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Synlett 2010(5): 822-826  
DOI: 10.1055/s-0029-1219389
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Total Synthesis of (±)-Lepadiformine A via Radical Translocation-Cyclization Reaction

Manabu Fujitani, Masami Tsuchiya, Kentaro Okano, Kiyosei Takasu, Masataka Ihara, Hidetoshi Tokuyama*
Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, 980-8578 Sendai, Japan
Fax: +81(22)7956877; e-Mail: tokuyama@mail.pharm.tohoku.ac.jp;
Further Information

Publication History

Received 19 November 2009
Publication Date:
10 February 2010 (online)

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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

    References and Notes

  • 3a Biard JF. Guyot S. Roussakis C. Verbist JF. Vercauteren J. Weber JF. Boukef K. Tetrahedron Lett.  1994,  35:  2691 
    Google Scholar
  • 3b Sauviat M.-P. Vercauteren J. Grimaud N. Jugé M. Nabil M. Petit J.-Y. Biard JF.
    J. Nat. Prod.  2006,  69:  558 
    Google Scholar
  • 4 Jugé M. Grimaud N. Biard JF. Sauviat M.-P. Nabil M. Verbist J.-F. Petit J.-Y. Toxicon  2001,  39:  1231 
    CrossrefPubMedGoogle Scholar
  • For total syntheses, see:
  • 5a Abe H. Aoyagi S. Kibayashi C. J. Am. Chem. Soc.  2000,  122:  4583 
    Google Scholar
  • 5b Sun P. Sun C. Weinreb SM. Org. Lett.  2001,  3:  3507 
    Google Scholar
  • 5c Greshock TJ. Funk RL. Org. Lett.  2001,  3:  3511 
    Google Scholar
  • 5d Sun P. Sun C. Weinreb SM. J. Org. Chem.  2002,  67:  4337 
    Google Scholar
  • 5e Abe H. Aoyagi S. Kibayashi C. Angew. Chem. Int. Ed.  2002,  41:  3017 
    Google Scholar
  • 5f Kibayashi C. Aoyagi S. Abe H. Bull. Chem. Soc. Jpn.  2003,  76:  2059 
    Google Scholar
  • 5g Liu J. Hsung RP. Peters SD. Org. Lett.  2004,  6:  3989 
    Google Scholar
  • 5h Abe H. Aoyagi S. Kibayashi C. J. Am. Chem. Soc.  2005,  127:  1473 
    Google Scholar
  • 5i Schär P. Renaud P. Org. Lett.  2006,  8:  1569 
    Google Scholar
  • 5j Caldwell JJ. Craig D. Angew. Chem. Int. Ed.  2007,  46:  2631 
    Google Scholar
  • 5k Kibayashi C. Aoyagi S. Abe H. J. Synth. Org. Chem. Jpn.  2007,  65:  805 
    Google Scholar
  • 5l Lygo B. Kirton EHM. Lumley C. Org. Biomol. Chem.  2008,  6:  3085 
    Google Scholar
  • For formal syntheses, see:
  • 5m Lee M. Lee T. Kim E.-Y. Ko H. Kim D. Kim S. Org. Lett.  2006,  8:  745 
    Google Scholar
  • 5n Mihara H. Shibuguchi T. Kuramochi A. Ohshima T. Shibasaki M. Heterocycles  2007,  72:  421 
    Google Scholar
  • 5o Shibuguchi T. Mihara H. Kuramochi A. Ohshima T. Shibasaki M. Chem. Asian J.  2007,  2:  794 
    Google Scholar
  • For reviews, see:
  • 5p Weinreb SM. Acc. Chem. Res.  2003,  36:  59 
    Google Scholar
  • 5q Weinreb SM. Chem. Rev.  2006,  106:  2531 
    Google Scholar
  • 5r Schär P. Cren S. Renaud P. Chimia  2006,  60:  131 
    Google Scholar
  • For synthetic studies, see:
  • 5s Pearson WH. Barta NS. Kampf JW. Tetrahedron Lett.  1997,  38:  3369 
    Google Scholar
  • 5t Pearson WH. Ren Y. J. Org. Chem.  1999,  64:  688 
    Google Scholar
  • For total syntheses of putative lepadiformine, see:
  • 5u Werner KM. de los Santos JM. Weinreb SM. Shang M. J. Org. Chem.  1999,  64:  686 
    Google Scholar
  • 5v Werner KM. de los Santos JM. Weinreb SM. Shang M. J. Org. Chem.  1999,  64:  4865 
    Google Scholar
  • 5w Abe H. Aoyagi S. Kibayashi C. Tetrahedron Lett.  2000,  41:  1205 
    Google Scholar
  • 5x Wang J. Swidorski JJ. Sydorenko N. Hsung RP. Coverdale HA. Kuyava JM. Liu J. Heterocycles  2006,  70:  423 
    Google Scholar
  • 6a Curran DP. Kim D. Liu HT. Shen W. J. Am. Chem. Soc.  1988,  110:  5900 
    Google Scholar
  • 6b For a review on a radical translocation-cyclization reaction, see: Robertson J. Pillai J. Lush RK. Chem. Soc. Rev.  2001,  30:  94 
    Google Scholar
  • 7 Takasu K. Ohsato H. Ihara M. Org. Lett.  2003,  5:  3017 
    CrossrefPubMedGoogle Scholar
  • 8a Steffen S, and Andreas K. inventors; WO  0127122. 
  • 8b

    Chloromethylation of m-iodoanisole gave some inseparable regioisomers, which were used for the next step without isolation of 2-iodo-4-methoxybenzyl chloride. After benzylation with succinimide, the desired isomer 12 could be separated by recrystallization.

  • 9a Brown DS. Charreau P. Ley SV. Synlett  1990,  749 
    Google Scholar
  • 9b Brown DS. Charreau P. Hansson T. Ley SV. Tetrahedron  1991,  47:  1311 
    Google Scholar
  • 10 Grela K. Bieniek M. Tetrahedron Lett.  2001,  42:  6425 
    CrossrefGoogle Scholar
  • 11a

    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

  • 11b Harrowven DC. Guy IL. Chem. Commun.  2004,  1968 
    Google Scholar
  • 13a Georg GI. Mashava PM. Akgün E. Milstead MW. Tetrahedron Lett.  1991,  32:  3151 
    Google Scholar
  • 13b Wang Y. Babirad SA. Kishi Y. J. Org. Chem.  1992,  57:  468 
    Google Scholar
  • 15 Bussolo VD. Fiasella A. Romano MR. Favero L. Pineschi M. Crotti P. Org. Lett.  2007,  9:  4479 
    CrossrefPubMedGoogle Scholar
  • 16 Yu W. Mei Y. Kang Y. Hua Z. Jin Z. Org. Lett.  2004,  6:  3217 
    CrossrefPubMedGoogle Scholar
1

Current address: Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.

2

Current address: Hoshi University, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.

12

A 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.

14

CCDC 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.