N-(tert-butoxycarbonyl)-L-isoleucine (1.24 g, 5.4 mmol, 1.0 eq.) was dissolved in 35 mL of tetrahydrofuran (THF), cooled to 0 °C and sodium hydride (60% dispersed in mineral oil; 0.64 g, 16.1 mmol, 3.0 eq.) was added slowly. Iodomethane (6.1 g, 42 mmol, 8.0 eq.) was then added and the reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction, ether was added and the organic layer was washed twice with deionized water. The combined aqueous layers were adjusted to pH 3 with citric acid and extracted with ethyl acetate (EtOAc). The combined organic phases were washed sequentially with sodium thiosulfate (Na2S2O3) solution and saturated brine and dried over anhydrous sodium sulfate (Na2SO4). The solvent was removed under reduced pressure to afford (2S,3S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylpentanoic acid as a colorless oil (1.18 g, 90% yield). The product was characterized by infrared spectroscopy (IR), nuclear magnetic resonance hydrogen spectroscopy (1H NMR), nuclear magnetic resonance carbon spectroscopy (13C NMR), and high-resolution mass spectrometry (HRMS) to confirm the correct structure. The specific optical rotation [α]20D was +2.6 (c 1.8, acetic acid).
