N-(ivDde)-D-serine (Structure C) was synthesized in the following steps: first, the target product was generated by the O-acylation of D-serine with ivDde-OH catalyzed by pyridine, followed by rearrangement. This was done as follows: a solution of isovaleryl chloride (13.5 mL, 13.3 g, 110 mmol) in dichloromethane (50 mL) was added dropwise to a solution of dichloromethane (150 mL) containing isoprene (14 g, 100 mmol) and pyridine (9.7 mL, 9.5 g, 120 mmol) over 15 min. The reaction mixture was stirred for 1.5 hours and then washed sequentially with aqueous 2N hydrochloric acid (2 x 50 mL), water and saturated aqueous sodium bicarbonate (50 mL), followed by drying with magnesium sulfate. The solvent was removed under vacuum by rotary evaporator to afford 5,5-dimethyl-3-oxocyclohex-1-enyl 3-methylbutyrate (22.4 g, 100% yield) as a light yellow oil. Next, a dichloromethane solution of 5,5-dimethyl-3-oxocyclohex-1-enyl 3-methylbutyrate (11.2 g, 50 mmol) was added dropwise to a dichloromethane (100 mL) suspension of aluminum chloride (16.0 g, 120 mmol) cooled in an ice bath, with dropwise time controlled at 30 minutes. The reaction mixture was then warmed to room temperature and stirred for 1 hour. The reaction mixture was slowly poured into a mixture of pre-cooled 37% aqueous hydrochloric acid (50 mL) and ice (150 g), maintaining the temperature at no more than 5°C. After addition of brine (200 mL), the product was extracted with dichloromethane (6 x 50 mL) and extraction completeness was confirmed by TLC. The combined organic phases were washed with brine (2 x 50 mL), dried over magnesium sulfate, and concentrated by rotary evaporator. The crude product was purified by silica gel column chromatography using a gradient elution from hexane to ethyl acetate:hexane (1:10) to afford ivDde-OH (10.5 g, 94% yield) as a light yellow oil.
