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Synlett 2009(14): 2301-2304  
DOI: 10.1055/s-0029-1217713
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Concise Asymmetric Synthesis of Antimalarial Alkaloid (+)-Febrifugine

Rui Wanga, Kai Fanga, Bing-Feng Suna, Ming-Hua Xu*a,b, Guo-Qiang Lin*a
a CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. of China
Fax: +86(21)64166263; e-Mail: lingq@mail.sioc.ac.cn;
b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. of China
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Publication History

Received 17 April 2009
Publication Date:
29 July 2009 (online)

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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

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.