Compound 2c

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Compound data: CIF

Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

Method A (main text figure 2, reaction): Andrographolide-3-oxime (45 mg, 0.13 mmol) was dissolved in THF, and NEt₃ (35 μL) was added, followed by TsCl (31 mg, 0.163 mmol, 1.3 equiv). The reaction was stirred for 36 hours at 40 ^oC, after which time a second portion of NEt₃ and TsCl were added. The reaction was heated at 40 ˚C for another 36 hours. Then, the reaction was allowed to cool to RT and filtered, and the solvent was evaporated. Chromatography on silica gel, eluting with a gradient of 0 to 5% MeOH in DCM gave 3,19-andrographolide isoxazole (25 mg, 55%).

Method B (main text figure 2, reaction): 3-keto-andrographolide (50 mg, 0.144 mmol) was combined with NH₂OSO₃H (33 mg, 0.288 mmol, 2 equiv) in 1:1 TFE:0.01% TFA(aq) (2.5 mL) and stirred at 50 ˚C for 24 hours. The reaction was then allowed to cool to RT, and saturated NaHCO₃ (2 mL) was added. The mixture was then extracted with 4:1 EA:THF (3 x 10 mL). The organic extracts were combined, dried over Na₂SO₄, and filtered, and the solvent was evaporated. The resulting residue was purified by silica gel chromatography with 0 to 5% MeOH in CHCl₃. Yield = 24.5 mg (49%).

Method C: The product was isolated as a side product from the synthesis of andrographolide lactam (main text figure 2, reaction). ¹H NMR (600 MHz, methanol-d₄) δ 6.84 (td, J = 6.7, 1.8 Hz, 1H), 5.03 (m, 1H), 4.97 (q, J = 1.3 Hz, 1H), 4.74 (q, J = 1.3 Hz, 1H), 4.47 (dd, J = 10.2, 6.1 Hz, 1H), 4.16 (dd, J = 10.2, 2.1 Hz, 1H), 4.01 (d, J = 7.8 Hz, 1H), 3.96 (d, J = 7.8 Hz, 1H), 2.70 – 2.56 (m, 4H), 2.43 (ddd, J = 12.9, 4.3, 2.4 Hz, 1H), 2.14-1.99 (m, 3H), 1.81 – 1.74 (m, 2H), 1.69 (ddt, J = 12.8, 5.6, 2.9 Hz, 1H), 1.42 (qd, J = 13.1, 4.3 Hz, 1H), 1.25 (s, 3H), 0.76 (s, 3H).¹³C NMR (151 MHz, methanol-d₄) δ 172.56, 167.52, 148.74, 148.00, 130.07, 110.50, 78.83, 76.12, 66.66, 55.66, 54.29, 53.13, 41.18, 38.34, 35.20, 26.21, 26.11, 24.94, 18.11, 13.96. HRMS (ESI+) calcd for [C₂₀H₂₈NO₄⁺]: 346.2013, found: 346.2013. IR (neat) (cm^-1) 1721.8, 1675.8, 1647.7. Product confirmed by x-ray crystallography.