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

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 
• 3b Sauviat M.-P. Vercauteren J. Grimaud N. Jugé M. Nabil M. Petit J.-Y. Biard JF.
  J. Nat. Prod.  2006,  69:  558 
• 4 Jugé M. Grimaud N. Biard JF. Sauviat M.-P. Nabil M. Verbist J.-F. Petit J.-Y. Toxicon  2001,  39:  1231 
• For total syntheses, see:
• 5a Abe H. Aoyagi S. Kibayashi C. J. Am. Chem. Soc.  2000,  122:  4583 
• 5b Sun P. Sun C. Weinreb SM. Org. Lett.  2001,  3:  3507 
• 5c Greshock TJ. Funk RL. Org. Lett.  2001,  3:  3511 
• 5d Sun P. Sun C. Weinreb SM. J. Org. Chem.  2002,  67:  4337 
• 5e Abe H. Aoyagi S. Kibayashi C. Angew. Chem. Int. Ed.  2002,  41:  3017 
• 5f Kibayashi C. Aoyagi S. Abe H. Bull. Chem. Soc. Jpn.  2003,  76:  2059 
• 5g Liu J. Hsung RP. Peters SD. Org. Lett.  2004,  6:  3989 
• 5h Abe H. Aoyagi S. Kibayashi C. J. Am. Chem. Soc.  2005,  127:  1473 
• 5i Schär P. Renaud P. Org. Lett.  2006,  8:  1569 
• 5j Caldwell JJ. Craig D. Angew. Chem. Int. Ed.  2007,  46:  2631 
• 5k Kibayashi C. Aoyagi S. Abe H. J. Synth. Org. Chem. Jpn.  2007,  65:  805 
• 5l Lygo B. Kirton EHM. Lumley C. Org. Biomol. Chem.  2008,  6:  3085 
• For formal syntheses, see:
• 5m Lee M. Lee T. Kim E.-Y. Ko H. Kim D. Kim S. Org. Lett.  2006,  8:  745 
• 5n Mihara H. Shibuguchi T. Kuramochi A. Ohshima T. Shibasaki M. Heterocycles  2007,  72:  421 
• 5o Shibuguchi T. Mihara H. Kuramochi A. Ohshima T. Shibasaki M. Chem. Asian J.  2007,  2:  794 
• For reviews, see:
• 5p Weinreb SM. Acc. Chem. Res.  2003,  36:  59 
• 5q Weinreb SM. Chem. Rev.  2006,  106:  2531 
• 5r Schär P. Cren S. Renaud P. Chimia  2006,  60:  131 
• For synthetic studies, see:
• 5s Pearson WH. Barta NS. Kampf JW. Tetrahedron Lett.  1997,  38:  3369 
• 5t Pearson WH. Ren Y. J. Org. Chem.  1999,  64:  688 
• For total syntheses of putative lepadiformine, see:
• 5u Werner KM. de los Santos JM. Weinreb SM. Shang M. J. Org. Chem.  1999,  64:  686 
• 5v Werner KM. de los Santos JM. Weinreb SM. Shang M. J. Org. Chem.  1999,  64:  4865 
• 5w Abe H. Aoyagi S. Kibayashi C. Tetrahedron Lett.  2000,  41:  1205 
• 5x Wang J. Swidorski JJ. Sydorenko N. Hsung RP. Coverdale HA. Kuyava JM. Liu J. Heterocycles  2006,  70:  423 
• 6a Curran DP. Kim D. Liu HT. Shen W. J. Am. Chem. Soc.  1988,  110:  5900 
• 6b For a review on a radical translocation-cyclization reaction, see: Robertson J. Pillai J. Lush RK. Chem. Soc. Rev.  2001,  30:  94 
• 7 Takasu K. Ohsato H. Ihara M. Org. Lett.  2003,  5:  3017 
• 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 
• 9b Brown DS. Charreau P. Hansson T. Ley SV. Tetrahedron  1991,  47:  1311 
• 10 Grela K. Bieniek M. Tetrahedron Lett.  2001,  42:  6425 
• 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 chromatography^¹¹b (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 
• 13a Georg GI. Mashava PM. Akgün E. Milstead MW. Tetrahedron Lett.  1991,  32:  3151 
• 13b Wang Y. Babirad SA. Kishi Y. J. Org. Chem.  1992,  57:  468 
• 15 Bussolo VD. Fiasella A. Romano MR. Favero L. Pineschi M. Crotti P. Org. Lett.  2007,  9:  4479 
• 16 Yu W. Mei Y. Kang Y. Hua Z. Jin Z. Org. Lett.  2004,  6:  3217 

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.