Conjugate Addition of a Cyano-Gilman Cuprate to an Acrylic Acid: Homologation of Artemisinic Acid and Subsequent Conversion to 16-Butylartemisinin

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• General Procedure for 9-pentylartemisinic acid 9 : To a flame-dried 50 mL round bottom flask was added artemisinic acid 2 (250 mg or 1.07 mmol) and THF (5 mL). The solution was cooled to 0°C, 2.5M n-BuLi was added (450 μL or 1.12 mmol) and after 15 minutes, chlorotrimethylsilane was added (145 μL or 1.12 mmol). After an additional 15 minutes, the solution was cooled to -78°C and chlorotrimethylsilane was added (270 μL or 2.14 mmol). The resultant solution was added via cannula to the cyano-Gilman butylcuprate (2.2 equivalents, made in situ using standard procedures). Upon completion, cold glacial acetic acid (0.5 mL or 11 mmol) was added and the mixture was allowed to stir overnight at room temperature. After standard aqueous workup, each isomer (11R and 11S) of 9 were separated by reverse phase semipreparative HPLC and calibration curves were run for both isomers on analytical reverse phase HPLC. The identity of each isomer was established by conversion to the known artemisinin analog 11, where the alternate isomer was assumed to be the corresponding α-epimer (11S).14,32 Known quantities from each run of dried, crude reaction product were then analyzed by HPLC and the yield and isomer ratios were quantitated relative to controls. In an example, isolated yields (silica gel flash chromatography, 20% EtOAc/hexane) were determined in order to validate the HPLC method (Table 1). 1H NMR 300 MHz (CDCl3): δ 5.12 (s, 1H), 2.51 (s, 1H), 2.43 (dddd, 1H, J = 3.8, 4.0, 11.1, 14.8 Hz), 2.36 (s, 1H), 1.9 (m, 5H), 1.62 (s, 3H), 1.31 (broad s, 3H), 1.14 (dddd, 1H, J = 3.2, 9.7, 12.9, 16.0 Hz), 0.87 (d, 3H, J = 6.5 Hz). IR (Neat): 3396, 2929, 3872, 1707, 1456, 1379, 1182, 1115, 1001. DCIMS-NH3 (as methyl ester): m/z 307 (M + H), 275, 162, 147 cm−1. Anal. calcd. for C20H34O2 (as methyl ester): C, 78.37; H, 11.19. Found: C, 78.57; H, 11.12. HRMS-DCI calcd. for C20H35O2 (as methyl ester + H): 307.2637. Found: 307. 2617.
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