A Radical Approach for the Construction of the Tricyclic Core of Stemoamide

Abstract

A rapid synthesis of (±)-9,10-bis-epi-stemoamide is presented. Three of the four contiguous stereocenters of this compound were set in a diastereoselective radical 7-exo-trig cyclization, which also allowed the construction of the tricyclic core of the molecule.

radical cyclization - metathesis - stereoselective syn­thesis

References

1a Ye Y. Qin G.-W. Xu R.-S. Phytochemistry  1994,  37:  1201 

1b Qin G.-W. Xu R.-S. Phytochemistry  1994,  37:  1205 

1c Qin G.-W. Xu R.-S. J. Nat. Prod.  1994,  57:  655 

1d Qin G.-W. Xu RS. Med. Res. Rev.  1998,  18:  375 

1e Lin W.-H. Ye Y. Xu R.-S. J. Nat. Prod.  1992,  55:  571 

1f Brem B. Seeger C. Pacher P. Hofer O. Vajrodaya S. Greger H. J. Agric. Food Chem.  2002,  50:  6383 

2a Wipf P. Rector SR. Takahashi H. J. Am. Chem. Soc.  2002,  124:  14848 

2b Padwa A. Gin JD. Org. Lett.  2002,  4:  1515 

2c Williams DR. Fromhold MG. Earley JD. Org. Lett.  2001,  3:  2721 

2d Chen C.-Y. Hart DJ. J. Org. Chem.  1993,  58:  3840 

2e Wipf P. Kim Y. Goldstein DM. J. Am. Chem. Soc.  1995,  117:  11106 

3a Williams DR. Reddy JP. Amato GS. Tetrahedron Lett.  1994,  35:  6417 

3b Kinoshita A. Mori M. J. Org. Chem.  1996,  61:  8356 

3c Kohno Y. Narasaka K. Bull. Chem. Soc. Jpn.  1996,  69:  2063 

3d Kinoshita A. Mori M. Heterocycles  1997,  46:  287 

3e Jacobi PA. Lee K. J. Am. Chem. Soc.  1997,  119:  3409 

3f Jacobi PA. Lee K. J. Am. Chem. Soc.  2000,  122:  4295 

3g Gurjar MK. Reddy DS. Tetrahedron Lett.  2002,  43:  295 

3h Sibi MP. Subramanian T. Synlett  2004,  1211 

4a Khim S.-K. Schultz AG. J. Org. Chem.  2004,  69:  7734 

4b For synthetic analogs of other members of the Stemona group see: Brüggemann M. McDonald AI. Overman LE. Rosen MD. Schwink L. Scott JP. J. Am. Chem. Soc.  2003,  125:  15284 

4c Kende AS. Hernando JIM. Milbank JBJ. Tetrahedron  2002,  58:  61 

4d Kende AS. Smalley TL. Hung H. J. Am. Chem. Soc.  1999,  121:  7431 

5 Giese B. Kopping B. Göbel T. Dickhaut J. Thoma G. Kulicke KJ. Trach F. In Organic Reactions   Vol. 48:  Paquette LA. John Wiley and Sons; New York: 1996.  p.301 

6 McClure CK. Jung K.-Y. J. Org. Chem.  1991,  56:  867 

7 Ewin RA. Jones K. Newton CG. J. Chem. Soc., Perkin Trans. 1  1996,  1107 

8a Schwab P. France MB. Ziller JW. Grubbs RH. Angew. Chem., Int. Ed. Engl.  1995,  34:  2039 

8b Schwab P. Grubbs RH. Ziller JW. J. Am. Chem. Soc.  1996,  118:  100 

8c Scholl M. Ding S. Lee CW. Grubbs RH. Org. Lett.  1999,  1:  953 

9a Kingsbury JS. Harrity JPA. Bonitatebus PJ. Hoveyda AH. J. Am. Chem. Soc.  1999,  121:  791 

9b Garber SB. Kingsbury JS. Gray BL. Hoveyda AH. J. Am. Chem. Soc.  2000,  122:  8168 

10

For general conditions of cyclization see ref. [11]

11

9,10-bis- epi -Stemoamide ( 10):
To a stirred solution of 9 (48 mg, 0.15 mmol) and AIBN (5 mg, 0.03 mmol) in degassed benzene (30 mL) at reflux, a solution of Bu₃SnH (100 µL, 0.37 mmol) in benzene (3 mL) was added over 4 h via a syringe pump. The crude mixture was treated with a sat. aq solution of KF, extracted by CH₂Cl₂, dried over MgSO₄, filtered, concentrated under reduced pressure, and purified by chromatography on silica gel (gradient: CH₂Cl₂ then CH₂Cl₂-MeOH 95:5) to afford compound 10 (6.7 mg, 0.03 mmol, 20%) as a single diastereomer. ¹H NMR (300 MHz, CDCl₃): δ = 1.39 (d, J = 7.2 Hz, 3 H), 1.61-2.15 (br m, 5 H), 2.23-2.62 (m, 5 H), 2.78 (ddd, J = 13.9, 10.4, 3.4 Hz, 1 H), 3.63 (dd, J = 9.0, 7.2 Hz, 1 H), 4.18 (dt, J = 13.9, 4.5 Hz, 1 H), 4.62 (ddd, J = 10.6, 7.9, 3.0 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 15.9, 24.0, 25.5, 28.9, 30.1, 39.1, 44.1, 50.9, 60.5, 80.7, 174.6, 177.9. MS (EI, 70eV): m/z (%) = 224 (12) [MH⁺ ], 223 (87) [M⁺ ], 208 (41), 180 (44), 98 (100), 97 (59).