Transition Metal Complexes in Organic Synthesis, Part 69. [1] Total Synthesis of the Amaryllidaceae Alkaloids Anhydrolycorinone and Hippadine Using Iron- and Palladium-Mediated Coupling Reactions

Abstract

A novel synthesis of the Amaryllidaceae alkaloids anhydrolycorinone and hippadine has been developed using an iron-mediated oxidative alkylamine cyclization and an intramolecular palladium-mediated biaryl coupling as the key steps.

alkaloids - cyclizations - dehydrogenations - iron - palladium

References

1 Part 68: Knölker H.-J. Wolpert M. Tetrahedron  2003,  59:  5317 

2a Ghosal S. Rao HP. Jaiswal DK. Kumar Y. Frahm WA. Phytochemistry  1981,  20:  2003 

2b Chattopadhyay S. Chattopadhyay U. Marthur PP. Saini KS. Ghosal S. Planta Med.  1983,  49:  252 

3 Pettit GR. Gaddamidi V. Goswami A. Cragg GM. J. Nat. Prod.  1984,  47:  796 

4 Ghosal S. Lochan R. Ashutosh R. Kumar Y. Srivastava RS. Phytochemistry  1985,  24:  1825 

For some recent syntheses, see:

5a Harrowven DC. Lai D. Lucas MC. Synthesis  1999,  1300 

5b Miki Y. Shirokoshi H. Matsushita K. Tetrahedron Lett.  1999,  40:  4347 

5c Padwa A. Brodney MA. Liu B. Satake K. Wu T. J. Org. Chem.  1999,  64:  3595 

5d Stark LM. Lin X.-F. Flippin LA. J. Org. Chem.  2000,  65:  3227 

5e Boger DL. Wolkenberg SE. J. Org. Chem.  2000,  65:  9120 

5f Wolkenberg SE. Boger DL. J. Org. Chem.  2002,  67:  7361 ; and references cited therein

6a Knölker H.-J. Synlett  1992,  371 

6b Knölker H.-J. In Transition Metals for Organic Synthesis   Vol. 1:  Beller M. Bolm C. Wiley-VCH; Weinheim: 1998.  p.534 

6c Knölker H.-J. Chem. Soc. Rev.  1999,  28:  151 

7 Knölker H.-J. Reddy KR. Chem. Rev.  2002,  102:  4303 

8 Knölker H.-J. El-Ahl A.-A. Weingärtner G. Synlett  1994,  194 

9a Cossy J. Tresnard L. Pardo DG. Tetrahedron Lett.  1999,  40:  1125 

9b Cossy J. Tresnard L. Pardo DG. Eur. J. Org. Chem.  1999,  1925 

10a Knölker H.-J. Baum E. Gonser P. Rohde G. Röttele H. Organometallics  1998,  17:  3916 

10b Knölker H.-J. Chem. Rev.  2000,  100:  2941 

11 Fischer EO. Fischer RD. Angew. Chem.  1960,  72:  919 

12 Pearson AJ. Kole SL. Yoon J. Organometallics  1986,  5:  2075 

13 Winterfeldt E. Synthesis  1975,  617 

14

All new compounds have been fully characterized (IR, ¹H NMR, ¹³C NMR, MS, and elemental analysis or HRMS). ¹³C NMR and DEPT spectral data (125 MHz, CDCl₃) of representative compounds. 17: δ = 30.75 (CH₂), 35.90 (CH), 40.27 (CH₂), 47.66 (CH₂), 57.97 (CH₂), 59.76 (CH), 66.57 (CH), 84.39 (CH), 85.53 (CH), 86.99 (C), 101.53 (CH₂), 109.71 (CH), 118.46 (CH), 135.61 (C), 147.35 (C), 148.34 (C), 212.06 (3 CO). 5: δ = 34.64 (CH₂), 43.22 (CH), 54.31 (CH₂), 60.16 (CH), 60.85 (CH₂), 63.78 (CH), 66.32 (CH), 85.85 (CH), 86.70 (CH), 87.25 (C), 101.53 (CH₂), 110.19 (CH), 118.45 (CH), 135.01 (C), 147.36 (C), 148.44 (C), 211.75 (3 CO). 18: δ = 32.95 (CH₂), 36.46 (CH), 49.25 (CH₂), 59.56 (CH), 62.43 (CH₂), 87.26 (C), 101.50 (CH₂), 110.51 (CH), 118.25 (CH), 119.80 (CH), 122.92 (CH), 124.79 (CH), 130.31 (CH), 135.29 (C), 147.33 (C), 148.43 (C). Anhydrolycorinone (1): δ = 27.45 (CH₂), 46.52 (CH₂), 100.89 (CH), 102.05 (CH₂), 106.83 (CH), 116.79 (C), 119.46 (CH), 123.10 (C), 123.27 (CH), 123.82 (CH), 130.66 (C), 130.87 (C), 139.39 (C), 148.43 (C), 151.85 (C), 159.52 (C=O). Hippadine (2): δ = 101.75 (CH), 102.29 (CH₂), 108.05 (CH), 110.82 (CH), 116.71 (C), 118.38 (CH), 122.51 (C), 122.63 (CH), 123.55 (CH), 124.00 (CH), 128.42 (C), 130.97 (C), 131.66 (C), 148.54 (C), 152.60 (C), 158.19 (C=O).

15

Iron-mediated oxidative alkylamine cyclization of 17 to 5: Ferricenium hexafluorophosphate (291 mg, 0.88 mmol) and anhyd. Na₂CO₃ (374 mg, 3.53 mmol) were added to a solution of complex 17 (185 mg, 0.354 mmol) in degassed anhyd CH₂Cl₂ (15 mL) under an argon atmosphere. The resulting dark green suspension was stirred at r.t. for 3 d. During this time the color turned to orange (formation of ferrocene). The reaction mixture was filtered through a short path of Celite which was subsequently washed with CH₂Cl₂. Removal of the solvent from the combined filtrates and flash chromatography (hexane-EtOAc, 9:1) of the residue on silica gel provided complex 5 as light yellow crystals, yield: 158 mg (86%), mp 122 °C.

16a Knölker H.-J. Bauermeister M. Pannek J.-B. Bläser D. Boese R. Tetrahedron  1993,  49:  841 

16b Knölker H.-J. Baum E. Hopfmann T. Tetrahedron  1999,  55:  10931 

16c Knölker H.-J. Hopfmann T. Tetrahedron  2002,  58:  8937 

17 Shvo Y. Hazum E. J. Chem. Soc., Chem. Commun.  1974,  336 

For compilations on the Heck reaction, see in:

18a Tsuji J. Palladium Reagents and Catalysts - Innovations in Organic Synthesis   Wiley; Chichester: 1995. 

18b Li JJ. Gribble GW. Palladium in Heterocyclic Chemistry - A Guide for the Synthetic Chemist   Pergamon; Oxford: 2000.