2,2-dimethoxyethanol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a suspension of 60% NaH/mineral oil (2.55 g, 63.96 mmol) in anhydrous DMF (70 mL) at 0° C. under nitrogen atmosphere was slowly added glycolaldehyde dimethyl acetal (Aldrich, 5.65 g, 53.3 mmol). The mixture was stirred at ambient temperature for 1 hour and then transferred to a solution of the product from step (a) (8.05 g, 50.76 mmol) in anhydrous DMF (70 mL) at -55° C. over 15 minutes. The mixture was allowed to warm to -20° C. over 2 hours and then neutralized with AcOH. Solvent was evaporated in vacuo and the residue partitioned between H2O and CH2Cl2. The aqueous phase was extracted with CH2Cl2 and the combined organic phase was dried (Na2SO4) and evaporated in vacuo. The residue was flash chromatographed (EtOAc/hexanes, 1:4) to give the desired product (7.92 g, 69%) as a colourless oil: 1H NMR (CDCl3): δ 1.37 (t, J=7.0 Hz, 3H), 3.44 (s, 6H), 4.36-4.43 (m, 4H), 4.78 (t, J=5.0 Hz, 1H), 6.34 (d, J=6.0 Hz, 1H), 8.15 (d, J=6.0 Hz, 1H); MS m/z229 (M=1, 13%), 197 (100%). Anal Calcd. for C10H16N2O4 : C, 52.62; H, 7.07; N, 12.27. Found: C, 52.45; H, 7.01; N, 12.26. to warm to -20° C. over 2 hours Solvent was evaporated in vacuo the residue partitioned between H2O and CH2Cl2 The aqueous phase was extracted with CH2Cl2 the combined organic phase was dried (Na2SO4) evaporated in vacuo chromatographed (EtOAc/hexanes, 1:4)

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

Procedure: A 100 mL, round bottom flask equipped with a magnetic stirrer and a nitrogen inlet is added N-benzyloxycarbonyl-L-valine (3.6 g), dichloromethane (25 mL), and 2,2-dimethoxyethanol (1.85 g) and the mixture is cooled using an ice bath (0-5° C.). DMAP (0.089 g) is added to the reaction mixture followed by the addition of DCC (3.6 g) over a period of 2 minutes. The suspended solid is filtered, the filter cake is washed with 3×10 mL of heptanes, and the filtrate is concentrated. The crude product is purified by silica gel chromatography (4:1, heptanes/ethyl acetate eluent) to provide 5.3 g of 2,2-dimethoxyethyl N-benzyloxycarbonyl-L-valinate. A 100 mL, round bottom flask equipped with a magnetic stirrer and a nitrogen inlet the mixture is cooled (0-5° C.) The suspended solid is filtered the filter cake is washed with 3×10 mL of heptanes the filtrate is concentrated The crude product is purified by silica gel chromatography (4:1, heptanes/ethyl acetate eluent)

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

Procedure: To a 100 mL, round bottom flask equipped with a magnetic stirrer and nitrogen inlet is added N-Benzyloxycarbonyl-L-proline (3.5 g), dichloromethane (25 mL) and 2,2-dimethoxyethanol (1.8 g). The mixture is cooled using an ice bath (0-5° C.) and DMAP (86 mg) is added. DCC (3.06 g) is added to the mixture over a period of 2 minutes. The resulting precipitate is filtered, washed with heptanes (2×10 mL) and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel chromatography using heptanes/ethyl acetate (4:1) as the eluent, and 4.5 g of 2,2-dimethoxyethyl N-benzyloxycarbonyl-L-prolinate was obtained. To a 100 mL, round bottom flask equipped with a magnetic stirrer and nitrogen inlet The mixture is cooled is added The resulting precipitate is filtered washed with heptanes (2×10 mL) the filtrate is concentrated under reduced pressure The residue was purified by silica gel chromatography

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

Procedure: To a 100 mL, round bottom flask equipped with a magnetic stirrer and nitrogen inlet is added N-Benzyloxycarbonyl-L-proline (3.5 g), dichloromethane (25 mL) and 2,2-dimethoxyethanol (1.8 g). The mixture is cooled using an ice bath (0-5° C.) and DMAP (86 mg) is added. DCC (3.06 g) is added to the mixture over a period of 2 minutes. The resulting precipitate is filtered, washed with heptanes (2×10 mL) and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel chromatography using heptanes/ethyl acetate (4:1) as the eluent, and 4.5 g of 2,2-dimethoxyethyl N-benzyloxycarbonyl-L-prolinate was obtained. To a 100 mL, round bottom flask equipped with a magnetic stirrer and nitrogen inlet The mixture is cooled is added The resulting precipitate is filtered washed with heptanes (2×10 mL) the filtrate is concentrated under reduced pressure The residue was purified by silica gel chromatography

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

Procedure: 2,2-Dimethoxyethanol (8.12 g), Et3N (8.99 g), DMAP (80 mg) and toluene (71 mL) are combined and stirred at room temperature. (S)-6-Methoxy-α-methyl-2-naphthaleneacetyl chloride (18.42 g) is added in portions over a period of 8 minutes. The resulting slurry is agitated (35-40° C.) until the reaction is judged to be complete. To the reaction mixture is added water (80 mL) and the phases are separated. The toluene phase is washed with saturated sodium bicarbonate (40 mL) and water (40 mL) and concentrated. Dichloromethane (20 mL) is added and the vacuum evaporation is repeated to produce 21.20 g of 2,2-dimethoxyethyl (S)-6-methoxy-α-methyl-2-naphthaleneacetate. The resulting slurry is agitated (35-40° C.) until the reaction the phases are separated The toluene phase is washed with saturated sodium bicarbonate (40 mL) and water (40 mL) concentrated Dichloromethane (20 mL) is added the vacuum evaporation

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

Procedure: To a stirred suspension of sodium hydride (60% oil dispersion, 1.2 g, 30 mmol) in DMF (6 mL) was added dropwise 2-hydroxyacetaldehyde dimethyl acetal (3.2 g, 30 mmol). The resulting mixture was left to stir for 0.5 h, then a solution of 1-chloroisoquinoline (1.6 g, 10 mmol) in DMF (2 mL) was added and the mixture was stirred at 80° C. for 24 h. The mixture was then poured into water (150 mL) and extracted with ether (2×150 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (10% ethyl acetate in hexane) to give 1-isoquinolinyloxyacetaldehyde dimethyl acetal (1.5 g, 64%). The resulting mixture was left the mixture was stirred at 80° C. for 24 h extracted with ether (2×150 mL) The combined organic extracts were dried over sodium sulfate evaporated in vacuo The residue was purified by silica gel chromatography (10% ethyl acetate in hexane)

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

Procedure: To a stirred suspension of sodium hydride (60% oil dispersion, 1.2 g, 30 mmol) in DMF (6 mL) was added dropwise 2-hydroxyacetaldehyde dimethyl acetal (3.2 g, 30 mmol). The resulting mixture was left to stir for 0.5 h, then a solution of 1-chloroisoquinoline (1.6 g, 10 mmol) in DMF (2 mL) was added and the mixture was stirred at 80° C. for 24 h. The mixture was then poured into water (150 mL) and extracted with ether (2×150 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (10% ethyl acetate in hexane) to give 1-isoquinolinyloxyacetaldehyde dimethyl acetal (1.5 g, 64%). The resulting mixture was left the mixture was stirred at 80° C. for 24 h extracted with ether (2×150 mL) The combined organic extracts were dried over sodium sulfate evaporated in vacuo The residue was purified by silica gel chromatography (10% ethyl acetate in hexane)

Conditions: temp:0.00; pressure:0.00; stir: