(3R)-3,4,4-trimethoxyoxane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of (R)-3,4,4-trimethoxytetrahydro-2H-pyran (as prepared in the previous step, 141 g, 0.80 mol), in THF (3.6 L) and H2O (1.1 L) in an ice/acetone bath at <0° C., was treated with a solution of HCl (conc., 595 mL, 7.21 mol) added via addition funnel over 45 min while keeping temperature <3° C. After the addition was complete, the reaction was allowed to stir for 1.5 h at 0° C. The reaction was evaporated until ˜1.9 L of concentrate remained. The concentrated was transferred to a separatory funnel and extracted with CH2Cl2 (3×1 L). The combined organic fractions were washed with sat. NaHCO3 (1 L), brine (1 L), dried over MgSO4, filtered and evaporated to afford the title compound (71.4 g, 69%, Chiral GC 92% ee) as an oil which solidified upon standing. Optical Rotation: [α]25(D) −6.97° (c=0.8222, MeOH); Elemental Analysis calc for C6H10O3: C, 53.59; H, 7.58. Found: C, 53.64; H, 7.65. added via addition funnel over 45 min temperature <3° C After the addition The reaction was evaporated until ˜1.9 L of concentrate The concentrated was transferred to a separatory funnel extracted with CH2Cl2 (3×1 L) The combined organic fractions were washed with sat. NaHCO3 (1 L), brine (1 L) dried over MgSO4 filtered evaporated

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

Procedure: A 12-L 4-neck round bottom flask equipped with a overhead air stirrer, addition funnel with nitrogen inlet adapter, condenser, and thermocouple was charged with (R)-4,4-dimethoxytetrahydro-2H-pyran-3-ol (as prepared in the previous step, 163 g, 1.0 mol) in THF (2.4 L) and stirred in ice/acetone bath until <0° C. KOtBu (113 g, 1.0 mol) was added in one portion, and after stirring 45 min, dimethyl sulfate (95 mL, 1.0 mol) was added via addition funnel over 15 min. The reaction was allowed to stir at room temperature for 2 h. The reaction mixture was poured into a reparatory flask containing H2O (1.2 L) and CH2Cl2 (1.2 L) and the layers were separated. The aqueous layer was back-extracted with CH2Cl2 (900 mL). The combined organic layers were washed with brine (1.0 L; Note: organic layer was on top), dried over MgSO4, filtered and evaporated to afford the title compound (177.1 g, 99%, chiral GC 94.4% ee) as a light yellow oil. A 12-L 4-neck round bottom flask equipped with a overhead air stirrer, addition funnel with nitrogen inlet adapter, condenser to stir at room temperature for 2 h The reaction mixture was poured into a reparatory flask the layers were separated The aqueous layer was back-extracted with CH2Cl2 (900 mL) The combined organic layers were washed with brine (1.0 L; Note: organic layer was on top) dried over MgSO4 filtered evaporated