Concise Asymmetric Synthesis of Antimalarial Alkaloid (+)-Febrifugine

Abstract

An asymmetric total synthesis of antimalarial alkaloid (+)-febrifugine is accomplished in 23% overall yield over 14 steps from readily available starting materials. The synthesis features a SmI₂-mediated reductive cross-coupling of chiral N-tert-butanesulfinyl imine with aldehyde.

Key words

antimalarial - asymmetric synthesis - febrifugine - cross-coupling

References and Notes

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6

Indeed, a preliminary study, which utilized aldehyde A and imine B (Scheme  [6] ) as the substrates to investigate the impact of a stereocenter adjacent to the reaction site, has established that the N-sulfinyl group determines the stereochemistry of the product C, whose structure was confirmed by X-ray crystallography (CCDC deposit no. 724597). These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Scheme 6

15

Selected Experiment and Spectroscopic DataPreparation of Compound 4
To the solution of SmI₂ (4.0 mmol in 20 mL of THF) the solution of imine 5 (480 mg, 1.90 mmol), aldehyde 6 (1.14 g, 3.80 mmol) and t-BuOH (380 µL, 4.0 mmol) in 20 mL of THF was dropped in slowly under argon at -78 ˚C.
The mixture was stirred vigorously for 7 h at the same temperature and then quenched by 10 mL sat. Na₂S₂O₃ aq solution. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed by sat. brine and then dried over anhyd MgSO₄, filtered, and concentrated under vacuum. After flash silica gel chromatography, 952 mg (85%) of the pure product 4 was obtained as yellow oil.
Compound 4: [α]_D ^²8 +33.0 (c 2.70, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 7.65 (d, J = 6.9 Hz, 4 H), 7.45-7.26 (m, 6 H), 4.46 (d, J = 4.8 Hz, 1 H), 4.29 (m, 1 H), 4.12 (dd, J = 8.1, 5.7 Hz, 1 H), 3.74-3.67 (m, 3 H), 3.52 (t, J = 7.8 Hz, 1 H), 3.42 (m, 1 H), 3.05 (d, J = 4.8 Hz, 1 H), 1.89-1.52 (m, 6 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.24 (s, 9 H), 1.05 (s, 9 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 135.48, 133.67, 129.55, 127.57, 109.57, 73.65, 72.59, 69.65, 63.79, 57.96, 55.57, 32.16, 29.77, 29.14, 26.83, 26.79, 25.73, 22.62, 19.11. FT-IR (thin film): 3414, 3283, 2983, 2959, 2933, 2860, 1112, 1052 cm^-¹. ESI-MS: m/z = 576.3 [M + H]⁺, 598.3 [M + Na]⁺. MALDI-HRMS: m/z calcd for C₃₁H₄₉NO₅SSiNa [M + Na]⁺: 598.2993; found: 598.3011.
Compound 14: [α]_D ^²5 +64.6 (c 0.60, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 8.26 (m, 1 H), 7.98 (s, 1 H), 7.81-7.73 (m, 2 H), 7.51 (m, 1 H), 7.32-7.24 (m, 5 H), 4.96 (d, J = 17.6 Hz, 1 H), 4.75 (d, J = 17.6 Hz, 1 H), 4.63-4.52 (m, 2 H), 4.42 (s, 1 H), 3.62-3.59 (m, 2 H), 3.11-3.03 (m, 2 H), 2.75 (m, 1 H), 2.05-1.92 (m, 2 H), 1.62-1.47 (m, 2 H), 1.38-1.33 (m, 9 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 200.67, 160.95, 148.33, 146.60, 138.18, 134.44, 128.26, 127.70, 127.61, 127.54, 127.29, 126.67, 121.86, 74.29, 70.81, 61.98, 54.80, 54.70, 43.16, 42.05, 24.10, 23.24, 19.62. FT-IR (thin film): 2928, 2870, 1308, 936 cm^-¹. ESI-MS: m/z = 512.4 [M + H]⁺, 534.4 [M + Na]⁺. ESI-HRMS: m/z calcd for C₂₇H₃₄N₃O₅S [M + H]⁺: 512.2214; found: 512.2232.
Compound 1: mp 137-139 ˚C; [α]_D ^²6 +27.3 (c 0.45, EtOH) [lit.^¹b mp 139-140 ˚C; [α]_D ^²5 +28.0 (c 0.5, EtOH)]. ^¹H NMR (500 MHz, CDCl₃): δ = 8.28 (m, 1 H), 7.89 (s, 1 H), 7.77-7.72 (m, 2 H), 7.52 (t, J = 6.7 Hz, 1 H), 4.90 (d, J = 17.7 Hz, 1 H), 4.81 (d, J = 17.7 Hz, 1 H), 3.28 (br s, 1 H), 3.11 (dd, J = 15.9, 3.9 Hz, 1 H), 2.96 (d, J = 11.0 Hz, 1 H), 2.87 (br d, J = 3.9 Hz, 1 H), 2.65 (dd, J = 15.9, 6.7 Hz, 1 H), 2.58 (m, 1 H), 2.08 (br d, J = 10.7 Hz, 1 H), 1.84 (br, 2 H), 1.70 (br d, J = 12.4 Hz, 1 H), 1.52 (br d, J = 12.8 Hz, 1 H), 1.34 (br d, J = 10.1 Hz, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 202.64, 161.01, 148.23, 146.39, 134.54, 127.64, 127.44, 126.80, 121.88, 72.26, 60.18, 54.85, 45.97, 44.04, 34.48, 25.65. FT-IR (thin film): 3304, 3287, 2941, 2931, 2858, 2814, 1722, 1674, 1614, 1475, 1363, 1084, 773, 698 cm^-¹. ESI-MS: m/z = 302.2 [M + H]⁺, 324.2 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₆H₂₀N₃O₃ [M + H]⁺: 302.1500; found: 302.1499.