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DOI: 10.1055/s-0029-1219389
Total Synthesis of (±)-Lepadiformine A via Radical Translocation-Cyclization Reaction
Publication History
Publication Date:
10 February 2010 (online)
Abstract
A total synthesis of (±)-lepadiformine A was accomplished through construction of the 1-azaspiro[4.5]decane skeleton by a sequential radical translocation-cyclization reaction.
Key words
radical reaction - cyclization - domino reaction - natural products - total synthesis
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n-Bu3SnH (97% purity) was purchased from Aldrich Chemical Company and was used as supplied. AIBN was purchased from Wako Pure Chemical Industries, Ltd. and was used as supplied. Anhydrous benzene was purchased from Kanto Chemical Co., Inc. and was degassed by bubbling with argon gas for 30 min before use.
General Procedure
A three-necked 1000 mL round-bottomed flask fitted with a reflux condenser, an inlet adapter with three-way stopcock, and a septum was charged with starting material 13 (4.8 g, 8.7 mmol). The flask was evacuated and backfilled with argon gas. To the flask was added degassed benzene (300 mL), and the resulting solution was heated at reflux. A benzene solution (20 mL) of AIBN (0.71 g, 4.4 mmol, 0.50 equiv) and n-Bu3SnH (4.7 mL, 17 mmol, 2.0 equiv) was added to the refluxing benzene solution of 13 (0.03 M) over 3 h via a syringe pump, and the reaction mixture was stirred for an additional three hours, after which time TLC (EtOAc) indicated complete consumption of starting material 13. The solvent was removed under reduced pressure to give a crude material, which was purified by silica gel-KF (10:1) column chromatography¹¹b (EtOAc) to afford the desired product 12 (2.5 g, 5.8 mmol, 67%) as a white solid. In the smaller scale reaction, 12 (63.3 mg, 0.152 mmol) was obtained from 13 (139 mg, 0.251 mmol), n-Bu3SnH (135 µL, 0.52 mmol), and AIBN (20.6 mg, 0.126 mmol) in the same way as described in the general procedure; mp 178-179 ˚C. IR (KBr): 2937, 1682, 1512, 1447, 1408, 1308, 1244, 1148 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 7.85 (dd, 2 H, J = 7.5, 1.0 Hz), 7.71-7.65 (m, 1 H), 7.60 (dd, 2 H, J = 7.5, 7.5 Hz), 7.17 (d, 2 H, J = 8.5 Hz), 6.81 (d, 2 H, J = 8.5 Hz), 4.70 (d, 1 H, J = 16.0 Hz), 3.80 (s, 3 H), 3.67 (d, 1 H, J = 16.0 Hz), 2.88 (dd, 1 H, J = 14.0, 1.5 Hz), 2.78 (dd, 1 H, J = 14.0, 11.0 Hz), 2.54-2.40 (m, 3 H), 2.32-2.22 (m, 1 H), 1.92-1.83 (m, 1 H), 1.75-1.52 (m, 2 H), 1.61-1.51 (m, 1 H), 1.34-1.18 (m, 5 H). ¹³C NMR (125 MHz, CDCl3): δ = 174.9, 158.6, 139.9, 133.8, 130.6, 129.4, 129.0, 127.8, 113.8, 66.9, 56.4, 55.2, 41.8, 37.8, 37.5, 29.3, 29.1, 25.1, 24.4, 22.9; HRMS (EI+): m/z calcd for C24H29NO4S [M+]: 427.1817; found: 427.1828 -
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References and Notes
Current address: Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
2Current address: Hoshi University, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
12A careful inspection of the ¹H NMR spectra of the crude material indicated that the trace amount (<5%) of the diastereomer of 12 was observed: however, we could not isolate and identify the diastereomer.
14CCDC 754968 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.