 3.57 (m, 1H), 3.62 (m, 1H), 3.68 (m, 1H), 4.52 (s, 2H), 7.31 (m, 5H) the mixture was evaporated the residue was purified by flash chromatography on silica gel

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

Procedure: A solution of 1.98 g of aldehyde 7 in 15 mL of tetrahydrofuran is cooled to 10° C. and is treated with the Grignard reagent prepared by treating 1.23 g of ((S)-2-bromomethyl-3-methylbutoxymethyl)-benzene with 0.12 g of magnesium in diethylether containing 0.043 g of 1,2-dibromoethane at 45° C. The reaction is stirred for 90 minutes at room temperature, then 20 mL of a 25% aqueous solution of ammonium chloride is added, followed by addition of 20 mL of tert-butylmethyl ether. The organic phase is separated and washed twice with 20 mL of water. The organic phase is concentrated in vacuum to give the crude alcohol 8 as an oil. Purification on silica-gel delivers e.g. 0.97 g of pure 8. A negative [a]d is found at c=1, CHCl3. M++H=628, M++H+Na=650. prepared The organic phase is separated washed twice with 20 mL of water The organic phase is concentrated in vacuum

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

Procedure: A solution of 1.98 g of aldehyde 7 in 15 mL of tetrahydrofuran is cooled to 10° C. and is treated with the Grignard reagent prepared by treating 1.23 g of ((S)-2-bromomethyl-3-methylbutoxymethyl)-benzene with 0.12 g of magnesium in diethylether containing 0.043 g of 1,2-dibromoethane at 45° C. The reaction is stirred for 90 minutes at room temperature, then 20 mL of a 25% aqueous solution of ammonium chloride is added, followed by addition of 20 mL of tert-butylmethyl ether. The organic phase is separated and washed twice with 20 mL of water. The organic phase is concentrated in vacuum to give the crude alcohol 8 as an oil. Purification on silica-gel delivers e.g. 0.97 g of pure 8. A negative [a]d is found at c=1, CHCl3. M++H=628, M++H+Na=650. prepared The organic phase is separated washed twice with 20 mL of water The organic phase is concentrated in vacuum

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

Procedure: Dissolve (R)-2-(benzyloxy-methyl)-3-methyl butanol (15.6 g, 75 mmol) and N,N-dimethyl formamide (0.6 g, 8.25 mmol) in methyl benzene (351 ml), add phosphorus oxybromide (25.8 g, 90 mmol) in droplets slowly, and control the temperature below 60° C. in that process; then, let them to react at 80° C. for 2 hours; cool down to room temperature, add water (702 ml), stir for 20 minutes, and separate the layers; extract the aqueous layer with petroleum ether for three cycles, combine the organic layers and wash twice with saturated sodium bicarbonate and saturated sodium chloride respectively; dry the organic layer with anhydrous sodium sulfate, filter, and condense the filtrate so as to obtain 17.5 g of oily matter; treat the oil matter by reduced pressure distillation to obtain 16.1 g of colorless transparent liquid; the yield is 79.2%, and the chiral purity is ≧99.9%. the temperature below 60° C. to react at 80° C. for 2 hours separate the layers extract the aqueous layer with petroleum ether for three cycles wash twice with saturated sodium bicarbonate and saturated sodium chloride respectively dry the organic layer with anhydrous sodium sulfate filter condense the filtrate so as to obtain 17.5 g of oily matter treat the oil matter by reduced pressure distillation

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

Procedure: Dissolve (R)-2-(benzyloxy-methyl)-3-methyl butanol (15.6 g, 75 mmol) in N,N-dimethyl formamide (246 ml), add phosphorus oxybromide (22.58 g, 78.75 mmol) in droplets slowly and control the temperature below 50° C. in that process, and then let them to react at 50° C. for 3 hours. Cool down to room temperature, and pour the reactant liquid into water (246 ml) slowly, extract with normal hexane for three cycles, combine the normal hexane layers, wash twice with saturated sodium bicarbonate and saturated sodium chloride respectively, dry the organic layer with anhydrous sodium sulfate, filter, and condense the filtrate so as to obtain 18.1 g of oily matter. Treat the oil matter by reduced pressure distillation to obtain 16.6 g of colorless transparent liquid; the yield is 81.1%, and the chiral purity is ≧99.9%. the temperature below 50° C. to react at 50° C. for 3 hours extract with normal hexane for three cycles wash twice with saturated sodium bicarbonate and saturated sodium chloride respectively dry the organic layer with anhydrous sodium sulfate filter condense the filtrate so as to obtain 18.1 g of oily matter Treat the oil matter by reduced pressure distillation

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine (15.4 g, 0.084 mol) in anhydrous THF (250 mL) at −78° C. was added dropwise 2.5 M n-BuLi in hexanes (34 mL, 0.085 mol) over 45 min. After stirring for 30 min at −78° C., a solution of (S)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene (15.6 g, 0.056 mol) in THF (100 L) was added dropwise over 30 min. The mixture was stirred for 2 h at −78° C. and then at −20° C. for 18 h. After evaporation, the residue was partitioned between H2O (200 mL) and EtOAc (3×200 mL). The combined organic layers were washed with brine (0.5 L), dried over MgSO4, evaporated, and purified by flash chromatography on silica gel eluting with 1:25 EtOAc/hexane to give (2S,5R)-2-((S)-2-(benzyloxymethyl)-3-methylbutyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine (18.5 g, 80%). 1H NMR (400 MHz, CDCl3): δ8.00 (s, 1H), 7.34-7.24 (m, 5H), 4.50 (s, 2H), 4.03 (m, 1H), 3.93 (m, 1H), 3.72 (s, 3H), 3.62 (s, 3H), 3.54-3.42 (m, 2H), 2.27 (m, 1H), 1.94-1.88 (m, 1H), 1.80-1.61 (m, 1H), 1.47-1.42 (m, 1H), 1.05 (d, J=6.4 Hz, 3H), 0.88 (d, J=6.4 Hz, 3H), 0.80 (d, J=6.4 Hz, 3H), 0.68 (d, J=6.4 Hz, 3H); MS: 403 (M++1). The mixture was stirred for 2 h at −78° C. at −20° C. for 18 h After evaporation the residue was partitioned between H2O (200 mL) and EtOAc (3×200 mL) The combined organic layers were washed with brine (0.5 L) dried over MgSO4 evaporated purified by flash chromatography on silica gel eluting with 1:25 EtOAc/hexane

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

Procedure: To a solution of (R)-2-(benzyloxymethyl)-3-methylbutan-1-ol (54 g, 0.26 mol) in dry CH2Cl2 (2 L) at 0° C., Ph3P (88 g, 0.31 mol) and NBS (55.5 g, 0.31 mol) were added in portions. After stirring for 18 h at rt, the mixture was evaporated and the residue was purified by flash chromatography on silica gel to give (S)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene (43 g, 61%). 1H NMR (400 MHz, CDCl3): 0.94 (m, 6H), 1.71 (m, 1H), 1.85 (m, 1H), 3.48 (m, 1H), 3.57 (m, 1H), 3.62 (m, 1H), 3.68 (m, 1H), 4.52 (s, 2H), 7.31 (m, 5H) the mixture was evaporated the residue was purified by flash chromatography on silica gel

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

Procedure: A solution of 1.98 g of aldehyde 7 in 15 mL of tetrahydrofuran is cooled to 10° C. and is treated with the Grignard reagent prepared by treating 1.23 g of ((S)-2-bromomethyl-3-methylbutoxymethyl)-benzene with 0.12 g of magnesium in diethylether containing 0.043 g of 1,2-dibromoethane at 45° C. The reaction is stirred for 90 minutes at room temperature, then 20 mL of a 25% aqueous solution of ammonium chloride is added, followed by addition of 20 mL of tert-butylmethyl ether. The organic phase is separated and washed twice with 20 mL of water. The organic phase is concentrated in vacuum to give the crude alcohol 8 as an oil. Purification on silica-gel delivers e.g. 0.97 g of pure 8. A negative [a]d is found at c=1, CHCl3. M++H=628, M++H+Na=650. prepared The organic phase is separated washed twice with 20 mL of water The organic phase is concentrated in vacuum